Mandell, Douglas and Bennett’s Infectious Disease …...Mandell, Douglas, and Bennett’s...
Transcript of Mandell, Douglas and Bennett’s Infectious Disease …...Mandell, Douglas, and Bennett’s...
ESSENTIALS
ELSEVIER
JOHN E. BENNETT RAPHAEL DOLIN
MARTIN J. BLASER
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Mandell, Douglas, and Bennett’s
Infectious Disease ESSENTIALS
Mandell, Douglas, and Bennett’s
Infectious Disease ESSENTIALS
JOHN E. BENNETT, MD, MACPAdjunct Professor of Medicine
Uniformed Services University of the Health SciencesF. Edward Hebert School of Medicine
Bethesda, Maryland
RAPHAEL DOLIN, MDMaxwell Finland Professor of Medicine (Microbiology and Molecular Genetics)
Harvard Medical School;Attending Physician
Beth Israel Deaconess Medical Center;Brigham and Women’s Hospital
Boston, Massachusetts
MARTIN J. BLASER, MDMuriel G. and George W. Singer Professor of Translational Medicine
Professor of MicrobiologyDirector, Human Microbiome Program
Departments of Medicine and MicrobiologyNew York University School of Medicine
Langone Medical CenterNew York, New York
1600 John F. Kennedy Blvd.Ste 1800Philadelphia, PA 19103-2899
MANDELL, DOUGLAS, AND BENNETT’S INFECTIOUS DISEASE ESSENTIALS ISBN: 978-0-323-43101-9
Copyright © 2017 by Elsevier Inc. All rights reserved.
Chapters listed below are in public domain; therefore the copyright line for these chapters is: 2017 Published by Elsevier Inc.46: Foodborne Disease by Rajal K. Mody and Patricia M. Griffin77: Human Herpesvirus Types 6 and 7 (Exanthem Subitum) by Jeffrey I. Cohen79: Herpes B Virus by Jeffrey I. Cohen162: Yersinia Species (Including Plague) by Paul S. Mead204: Trypanosoma Species (American Trypanosomiasis, Chagas’ Disease): Biology of Trypanosomes by Louis V. Kirchhoff205: Agents of African Trypanosomiasis (Sleeping Sickness) by Louis V. Kirchhoff217: Visceral Larva Migrans and Other Uncommon Helminth Infections by Theodore E. Nash224: Infections Caused by Percutaneous Intravascular Devices by Susan E. Beekmann and David K. Henderson228: Transfusion- and Transplantation-Transmitted Infections by Matthew J. Kuehnert and Sridhar V. Basavaraju
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
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Library of Congress Cataloging-in-Publication DataNames: Bennett, John E. (John Eugene), 1933- , editor. | Dolin, Raphael, editor. | Blaser, Martin J., editor.Title: Mandell, Douglas, and Bennett’s infectious disease essentials / [edited by] John E. Bennett, Raphael Dolin,
Martin J. Blaser.Other titles: Infectious disease essentialsDescription: Philadelphia, PA : Elsevier, [2017]Identifiers: LCCN 2015048664 | ISBN 9780323431019 (paperback : alk. paper)Subjects: | MESH: Communicable Diseases | HandbooksClassification: LCC RA643 | NLM WC 39 | DDC 616.9–dc23 LC record available at http://lccn.loc.gov/2015048664
Senior Content Strategist: Suzanne ToppySenior Content Development Manager: Taylor BallPublishing Services Manager: Catherine JacksonBook Production Specialist: Kristine FeehertyDesign Direction: Renee Duenow
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
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Contributors
Fredrick M. Abrahamian, DOProfessor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Director of Education, Department of Emergency Medicine, Olive View–UCLA Medical Center, Sylmar, CaliforniaBites
Ban Mishu Allos, MDAssociate Professor, Departments of Medicine and Preventive Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TennesseeCampylobacter jejuni and Related Species
Michael A. Apicella, MDProfessor and Head, Department of Microbiology, University of Iowa Carver College of Medicine, Iowa City, IowaNeisseria meningitidis; Neisseria gonorrhoeae (Gonorrhea)
Kevin L. Ard, MD, MPHInstructor in Medicine, Harvard Medical School; Associate Physician, Department of Medicine, Brigham and Women’s Hospital, Boston, MassachusettsPulmonary Manifestations of Human Immunodeficiency Virus Infection
Cesar A. Arias, MD, MSc, PhDAssociate Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases and Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, Texas; Director, Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, ColombiaEnterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc Species
Michael H. Augenbraun, MDProfessor of Medicine, Chief, Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New YorkGenital Skin and Mucous Membrane Lesions; Urethritis; Vulvovaginitis and Cervicitis
Francisco Averhoff, MD, MPHDivision of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GeorgiaHepatitis A Virus
Dimitri T. Azar, MD, MBADean and B.A. Field Chair of Ophthalmologic Research, Distinguished Professor of Ophthalmology, Pharmacology, and Bioengineering, College of Medicine, University of Illinois at Chicago, Chicago, IllinoisMicrobial Conjunctivitis; Microbial Keratitis
Larry M. Baddour, MDProfessor of Medicine, Mayo Clinic College of Medicine; Consultant, Infectious Diseases, Mayo Clinic, Rochester, MinnesotaProsthetic Valve Endocarditis
Carol J. Baker, MDProfessor of Pediatrics, Molecular Virology, and Microbiology, Department of Pediatrics, Infectious Diseases Section, Baylor College of Medicine; Attending Physician, Texas Children’s Hospital, Houston, TexasStreptococcus agalactiae (Group B Streptococcus)
Ronald C. Ballard, MSB, PhDAssociate Director for Laboratory Science, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GeorgiaKlebsiella granulomatis (Donovanosis, Granuloma Inguinale)
Scott D. Barnes, MDChief, Warfighter Refractive Eye Surgery Clinic, Womack Army Medical Center, Fort Bragg, North CarolinaMicrobial Conjunctivitis; Microbial Keratitis
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Dan H. Barouch, MD, PhDProfessor of Medicine, Harvard Medical School; Director, Center for Virology and Vaccine Research, Staff Physician, Beth Israel Deaconess Medical Center; Associate Physician, Brigham and Women’s Hospital, Boston, MassachusettsAdenoviruses
Alan D. Barrett, PhDDirector, Sealy Center for Vaccine Development, Professor, Departments of Pathology and Microbiology & Immunology, University of Texas Medical Branch, Galveston, TexasFlaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)
Miriam Baron Barshak, MDAssistant Professor of Medicine, Harvard Medical School; Associate Physician, Department of Medicine, Massachusetts General Hospital, Boston, MassachusettsPancreatic Infection
Sridhar V. Basavaraju, MDCenters for Disease Control and Prevention, Atlanta, GeorgiaTransfusion- and Transplantation-Transmitted Infections
Byron E. Batteiger, MDProfessor of Medicine, Microbiology, and Immunology, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, IndianaChlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)
Stephen G. Baum, MDProfessor of Medicine, Microbiology, and Immunology, Albert Einstein College of Medicine, Bronx, New YorkMumps Virus
Arnold S. Bayer, MDProfessor of Medicine, Department of Internal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Associate Chief, Adult Infectious Diseases, Department of Internal Medicine, Harbor-UCLA Medical Center; Senior Investigator, St. John’s Cardiovascular Research Center, Los Angeles Biomedical Research Institute, Torrance, CaliforniaEndocarditis and Intravascular Infections
J. David Beckham, MDAssistant Professor, Departments of Medicine, Neurology, and Microbiology, Division of Infectious Diseases, Director, Infectious Disease Fellowship Training Program, Medical Director, Occupational Health, University of Colorado Anschutz Medical Campus, Aurora, ColoradoEncephalitis
Susan E. Beekmann, RN, MPHUniversity of Iowa Carver College of Medicine, Iowa City, IowaInfections Caused by Percutaneous Intravascular Devices
Beth P. Bell, MD, MPHDirector, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GeorgiaHepatitis A Virus
John E. Bennett, MD, MACPAdjunct Professor of Medicine, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, MarylandChronic Meningitis
Dennis A. Bente, DVM, PhDAssistant Professor, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TexasCalifornia Encephalitis, Hantavirus Pulmonary Syndrome, and Bunyavirus Hemorrhagic Fevers
Elie F. Berbari, MDProfessor of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MinnesotaOsteomyelitis
Adarsh Bhimraj, MDHead, Section of Neurologic Infectious Diseases, Associate Program Director, Internal Medicine Residency Program, Cleveland Clinic, Cleveland, OhioCerebrospinal Fluid Shunt and Drain Infections
Alan L. Bisno, MDProfessor Emeritus, Department of Medicine, University of Miami Miller School of Medicine; Staff Physician, Miami Veterans Affairs Medical Center, Miami, FloridaNonsuppurative Poststreptococcal Sequelae: Rheumatic Fever and Glomerulonephritis
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Brian G. Blackburn, MDClinical Associate Professor, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Attending Physician, Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford Hospital and Clinics, Stanford, CaliforniaFree-Living Amebae
Lucas S. Blanton, MDAssistant Professor, Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TexasRickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers); Rickettsia prowazekii (Epidemic or Louse-Borne Typhus); Rickettsia typhi (Murine Typhus)
Martin J. Blaser, MDMuriel G. and George W. Singer Professor of Translational Medicine, Professor of Microbiology, Director, Human Microbiome Program, Departments of Medicine and Microbiology, New York University School of Medicine, Langone Medical Center, New York, New YorkCampylobacter jejuni and Related Species; Helicobacter pylori and Other Gastric Helicobacter Species
Thomas P. Bleck, MDProfessor of Neurological Sciences, Neurosurgery, Medicine, and Anesthesiology, Rush Medical College; Associate Chief Medical Officer (Critical Care), Associate Vice President, Director, Laboratory of Electroencephalography and Evoked Potentials, Rush University Medical Center, Chicago, IllinoisRabies (Rhabdoviruses); Tetanus (Clostridium tetani); Botulism (Clostridium botulinum)
David A. Bobak, MDAssociate Professor of Medicine, Associate Chair for Clinical Affairs, Division of Infectious Diseases and HIV Medicine, Case Western Reserve University School of Medicine; Director, Traveler’s Healthcare Center, Chair, Health System Medication Safety and Therapeutics Committee, Staff Physician, Transplant Infectious Diseases Clinic, University Hospitals Case Medical Center, Cleveland, OhioNausea, Vomiting, and Noninflammatory Diarrhea
William Bonnez, MDProfessor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Rochester School of Medicine and Dentistry, Rochester, New YorkPapillomaviruses
John C. Boothroyd, MDProfessor of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CaliforniaToxoplasma gondii
Patrick J. Bosque, MDAssociate Professor, Department of Neurology, University of Colorado Denver School of Medicine; Neurologist, Department of Medicine, Denver Health Medical Center, Denver, ColoradoPrions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases)
John Bower, MDAssociate Professor of Pediatrics, Northeast Ohio Medical University, Rootstown, OhioCroup in Children (Acute Laryngotracheobronchitis); Bronchiolitis
Robert W. Bradsher, Jr., MDEbert Professor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, ArkansasBlastomycosis
Kevin E. Brown, MD, MRCPConsultant Medical Virologist, Virus Reference Department, Public Health England, Microbiology Services, London, United KingdomHuman Parvoviruses, Including Parvovirus B19V and Human Bocaparvoviruses
Patricia D. Brown, MDProfessor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine; Corporate Vice President of Quality and Patient Safety, Detroit Medical Center, Detroit, MichiganInfections in Injection Drug Users
Barbara A. Brown-Elliott, MS, MT(ASCP)SMResearch Assistant Professor, Microbiology, Supervisor, Mycobacteria/Nocardia Laboratory, University of Texas Health Science Center, Tyler, TexasInfections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex
Roberta L. Bruhn, MS, PhDStaff Scientist, Department of Epidemiology, Blood Systems Research Institute, San Francisco, CaliforniaHuman T-Lymphotropic Virus (HTLV)
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Amy E. Bryant, PhDResearch Career Scientist, Infectious Diseases Section, Veterans Affairs Medical Center, Boise, IdahoStreptococcus pyogenes
Eileen M. Burd, PhDAssociate Professor, Department of Pathology and Laboratory Medicine, Emory University School of Medicine; Director, Clinical Microbiology, Emory University Hospital, Atlanta, GeorgiaOther Gram-Negative and Gram-Variable Bacilli
Jane C. Burns, MDProfessor of Pediatrics, University of California San Diego School of Medicine, La Jolla, CaliforniaKawasaki Disease
Larry M. Bush, MDAffiliated Associate Professor of Medicine, University of Miami Miller School of Medicine, JFK Medical Center, Palm Beach County, Florida; Affiliated Professor of Medicine, Charles E. Schmidt School of Medicine, Florida Atlantic University, Boca Raton, FloridaPeritonitis and Intraperitoneal Abscesses
Luz Elena Cano, PhDHead of Medical and Experimental Mycology Group, Corporación para Investigaciones Biológicas; Titular Professor, Microbiology School, Universidad de Antioquia, Medellín, ColombiaParacoccidioidomycosis
Charles C. J. Carpenter, MDProfessor of Medicine, Warren Alpert Medical School of Brown University; Attending Physician, Division of Infectious Diseases, Miriam Hospital, Providence, Rhode IslandOther Pathogenic Vibrios
Mary T. Caserta, MDProfessor of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New YorkPharyngitis; Acute Laryngitis
Elio Castagnola, MDInfectious Diseases Unit, Istituto Giannina Gaslini, Genova, ItalyProphylaxis and Empirical Therapy of Infection in Cancer Patients
Richard E. Chaisson, MDProfessor of Medicine, Epidemiology, and International Health, Johns Hopkins University School of Medicine, Baltimore, MarylandGeneral Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases)
Sharon C-A. Chen, MBBS, PhDClinical Associate Professor, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Senior Staff Specialist, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, AustraliaNocardia Species
Anthony W. Chow, MDProfessor Emeritus, Department of Internal Medicine, Division of Infectious Diseases, University of British Columbia; Honorary Consultant, Department of Internal Medicine, Division of Infectious Diseases, Vancouver Hospital, Vancouver, British Columbia, CanadaInfections of the Oral Cavity, Neck, and Head
Jeffrey I. Cohen, MDChief, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandIntroduction to Herpesviridae; Human Herpesvirus Types 6 and 7 (Exanthem Subitum); Herpes B Virus
Myron S. Cohen, MDYergin-Bates Eminent Professor of Medicine, Microbiology, and Epidemiology, Director, Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North CarolinaThe Acutely Ill Patient with Fever and Rash
Lawrence Corey, MDProfessor of Medicine and Laboratory Medicine, University of Washington School of Medicine; President and Director, Fred Hutchinson Cancer Research Center, Seattle, WashingtonHerpes Simplex Virus
Timothy L. Cover, MDProfessor of Medicine, Professor of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TennesseeHelicobacter pylori and Other Gastric Helicobacter Species
Kent B. Crossley, MD, MHAProfessor, Department of Medicine, University of Minnesota Medical School; Chief of Staff, Minneapolis Veterans Administration Healthcare System, Minneapolis, MinnesotaInfections in the Elderly
Clyde S. Crumpacker II, MDProfessor of Medicine, Harvard Medical School; Attending Physician, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MassachusettsCytomegalovirus (CMV)
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Bart J. Currie, MBBS, DTM&HProfessor in Medicine, Department of Infectious Diseases, Royal Darwin Hospital; Global and Tropical Health Division, Menzies School of Health Research, Darwin, AustraliaBurkholderia pseudomallei and Burkholderia mallei: Melioidosis and Glanders
Erika D’Agata, MD, MPHAssociate Professor of Medicine, Brown University; Department of Medicine, Division of Infectious Diseases, Rhode Island Hospital, Providence, Rhode IslandPseudomonas aeruginosa and Other Pseudomonas Species
Inger K. Damon, MD, PhDAdjunct Clinical Faculty, Department of Medicine, Emory University School of Medicine; Director, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GeorgiaOrthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox; Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and Yatapoxviruses
Rabih O. Darouiche, MDVA Distinguished Service Professor, Departments of Medicine, Surgery, and Physical Medicine and Rehabilitation, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TexasInfections in Patients with Spinal Cord Injury
Roberta L. DeBiasi, MDActing Chief, Division of Pediatric Infectious Diseases, Children’s National Medical Center; Professor of Pediatrics and Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine; Principal Investigator, Center for Clinical and Translational Science, Children’s Research Institute, Washington, DCOrthoreoviruses and Orbiviruses; Coltiviruses and Seadornaviruses
George S. Deepe, Jr., MDProfessor, Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OhioHistoplasma capsulatum (Histoplasmosis)
Andrew S. Delemos, MDTransplant Hepatologist, Carolinas Healthcare System, Charlotte, North CarolinaViral Hepatitis
Gregory P. DeMuri, MDAssociate Professor, University of Wisconsin School of Medicine and Public Health; Attending Physician, American Family Children’s Hospital, Madison, WisconsinSinusitis
Robin Dewar, PhDPrincipal Scientist, Leidos Biomedical Research—Frederick, National Cancer Institute—Frederick, Frederick, MarylandDiagnosis of Human Immunodeficiency Virus Infection
James H. Diaz, MD, MPHTM, DrPHProfessor of Public Health and Preventive Medicine, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LouisianaIntroduction to Ectoparasitic Diseases; Lice (Pediculosis); Scabies; Myiasis and Tungiasis; Mites, Including Chiggers; Ticks, Including Tick Paralysis
Jules L. Dienstag, MDDean for Medical Education, Carl W. Walter Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, MassachusettsViral Hepatitis
Raphael Dolin, MDMaxwell Finland Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Attending Physician, Beth Israel Deaconess Medical Center; Brigham and Women’s Hospital, Boston, MassachusettsZoonotic Paramyxoviruses: Nipah, Hendra, and Menangle; Noroviruses and Sapoviruses (Caliciviruses); Astroviruses and Picobirnaviruses
Michael S. Donnenberg, MDProfessor of Medicine, Microbiology, and Immunology, University of Maryland School of Medicine, Baltimore, MarylandEnterobacteriaceae
Gerald R. Donowitz, MDProfessor of Medicine and Infectious Diseases/International Health, Department of Medicine, University of Virginia, Charlottesville, VirginiaAcute Pneumonia
Philip R. Dormitzer, MD, PhDHead of U.S. Research, Global Head of Virology, Vice President, Novartis Vaccines, Cambridge, MassachusettsRotaviruses
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James M. Drake, MB BCh, MScProfessor of Surgery, University of Toronto Faculty of Medicine; Neurosurgeon-in-Chief and Harold Hoffman Shopper’s Drug Mart Chair in Pediatric Neurosurgery, Division of Neurosurgery, Hospital for Sick Children, Toronto, Ontario, CanadaCerebrospinal Fluid Shunt and Drain Infections
J. Stephen Dumler, MDProfessor, Departments of Pathology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MarylandRickettsia typhi (Murine Typhus)
Herbert L. DuPont, MDProfessor and Director, Center for Infectious Diseases, University of Texas School of Public Health; Chief, Internal Medicine Service, Baylor St. Luke’s Medical Center; Professor and Vice Chairman, Department of Medicine, Baylor College of Medicine, Houston, TexasBacillary Dysentery: Shigella and Enteroinvasive Escherichia coli
David T. Durack, MB, DPhilConsulting Professor of Medicine, Duke University School of Medicine, Durham, North CarolinaProphylaxis of Infective Endocarditis
Marlene L. Durand, MDAssociate Professor of Medicine, Harvard Medical School; Physician, Infectious Disease Unit, Massachusetts General Hospital; Director, Infectious Disease Service, Massachusetts Eye and Ear Infirmary, Boston, MassachusettsEndophthalmitis; Infectious Causes of Uveitis; Periocular Infections
Paul H. Edelstein, MDProfessor of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine; Director of Clinical Microbiology, Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PennsylvaniaLegionnaires’ Disease and Pontiac Fever
Morven S. Edwards, MDProfessor of Pediatrics, Baylor College of Medicine; Attending Physician, Department of Pediatrics, Infectious Diseases Section, Texas Children’s Hospital, Houston, TexasStreptococcus agalactiae (Group B Streptococcus)
Richard T. Ellison III, MDProfessor, Departments of Medicine and Microbiology & Physiological Systems, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MassachusettsAcute Pneumonia
Timothy P. Endy, MD, MPHProfessor of Medicine, Division Chief of Infectious Diseases, Upstate Medical University, State University of New York, Syracuse, New YorkFlaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)
N. Cary Engleberg, MDProfessor, Departments of Infectious Diseases and Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MichiganChronic Fatigue Syndrome
Hakan Erdem, MDDepartment of Infectious Diseases and Clinical Microbiology, GATA Haydarpasa Training Hospital, Istanbul, TurkeyBrucellosis (Brucella Species)
Joel D. Ernst, MDProfessor, Departments of Medicine, Pathology, and Microbiology, New York University School of Medicine, New York, New YorkMycobacterium leprae (Leprosy)
Rick M. Fairhurst, MD, PhDChief, Malaria Pathogenesis and Human Immunity Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, MarylandMalaria (Plasmodium Species)
Jessica K. Fairley, MDAssistant Professor of Medicine, Emory University School of Medicine, The Emory Clinic, Atlanta, GeorgiaTapeworms (Cestodes)
Ann R. Falsey, MDProfessor of Medicine, Infectious Diseases Unit, University of Rochester School of Medicine, Rochester, New YorkHuman Metapneumovirus
Thomas Fekete, MDProfessor of Medicine and Chief, Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PennsylvaniaBacillus Species and Related Genera Other Than Bacillus anthracis
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Paul D. Fey, PhDProfessor, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NebraskaStaphylococcus epidermidis and Other Coagulase-Negative Staphylococci
Steven M. Fine, MD, PhDAssociate Professor of Medicine, Division of Infectious Diseases, University of Rochester Medical Center, Rochester, New YorkVesicular Stomatitis Virus and Related Vesiculoviruses
Daniel W. Fitzgerald, MDAssociate Professor of Medicine, Microbiology, and Immunology, Weill Cornell Medical College, New York, New YorkMycobacterium tuberculosis
Anthony R. Flores, MD, MPH, PhDAssistant Professor, Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, Houston, TexasPharyngitis
Derek Forster, MDSection on Infectious Diseases, Wake Forest School of Medicine, Winston-Salem, North CarolinaInfectious Arthritis of Native Joints
Vance G. Fowler, Jr., MD, MHSProfessor of Medicine, Division of Infectious Diseases, Duke University School of Medicine, Durham, North CarolinaEndocarditis and Intravascular Infections
David O. Freedman, MDProfessor of Medicine and Epidemiology, Gorgas Center for Geographic Medicine, Division of Infectious Diseases, University of Alabama at Birmingham School of Medicine; Director, University of Alabama at Birmingham Travelers Health Clinic, University of Alabama at Birmingham Health System, Birmingham, AlabamaProtection of Travelers; Infections in Returning Travelers
Arthur M. Friedlander, MDAdjunct Professor of Medicine, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Senior Scientist, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MarylandBacillus anthracis (Anthrax)
John N. Galgiani, MDProfessor of Internal Medicine, Director, Valley Fever Center for Excellence, University of Arizona College of Medicine; Chief Medical Officer, Valley Fever Solutions, Tucson, ArizonaCoccidioidomycosis (Coccidioides Species)
Robert C. Gallo, MDDirector, Institute of Human Virology, Professor, Department of Medicine, University of Maryland School of Medicine, Baltimore, MarylandHuman Immunodeficiency Viruses
Tejal N. Gandhi, MDClinical Assistant Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, MichiganBartonella, Including Cat-Scratch Disease
Wendy S. Garrett, MD, PhDAssistant Professor, Immunology & Infectious Diseases and Genetic & Complex Diseases, Department of Medicine, Harvard School of Public Health; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MassachusettsGas Gangrene and Other Clostridium-Associated Diseases; Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)
Charlotte A. Gaydos, DrPH, MPH, MSProfessor of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine; Emergency Medicine Department and Epidemiology, Population, Family and Reproductive Health, Bloomberg Johns Hopkins School of Public Health; Director, International Sexually Transmitted Diseases Research Laboratory, Baltimore, MarylandChlamydia pneumoniae
Thomas W. Geisbert, PhDProfessor, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TexasMarburg and Ebola Hemorrhagic Fevers (Filoviruses)
Jeffrey A. Gelfand, MDClinical Professor of Medicine, Harvard Medical School; Attending Physician, Infectious Diseases Division, Massachusetts General Hospital, Boston, MassachusettsBabesia Species
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Dale N. Gerding, MDProfessor of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Research Physician, Department of Medicine, Edward Hines, Jr., Veterans Affairs Hospital, Hines, IllinoisClostridium difficile Infection
Anne A. Gershon, MDProfessor of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New YorkRubella Virus (German Measles); Measles Virus (Rubeola)
Janet R. Gilsdorf, MDRobert P. Kelch Research Professor of Pediatrics and Communicable Diseases, University of Michigan Medical School and C.S. Mott Children’s Hospital, Ann Arbor, MichiganInfections in Asplenic Patients
Ellie J. C. Goldstein, MDClinical Professor of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California; Director, R.M. Alden Research Laboratory, Santa Monica, CaliforniaBites
Fred M. Gordin, MDProfessor of Medicine, George Washington University School of Medicine; Chief, Infectious Diseases, Veterans Affairs Medical Center, Washington, DCMycobacterium avium Complex
Paul S. Graman, MDProfessor of Medicine, University of Rochester School of Medicine and Dentistry; Attending Physician and Clinical Director, Infectious Diseases Division, Strong Memorial Hospital, Rochester, New YorkEsophagitis
Patricia M. Griffin, MDChief, Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GeorgiaFoodborne Disease
Richard L. Guerrant, MDProfessor of Medicine, Infectious Diseases, and International Health, University of Virginia School of Medicine, Charlottesville, VirginiaNausea, Vomiting, and Noninflammatory Diarrhea; Bacterial Inflammatory Enteritides
H. Cem Gul, MDDepartment of Infectious Diseases and Microbiology, Gulhane Military Medical Academy, Ankara, TurkeyBrucellosis (Brucella Species)
David A. Haake, MDProfessor, Departments of Medicine, Urology, and Microbiology, Immunology, & Molecular Genetics, The David Geffen School of Medicine at UCLA; Staff Physician, Department of Medicine, Division of Infectious Diseases, The Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CaliforniaLeptospira Species (Leptospirosis)
David W. Haas, MDProfessor of Medicine, Pharmacology, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TennesseeMycobacterium tuberculosis
Charles Haines, MD, PhDDivision of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MarylandGastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus Infection
Caroline Breese Hall, MD†
Professor of Pediatrics and Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New YorkRespiratory Syncytial Virus (RSV)
Joelle Hallak, BS, MSResearch Assistant, Department of Ophthalmology and Visual Science, University of Illinois at Chicago, Chicago, IllinoisMicrobial Keratitis
Scott A. Halperin, MDProfessor, Departments of Pediatrics and Microbiology & Immunology, Director, Canadian Center for Vaccinology, Dalhousie University; Head, Pediatric Infectious Diseases, IWK Health Centre, Halifax, Nova Scotia, CanadaBordetella pertussis
Margaret R. Hammerschlag, MDProfessor of Pediatrics and Medicine, State University of New York Downstate College of Medicine; Director, Division of Pediatric Infectious Diseases, State University of New York Downstate Medical Center, Brooklyn, New YorkChlamydia pneumoniae
†Deceased.
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Rashidul Haque, MDScientist and Head of Parasitology Laboratory, Laboratory Sciences Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, BangladeshEntamoeba Species, Including Amebic Colitis and Liver Abscess
Jason B. Harris, MD, MPHAssistant Professor of Pediatrics, Harvard Medical School; Division of Infectious Diseases, MassGeneral Hospital for Children, Boston, MassachusettsEnteric Fever and Other Causes of Fever and Abdominal Symptoms
Claudia Hawkins, MD, MPHAssistant Professor, Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IllinoisHepatitis B Virus and Hepatitis Delta Virus
Roderick J. Hay, DMProfessor of Cutaneous Infection, Department of Dermatology (KCH Campus), Kings College London, London, United KingdomDermatophytosis (Ringworm) and Other Superficial Mycoses
David K. Henderson, MDDeputy Director for Clinical Care, Clinical Center, National Institutes of Health, Bethesda, MarylandInfections Caused by Percutaneous Intravascular Devices; Human Immunodeficiency Virus in Health Care Settings; Nosocomial Herpesvirus Infections
David R. Hill, MD, DTM&HProfessor, Department of Medical Sciences, Director, Global Public Health, Frank H. Netter MD School of Medicine, Quinnipiac University, Hamden, ConnecticutGiardia lamblia
Martin S. Hirsch, MDProfessor of Medicine, Harvard Medical School; Professor of Infectious Diseases and Immunology, Harvard School of Public Health; Senior Physician, Infectious Diseases Service, Massachusetts General Hospital, Boston, MassachusettsAntiretroviral Therapy for Human Immunodeficiency Virus Infection
Aimee Hodowanec, MDAssistant Professor, Department of Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, IllinoisTetanus (Clostridium tetani); Botulism (Clostridium botulinum)
Robert S. Holzman, MDProfessor Emeritus of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine, New York, New YorkMycoplasma pneumoniae and Atypical Pneumonia
Edward W. Hook III, MDProfessor and Director, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AlabamaEndemic Treponematoses
Thomas M. Hooton, MDProfessor of Clinical Medicine, Department of Medicine, Clinical Director, Division of Infectious Diseases, University of Miami Miller School of Medicine; Chief of Medicine, Miami Veterans Affairs Healthcare System, Miami, FloridaNosocomial Urinary Tract Infections
Harold W. Horowitz, MDProfessor of Medicine, Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine; Chief of Service Infectious Diseases, Bellevue Hospital Center, New York, New YorkAcute Exacerbations of Chronic Obstructive Pulmonary Disease
C. Robert Horsburgh, Jr., MD, MUSProfessor of Epidemiology, Biostatistics, and Medicine, Boston University Schools of Public Health and Medicine, Boston, MassachusettsMycobacterium avium Complex
James M. Horton, MDChief, Division of Infectious Diseases, Department of Internal Medicine, Carolinas Medical Center, Charlotte, North CarolinaRelapsing Fever Caused by Borrelia Species
Duane R. Hospenthal, MD, PhDAdjunct Professor of Medicine, Department of Medicine, Infectious Disease Division, University of Texas Health Science Center at San Antonio, San Antonio, TexasAgents of Chromoblastomycosis; Agents of Mycetoma; Uncommon Fungi and Related Species
Nicole M. Iovine, MD, PhDAssistant Professor of Medicine, Director, Antimicrobial Stewardship Program, Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida School of Medicine, Gainesville, FloridaCampylobacter jejuni and Related Species
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Jonathan R. Iredell, MBBS, PhDAssociate Professor, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Director, Department of Infectious Diseases, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, AustraliaNocardia Species
Michael G. Ison, MD, MSAssociate Professor, Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IllinoisParainfluenza Viruses
J. Michael Janda, PhD, D(ABMM)Laboratory Director, Public Health Laboratory, Department of Public Health, County of Los Angeles, Downey, CaliforniaCapnocytophaga
Edward N. Janoff, MDProfessor of Medicine, Microbiology, and Immunology, Departments of Medicine and Infectious Diseases, University of Colorado Denver, Aurora, Colorado; Director, Mucosal and Vaccine Research Center, Denver Veterans Affairs Medical Center, Denver, ColoradoStreptococcus pneumoniae
Eric C. Johannsen, MDAssistant Professor of Medicine, University of Wisconsin School of Medicine and Public Health; Physician, Division of Infectious Diseases, University of Wisconsin Hospitals and Clinics, Madison, WisconsinEpstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases)
Donald Kaye, MDProfessor of Medicine, Drexel University College of Medicine, Philadelphia, PennsylvaniaUrinary Tract Infections
Kenneth M. Kaye, MDAssociate Professor, Department of Medicine, Harvard Medical School; Attending Physician, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MassachusettsEpstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases); Kaposi’s Sarcoma–Associated Herpesvirus (Human Herpesvirus 8)
James W. Kazura, MDProfessor of International Health, Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, OhioTissue Nematodes (Trichinellosis, Dracunculiasis, Filariasis, Loiasis, and Onchocerciasis)
Jay S. Keystone, MD, MSc (CTM)Professor of Medicine, University of Toronto; Senior Staff Physician, Tropical Disease Unit, Toronto General Hospital, Toronto, CanadaCyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species
Yury Khudyakov, PhDDivision of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GeorgiaHepatitis A Virus
Rose Kim, MDAssociate Professor of Medicine, Division of Infectious Diseases, Cooper Medical School of Rowan University, Cooper University Hospital, Camden, New JerseyOther Coryneform Bacteria and Rhodococci
Charles H. King, MDProfessor of International Health, Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OhioTapeworms (Cestodes)
Louis V. Kirchhoff, MD, MPHProfessor of Internal Medicine, University of Iowa; Staff Physician, Medical Service, Department of Veterans Affairs Medical Center, Iowa City, Iowa; Professor of Medicine, State University of New York Upstate Medical University, Syracuse, New YorkTrypanosoma Species (American Trypanosomiasis, Chagas’ Disease): Biology of Trypanosomes; Agents of African Trypanosomiasis (Sleeping Sickness)
Jerome O. Klein, MDProfessor, Department of Pediatrics, Boston University School of Medicine; Former Director, Division of Pediatric Infectious Diseases, Boston Medical Center, Boston, MassachusettsOtitis Externa, Otitis Media, and Mastoiditis
Michael Klompas, MD, MPHAssociate Professor of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute; Associate Hospital Epidemiologist, Brigham and Women’s Hospital, Boston, MassachusettsNosocomial Pneumonia
Bettina M. Knoll, MD, PhDAssistant Professor of Medicine, Warren Alpert Medical School of Brown University; Physician, Miriam Hospital and Rhode Island Hospital, Providence, Rhode IslandProsthetic Valve Endocarditis
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Kirk U. Knowlton, MDProfessor of Medicine, Chief of Cardiology, University of California San Diego School of Medicine, La Jolla, CaliforniaMyocarditis and Pericarditis
Jane E. Koehler, MA, MDProfessor of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CaliforniaBartonella, Including Cat-Scratch Disease
Stephan A. Kohlhoff, MDAssistant Professor of Pediatrics and Medicine, State University of New York Downstate College of Medicine; Co-Director, Division of Pediatric Infectious Diseases, State University of New York Downstate Medical Center, Brooklyn, New YorkChlamydia pneumoniae
Dimitrios P. Kontoyiannis, MDFrances King Black Endowed Professor, Department of Infectious Diseases, Deputy Head, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TexasAgents of Mucormycosis and Entomophthoramycosis
Igor J. Koralnik, MDProfessor of Neurology, Harvard Medical School; Chief, Division of Neuro-Virology, Director, HIV/Neurology Center, Beth Israel Deaconess Medical Center, Boston, MassachusettsJC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML)
Anita A. Koshy, MDAssistant Professor, Departments of Neurology and Immunobiology, University of Arizona, Tucson, ArizonaFree-Living Amebae
Joseph A. Kovacs, MDSenior Investigator, Head, AIDS Section, Critical Care Medicine Department, National Institute of Health Clinical Center, Bethesda, MarylandToxoplasma gondii
Phyllis Kozarsky, MDProfessor of Medicine, Division of Infectious Diseases, Emory University School of Medicine; Medical Director, TravelWell, Emory University Hospital, Atlanta, GeorgiaCyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species
John Krieger, MDProfessor, Department of Urology, University of Washington; Chief, Urology Section, Veterans Affairs Puget Sound Health Care System, Seattle, WashingtonProstatitis, Epididymitis, and Orchitis
Matthew J. Kuehnert, MDDirector, Office of Blood, Organ, and Other Tissue Safety, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, GeorgiaTransfusion- and Transplantation-Transmitted Infections
Nalin M. Kumar, DPhilProfessor, Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, IllinoisMicrobial Conjunctivitis
Paul N. Levett, PhD, DScAssistant Clinical Director, Saskatchewan Disease Control Laboratory, Regina, Saskatchewan, CanadaLeptospira Species (Leptospirosis)
Donald P. Levine, MDProfessor of Medicine, Associate Vice Chair for Continuing Medical Education and Community Affairs, Department of Medicine, Wayne State University, Detroit, MichiganInfections in Injection Drug Users
Matthew E. Levison, MDProfessor of Public Health, Drexel University School of Public Health; Adjunct Professor of Medicine, Drexel University College of Medicine, Philadelphia, PennsylvaniaPeritonitis and Intraperitoneal Abscesses
Russell E. Lewis, PharmDAssociate Professor, Department of Medical Sciences and Surgery, University of Bologna Infectious Diseases Unit, S. Orsola Malpighi Hospital, Bologna, ItalyAgents of Mucormycosis and Entomophthoramycosis
Aldo A. M. Lima, MD, PhDProfessor, Institute of Biomedicine, Federal University of Ceara, Fortaleza, Ceará, BrazilBacterial Inflammatory Enteritides
Ajit P. Limaye, MDProfessor, Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WashingtonInfections in Solid-Organ Transplant Recipients
W. Ian Lipkin, MDDirector, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New YorkZoonoses
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Nathan Litman, MDProfessor of Pediatrics, Albert Einstein College of Medicine; Vice Chair, Clinical Affairs, Department of Pediatrics, Chief, Division of Pediatric Infectious Diseases, Children’s Hospital at Montefiore, Bronx, New YorkMumps Virus
Bennett Lorber, MD, DSc (Hon)Thomas M. Durant Professor of Medicine, Professor of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PennsylvaniaBacterial Lung Abscess; Listeria monocytogenes
Rob Roy MacGregor, MDProfessor, Department of Medicine, Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaCorynebacterium diphtheriae (Diphtheria)
Philip A. Mackowiak, MD, MBAProfessor and Vice Chairman, Department of Medicine, University of Maryland School of Medicine; Chief, Medical Care Clinical Center, Veterans Affairs Maryland Health Care System, Baltimore, MarylandFever of Unknown Origin
Lawrence C. Madoff, MDProfessor of Medicine, University of Massachusetts Medical School; Director, Division of Epidemiology and Immunization, Massachusetts Department of Public Health; Division of Infectious Disease and Immunology, University of Massachusetts Memorial Medical Center, Worcester, MassachusettsInfections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis); Splenic Abscess
Alan J. Magill, MDDirector, Malaria, Bill and Melinda Gates Foundation, Seattle, WashingtonLeishmania Species: Visceral (Kala-Azar), Cutaneous, and Mucosal Leishmaniasis
James H. Maguire, MD, MPHProfessor of Medicine, Harvard Medical School; Senior Physician, Division of Infectious Disease, Brigham and Women’s Hospital, Boston, MassachusettsIntestinal Nematodes (Roundworms); Trematodes (Schistosomes and Liver, Intestinal, and Lung Flukes)
Frank Maldarelli, MD, PhDHead, Clinical Retrovirology Section, HIV Drug Resistance Program, National Cancer Institute—Frederick, National Institutes of Health, Frederick, MarylandDiagnosis of Human Immunodeficiency Virus Infection
Lewis Markoff, MDChief, Laboratory of Vector-Borne Virus Diseases, Office of Vaccines, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MarylandAlphaviruses
Jeanne M. Marrazzo, MD, MPHAssociate Professor of Medicine, Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WashingtonNeisseria gonorrhoeae (Gonorrhea)
Thomas J. Marrie, MDDean, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, CanadaCoxiella burnetii (Q Fever)
Thomas Marth, MDProfessor of Internal Medicine, Chief, Division of Internal Medicine, Krankenhaus Maria Hilf, Daun, GermanyWhipple’s Disease
David H. Martin, MDHarry E. Dascomb, M.D., Professor of Medicine, Department of Internal Medicine, Professor of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LouisianaGenital Mycoplasmas: Mycoplasma genitalium, Mycoplasma hominis, and Ureaplasma Species
Gregory J. Martin, MDChief, Infectious Diseases—Tropical Medicine, Office of Medical Services, U.S. Department of State, Washington, DC; Associate Professor of Medicine and Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, MarylandBacillus anthracis (Anthrax)
Francisco M. Marty, MDAssociate Professor of Medicine, Department of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, MassachusettsCystic Fibrosis
Henry Masur, MDChief, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MarylandManagement of Opportunistic Infections Associated with Human Immunodeficiency Virus Infection
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John T. McBride, MDProfessor of Pediatrics, Northeast Ohio Medical University, Rootstown, Ohio; Vice Chair, Department of Pediatrics, Akron Children’s Hospital, Akron, OhioCroup in Children (Acute Laryngotracheobronchitis); Bronchiolitis
William M. McCormack, MDDistinguished Teaching Professor of Medicine and of Obstetrics and Gynecology, Emeritus, Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New YorkUrethritis; Vulvovaginitis and Cervicitis
Catherine C. McGowan, MDAssociate Professor, Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TennesseeProstatitis, Epididymitis, and Orchitis
Kenneth McIntosh, MDProfessor of Pediatrics, Harvard Medical School; Senior Physician, Department of Medicine, Children’s Hospital, Boston, MassachusettsCoronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)
Paul S. Mead, MD, MPHChief, Epidemiology and Surveillance Activity, Bacterial Disease Branch, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Fort Collins, ColoradoYersinia Species (Including Plague)
Malgorzata Mikulska, MDDivision of Infectious Diseases, IRCCS AOU San Martino-IST; Department of Health Sciences, University of Genova, Genova, ItalyProphylaxis and Empirical Therapy of Infection in Cancer Patients
Robert F. Miller, MBBSReader in Clinical Infection, Honorary Professor, London School of Hygiene and Tropical Medicine; Honorary Consultant Physician, Camden Provider Services, Central and North West London NHS Foundation Trust, and at University College London Hospitals, University College London, London, United KingdomPneumocystis Species
Samuel I. Miller, MDProfessor of Medicine, Microbiology, Genome Sciences, and Immunology, Department of Immunology, University of Washington School of Medicine, Seattle, WashingtonSalmonella Species
David H. Mitchell, MBBSClinical Senior Lecturer, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Senior Staff Specialist, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, AustraliaNocardia Species
John F. Modlin, MDProfessor of Pediatrics and Medicine, Chair, Department of Pediatrics, Senior Advising Dean, Geisel School of Medicine at Dartmouth; Interim Director, Children’s Hospital at Dartmouth, Lebanon, New HampshirePoliovirus; Coxsackieviruses, Echoviruses, and Numbered Enteroviruses; Human Parechoviruses
Rajal K. Mody, MD, MPHLead, National Surveillance Team, Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Diseases, Centers for Disease Control and Prevention, Atlanta, GeorgiaFoodborne Disease
José G. Montoya, MDProfessor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CaliforniaToxoplasma gondii
Philippe Moreillon, MD, PhDProfessor and Vice Rector for Research, Department of Fundamental Microbiology, University of Lausanne, Lausanne, SwitzerlandStaphylococcus aureus (Including Staphylococcal Toxic Shock Syndrome)
J. Glenn Morris, Jr., MD, MPH&TMDirector, Emerging Pathogens Institute, University of Florida; Professor of Medicine, Division of Infectious Diseases, University of Florida College of Medicine, Gainesville, FloridaHuman Illness Associated with Harmful Algal Blooms
Robert S. Munford, MDSenior Clinician, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSepsis, Severe Sepsis, and Septic Shock
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Edward L. Murphy, MD, MPHProfessor, Departments of Laboratory Medicine and Epidemiology/Biostatistics, University of California School of Medicine; Senior Investigator, Blood Systems Research Institute, San Francisco, CaliforniaHuman T-Lymphotropic Virus (HTLV)
Timothy F. Murphy, MDSUNY Distinguished Professor, Clinical and Translational Research Center, University at Buffalo, State University of New York, Buffalo, New YorkMoraxella catarrhalis, Kingella, and Other Gram-Negative Cocci; Haemophilus Species, including H. influenzae and H. ducreyi (Chancroid)
Barbara E. Murray, MDJ. Ralph Meadows Professor and Director, Division of Infectious Diseases, Department of Internal Medicine and Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, TexasEnterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc Species
Clinton K. Murray, MDChief, Infectious Disease, Brooke Army Medical Center, Fort Sam Houston, Houston, Texas; Professor of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Clinical Professor of Medicine and Infectious Diseases, University of Texas Health Sciences Center, San Antonio, TexasBurns
Daniel M. Musher, MDProfessor of Medicine and of Molecular Virology and Microbiology, Distinguished Service Professor, Baylor College of Medicine; Infectious Disease Section, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TexasStreptococcus pneumoniae
Anna Narezkina, MDFellow, Division of Cardiology, University of California San Diego School of Medicine, La Jolla, CaliforniaMyocarditis and Pericarditis
Theodore E. Nash, MDHead, Gastrointestinal Parasites Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandGiardia lamblia; Visceral Larva Migrans and Other Uncommon Helminth Infections
Jennifer L. Nayak, MDAssistant Professor, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New YorkEpiglottitis
Marguerite A. Neill, MDAssociate Professor of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Attending Physician, Division of Infectious Diseases, Memorial Hospital of Rhode Island, Pawtucket, Rhode IslandOther Pathogenic Vibrios
Christopher A. Ohl, MDProfessor of Medicine, Section on Infectious Diseases, Wake Forest School of Medicine; Medical Director, Center for Antimicrobial Utilization, Stewardship, and Epidemiology, Wake Forest Baptist Medical Center, Winston-Salem, North CarolinaInfectious Arthritis of Native Joints
Pablo C. Okhuysen, MDProfessor, Department of Infectious Diseases, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, TexasSporothrix schenckii
Andrew B. Onderdonk, PhDProfessor of Pathology, Harvard Medical School; Microbiology Laboratory, Brigham and Women’s Hospital, Boston, MassachusettsGas Gangrene and Other Clostridium-Associated Diseases; Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)
Douglas R. Osmon, MDProfessor of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MinnesotaOsteomyelitis
Michael N. Oxman, MDProfessor of Medicine and Pathology, University of California San Diego School of Medicine, La Jolla, California; Staff Physician, Infectious Diseases, Veterans Affairs San Diego Healthcare System, San Diego, CaliforniaMyocarditis and Pericarditis
Slobodan Paessler, DVM, PhDProfessor, Department of Pathology, Director, Preclinical Studies Core, Director, Animal Biosafety Level 3, Galveston National Laboratory, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TexasLymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)
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Raj Palraj, MBBSInstructor of Medicine, Mayo Clinic College of Medicine; Senior Associate Consultant, Infectious Diseases, Mayo Clinic, Rochester, MinnesotaProsthetic Valve Endocarditis
Peter G. Pappas, MDProfessor of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AlabamaChronic Pneumonia
Mark S. Pasternack, MDChief, Pediatric Infectious Disease Unit, Massachusetts General Hospital, Boston, MassachusettsCellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue Infections; Myositis and Myonecrosis
Thomas F. Patterson, MDProfessor, Department of Medicine, Division of Infectious Diseases, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TexasAspergillus Species
Deborah Pavan-Langston, MDProfessor, Department of Ophthalmology, Harvard Medical School; Attending Physician, Massachusetts Eye and Ear Infirmary, Boston, MassachusettsMicrobial Conjunctivitis; Microbial Keratitis
David A. Pegues, MDProfessor of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania; Medical Director, Healthcare Epidemiology, Infection Prevention and Control; Antimicrobial Management Program, Hospital of the University of Pennsylvania, Philadelphia, PennsylvaniaSalmonella Species
Robert L. Penn, MDProfessor of Medicine, Infectious Diseases Section, Louisiana State University School of Medicine in Shreveport; Physician, Infectious Diseases Section, Overton Brooks Veterans Affairs Medical Center, Shreveport, LouisianaFrancisella tularensis (Tularemia)
John R. Perfect, MDJames B. Duke Professor of Medicine, Chief, Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North CarolinaCryptococcosis (Cryptococcus neoformans and Cryptococcus gattii)
Stanley Perlman, MD, PhDProfessor, Department of Microbiology and Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IowaCoronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)
Brett W. Petersen, MD, MPHMedical Officer, Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GeorgiaOrthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox; Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and Yatapoxviruses
Phillip K. Peterson, MDProfessor of Medicine, Director, International Medical Education and Research, University of Minnesota Medical School, Minneapolis, MinnesotaInfections in the Elderly
William A. Petri, Jr., MD, PhDWade Hampton Frost Professor of Epidemiology, University of Virginia; Chief, Division of Infectious Disease and International Health, University of Virginia Health System, Charlottesville, VirginiaEntamoeba Species, Including Amebic Colitis and Liver Abscess
Cathy A. Petti, MDCEO, HealthSpring Global, Inc., Bradenton, FloridaStreptococcus anginosus Group
Michael Phillips, MDAssociate Professor (Clinical), Associate Director for Clinical Affairs, Division of Infectious Disease and Immunology, New York University School of Medicine; Hospital Epidemiologist and Director of Infection Prevention and Control, NYU Langone Medical Center, New York, New YorkAcinetobacter Species
Yok-Ai Que, MD, PhDInstructor and Researcher, University of Lausanne School of Medicine; Attending Physician, Department of Critical Care Medicine, Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, SwitzerlandStaphylococcus aureus (Including Staphylococcal Toxic Shock Syndrome)
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Justin D. Radolf, MDProfessor, Departments of Medicine, Pediatrics, Immunology, Genetics & Developmental Biology, and Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut; Senior Scientific Advisor, Connecticut Children’s Medical Center, Hartford, ConnecticutSyphilis (Treponema pallidum)
Didier Raoult, MD, PhDProfessor and President, Aix Marseille Université; Director, Clinical Microbiology Laboratory for the University Hospitals; Founder, WHO Collaborative Center; President, Universite de la Mediteranee in Marseille, Marseille, FranceRickettsia akari (Rickettsialpox); Coxiella burnetii (Q Fever); Orientia tsutsugamushi (Scrub Typhus)
Stuart C. Ray, MDProfessor of Medicine, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MarylandHepatitis C
Annette C. Reboli, MDFounding Vice Dean, Professor of Medicine, Division of Infectious Diseases, Cooper Medical School of Rowan University, Cooper University Hospital, Camden, New JerseyOther Coryneform Bacteria and Rhodococci; Erysipelothrix rhusiopathiae
Marvin S. Reitz, Jr., PhDProfessor, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MarylandHuman Immunodeficiency Viruses
Cybèle A. Renault, MD, DTM&HClinical Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, California; Attending Physician, Veterans Affairs Palo Alto Health Care, Palo Alto, CaliforniaMycobacterium leprae (Leprosy)
Angela Restrepo, MSc, PhDSenior Researcher, Medical and Experimental Mycology Unit, Corporación para Investigaciones Biológicas, Medellín, Antioquia, ColombiaParacoccidioidomycosis
John H. Rex, MDAdjunct Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Center for the Study of Emerging and Reemerging Pathogens, University of Texas Medical School, Houston, Texas; Head of Infection, Global Medicines Development, AstraZeneca Pharmaceuticals, Waltham, MassachusettsSporothrix schenckii
Elizabeth G. Rhee, MDDirector, Clinical Research, Department of Clinical Pharmacology, Merck Research Laboratories, Kenilworth, New JerseyAdenoviruses
José R. Romero, MDHorace C. Cabe Professor of Infectious Diseases, Department of Pediatrics, University of Arkansas for Medical Sciences; Director, Pediatric Infectious Diseases Section, Department of Pediatrics, Arkansas Children’s Hospital; Director, Clinical Trials Research, Arkansas Children’s Hospital Research Institute, Little Rock, ArkansasPoliovirus; Coxsackieviruses, Echoviruses, and Numbered Enteroviruses; Human Parechoviruses
Alan L. Rothman, MDResearch Professor, Institute for Immunology and Informatics and Department of Cell and Molecular Biology, University of Rhode Island, Providence, Rhode IslandFlaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)
Craig R. Roy, PhDProfessor, Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, ConnecticutLegionnaires’ Disease and Pontiac Fever
Mark E. Rupp, MDProfessor and Chief, Infectious Diseases, University of Nebraska Medical Center; Medical Director, Infection Control and Epidemiology, The Nebraska Medical Center, Omaha, NebraskaMediastinitis; Staphylococcus epidermidis and Other Coagulase-Negative Staphylococci
Charles E. Rupprecht, VMD, PhDResearch Coordinator at Global Alliance for Rabies Control, Atlanta, Georgia; Professor, Ross University School of Veterinary Medicine, Basseterre St. Kitts, West IndiesRabies (Rhabdoviruses)
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Thomas A. Russo, MD, CMProfessor of Medicine and Microbiology, Division of Infectious Diseases, State University of New York at Buffalo School of Medicine and Biomedical Sciences; Staff Physician, Veterans Affairs Western New York Health Care System, Buffalo, New YorkAgents of Actinomycosis
William A. Rutala, MS, PhD, MPHProfessor of Medicine, Director, Statewide Program for Infection Control and Epidemiology, University of North Carolina at Chapel Hill School of Medicine; Director, Hospital Epidemiology, Occupational Health and Safety, University of North Carolina Health Care, Chapel Hill, North CarolinaThe Acutely Ill Patient with Fever and Rash
Edward T. Ryan, MDProfessor of Medicine, Harvard Medical School; Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Director, Tropical Medicine, Massachusetts General Hospital, Boston, MassachusettsEnteric Fever and Other Causes of Fever and Abdominal Symptoms; Vibrio cholerae
Amar Safdar, MD, MBBSAssociate Professor of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine; Director, Transplant Infectious Diseases, Department of Medicine, NYU Langone Medical Center, New York, New YorkStenotrophomonas maltophilia and Burkholderia cepacia
Juan C. Salazar, MD, MPHProfessor and Chairman, Department of Pediatrics, University of Connecticut School of Medicine, Farmington, Connecticut; Physician-in-Chief, Head of Division of Pediatric Infectious Diseases and Immunology, Connecticut Children’s Medical Center, Hartford, ConnecticutSyphilis (Treponema pallidum)
Maria C. Savoia, MDDean for Medical Education, Professor of Medicine, University of California San Diego School of Medicine, La Jolla, CaliforniaMyocarditis and Pericarditis
Paul E. Sax, MDProfessor of Medicine, Harvard Medical School; Clinical Director, Division of Infectious Diseases and Human Immunodeficiency Virus Program, Brigham and Women’s Hospital, Boston, MassachusettsPulmonary Manifestations of Human Immunodeficiency Virus Infection
W. Michael Scheld, MDGerald L. Mandell–Bayer Professor of Infectious Diseases, Professor of Medicine, University of Virginia School of Medicine; Clinical Professor of Neurosurgery, Director, Pfizer Initiative in International Health, University of Virginia Health System, Charlottesville, VirginiaEndocarditis and Intravascular Infections; Acute Meningitis
Joshua T. Schiffer, MD, MScAssistant Professor, Department of Medicine, University of Washington; Assistant Member, Vaccine and Infectious Diseases Division, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WashingtonHerpes Simplex Virus
David Schlossberg, MDProfessor, Department of Medicine, Temple University School of Medicine; Medical Director, Tuberculosis Control Program, Philadelphia Department of Public Health, Philadelphia, PennsylvaniaPsittacosis (Due to Chlamydia psittaci)
Thomas Schneider, MD, PhDProfessor of Infectious Diseases, Charité University Hospital, Benjamin Franklin Campus, Berlin, GermanyWhipple’s Disease
Jane R. Schwebke, MDProfessor of Medicine, Medicine/Infectious Diseases, University of Alabama at Birmingham, Birmingham, AlabamaTrichomonas vaginalis
Leopoldo N. Segal, MDAssistant Professor, Department of Medicine, New York University School of Medicine, New York, New YorkAcute Exacerbations of Chronic Obstructive Pulmonary Disease
Parham Sendi, MDConsultant and Lecturer, Basel University Medical Clinic, Liestal, Switzerland; Department of Infectious Diseases, University Hospital and Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandOrthopedic Implant–Associated Infections
Kent A. Sepkowitz, MDDeputy Physician-in-Chief, Quality and Safety, Memorial Sloan Kettering Cancer Center; Professor of Medicine, Weill Cornell Medical College, New York, New YorkHealth Care–Acquired Hepatitis
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Edward J. Septimus, MDClinical Professor, Department of Internal Medicine, Texas A&M Health Science Center, Houston, Texas; Medical Director, Infection Prevention and Epidemiology, Clinical Services Group, HCA, Inc., Nashville, TennesseePleural Effusion and Empyema
Alexey Seregin, PhDResearch Scientist, Department of Pathology, University of Texas Medical Branch, Galveston, TexasLymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)
Stanford T. Shulman, MDVirginia H. Rogers Professor of Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine; Chief, Division of Infectious Diseases, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IllinoisNonsuppurative Poststreptococcal Sequelae: Rheumatic Fever and Glomerulonephritis
George K. Siberry, MD, MPHMedical Officer, Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MarylandPediatric Human Immunodeficiency Virus Infection
Omar K. Siddiqi, MDClinical Instructor, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Honorary Lecturer, Department Medicine, University of Zambia School of Medicine, Lusaka, ZambiaNeurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections
Costi D. Sifri, MDAssociate Professor of Medicine, Division of Infectious Diseases and International Health, University of Virginia School of Medicine; Attending Physician, Department of Medicine, University of Virginia Health System, Charlottesville, VirginiaInfections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis)
Michael S. Simberkoff, MDProfessor of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine, New York, New YorkMycoplasma pneumoniae and Atypical Pneumonia
Francesco R. Simonetti, MDGuest Researcher, HIV Drug Resistance Program, National Cancer Institute—Frederick, National Institutes of Health, Frederick, MarylandDiagnosis of Human Immunodeficiency Virus Infection
Kamaljit Singh, MD, D(ABMM)Associate Professor, Departments of Medicine and Pathology, Rush University Medical Center, Chicago, IllinoisRabies (Rhabdoviruses)
Nina Singh, MDProfessor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Pittsburgh and VA Pittsburgh Healthcare System, Pittsburgh, PennsylvaniaInfections in Solid-Organ Transplant Recipients
Upinder Singh, MDAssociate Professor of Medicine, Departments of Infectious Diseases and Microbiology & Immunology, Stanford School of Medicine, Stanford, CaliforniaFree-Living Amebae
Scott W. Sinner, MDHyperbaric Medical Director, Mercy-Clermont Hospital, Batavia, OhioViridans Streptococci, Nutritionally Variant Streptococci, Groups C and G Streptococci, and Other Related Organisms
Leonard N. Slater, MDProfessor of Infectious Diseases, Department of Internal Medicine, College of Medicine, University of Oklahoma, Oklahoma City, OklahomaBartonella, Including Cat-Scratch Disease
A. George Smulian, MB BCh, MScAssociate Professor, University of Cincinnati College of Medicine; Chief, Infectious Disease Section, Veterans Affairs Cincinnati Medical Center, Cincinnati, OhioPneumocystis Species
Jack D. Sobel, MDProfessor of Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, MichiganUrinary Tract Infections
M. Rizwan Sohail, MDAssociate Professor of Medicine, Divisions of Infectious Diseases and Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MinnesotaInfections of Nonvalvular Cardiovascular Devices
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David E. Soper, MDProfessor and Vice Chairman, Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, South CarolinaInfections of the Female Pelvis
Tania C. Sorrell, AM, MD, MBBSProfessor and Director, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, New South Wales, Australia; Director, Centre for Infectious Diseases and Microbiology and Service Director, Infectious Diseases and Sexual Health, Westmead, New South Wales, AustraliaNocardia Species
James M. Steckelberg, MDProfessor of Medicine, Consultant, Division of Infectious Diseases, Mayo Clinic, Rochester, MinnesotaOsteomyelitis
Allen C. Steere, MDProfessor of Medicine, Harvard Medical School, Harvard University; Director, Translational Research in Rheumatology, Massachusetts General Hospital, Boston, MassachusettsLyme Disease (Lyme Borreliosis) Due to Borrelia burgdorferi
James P. Steinberg, MDProfessor of Medicine, Division of Infectious Diseases, Emory University School of Medicine; Chief Medical Officer, Emory University Hospital Midtown, Atlanta, GeorgiaOther Gram-Negative and Gram-Variable Bacilli
David S. Stephens, MDStephen W. Schwarzmann Distinguished Professor of Medicine, Chair, Department of Medicine, Emory University School of Medicine; Vice President for Research, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, GeorgiaNeisseria meningitidis
Timothy R. Sterling, MDProfessor of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TennesseeGeneral Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases); Mycobacterium tuberculosis
Dennis L. Stevens, MD, PhDAssociate Chief of Staff, Research and Development Service, Veterans Affairs Medical Center, Boise, Idaho; Professor of Medicine, Department of Medicine, University of Washington, Seattle, WashingtonStreptococcus pyogenes
Charles W. Stratton IV, MDAssociate Professor of Pathology and Medicine, Vanderbilt University School of Medicine; Director, Clinical Microbiology Laboratory, Vanderbilt University Medical Center, Nashville, TennesseeStreptococcus anginosus Group
Anthony F. Suffredini, MDSenior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MarylandSepsis, Severe Sepsis, and Septic Shock
Kathryn N. Suh, MD, MScAssociate Professor of Medicine, University of Ottawa; Division of Infectious Diseases, The Ottawa Hospital, Ottawa, CanadaCyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species
Mark S. Sulkowski, MDProfessor of Medicine, Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology, Johns Hopkins University School of Medicine, Baltimore, MarylandGastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus Infection
Morton N. Swartz, MD†
Associate Firm Chief, Infectious Diseases Unit, Massachusetts General Hospital, Boston, MassachusettsCellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue Infections; Myositis and Myonecrosis
Thomas R. Talbot, MD, MPHAssociate Professor of Medicine and Health Policy, Vanderbilt University School of Medicine; Chief Hospital Epidemiologist, Vanderbilt University Medical Center, Nashville, TennesseeSurgical Site Infections and Antimicrobial Prophylaxis
C. Sabrina Tan, MDAssistant Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MassachusettsJC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML)
Ming Tan, MDProfessor of Medicine, Microbiology and Molecular Genetics, University of California at Irvine School of Medicine, Irvine, CaliforniaChlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)
†Deceased.
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Chloe Lynne Thio, MDAssociate Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MarylandHepatitis B Virus and Hepatitis Delta Virus
David L. Thomas, MD, MPHProfessor of Medicine, Director, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MarylandHepatitis C
Stephen J. Thomas, MDDirector, Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MarylandFlaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)
Anna R. Thorner, MDAssistant Clinical Professor of Medicine, Department of Medicine, Harvard Medical School; Associate Physician, Division of Infectious Disease, Brigham and Women’s Hospital, Boston, MassachusettsZoonotic Paramyxoviruses: Nipah, Hendra, and Menangle
Angela María Tobón, MDDirector, Chronic Infectious Diseases Unit, Department of Internal Medicine, Corporación para Investigaciones Biológicas, Medellín, ColombiaParacoccidioidomycosis
Edmund C. Tramont, MDAssociate Director, Special Projects, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSyphilis (Treponema pallidum)
John J. Treanor, MDChief, Division of Infectious Diseases, Department of Medicine, University of Rochester Medical Center, Rochester, New YorkInfluenza (Including Avian Influenza and Swine Influenza); Noroviruses and Sapoviruses (Caliciviruses); Astroviruses and Picobirnaviruses
Athe M. N. Tsibris, MD, MSAssistant Professor in Medicine, Division of Infectious Diseases, Harvard Medical School; Brigham and Women’s Hospital, Boston, MassachusettsAntiretroviral Therapy for Human Immunodeficiency Virus Infection
Allan R. Tunkel, MD, PhD, MACPProfessor of Medicine, Associate Dean for Medical Education, Warren Alpert Medical School of Brown University, Providence, Rhode IslandAcute Meningitis; Brain Abscess; Subdural Empyema, Epidural Abscess, and Suppurative Intracranial Thrombophlebitis; Cerebrospinal Fluid Shunt and Drain Infections; Viridans Streptococci, Nutritionally Variant Streptococci, Groups C and G Streptococci, and Other Related Organisms
Ronald B. Turner, MDProfessor of Pediatrics, University of Virginia School of Medicine, Charlottesville, VirginiaThe Common Cold; Rhinovirus
Kenneth L. Tyler, MDReuler-Lewin Family Professor of Neurology and Professor of Medicine and Microbiology, University of Colorado Denver School of Medicine, Aurora, Colorado; Chief, Neurology Service, Denver Veterans Affairs Medical Center, Denver, ColoradoEncephalitis; Orthoreoviruses and Orbiviruses; Coltiviruses and Seadornaviruses; Prions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases)
Ahmet Uluer, DO, MSAssistant Professor of Pediatrics, Department of Medicine, Harvard Medical School; Boston Children’s Hospital, Boston, MassachusettsCystic Fibrosis
Diederik van de Beek, MD, PhDProfessor, Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsAcute Meningitis
Edouard G. Vannier, PharmD, PhDAssistant Professor of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center and Tufts University School of Medicine, Boston, MassachusettsBabesia Species
Trevor C. Van Schooneveld, MDAssistant Professor of Infectious Diseases, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NebraskaMediastinitis
Claudio Viscoli, MDDivision of Infectious Diseases, IRCCS AOU San Martino-IST; Department of Health Sciences, University of Genova, Genova, ItalyProphylaxis and Empirical Therapy of Infection in Cancer Patients
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Ellen R. Wald, MDAlfred Dorrance Daniels Professor on Diseases of Children, University of Wisconsin School of Medicine and Public Health; Pediatrician-in-Chief, American Family Children’s Hospital, Madison, WisconsinSinusitis
Matthew K. Waldor, MD, PhDEdward H. Kass Professor of Medicine, Harvard Medical School; Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MassachusettsVibrio cholerae
David H. Walker, MDProfessor, Department of Pathology, University of Texas Medical Branch; Executive Director, Center for Biodefense and Emerging Infectious Diseases, Galveston, TexasRickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers); Rickettsia prowazekii (Epidemic or Louse-Borne Typhus); Rickettsia typhi (Murine Typhus); Ehrlichia chaffeensis (Human Monocytotropic Ehrlichiosis), Anaplasma phagocytophilum (Human Granulocytotropic Anaplasmosis), and Other Anaplasmataceae
Richard J. Wallace, Jr., MDChairman, Department of Microbiology, University of Texas Health Northeast, Tyler, TexasInfections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex
Edward E. Walsh, MDProfessor of Medicine, Department of Infectious Diseases, University of Rochester School of Medicine and Dentistry, Rochester, New YorkAcute Bronchitis; Respiratory Syncytial Virus (RSV)
Stephen R. Walsh, MDAssistant Professor of Medicine, Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, MassachusettsHepatitis E Virus
Peter D. Walzer, MD, MScEmeritus Professor of Medicine, University of Cincinnati; Retired Associate Chief of Staff for Research, Cincinnati VA Medical Center, Cincinnati, OhioPneumocystis Species
Christine A. Wanke, MDProfessor, Department of Medicine, Associate Chair, Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MassachusettsTropical Sprue: Enteropathy
Cirle A. Warren, MDAssistant Professor, Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VirginiaBacterial Inflammatory Enteritides
Ronald G. Washburn, MDAssociate Chief of Staff for Research and Development, Medical Research, Chief of Infectious Diseases, Medical Service, Shreveport Veterans Affairs Medical Center; Professor of Medicine, Infectious Diseases Section, Louisiana State University Health Sciences Center, Shreveport, LouisianaRat-Bite Fever: Streptobacillus moniliformis and Spirillum minus
Valerie Waters, MD, MScAssociate Professor, Department of Pediatric Infectious Diseases, Hospital for Sick Children, Toronto, Ontario, CanadaBordetella pertussis
David J. Weber, MD, MPHProfessor of Medicine, Pediatrics, and Epidemiology, University of North Carolina at Chapel Hill School of Medicine; Associate Chief of Staff and Medical Director, Hospital Epidemiology and Occupational Health, University of North Carolina Health Care, Chapel Hill, North CarolinaThe Acutely Ill Patient with Fever and Rash
Michael D. Weiden, MDAssociate Professor, Departments of Medicine and Environmental Medicine, New York University School of Medicine, Langone Medical Center, New York, New YorkAcute Exacerbations of Chronic Obstructive Pulmonary Disease
Geoffrey A. Weinberg, MDProfessor of Pediatrics, Department of Pediatrics, University of Rochester School of Medicine and Dentistry; Director, Pediatric HIV Program, Golisano Children’s Hospital, University of Rochester Medical Center, Rochester, New YorkEpiglottitis; Pediatric Human Immunodeficiency Virus Infection
Daniel J. Weisdorf, MDProfessor of Medicine, Division of Hematology, Oncology, and Transplantation, Director, Adult Blood and Marrow Transplant Program, University of Minnesota Medical School, Minneapolis, MinnesotaInfections in Recipients of Hematopoietic Stem Cell Transplants
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Louis M. Weiss, MD, MPHProfessor, Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, New YorkMicrosporidiosis
David F. Welch, PhDClinical Consultant, Medical Microbiology Consulting, LLC, Dallas, TexasBartonella, Including Cat-Scratch Disease
Thomas E. Wellems, MD, PhDChief, Laboratory of Malaria and Vector Research, Chief, Malaria Genetics Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, MarylandMalaria (Plasmodium Species)
A. Clinton White, Jr., MDPaul R. Stalnaker Distinguished Professor, Director, Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TexasCryptosporidiosis (Cryptosporidium Species)
Richard J. Whitley, MDDistinguished Professor of Pediatrics, Loeb Eminent Scholar Chair in Pediatrics, Professor of Microbiology, Medicine, and Neurosurgery, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AlabamaChickenpox and Herpes Zoster (Varicella-Zoster Virus)
Walter R. Wilson, MDProfessor of Medicine and Assistant Professor of Microbiology, Mayo Clinic College of Medicine; Consultant, Infectious Diseases, Mayo Clinic, Rochester, MinnesotaProsthetic Valve Endocarditis
William F. Wright, DO, MPHAssistant Professor of Medicine and Microbiology, Division of Infectious Diseases and Travel Medicine, Georgetown University School of Medicine, Washington, DCFever of Unknown Origin
Jo-Anne H. Young, MDProfessor of Medicine, Division of Infectious Disease and International Medicine, Medical Director of the Program in Adult Transplant Infectious Disease University of Minnesota, Minneapolis, Minnesota; Editor-in-Chief, Clinical Microbiology Reviews, American Society of Microbiology, Washington, DCInfections in Recipients of Hematopoietic Stem Cell Transplants
Vincent B. Young, MD, PhDAssociate Professor, Department of Internal Medicine, Division of Infectious Diseases, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MichiganClostridium difficile Infection
Nadezhda Yun, MDAssistant Professor, Department of Pathology, Assistant Director, Preclinical Studies Core, Galveston National Laboratory, University of Texas Medical Branch, Galveston, TexasLymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)
Werner Zimmerli, MDProfessor, Basel University Medical Clinic, Liestal, SwitzerlandOrthopedic Implant–Associated Infections
John J. Zurlo, MDProfessor of Medicine, Department of Medicine/Infectious Diseases, Penn State Hershey Medical Center, Hershey, PennsylvaniaPasteurella Species
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Preface
This handbook is an introduction to Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, also known as PPID, which is the detailed, authoritative reference book for the field. The handbook consists of “short view summaries” that introduce 241 of the 324 chapters in the 8th edition of PPID and that appear at the beginning of each chapter in a template format. The summaries are accompanied by tables and figures that illustrate the material contained therein. In addition, this handbook reflects the annual updates that appear in the electronic version of PPID.
The field of infectious disease is undergo-ing an extraordinary expansion of knowl-edge, with dramatic advances in diagnosis, therapy, and prevention of infectious dis-eases, as well as recognition of novel patho-gens and diseases. The handbook is intended to provide information on these topics in an easy-to-use form, and to facilitate access to further information as needed. In this regard,
the handbook is organized on the same basis as the parent textbook, PPID. Information is presented according to major infectious clinical syndromes, and individual pathogens are addressed in more detail subsequently. Examples of topics in which important new developments have occurred include hepati-tis B and C, Ebola, influenza, Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), tuberculosis, human immu-nodeficiency virus, and Middle East respira-tory syndrome (MERS).
We hope this handbook will be a conve-nient, useful, and current source of informa-tion for those interested in infectious diseases, and that it will serve as an introduction to the more detailed and comprehensive material that can be found in the parent text, PPID.
John E. Bennett, MD, MACPRaphael Dolin, MD
Martin J. Blaser, MD
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Contents
I MAJORCLINICALSYNDROMES
A FEVER 1 FeverofUnknownOrigin 2
William F. Wright and Philip A. Mackowiak
2 TheAcutelyIllPatientwithFeverandRash 3David J. Weber, Myron S. Cohen, and William A. Rutala
B UPPERRESPIRATORYTRACTINFECTIONS 3 TheCommonCold 5
Ronald B. Turner
4 Pharyngitis 6Anthony R. Flores and Mary T. Caserta
5 AcuteLaryngitis 10Mary T. Caserta
6 CroupinChildren(AcuteLaryngotracheobronchitis) 11John Bower and John T. McBride
7 OtitisExterna,OtitisMedia,andMastoiditis 12Jerome O. Klein
8 Sinusitis 14Gregory P. DeMuri and Ellen R. Wald
9 Epiglottitis 15Jennifer L. Nayak and Geoffrey A. Weinberg
10 InfectionsoftheOralCavity,Neck,andHead 17Anthony W. Chow
C PLEUROPULMONARYANDBRONCHIALINFECTIONS 11 AcuteBronchitis 22
Edward E. Walsh
12 AcuteExacerbationsofChronicObstructivePulmonaryDisease 23Leopoldo N. Segal, Michael D. Weiden, and Harold W. Horowitz
13 Bronchiolitis 24John Bower and John T. McBride
14 AcutePneumonia 25Richard T. Ellison III and Gerald R. Donowitz
15 PleuralEffusionandEmpyema 28Edward J. Septimus
16 BacterialLungAbscess 30Bennett Lorber
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17 ChronicPneumonia 31Peter G. Pappas
18 CysticFibrosis 33Ahmet Uluer and Francisco M. Marty
D URINARYTRACTINFECTIONS 19 UrinaryTractInfections 37
Jack D. Sobel and Donald Kaye
E SEPSIS 20 Sepsis,SevereSepsis,andSepticShock 40
Robert S. Munford and Anthony F. Suffredini
F INTRA-ABDOMINALINFECTIONS 21 PeritonitisandIntraperitonealAbscesses 42
Matthew E. Levison and Larry M. Bush
22 InfectionsoftheLiverandBiliarySystem(LiverAbscess,Cholangitis,Cholecystitis) 48Costi D. Sifri and Lawrence C. Madoff
23 PancreaticInfection 49Miriam Baron Barshak
24 SplenicAbscess 54Lawrence C. Madoff
25 Appendicitis 55Costi D. Sifri and Lawrence C. Madoff
26 DiverticulitisandTyphlitis 56Costi D. Sifri and Lawrence C. Madoff
G CARDIOVASCULARINFECTIONS 27 EndocarditisandIntravascularInfections 58
Vance G. Fowler, Jr., W. Michael Scheld, and Arnold S. Bayer
28 ProstheticValveEndocarditis 63Raj Palraj, Bettina M. Knoll, Larry M. Baddour, and Walter R. Wilson
29 InfectionsofNonvalvularCardiovascularDevices 65M. Rizwan Sohail, Walter R. Wilson, and Larry M. Baddour
30 ProphylaxisofInfectiveEndocarditis 67David T. Durack
31 MyocarditisandPericarditis 69Kirk U. Knowlton, Anna Narezkina, Maria C. Savoia, and Michael N. Oxman
32 Mediastinitis 72Trevor C. Van Schooneveld and Mark E. Rupp
H CENTRALNERVOUSSYSTEMINFECTIONS 33 AcuteMeningitis 75
Allan R. Tunkel, Diederik van de Beek, and W. Michael Scheld
34 ChronicMeningitis 78John E. Bennett
35 Encephalitis 80J. David Beckham and Kenneth L. Tyler
36 BrainAbscess 84Allan R. Tunkel
37 SubduralEmpyema,EpiduralAbscess,andSuppurativeIntracranialThrombophlebitis 86Allan R. Tunkel
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38 CerebrospinalFluidShuntandDrainInfections 88Adarsh Bhimraj, James M. Drake, and Allan R. Tunkel
I SKINANDSOFTTISSUEINFECTIONS 39 Cellulitis,NecrotizingFasciitis,andSubcutaneousTissueInfections 90
Mark S. Pasternack and Morton N. Swartz
40 MyositisandMyonecrosis 92Mark S. Pasternack and Morton N. Swartz
41 LymphadenitisandLymphangitis 94Mark S. Pasternack and Morton N. Swartz
J GASTROINTESTINALINFECTIONSANDFOODPOISONING 42 Esophagitis 98
Paul S. Graman
43 Nausea,Vomiting,andNoninflammatoryDiarrhea 100David A. Bobak and Richard L. Guerrant
44 BacterialInflammatoryEnteritides 102Aldo A. M. Lima, Cirle A. Warren, and Richard L. Guerrant
45 EntericFeverandOtherCausesofFeverandAbdominalSymptoms 104Jason B. Harris and Edward T. Ryan
46 FoodborneDisease 105Rajal K. Mody and Patricia M. Griffin
47 TropicalSprue:Enteropathy 107Christine A. Wanke
K BONEANDJOINTINFECTIONS 48 InfectiousArthritisofNativeJoints 108
Christopher A. Ohl and Derek Forster
49 Osteomyelitis 111Elie F. Berbari, James M. Steckelberg, and Douglas R. Osmon
50 OrthopedicImplant–AssociatedInfections 113Werner Zimmerli and Parham Sendi
L DISEASESOFTHEREPRODUCTIVEORGANSANDSEXUALLYTRANSMITTEDDISEASES
51 GenitalSkinandMucousMembraneLesions 116Michael H. Augenbraun
52 Urethritis 117Michael H. Augenbraun and William M. McCormack
53 VulvovaginitisandCervicitis 118William M. McCormack and Michael H. Augenbraun
54 InfectionsoftheFemalePelvis 119David E. Soper
55 Prostatitis,Epididymitis,andOrchitis 120Catherine C. McGowan and John Krieger
M EYEINFECTIONS 56 MicrobialConjunctivitis 122
Scott D. Barnes, Nalin M. Kumar, Deborah Pavan-Langston, and Dimitri T. Azar
57 MicrobialKeratitis 124Scott D. Barnes, Joelle Hallak, Deborah Pavan-Langston, and Dimitri T. Azar
58 Endophthalmitis 125Marlene L. Durand
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59 InfectiousCausesofUveitis 127Marlene L. Durand
60 PeriocularInfections 129Marlene L. Durand
N HEPATITIS 61 ViralHepatitis 130
Jules L. Dienstag and Andrew S. Delemos
O ACQUIREDIMMUNODEFICIENCYSYNDROME 62 DiagnosisofHumanImmunodeficiencyVirusInfection 138
Francesco R. Simonetti, Robin Dewar, and Frank Maldarelli
63 GeneralClinicalManifestationsofHumanImmunodeficiencyVirusInfection(IncludingAcuteRetroviralSyndromeandOral,Cutaneous,Renal,Ocular,Metabolic,andCardiacDiseases) 140Timothy R. Sterling and Richard E. Chaisson
64 PulmonaryManifestationsofHumanImmunodeficiencyVirusInfection 142Paul E. Sax and Kevin L. Ard
65 Gastrointestinal,Hepatobiliary,andPancreaticManifestationsofHumanImmunodeficiencyVirusInfection 144Charles Haines and Mark S. Sulkowski
66 NeurologicDiseasesCausedbyHumanImmunodeficiencyVirusType1andOpportunisticInfections 146Omar K. Siddiqi and Igor J. Koralnik
67 PediatricHumanImmunodeficiencyVirusInfection 147Geoffrey A. Weinberg and George K. Siberry
68 AntiretroviralTherapyforHumanImmunodeficiencyVirusInfection 149Athe M. N. Tsibris and Martin S. Hirsch
69 ManagementofOpportunisticInfectionsAssociatedwithHumanImmunodeficiencyVirusInfection 155Henry Masur
P MISCELLANEOUSSYNDROMES 70 ChronicFatigueSyndrome 172
N. Cary Engleberg
II INFECTIOUSDISEASESANDTHEIRETIOLOGICAGENTS
A VIRALDISEASES 71 Orthopoxviruses:Vaccinia(SmallpoxVaccine),Variola(Smallpox),Monkeypox,
andCowpox 176Brett W. Petersen and Inger K. Damon
72 OtherPoxvirusesThatInfectHumans:Parapoxviruses(IncludingOrfVirus),MolluscumContagiosum,andYatapoxviruses 178Brett W. Petersen and Inger K. Damon
73 HerpesSimplexVirus 179Joshua T. Schiffer and Lawrence Corey
74 ChickenpoxandHerpesZoster(Varicella-ZosterVirus) 183Richard J. Whitley
75 Cytomegalovirus(CMV) 185Clyde S. Crumpacker II
76 Epstein-BarrVirus(InfectiousMononucleosis,Epstein-BarrVirus–AssociatedMalignantDiseases,andOtherDiseases) 186Eric C. Johannsen and Kenneth M. Kaye
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77 HumanHerpesvirusTypes6and7(ExanthemSubitum) 188Jeffrey I. Cohen
78 Kaposi’sSarcoma–AssociatedHerpesvirus(HumanHerpesvirus8) 189Kenneth M. Kaye
79 HerpesBVirus 190Jeffrey I. Cohen
80 Adenoviruses 192Elizabeth G. Rhee and Dan H. Barouch
81 Papillomaviruses 194William Bonnez
82 JC,BK,andOtherPolyomaviruses:ProgressiveMultifocalLeukoencephalopathy(PML) 196C. Sabrina Tan and Igor J. Koralnik
83 HepatitisBVirusandHepatitisDeltaVirus 198Chloe Lynne Thio and Claudia Hawkins
84 HumanParvoviruses,IncludingParvovirusB19VandHumanBocaparvoviruses 202Kevin E. Brown
85 OrthoreovirusesandOrbiviruses 203Roberta L. DeBiasi and Kenneth L. Tyler
86 ColtivirusesandSeadornaviruses 204Roberta L. DeBiasi and Kenneth L. Tyler
87 Rotaviruses 205Philip R. Dormitzer
88 Alphaviruses 207Lewis Markoff
89 RubellaVirus(GermanMeasles) 209Anne A. Gershon
90 Flaviviruses(Dengue,YellowFever,JapaneseEncephalitis,WestNileEncephalitis,St.LouisEncephalitis,Tick-BorneEncephalitis,KyasanurForestDisease,AlkhurmaHemorrhagicFever,Zika) 210Stephen J. Thomas, Timothy P. Endy, Alan L. Rothman, and Alan D. Barrett
91 HepatitisC 212Stuart C. Ray and David L. Thomas
92 Coronaviruses,IncludingSevereAcuteRespiratorySyndrome(SARS)andMiddleEastRespiratorySyndrome(MERS) 215Kenneth McIntosh and Stanley Perlman
93 ParainfluenzaViruses 216Michael G. Ison
94 MumpsVirus 217Nathan Litman and Stephen G. Baum
95 RespiratorySyncytialVirus(RSV) 218Edward E. Walsh and Caroline Breese Hall
96 HumanMetapneumovirus 219Ann R. Falsey
97 MeaslesVirus(Rubeola) 220Anne A. Gershon
98 ZoonoticParamyxoviruses:Nipah,Hendra,andMenangle 222Anna R. Thorner and Raphael Dolin
99 VesicularStomatitisVirusandRelatedVesiculoviruses 224Steven M. Fine
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100 Rabies(Rhabdoviruses) 225Kamaljit Singh, Charles E. Rupprecht, and Thomas P. Bleck
101 MarburgandEbolaHemorrhagicFevers(MarburgandEbolaViralDiseases)(Filoviruses) 227Thomas W. Geisbert
102 Influenza(IncludingAvianInfluenzaandSwineInfluenza) 228John J. Treanor
103 CaliforniaEncephalitis,HantavirusPulmonarySyndrome,andBunyavirusHemorrhagicFevers 231Dennis A. Bente
104 LymphocyticChoriomeningitis,LassaFever,andtheSouthAmericanHemorrhagicFevers(Arenaviruses) 232Alexey Seregin, Nadezhda Yun, and Slobodan Paessler
105 HumanT-LymphotropicVirus(HTLV) 234Edward L. Murphy and Roberta L. Bruhn
106 HumanImmunodeficiencyViruses 236Marvin S. Reitz, Jr., and Robert C. Gallo
107 Poliovirus 237José R. Romero and John F. Modlin
108 Coxsackieviruses,Echoviruses,andNumberedEnteroviruses(EV-D68) 238José R. Romero and John F. Modlin
109 HumanParechoviruses 239José R. Romero and John F. Modlin
110 HepatitisAVirus 240Francisco Averhoff, Yury Khudyakov, and Beth P. Bell
111 Rhinovirus 243Ronald B. Turner
112 NorovirusesandSapoviruses(Caliciviruses) 244Raphael Dolin and John J. Treanor
113 AstrovirusesandPicobirnaviruses 246Raphael Dolin and John J. Treanor
114 HepatitisEVirus 247Stephen R. Walsh
B PRIONDISEASES115 PrionsandPrionDiseasesoftheCentralNervousSystem(Transmissible
NeurodegenerativeDiseases) 248Patrick J. Bosque and Kenneth L. Tyler
C CHLAMYDIALDISEASES
116 Chlamydia trachomatis(Trachoma,GenitalInfections,PerinatalInfections,andLymphogranulomaVenereum) 249Byron E. Batteiger and Ming Tan
117 Psittacosis(DuetoChlamydia psittaci) 253David Schlossberg
118 Chlamydia pneumoniae 254Margaret R. Hammerschlag, Stephan A. Kohlhoff, and Charlotte A. Gaydos
D MYCOPLASMADISEASES119 Mycoplasma pneumoniaeandAtypicalPneumonia 255
Robert S. Holzman and Michael S. Simberkoff
120 GenitalMycoplasmas:Mycoplasma genitalium, Mycoplasma hominis,andUreaplasmaSpecies 256David H. Martin
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E RICKETTSIOSES,EHRLICHIOSES,ANDANAPLASMOSIS121 Rickettsia rickettsiiandOtherSpottedFeverGroupRickettsiae(RockyMountain
SpottedFeverandOtherSpottedFevers) 257David H. Walker and Lucas S. Blanton
122 Rickettsia akari(Rickettsialpox) 259Didier Raoult
123 Coxiella burnetii(QFever) 260Thomas J. Marrie and Didier Raoult
124 Rickettsia prowazekii(EpidemicorLouse-BorneTyphus) 262Lucas S. Blanton and David H. Walker
125 Rickettsia typhi(MurineTyphus) 264Lucas S. Blanton, J. Stephen Dumler, and David H. Walker
126 Orientia tsutsugamushi(ScrubTyphus) 265Didier Raoult
127 Ehrlichia chaffeensis(HumanMonocytotropicEhrlichiosis),Anaplasma phagocytophilum(HumanGranulocytotropicAnaplasmosis),andOtherAnaplasmataceae 266J. Stephen Dumler and David H. Walker
F BACTERIALDISEASES128 Staphylococcus aureus(IncludingStaphylococcalToxicShockSyndrome) 268
Yok-Ai Que and Philippe Moreillon
129 Staphylococcus epidermidisandOtherCoagulase-NegativeStaphylococci 275Mark E. Rupp and Paul D. Fey
130 Streptococcus pyogenes 277Amy E. Bryant and Dennis L. Stevens
131 NonsuppurativePoststreptococcalSequelae:RheumaticFeverandGlomerulonephritis 279Stanford T. Shulman and Alan L. Bisno
132 Streptococcus pneumoniae 281Edward N. Janoff and Daniel M. Musher
133 EnterococcusSpecies,Streptococcus gallolyticusGroup,andLeuconostocSpecies 283Cesar A. Arias and Barbara E. Murray
134 Streptococcus agalactiae(GroupBStreptococcus) 285Morven S. Edwards and Carol J. Baker
135 ViridansStreptococci,NutritionallyVariantStreptococci,GroupsCandGStreptococci,andOtherRelatedOrganisms 287Scott W. Sinner and Allan R. Tunkel
136 Streptococcus anginosusGroup 289Cathy A. Petti and Charles W. Stratton IV
137 Corynebacterium diphtheriae(Diphtheria) 290Rob Roy MacGregor
138 OtherCoryneformBacteriaandRhodococci 292Rose Kim and Annette C. Reboli
139 Listeria monocytogenes 293Bennett Lorber
140 Bacillus anthracis(Anthrax) 296Gregory J. Martin and Arthur M. Friedlander
141 BacillusSpeciesandRelatedGeneraOtherThanBacillus anthracis 298Thomas Fekete
142 Erysipelothrix rhusiopathiae 299Annette C. Reboli
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143 Whipple’sDisease 300Thomas Marth and Thomas Schneider
144 Neisseria meningitidis 301David S. Stephens and Michael A. Apicella
145 Neisseria gonorrhoeae(Gonorrhea) 305Jeanne M. Marrazzo and Michael A. Apicella
146 Moraxella catarrhalis, Kingella,andOtherGram-NegativeCocci 307Timothy F. Murphy
147 Vibrio cholerae 308Matthew K. Waldor and Edward T. Ryan
148 OtherPathogenicVibrios 312Marguerite A. Neill and Charles C. J. Carpenter
149 Campylobacter jejuniandRelatedSpecies 314Ban Mishu Allos, Nicole M. Iovine, and Martin J. Blaser
150 Helicobacter pyloriandOtherGastricHelicobacterSpecies 315Timothy L. Cover and Martin J. Blaser
151 Enterobacteriaceae 316Michael S. Donnenberg
152 Pseudomonas aeruginosaandOtherPseudomonasSpecies 317Erika D’Agata
153 Stenotrophomonas maltophiliaandBurkholderia cepacia 318Amar Safdar
154 Burkholderia pseudomalleiandBurkholderia mallei: MelioidosisandGlanders 320Bart J. Currie
155 AcinetobacterSpecies 323Michael Phillips
156 SalmonellaSpecies 324David A. Pegues and Samuel I. Miller
157 BacillaryDysentery:ShigellaandEnteroinvasiveEscherichia coli 325Herbert L. DuPont
158 HaemophilusSpecies,IncludingH. influenzaeandH. ducreyi(Chancroid) 326Timothy F. Murphy
159 Brucellosis(BrucellaSpecies) 328H. Cem Gul and Hakan Erdem
160 Francisella tularensis(Tularemia) 330Robert L. Penn
161 PasteurellaSpecies 335John J. Zurlo
162 YersiniaSpecies(IncludingPlague) 337Paul S. Mead
163 Bordetella pertussis 339Valerie Waters and Scott A. Halperin
164 Rat-BiteFever:Streptobacillus moniliformisandSpirillum minus 341Ronald G. Washburn
165 Legionnaires’DiseaseandPontiacFever 342Paul H. Edelstein and Craig R. Roy
166 Capnocytophaga 344J. Michael Janda
167 Bartonella,IncludingCat-ScratchDisease 346Tejal N. Gandhi, Leonard N. Slater, David F. Welch, and Jane E. Koehler
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168 Klebsiella granulomatis(Donovanosis,GranulomaInguinale) 348Ronald C. Ballard
169 OtherGram-NegativeandGram-VariableBacilli 349James P. Steinberg and Eileen M. Burd
170 Syphilis(Treponema pallidum) 351Justin D. Radolf, Edmund C. Tramont, and Juan C. Salazar
171 EndemicTreponematoses 353Edward W. Hook III
172 LeptospiraSpecies(Leptospirosis) 354David A. Haake and Paul N. Levett
173 RelapsingFeverCausedbyBorreliaSpecies 356James M. Horton
174 LymeDisease(LymeBorreliosis)DuetoBorrelia burgdorferi 357Allen C. Steere
175 Clostridium difficileInfection 358Dale N. Gerding and Vincent B. Young
176 Tetanus(Clostridium tetani) 360Aimee Hodowanec and Thomas P. Bleck
177 Botulism(Clostridium botulinum) 361Aimee Hodowanec and Thomas P. Bleck
178 GasGangreneandOtherClostridium-AssociatedDiseases 362Andrew B. Onderdonk and Wendy S. Garrett
179 Bacteroides, Prevotella, Porphyromonas,andFusobacteriumSpecies(andOtherMedicallyImportantAnaerobicGram-NegativeBacilli) 364Wendy S. Garrett and Andrew B. Onderdonk
180 Mycobacterium tuberculosis 365Daniel W. Fitzgerald, Timothy R. Sterling, and David W. Haas
181 Mycobacterium leprae(Leprosy) 371Cybèle A. Renault and Joel D. Ernst
182 Mycobacterium aviumComplex 373Fred M. Gordin and C. Robert Horsburgh, Jr.
183 InfectionsCausedbyNontuberculousMycobacteriaOtherThanMycobacterium AviumComplex 375Barbara A. Brown-Elliott and Richard J. Wallace, Jr.
184 NocardiaSpecies 378Tania C. Sorrell, David H. Mitchell, Jonathan R. Iredell, and Sharon C-A. Chen
185 AgentsofActinomycosis 380Thomas A. Russo
G MYCOSES186 AspergillusSpecies 381
Thomas F. Patterson
187 AgentsofMucormycosisandEntomophthoramycosis 385Dimitrios P. Kontoyiannis and Russell E. Lewis
188 Sporothrix schenckii 386John H. Rex and Pablo C. Okhuysen
189 AgentsofChromoblastomycosis 387Duane R. Hospenthal
190 AgentsofMycetoma 388Duane R. Hospenthal
191 Cryptococcosis(Cryptococcus neoformansandCryptococcus gattii) 390John R. Perfect
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192 Histoplasma capsulatum(Histoplasmosis) 393George S. Deepe, Jr.
193 Blastomycosis 396Robert W. Bradsher, Jr.
194 Coccidioidomycosis(CoccidioidesSpecies) 398John N. Galgiani
195 Dermatophytosis(Ringworm)andOtherSuperficialMycoses 400Roderick J. Hay
196 Paracoccidioidomycosis 402Angela Restrepo, Angela María Tobón, and Luz Elena Cano
197 UncommonFungiandRelatedSpecies 404Duane R. Hospenthal
198 PneumocystisSpecies 410Peter D. Walzer, A. George Smulian, and Robert F. Miller
199 Microsporidiosis 412Louis M. Weiss
H PROTOZOALDISEASES200 EntamoebaSpecies,IncludingAmebicColitisandLiverAbscess 413
William A. Petri, Jr., and Rashidul Haque
201 Free-LivingAmebae 415Anita A. Koshy, Brian G. Blackburn, and Upinder Singh
202 Malaria(PlasmodiumSpecies) 417Rick M. Fairhurst and Thomas E. Wellems
203 LeishmaniaSpecies:Visceral(Kala-Azar),Cutaneous,andMucosalLeishmaniasis 419Alan J. Magill
204 TrypanosomaSpecies(AmericanTrypanosomiasis,Chagas’Disease):BiologyofTrypanosomes 420Louis V. Kirchhoff
205 AgentsofAfricanTrypanosomiasis(SleepingSickness) 422Louis V. Kirchhoff
206 Toxoplasma gondii 424José G. Montoya, John C. Boothroyd, and Joseph A. Kovacs
207 Giardia lamblia 426David R. Hill and Theodore E. Nash
208 Trichomonas vaginalis 428Jane R. Schwebke
209 BabesiaSpecies 429Jeffrey A. Gelfand and Edouard G. Vannier
210 Cryptosporidiosis(CryptosporidiumSpecies) 431A. Clinton White, Jr.
211 Cyclospora cayetanensis, Cystoisospora (Isospora) belli, SarcocystisSpecies,Balantidium coli,andBlastocystisSpecies 432Kathryn N. Suh, Phyllis Kozarsky, and Jay S. Keystone
I DISEASESDUETOTOXICALGAE212 HumanIllnessAssociatedwithHarmfulAlgalBlooms 435
J. Glenn Morris, Jr.
J DISEASESDUETOHELMINTHS213 IntestinalNematodes(Roundworms) 437
James H. Maguire
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214 TissueNematodes(Trichinellosis,Dracunculiasis,Filariasis,Loiasis,andOnchocerciasis) 439James W. Kazura
215 Trematodes(SchistosomesandLiver,Intestinal,andLungFlukes) 440James H. Maguire
216 Tapeworms(Cestodes) 443Charles H. King and Jessica K. Fairley
217 VisceralLarvaMigransandOtherUncommonHelminthInfections 445Theodore E. Nash
K ECTOPARASITICDISEASES218 Lice(Pediculosis) 446
James H. Diaz
219 Scabies 448James H. Diaz
220 MyiasisandTungiasis 450James H. Diaz
221 Mites,IncludingChiggers 452James H. Diaz
222 Ticks,IncludingTickParalysis 453James H. Diaz
L DISEASESOFUNKNOWNETIOLOGY223 KawasakiDisease 454
Jane C. Burns
III SPECIALPROBLEMS
A NOSOCOMIALINFECTIONS224 InfectionsCausedbyPercutaneousIntravascularDevices 456
Susan E. Beekmann and David K. Henderson
225 NosocomialPneumonia 458Michael Klompas
226 NosocomialUrinaryTractInfections 460Thomas M. Hooton
227 HealthCare–AcquiredHepatitis 462Kent A. Sepkowitz
228 Transfusion-andTransplantation-TransmittedInfections 463Matthew J. Kuehnert and Sridhar V. Basavaraju
B INFECTIONSINSPECIALHOSTS229 ProphylaxisandEmpiricalTherapyofInfectioninCancerPatients 464
Elio Castagnola, Małgorzata Mikulska, and Claudio Viscoli
230 InfectionsinRecipientsofHematopoieticStemCellTransplants 470Jo-Anne H. Young and Daniel J. Weisdorf
231 InfectionsinSolid-OrganTransplantRecipients 474Nina Singh and Ajit P. Limaye
232 InfectionsinPatientswithSpinalCordInjury 475Rabih O. Darouiche
233 InfectionsintheElderly 476Kent B. Crossley and Phillip K. Peterson
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234 InfectionsinAsplenicPatients 477Janet R. Gilsdorf
235 InfectionsinInjectionDrugUsers 479Donald P. Levine and Patricia D. Brown
236 SurgicalSiteInfectionsandAntimicrobialProphylaxis 482Thomas R. Talbot
C SURGICAL-ANDTRAUMA-RELATEDINFECTIONS237 Burns 486
Clinton K. Murray
238 Bites 487Ellie J. C. Goldstein and Fredrick M. Abrahamian
D ZOONOSES239 Zoonoses 490
W. Ian Lipkin
E PROTECTIONOFTRAVELERS240 ProtectionofTravelers 491
David O. Freedman
241 InfectionsinReturningTravelers 493David O. Freedman
PART I
Major Clinical Syndromes
2
A Fever
1 Fever of Unknown OriginWilliam F. Wright and Philip A. Mackowiak
DEFINITION• Occurrenceofseveraloccasionsoffeverhigherthan38.3°C(101°F)withadurationgreater
thanat least3weeksdespite1weekofhospitalevaluationisstillrecognizedastheclassicdefinitionforfeverofunknownorigin(FUO).
• Theadventof improveddiagnostic testingmodalitiescoupledwithan increasingnumberof immunocompromised patients led to a revised definition in which cases of FUO arecurrently codified into four distinct subclasses: classic FUO, health care–associated FUO,immune-deficientFUO,andhumanimmunodeficiencyvirus(HIV)-relatedFUO.
ETIOLOGY AND EPIDEMIOLOGY• Infections, neoplasms, connective tissue diseases, miscellaneous causes, and undiagnosed
feversremainthemostcommoncausesofclassicFUO.• The frequencywithwhich infectionsandneoplasmshavebeen identifiedas thecausesof
classic FUO has decreased steadily, whereas the proportion of miscellaneous causes andundiagnosedconditionshasriseninrecentyears.
DIAGNOSIS• Acomprehensivemedicalhistorywithverificationoffeverandadetailedphysicalexamina-
tionareessentialindirectingformallaboratorytesting.
THERAPY• Empirical therapeutic trials of antimicrobial agents continue to have a limited role in the
managementofpatientswithFUO.• Owingtotherelativelyhighprevalenceofseriousbacterialinfectionsresponsibleforfevers
inpatientswithneutropenia,suchpatientsshouldreceivebroad-spectrumantipseudomonaltherapyimmediatelyaftersamplesforappropriatecultureshavebeenobtained.
PROGNOSIS• AlthoughtheprognosisofanFUOisdeterminedby itsetiologyandunderlyingdiseases,
mostpatientswithprolongedundiagnosedFUOgenerallyhaveafavorableoutcome.
3
2 The Acutely Ill Patient with Fever and RashDavid J. Weber, Myron S. Cohen, and William A. Rutala
DEFINITION• Skinlesionsarefrequentlypresentinacutelyillpatientswithseriousinfectiousdiseasesand
mayprovideimportantcluesthataidinearlydiagnosisandtreatment.
EPIDEMIOLOGY• Acutelyillpatientswithapotentialinfectiousdiseaseandskinlesions(orrash)shouldhave
ahistoryobtainedthatelicits the following:recentdrug ingestion; traveloutside the localarea;potentialoccupationalexposures;recentimmunizations;riskfactorsforsexuallytrans-mittedinfections,includinghumanimmunodeficiencyvirusinfection;factorsaffectinghostresistanceor immunocompromisingconditions;priorallergies toantibiotics;recentexpo-surestofebrileorillpersons;exposuretoruralhabits,insects,arthropods,andwildanimals;andexposuretopetsoranimals.
• Patientswithskinlesionsorrashesconsistentwithacommunicableinfectiousdisease(e.g.,invasive meningococcal infection) should be immediately placed on appropriate isolationprecautions(i.e.,contact,droplet,orairborne).
• Infectiousdiseasephysiciansshouldbe familiarwith theskin lesions(orrash) thatmightaccompanyapatientwithdisease that couldbe the resultof the intentionaluseof abio-weapon(e.g.,anthrax,smallpox,plague,viralhemorrhagicfevers).
MICROBIOLOGY• Serious bacterial infections with skin lesions include Staphylococcus aureus (toxic shock
syndrome,scaldedskinsyndrome),Streptococcus pyogenes(toxicshocksyndrome),Salmonella entericaserotypeTyphi,Neisseria meningitidis,andRickettsia rickettsii.
• Potentiallyseriousviral infectionswithskin lesions includemeasles, rubella,Epstein-Barrinfection,cytomegalovirus,humanherpesvirus6,andviralhemorrhagicfevers(e.g.,Ebola,Marburg,Lassa).
• Life-threatening drug reactions may result from antibiotic therapy for disorders such asStevens-Johnsonsyndrome/toxicepidermolysisnecrosisandfromdrugreactionwitheosin-ophiliaandsystemicsymptoms(DRESS).
DIAGNOSIS• Keyaspectsofskinlesionsthataidinaproperdiagnosisinclude(1)primarytype(s)ofskin
lesions,(2)distributionofthelesions,(3)patternofprogressionoftherash,and(4)timingofonsetoftherashrelativetotheonsetoffeverandothersystemicsigns.
• The appearance of skin lesions may be very useful in the diagnosis of specific infectiousdiseases. Maculopapular rashes are usually seen in viral illnesses, drug eruptions, andimmune complex–mediated diseases. Nodular lesions are suggestive of mycobacteria orfungalinfections.Diffuseerythemasuggestsscarletfever,toxicshocksyndrome,Kawasakidisease, or Stevens-Johnson syndrome/toxic epidermal necrolysis. Bullous lesions suggeststreptococcal erysipelas with necrotizing fasciitis, ecthyma gangrenosum, and Vibrio
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infections.Petechialeruptionssuggestgram-negativesepsis,invasiveNeisseria meningitidisinfection,andrickettsialinfections.
• Considerationshouldbegiventobiopsyofskinlesions, ifpresent, inacutelyill immuno-compromisedpatientsforappropriatestains(e.g.,Gramstain,fungalstain)andculturesandforpathologicstudy.
THERAPY• Empiricaltherapyshouldoftenbeinitiatedinacutelyillpatientswithskinlesionsbasedon
theclinicaldiagnosis.• Mostacutelyillpatientswithskinlesionswillrequiresystemictherapy.
PREVENTION• Standard vaccines should be provided to children and adults because many vaccine-
preventablediseasesproducerashes(e.g.,measles,rubella,varicella).• Underlyingnoninfectiousdiseasesthatleadtodisruptionofskinshouldbetreatedbecause
thedamagedskinservesasriskfactorforinfection.
5
B Upper Respiratory Tract Infections
3 The Common ColdRonald B. Turner
DEFINITION• Thecommoncoldisanupperrespiratoryillnessthatincludesrhinorrheaandnasalobstruc-
tionasprominentsymptoms.
EPIDEMIOLOGY• Commoncoldillnessesoccur5to7timesperyearinchildrenand2to3timesperyearin
adults.• Illnesses occur most commonly between the early fall and late spring in temperate
climates.• Transmissionoftheviralpathogenscausingthecommoncoldmayoccurviadirectcontact,
large-particleaerosol,orsmall-particleaerosol.
MICROBIOLOGY• Therhinovirusesareresponsibleforthemajorityofcommoncoldillnesses.• Coronavirus,respiratorysyncytialvirus,andmetapneumovirusmayalsobeassociatedwith
thecommoncoldsyndrome.• Otherrespiratoryvirusesmaycausecommoncoldsymptomsbutarefrequentlyassociated
withlowerrespiratorysymptomsinadditiontotheupperrespiratoryillness.• Coinfectionwithmorethanonepathogeniscommonintheseillnesses.
DIAGNOSIS• Thediagnosisofthecommoncoldisaclinicaldiagnosis.• Theresponsiblepathogen(s)canbedeterminedbypolymerasechainreactionassay,butthis
israrelyusefulinthemanagementofthepatient.
THERAPY• Therearenospecificantiviralagentsthatareusefulfortreatmentofthecommoncold.• Managementdependsonsymptomatictherapywithtreatmentdirectedatthemostbother-
somesymptoms.
PREVENTION• Therearenoproveninterventionsforpreventionofthecommoncold.
6
4 PharyngitisAnthony R. Flores and Mary T. Caserta
DEFINITION• Pharyngitisisdefinedasthetriadofsorethroat,fever,andpharyngealinflammation.• Generallyaprimarydisease,pharyngitismaybeassociatedwithsystemicdisorders.
EPIDEMIOLOGY• Pharyngitis isoneof themostcommondisorders inadultsandchildren,withmore than
10millionambulatoryvisitsperyear.• The highest burden of disease is found in children and young adults, with 50% of cases
identifiedbetweentheagesof5to24years.• In temperate climates, most cases occur in winter months, corresponding with peaks in
respiratoryviruses.
MICROBIOLOGY• Virusesarethesinglemostcommoncauseofpharyngitis,withadenovirusbeingthemost
commonlyidentified(seeTable4-1).• Group A Streptococcus (GAS) is the bacterial cause for which ample evidence exists for
antibiotictherapytopreventpostinfectioussequelae.• Fusobacterium necrophorum has been recently recognized as a cause of pharyngitis with
potentialseverecomplications(i.e.,Lemierresyndrome),especiallyinyoungadults.
DIAGNOSIS• Essential to diagnosis is the identification of treatable causes (e.g., GAS) to prevent
complications.• SignsandsymptomsofGASpharyngitisincludeacuteonsetofsorethroatwithtonsillaror
pharyngealexudates,tenderanteriorcervicallymphadenopathy,andfever(seeTable4-2).• Signs and symptoms consistent with viral etiologies include conjunctivitis, coryza, oral
ulcers,cough,anddiarrhea.• TestingforGASpharyngitisshouldnotbepursuedinthosewithsignsandsymptomsindica-
tiveofaviraletiology(seeTable4-3).• Rapidantigendetectiontests(RADTs)alonearesufficientforthediagnosisofGASinadults,
butnegativeresultsshouldbebackedupbythroatcultureinchildren.• Specifictechniquesshouldbeusedtoidentifyothercauseswhereappropriate.
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THERAPY• Treatment of pharyngitis is focused on prevention of postinfectious sequelae (e.g., acute
rheumaticfever)fromGAS.• Penicillin and its derivatives remain the primary treatment for GAS pharyngitis (see
Table4-4).• Antimicrobial therapy should not be used to prevent GAS pharyngitis except in special
circumstances.• Given thepotential severityofcomplications frompharyngitis causedbyF. necrophorum,
signs of bacteremia or neck swelling warrant expansion of antibiotic therapy and furtherevaluation.
TABLE 4-1 Microbial Causes of Acute Pharyngitis
PATHOGEN ASSOCIATED DISORDER(S)
BacteriaStreptococcus, group A Pharyngitis, tonsillitis, scarlet fever
Streptococcus, groups C and G Pharyngitis, tonsillitis
Mixed anaerobes Vincent’s angina
Fusobacterium necrophorum Pharyngitis, tonsillitis, Lemierre syndrome
Neisseria gonorrhoeae Pharyngitis, tonsillitis
Corynebacterium diphtheria Diphtheria
Arcanobacterium haemolyticum Pharyngitis, scarlatiniform rash
Yersinia pestis Plague
Francisella tularensis Tularemia, oropharyngeal form
Treponema pallidum Secondary syphilis
VirusesRhinovirus Common cold
Coronavirus Common cold
Adenovirus Pharyngoconjunctival fever
Herpes simplex type 1 and 2 Pharyngitis, gingivostomatitis
Parainfluenza Cold, croup
Enteroviruses Herpangina, hand-foot-mouth disease
Epstein-Barr virus Infectious mononucleosis
Cytomegalovirus CMV mononucleosis
Human immunodeficiency virus Primary HIV infection
Influenza A and B Influenza
Respiratory syncytial virus Cold, bronchiolitis, pneumonia
Human metapneumovirus Cold, bronchiolitis, pneumonia
MycoplasmaMycoplasma pneumoniae Pneumonia, bronchitis, pharyngitis
ChlamydiaChlamydia psittaci Acute respiratory disease, pneumonia
Chlamydia pneumoniae Pneumonia, pharyngitis
CMV, cytomegalovirus; HIV, human immunodeficiency virus.Modified from Alcaide ML, Bisno AL. Pharyngitis and epiglottitis. Infect Dis Clin North Am. 2007;21:449-469, vii;
with permission.
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TABLE 4-2 Clinical and Epidemiologic Findings Associated with Group A Streptococcus Pharyngitis
Suggestive of Group A StreptococcusSudden onsetSore throatFeverHeadacheNausea, vomiting, and abdominal painInflammation of pharynx and tonsilsPatchy discrete exudatesTender, enlarged anterior cervical nodesPatient aged 5-15 yrPresentation in winter or early springHistory of exposure
Suggestive of Viral EtiologyConjunctivitisCoryzaCoughDiarrheaDiscrete ulcerative lesions
Suggestive of Complications of PharyngitisDysphagiaStridorDroolingDysphoniaMarked neck swellingRespiratory distressPharyngeal pseudomembraneHemodynamic instabilityHIV behavioral riskTravel to or exposure to individuals from a region endemic for diphtheriaLack of diphtheria immunization
HIV, human immunodeficiency virus.Modified from Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and manage-
ment of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55:e86-e102; and Kociolek LK, Shulman ST. In the clinic. Pharyngitis. Ann Intern Med. 2012;157:ITC3-1-ITC3-16; with permission.
TABLE 4-3 Modified Centor Score and Culture Management Approach for Pharyngitis
CRITERIA POINTSTemperature >38° C 1
Absence of cough 1
Swollen, tender anterior cervical nodes 1
Tonsillar swelling or exudate 1
Age3-14 yr 1
15-44 yr 0
45 yr or older −1
SCORERISK OF STREPTOCOCCAL INFECTION
SUGGESTED MANAGEMENT
≤0 1%-2.5% No further testing or antibiotic
1 5%-10%
2 11%-17% Culture all: antibiotics only for positive culture results3 28%-35%
≥4 51%-53% Treat empirically with antibiotics and/or culture
From McIsaac WJ, Kellner JD, Aufricht P, et al. Empirical validation of guidelines for the management of pharyngitis in children and adults. JAMA. 2004;291:1587-1595; with permission.
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TABLE 4-4 Antimicrobial Therapy for Group A Streptococcal Pharyngitis
DRUG DOSE DURATION
Oral RegimensPenicillin V Children: 250 mg bid or tid
Adolescents and adults: 250 mg tid or qid or 500 mg bid10 days
Amoxicillin 50 mg/kg once daily (maximum 1000 mg)Alternative: 25 mg/kg bid (maximum 500 mg)
10 days
For Penicillin-Allergic PatientsErythromycin Varies with formulation 10 days
First-generation cephalosporins Varies with agent 10 days
Intramuscular RegimensBenzathine penicillin G 600,000 units for patients <27 kg 1 dose
1.2 million units for patients ≥27 kg 1 dose
Mixtures of benzathine and procaine penicillin G
Varies with formulation 1 dose
Modified from Alcaide ML, Bisno AL. Pharyngitis and epiglottitis. Infect Dis Clin North Am. 2007;21:449-469, vii; with permission.
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5 Acute LaryngitisMary T. Caserta
DEFINITION• Acutelaryngitisisaclinicalsyndromecharacterizedbyahoarsevoicewithdecreasedphona-
tionandvoiceprojection,usuallyoccurringafteranupperrespiratorytractinfectionwithcough.
EPIDEMIOLOGY• Approximately1%ofmedicalcareclaimsareduetodysphonia,with42%ofthoseclassified
asacutelaryngitis.• Two percent of individuals with acute respiratory symptoms are diagnosed with acute
laryngitis.• Acute laryngitis is diagnosed more frequently in women (mean age, 36 years) than men
(meanage,41years).• Morecasesarediagnosedinthecoldermonthsoftheyear.
MICROBIOLOGY• Aviralupperrespiratorytractinfectionisoftenassociated(seeTable5-1).• Bacterialinfectionsoftheupperrespiratorytracthavealsobeenimplicated.• Unusualcausesincludetuberculosis,blastomycosis,histoplasmosis,coccidiomycosis,cryp-
tococcosis,andherpesvirusinfectionsofthelarynx.
DIAGNOSIS• Clinicaldiagnosisisbasedontheappropriatehistoryandchangesofthevoice.• Visualizationofthelarynxrevealsedemaandvascularengorgementofthemucousmem-
braneswithhyperemicanderythematousvocalfolds.
THERAPY• Treatmentisbasedontheunderlyingcauseofthelaryngealpathologicprocess.• Often,symptomatictherapywithvoicerest,analgesics,andhumidificationissufficient.
TABLE 5-1 Frequency of Laryngitis Associated with Common Respiratory Pathogens
PATHOGEN FREQUENCY (%)Rhinovirus 25-29
Influenza 28-35
Parainfluenza 8.5
Adenovirus 22-35
Coronavirus 25
Mycoplasma pneumoniae 3-37
Chlamydia pneumoniae 30
Group A β-hemolytic streptococcus 2.3-19
Human metapneumovirus 3-91
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6 Croup in Children (Acute Laryngotracheobronchitis)John Bower and John T. McBride
DEFINITION• Croupisanacuteviralinfectionoftheupperairwaypresentingasstridorandabrassycough.• Mostchildrendevelopcrouponlyonce,butafewchildrendeveloprecurrentepisodescalled
spasmodiccroup.
EPIDEMIOLOGY• Croupcanbesporadicbutusuallyoccursinepidemicsinthefallthatintemperateclimates
recentlyhavebeenworseinodd-numberedyears.
ETIOLOGY AND MICROBIOLOGY• Parainfluenzatype1virusinfectionisthemostcommoncauseofviralcroup.• Theotherparainfluenzaviruses,respiratorysyncytialvirus(RSV),adenovirus,andmeasles
areafewoftheotheragentsassociatedwithviralcroup.• Bacterialinfectionsoftheairway,includingepiglottitis(Haemophilus influenzaetypeb)and
tracheitis(Staphylococcus aureus, Streptococcus),representmedicalemergenciesandshouldberapidlydiscriminatedfromviralcroup.
• Diphtheria should be considered in the developing world and in nonimmunizedpopulations.
DIAGNOSIS• Diagnosisisclinical,althoughradiographsoftheupperairwaymaybehelpful.• Children with epiglottitis and bacterial tracheitis are typically toxic and have difficulty
swallowingandusuallylackthebrassycoughandharshstridor.• Recurrent(spasmodic)croupmaybemorecommoninchildrenwithatopyorgastroesopha-
gealreflux.
THERAPY• Homeremediesincludingmistandcoldairhavenotbeenproventobeeffective.• Asingledoseofasystemiccorticosteroiddecreasestheseverityandlengthofcroup.
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7 Otitis Externa, Otitis Media, and MastoiditisJerome O. Klein
DEFINITIONOtitis Externa• Otitisexternaisaninfectionandinflammationoftheexternalauditorycanal.
Otitis Media• Acuteotitismedia(AOM)isanacuteillnessmarkedbythepresenceoffluidinthemiddle
earandinflammationof themucosa liningthemiddleearspace.Fluidmaypersist inthemiddleearforweekstomonthsafterappropriatelytreatedAOMandistermedotitismediawitheffusion.
Mastoiditis• Mastoiditis is infectionandinflammationofthemastoidaircellsandusuallyresultsfrom
episodesofsevereAOM.
EPIDEMIOLOGYOtitis Externa• Acutediffuseotitisexternaorswimmer’searoccursinhothumidweather.• Invasiveormalignantotitis externaoccurs indiabetic, immunocompromised,anddebili-
tatedpatients.• Childrenarepronetoplaceforeignobjectsintheexternalearcanal,whichmaycausemac-
erationandinfectionoftheskinliningtheexternalcanal.
Otitis Media• Otitismediaoccursatallages,butthepeakagegroupischildreninthefirst3yearsoflife.• Childrenatriskforsevereandrecurrentotitismediaaremorefrequentlymale,haveagenetic
predisposition to ear infections, and may be in large-group daycare exposed to frequentrespiratoryvirusesandbacterialpathogens.
Mastoiditis• Theepidemiologyofmastoiditisparallelsthatofotitismedia.
MICROBIOLOGYOtitis Externa• Themicrobialmicrobiotaoftheexternalearcanalresponsibleforotitisexternaissimilarto
thatofskinelsewhere,includingstaphylococcalspeciesandanaerobicbacteria.• Pseudomonas aeruginosaisafrequentcauseofswimmer’searandmalignantotitisexterna.
Otitis Media• Streptococcus pneumoniae and nontypeable Haemophilus influenzae are the most frequent
bacterialpathogensinallagegroups.• Moraxella catarrhalis, group A Streptococcus and Staphylococcus aureus are less frequent
causesofAOM.• RespiratoryvirusesarefrequentcausesofAOMaloneorassociatedwithbacterialpathogens.
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Mastoiditis• ThemicrobiologyofmastoiditisissimilartothatofAOM.• Patients with persistent perforation of the tympanic membrane may have invasion of
the mastoid by organisms present in the external ear canal, including S. aureus andP. aeruginosa.
DIAGNOSISOtitis Externa• Acute localized otitis externa may occur as a pustule or furuncle that is visualized in the
canal.• Swimmer’searisidentifiedbyedema,swelling,anderythemaofthecanalwall.• Malignantotitisexternaisassociatedwithseverepainandtendernessofthetissuesaround
thepinnaandmastoid;pusmaybepresentinthecanal.
Otitis Media• AOMisanacuteillnesswithfluidinthemiddleearandbulgingordecreasedmobilityand
inflammationofthetympanicmembrane.
Mastoiditis• Thesignsofmastoiditisincludeswelling,redness,andtendernessoverthemastoidbone.• The pinna is displaced downward and outward, and a purulent discharge may emerge
throughaperforationofthetympanicmembrane.
THERAPYOtitis Externa• Swimmer’searmaybemanagedwithgentlecleansingandirrigationoftheexternalcanal.• Antibiotic solutions, including fluoroquinolone eardrops, are effective in localized
infections.• Systemic antimicrobial therapy, including activity against P. aeruginosa, is necessary to
manageinvasiveexternalotitis.
Otitis Media• High-doseamoxicillinisthepreferreddrugforpatientswithAOM.• Ifamoxicillinfails,amoxicillin-clavulanateorparenteralceftriaxoneispreferred.• SomechildrenwithAOMimprovewithoutuseofantimicrobialagents.• Placementoftympanostomytubesmaybewarrantedforchildrenwithsevereandrecurrent
episodesofAOM.
Mastoiditis• AntimicrobialtherapyissimilartothatofAOM.• Incisionanddrainagemaybenecessarywhenabscessesforminthemastoidaircells.
PREVENTIONOtitis Externa• Patientsshouldbedissuadedfromplacingforeignobjects,includingcotton-tippedapplica-
tors,intheexternalcanal.
Otitis Media• Chemoprophylaxis may be of value for prevention of episodes of AOM in children with
severeandrecurrentdisease.• PneumococcalconjugatevaccineshavebeeneffectiveinreducingepisodesofAOMdueto
vaccineserotypes.• InfluenzavirusvaccinesreducetheincidenceofAOMduringthewinterrespiratoryseason.
Mastoiditis• PreventionissimilartothatofAOM.
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8 SinusitisGregory P. DeMuri and Ellen R. Wald
DEFINITION• Sinusitisisdefinedasaninflammatorydisorderoftheparanasalsinuses.
EPIDEMIOLOGY• Bacterialinfectionofthesinusesisestimatedtooccurin0.5%to2%ofcasesofviralupper
respiratoryinfection(URI)inadultsand6%to13%ofchildren.
MICROBIOLOGY• Classicstudiesofthebacteriologyofsinusitishaveobtainedaspecimenofsinussecretions
bypunctureofthemaxillaryantrumtoreducetheriskofnasalcontamination.• Streptococcus pneumoniaeisthemostfrequentlyisolatedorganism,followedbynontypeable
Haemophilus influenzaeandMoraxella catarrhalis.• Staphylococcus aureusisnotlikelyasignificantcauseofacutesinusitisbutdoesplayarole
inthecomplicationsofsinusitis.• The frequency of isolation of S. pneumoniae is decreasing recently with an increase in
β-lactamase–producingH. influenzae.
DIAGNOSIS• Imaging studies are not indicated for the routine diagnosis of acute sinusitis but may be
usefulwhencomplicationsaresuspected.• The following three clinical presentations will identify patients with acute bacterial
sinusitis:• Onset with persistent symptoms or signs, lasting at least 10 days without evidence of
clinicalimprovement• Onsetwithseveresymptomsorsignsofhighfever(≥39°C)andpurulentnasaldischarge
lastingfor3to4consecutivedays• Onsetwithworseningsymptomsorsignscharacterizedbythenewdevelopmentoffever,
headache,or increasednasaldischargeaftera typicalviralURI that lasted5 to6dayswithinitialimprovement
THERAPY• Formostadultsandchildren,amoxicillinwithorwithoutclavulanateremainsanexcellent
first-lineagentforthetreatmentofsinusitis.• Second-line agents include fluoroquinolones, cefdinir, cefuroxime, or the combination of
cefiximewitheitherclindamycinorlinezolid.• The duration of therapy should be for 7 days after the patient becomes free of signs and
symptoms.• Adjunctivetherapiessuchasantihistamines,decongestants,nasalsteroids,andnasalwashes
haveprovidedminimalimprovementinacutesinusitis.• Surgicaldrainageisindicatedforthecomplicationsofacutebacterialsinusitis.
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9 EpiglottitisJennifer L. Nayak and Geoffrey A. Weinberg
EPIDEMIOLOGY AND ETIOLOGY• Pediatric epiglottitis: a localized, invasive Haemophilus influenzae type b infection of the
supraglotticarea, including theepiglottis, that canbeassociatedwithbacteremia (60% to98%);routineconjugatevaccinationhaslargelyeliminatedthisformofepiglottitis.
• Adult epiglottitis:ofteninvolvesmoreofthesupraglotticstructures(aryepiglotticfolds,val-lecula,tonguebase)andisnotassociatedwithbacteremia(<15%);whenabacterialpathogenis identified, it is more likely to be Streptococcus pneumoniae, Streptococcus pyogenes, orNeisseria meningitidis.
• BeforeroutineinfantimmunizationwithH. influenzaetypebconjugatevaccines65%to75%ofallpatientswithepiglottitiswerechildren1to4yearsofage;currently,90%to95%areadults.
• Incidenceofadultepiglottitis in theUnitedStatesandEurope isapproximately2/100,000population.
CLINICAL MANIFESTATIONS• Pediatric epiglottitis:anabruptillnessinafebrileyoungchildwithatoxicappearance,dys-
phagia or sore throat, a muffled or hoarse voice, stridor, drooling, and often a distinctiveposture—the“tripodposition,”comprisingapprehension,sittingverystill,preferringtoleanforward with hyperextension of the neck, and protrusion of the chin. Cough is distinctlyuncommon.
• Adult epiglottitis:80%to95%haveodynophagiaandsorethroat;only20%to40%havefever,drooling,orstridor.
DIAGNOSIS• Airwaymanagementshouldbepromptlyevaluatedassoonasthediagnosisisconsidered.
Laboratoryandradiologictestinginachildwithsuspectedepiglottitisshouldbeperformedonlyinasafeenvironment(i.e.,intheoperatingroom,emergencydepartment,orintensivecareunit,withanindividualtrainedinpediatricairwayintubation),becauseofthepropen-sitytodevelopacuteairwayobstruction(althoughairwayobstructionismuchlesscommoninadults).
• Peripheral leukocytosis is common but not universal. Lateral and anteroposterior neckradiographsshowenlargementoftheepiglottis(the“thumbsign,”asopposedtothe“pencil-pointnarrowing”oftheairwayinviralcroup).
• Directorindirectlaryngoscopyandfiberopticnasopharyngealendoscopyarethedefinitivediagnostictests.
DIFFERENTIAL DIAGNOSIS• Stridorwithtoxicityanddroolingbutlackofcoughfavorsepiglottitis;stridor,barkingcough,
and lack of drooling favors viral croup (laryngotracheobronchitis). Other conditions thatmimicinfectiousepiglottitisincludebacterialtracheitis,thermalepiglottitis(scaldburnfrom
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smoke or hot beverages), possibly angioneurotic edema, retropharyngeal or peritonsillarabscesses,uvulitis,anddiphtheria.
THERAPY• Pediatric epiglottitis:Ideally,diagnosisisconfirmedbyvisualizationatthetimetheairwayis
securedbyintubation,atwhichtimelaryngealandbloodculturesandcompletebloodcellcountsmaybeobtained.Emergenttracheotomyorcricothyroidotomyisrarelyrequired.
• Adult epiglottitis: In contrast to children, adults with epiglottitis generally tolerate directvisualizationoftheepiglottisfordiagnosis.Hospitalizationinanintensivecareunitduringtheacutephaseoftheillnessissuggested;however,inmostadults(75%to80%)theinfectionissuccessfullymanagedwithoutendotrachealintubationortracheotomy.
• Empiricaltherapyforepiglottitisincludesintravenouscefotaxime,ceftriaxone,orampicillin-sulbactam to treat streptococci, pneumococci, H. influenzae, and meningococci. Inareaswithahighproportionofdrug-resistantpneumococci, empirical therapy shouldbebroadened.
• TherapydirectedagainstStaphylococcus aureus shouldbeconsideredifbacterial tracheitiscannotbeexcluded.
PREVENTION• ChemoprophylaxisforhouseholdcontactsofchildrenwithH. influenzaetypebepiglottitis
shouldbegivenforthosehouseholdscontainingunderimmunizedornonimmunizedchil-drenyoungerthan4yearsofageorimmunocompromisedchildren.
• Contactsofadultswithepiglottitisareunlikelytorequireanyprophylaxis,exceptintherareinstanceofprovenH. influenzaetypebormeningococcalinfection.
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10 Infections of the Oral Cavity, Neck, and HeadAnthony W. Chow
DEFINITION• Infections of the oral cavity, neck, and head are diverse in etiology and clinical
presentation.• Although uncommon in the postantibiotic era, deep fascial space infections and vascular
complications are potentially life-threatening. These include Lemierre syndrome andLudwig’sangina.
• A clear understanding of their interrelationships, anatomic routes of spread, and salientclinicalfeaturesiscriticaltodiagnosisandmanagement.
EPIDEMIOLOGY• Infectionsoftheoralcavityaremostcommonlyodontogenicinoriginandincludedental
caries,periodontaldisease,anddeepfascialspaceinfections.• Nonodontogenicinfectionsoftheoralcavityincludethoseoftheoralmucosaandinfections
ofthemajorsalivaryglands.• Miscellaneousinfectionsoftheheadandneckmostcommonlyresultfromhumanoranimal
bites, irradiation, or surgical procedures but may also arise from suppurative adenitis,infectedembryologiccysts,andsuppurativethyroiditis.
MICROBIOLOGY• Themicrobiotaassociatedwithodontogenicinfectionsgenerallyreflecttheindigenousoral
microbiotaandare typicallypolymicrobial involvingbothstrictanaerobesand facultativebacteria.
• Dentalcariesoriginatefrom“cariogenic”bacteriaresidingwithinthesupragingivalplaque,whereas periodontal disease arises from “periodontopathic” bacteria residing within thesubgingivalplaque.
• Importantdifferenceswithinthesecomplexbacterialcompositionssupporttheconceptofthe“specific”plaquehypothesisofdentalcariesandperiodontaldisease.
DIAGNOSIS• Microbiologic investigation requires proper specimen collection, taking care to minimize
contaminationbyresidentcommensalmicrobiota.• Needle aspiration of loculated pus by an extraoral approach is desirable, and specimens
shouldbetransportedimmediatelytothelaboratoryunderanaerobicconditions.• Tissuebiopsyspecimensshouldberoutinelyexaminedforhistopathologicevidenceofacute
orchronicinflammationandinfection.• ImmunofluorescencestainingandrapidmoleculardiagnostictoolssuchasDNAprobesor
polymerase chain reaction are valuable for the detection of fastidious or noncultivablepathogens.
• Computedtomography(CT)withcontrastisthemosteffectivetoolforlocalizingandevalu-atingtheextentofdeepspaceinfectionsoftheoralcavity,head,andneck.
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• Magneticresonanceimaging(MRI)withorwithoutangiographyismoresensitivethanCTforassessingsofttissueandboneinvolvement,aswellasvascularcomplications.
• Technetiumbonescansincombinationwithgallium-orindium-labeledwhitebloodcellsmaybeusefulforthediagnosisofacuteorchronicosteomyelitis.
THERAPY• Surgicaldrainageofloculatedinfectionandremovalofnecrotictissuearethekeystoman-
agementofdeepfascialspaceinfectionsoftheoralcavity,head,andneck.• Antimicrobialtherapyisimportantinhaltingthelocalspreadofinfectionandinpreventing
hematogenousdissemination.• Choiceofantimicrobialregimensisempirical,dependingontheprimarysource(e.g.,odon-
togenicororopharyngealvs.rhinogenicorotogenic),anticipatedcausativemicroorganisms,andimmunityofthehost(seeTables10-1and10-2).
PREVENTION• Oralhygieneanddentaltreatmenttopreventcariesandadvancedperiodontaldisease• Dietarycounselinganduseoftopicalfluoridesandchlorhexidineoralrinsesforpatientsat
highriskfordentalcaries• Behavioralmodificationofriskfactorssuchastobaccosmoking
TABLE 10-1 Antimicrobial Regimens for Various Odontogenic and Nonodontogenic Orofacial Infections
CLINICAL ENTITYCOMMON CAUSATIVE ORGANISMS ANTIMICROBIAL REGIMENS
OdontogenicSupragingival dental plaque and dental caries prevention
Streptococcus mutans, other streptococci, Actinomyces spp.
Fluoride-containing toothpaste or oral rinses (e.g., sodium fluoride 1.1% or stannous fluoride 0.4%) two or three times daily
with or without
Fluoride-containing varnishes (e.g., sodium fluoride 5%) applied three or four times yearly
with or without
Chlorhexidine 0.12% oral rinses
Acute simple gingivitis
Streptococci, Actinomyces spp., oral spirochetes
Penicillin G, 2-4 MU IV q4-6h (or penicillin V, 500 mg q8h) plus metronidazole, 500 mg PO or IV q8h
or
Ampicillin-sulbactam, 1.5-3 g IV q6-8h
or
Amoxicillin-clavulanate, 500 mg PO q8h
or
Clindamycin, 450 mg PO q6-8h or 600 mg IV q6-8h
Acute necrotizing ulcerative gingivitis (ANUG), or Vincent’s angina
Prevotella intermedia, Fusobacterium spp., Tannerella forsythensis, Treponema denticola, other oral spirochetes
Metronidazole, 500 mg PO or IV q8h
or
Amoxicillin-clavulanate, 500 mg PO q8h
or
Ampicillin-sulbactam, 1.5-3 g IV q6h
or
Clindamycin, 450 mg PO q6h or 600 mg IV q6-8h
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CLINICAL ENTITYCOMMON CAUSATIVE ORGANISMS ANTIMICROBIAL REGIMENS
Early-onset, “aggressive,” or “localized juvenile” periodontitis
Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, Prevotella intermedia
Doxycycline, 200 mg PO or IV q12h (only in patients ≥8 yr of age)
or
Metronidazole, 500 mg PO or IV q8h
Adult or “established“ periodontitis
Treponema denticola, other oral spirochetes, black-pigmented Bacteroides spp. (Porphyromonas gingivalis and Prevotella melaninogenica), Tannerella forsythensis
Topical application of minocycline microspheres (Arestin)
or
Topical application of doxycycline hyclate periodontal extended-release liquid (Atridox)
NonodontogenicGangrenous stomatitis (noma)
Fusobacterium nucleatum, Borrelia vincentii, Prevotella melaninogenica, other oral anaerobes
Penicillin G, 2-4 MU IV q4-6h plus metronidazole, 500 mg PO or IV q8h
or
Ampicillin-sulbactam, 1.5-3 g IV q6-8h
or
Amoxicillin-clavulanate, 500 mg PO q8h
or
Clindamycin, 450 mg PO q6-8h or 600 mg IV q6-8h
Severe oral mucositis in immunocompromised hosts
Viridans and other streptococci, Bacteroides spp., Peptostreptococcus spp., and other oral anaerobes, facultative gram-negative bacilli
Topical chlorhexidine (0.1%) mouth rinses TID plus one of the following:
Cefotaxime, 2 g IV q6h
or
Ticarcillin-clavulanate, 3.1 g IV q4h
or
Piperacillin-tazobactam, 3.375 g IV q6h
or
Imipenem, 500 mg IV q6h
or
Meropenem, 1 g IV q8h
Sialadenitis and suppurative parotitis
Staphylococcus aureus,* Streptococcus viridans and other streptococci, Bacteroides spp., Peptostreptococcus spp., and other oral anaerobes
Nafcillin, 2 g IV q4h, or vancomycin, 1 g IV q12h plus either
Metronidazole, 0.5 g IV q6h
or
Clindamycin, 600 mg IV q6h
IV, intravenously; MU, million units; PO, orally; TID, three times a day.*For Staphylococcus aureus infections in which methicillin-resistant S. aureus is suspected, replace nafcillin with
vancomycin, 1 g IV q12h; in immunosuppressed hosts, cefotaxime or ceftriaxone or imipenem, as described in the table, can be added.
TABLE 10-1 Antimicrobial Regimens for Various Odontogenic and Nonodontogenic Orofacial Infections—cont’d
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TABLE 10-2 Initial Empirical Antimicrobial Regimens for Suppurative Infections of the Head and Neck
INFECTIONUSUAL CAUSATIVE ORGANISMS
ANTIBIOTIC REGIMENS, NORMAL HOST*
Suppurative orofacial odontogenic infections, including Ludwig’s angina
Streptococcus viridans and other streptococci, Peptostreptococcus spp., Bacteroides spp., and other oral anaerobes
Penicillin G, 2-4 MU IV q4-6h plus metronidazole, 0.5 g IV q6h
or
Ampicillin-sulbactam, 2 g IV q4h
or
Clindamycin, 600 mg IV q6h
or
Cefoxitin, 1-2 g IV q6h
Lateral pharyngeal or retropharyngeal space infections
Odontogenic S. viridans and other streptococci, Staphylococcus spp., Peptostreptococcus spp., Bacteroides spp., and other oral anaerobes
Penicillin G, 2-4 MU IV q4-6h plus metronidazole 0.5 g IV q6h
or
Ampicillin-sulbactam 2 g IV q4h
or
Clindamycin 600 mg IV q6h
Rhinogenic Streptococcus pneumoniae, Haemophilus influenzae, viridans and other streptococci, Bacteroides spp., Peptostreptococcus spp., and other oral anaerobes
One of the following:(1) Penicillin G, 2-4 MU IV q4-6h, or
levofloxacin, 500 mg IV q24h, or ciprofloxacin, 750 mg IV q12h
plus
Metronidazole, 0.5 g IV q6h, or clindamycin, 600 mg IV q6h
or
(2) Moxifloxacin, 400 mg IV q24h
Otogenic Same as for rhinogenic space infections
Same as for rhinogenic space infections
Suppurative cervical adenitis and infected embryologic cysts
Streptococcus pyogenes, Peptostreptococcus spp., Fusobacterium spp., oral anaerobes
One of the following:(1) Penicillin G, 2-4 MU IV q4h, plus
metronidazole, 500 mg IV q6h
or
(2) Ampicillin-sulbactam, 2 g IV q4h
or
(3) Clindamycin, 600 mg IV q6h
or
(4) Cefoxitin, 1-2 g IV q6h
Suppurative thyroiditis S. aureus, S. pyogenes, S. pneumoniae, Haemophilus influenzae, Streptococcus viridans and other streptococci, oral anaerobes
Nafcillin, 2 g IV q4-6h, or vancomycin, 1 g IV q12h plus either
Metronidazole, 500 mg IV q6h
or
Clindamycin, 600 mg IV q6h
Cervicofacial actinomycosis
Actinomyces israelii, Arachnia propionica, Actinobacillus actinomycetemcomitans
One of the following:(1) Penicillin G, 2-4 MU IV q4-6h
or
(2) Doxycycline, 200 mg PO or IV q12h
or
(3) Clindamycin, 450 mg PO q6h or 600 mg IV q6h
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INFECTIONUSUAL CAUSATIVE ORGANISMS
ANTIBIOTIC REGIMENS, NORMAL HOST*
Human or animal bites S. pyogenes, S. aureus, Eikenella corrodens, oral anaerobes Pasteurella multocida
One of the following:(1) Ampicillin-sulbactam, 2 g IV q4h
or
(2) Amoxicillin-clavulanate, 500 mg PO q8h
or
(3) Moxifloxacin, 400 mg IV or PO q12h
Maxillofacial trauma, postsurgical wound infections
S. aureus, S. pyogenes, Peptostreptococcus spp., other oral anaerobes, Pseudomonas aeruginosa, Enterobacteriaceae spp.
Nafcillin, 2 g IV q4h, or vancomycin, 1 g IV q12h plus one of the following:
(1) Ticarcillin-clavulanate, 3.1 g IV q4h
or
(2) Piperacillin-tazobactam, 3.375 g IV q6h
or
(3) Imipenem-cilastatin, 500 mg IV q6h
or
(4) Meropenem, 1 g IV q8h
or
(5) Moxifloxacin, 400 mg IV or PO q24h
or
(6) Tigecycline, 100 mg IV, then 50 mg IV q12h
Suppurative jugular thrombophlebitis (Lemierre syndrome)
Fusobacterium necrophorum; same as for odontogenic space infections
Same as for odontogenic space infections
Suppurative cavernous sinus thrombosis
Same as for odontogenic, rhinogenic, or otogenic space infections
Same as for odontogenic, rhinogenic, or otogenic space infections
Mandibular osteomyelitis Same as for odontogenic space infections
Clindamycin, 600 mg IV q6h
or
Moxifloxacin, 400 mg PO or IV q24h
Extension of osteomyelitis from prevertebral space infection
Staphylococcus aureus,† facultative gram-negative bacilli
Either nafcillin, 2 g IV q4h, or vancomycin, 1 g IV q12h plus
Either tobramycin, 1.7 mg/kg IV q8h, or ciprofloxacin, 400 mg IV q12h
IV, intravenously; MU, million units; PO, orally.*For immunocompromised hosts, consider replacing penicillin G with one of the following: cefotaxime, 2 g IV
q4h; ceftriaxone, 1 g IV q12h; or cefepime, 2 g IV q12h. Other regimens to consider are ticarcillin-clavulanate, 3.1 g IV q64h; piperacillin/tazobactam, 3.375 g IV q6h; imipenem, 500 mg IV q6h; meropenem, 1 g IV q8h; moxi-floxacin, 400 mg IV q24h; or tigecycline, 100 mg IV, then 50 mg IV q12h.
†For Staphylococcus aureus infections in which methicillin-resistant S. aureus is suspected, replace nafcillin with vancomycin, 1 g IV q12h; in immunosuppressed hosts, cefotaxime or ceftriaxone or imipenem, as described in the table, can be added.
TABLE 10-2 Initial Empirical Antimicrobial Regimens for Suppurative Infections of the Head and Neck—cont’d
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11 Acute BronchitisEdward E. Walsh
DEFINITION• Acutebronchitis is a self-limited syndromecharacterizedbyacutecoughwithorwithout
sputumbutwithoutsignsofpneumonia.
EPIDEMIOLOGY• Acutebronchitisoccursyear-roundandiscausedbyalargenumberofrespiratorypathogens
accordingtothetypicalepidemiologyofeachpathogen.
MICROBIOLOGY• Acutebronchitisisprimarilycausedbyviralinfections.Mostcommonarerhinovirus,influ-
enzaviruses,respiratorysyncytialvirus,metapneumovirus,coronaviruses,andadenovirus.Fewer than10%ofcasesarecausedbyMycoplasma pneumoniae, Chlamydia pneumoniae,andBordetellapertussis.
DIAGNOSIS• Diagnosisisprimarilymadebytheclinicalpresentationintheabsenceofsignsandsymp-
tomsofpneumonia.
THERAPY• Therapyissymptomaticbecauseantibioticsareuncommonlyrequiredandunnecessaryin
themajorityofcases.
PREVENTION• Prevention is directed at specific pathogens when possible (e.g., influenza and pertussis
vaccination).
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12 Acute Exacerbations of Chronic Obstructive Pulmonary DiseaseLeopoldo N. Segal, Michael D. Weiden, and Harold W. Horowitz
DEFINITION• Chronic lung disease with irreversible airflow limitation with reduced forced expiratory
volumein1second(FEV1)andFEV1/forcedvitalcapacity(FVC)ratio• Acute exacerbation indicated by acute change from a patient’s baseline with increased
dyspnea, sputum volume, or sputum purulence; number of changes clinically definesseverity
EPIDEMIOLOGY• Prevalence expected to reach 10% of the overall population and 50% of smokers; fourth
leadingcauseofdeathworldwide• Increasedriskforacuteexacerbationinwinter• Riskfactors:cigarettesmoking,environmentalparticulatematter,geneticpredisposition
PATHOGENESIS• Intermittentprogressiveairwayinflammation;remodelingandlossoflungfunction• Ciliary dysfunction; excess mucus production; impaired phagocytosis leading to bacterial
colonization
MICROBIOLOGY• Airways of patients with stable disease are frequently colonized with Streptococcus pneu-
moniae, Haemophilus influenzae, and Moraxella catarrhalis; respiratory syncytial virus ismostfrequentcolonizingvirus.
• Microaspirationinstablediseaseintroducesoralanaerobes(e.g.,PrevotellaandVeillonellaspp.)intolowerairway.
• Duringacute exacerbation,bacteriaorvirusesorbothmaybe isolated,withmoregram-negative rods found with worsening lung function. “Atypical” bacteria are not frequentlyisolated.Acquisitionofnewpathogenisassociatedwithexacerbation.
DIAGNOSIS• Acuteexacerbationisdefinedbyincreasedsputumpurulence,volume,anddyspnea.
THERAPY• Useofbronchodilatorshasincreasedformildexacerbationwithoutantibiotictherapy.• Oralorintravenouslyadministeredcorticosteroidsandearlyempiricalantibiotictherapyare
advisedformoderatetosevereexacerbations.
PREVENTION• Avoidexposuretoparticulatematterandceasesmoking.• Administerinfluenza,pneumococcal,andpertussisvaccines.• Prescribeprophylacticdailyazithromycininpatientswithadvanceddiseasewithahistory
ofexacerbationandnocardiacriskfactors.
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13 BronchiolitisJohn Bower and John T. McBride
DEFINITION• Bronchiolitisissmallairwayinflammation/obstructionmostfrequentlycausedbyinfection
withrespiratorysyncytialvirus(RSV)inthefirstyearsoflife.
EPIDEMIOLOGY• RSVbronchiolitisoccursinwinterepidemicsintemperateclimatesandsporadicallyinthe
tropics.• Bronchiolitis is a leading cause of hospitalization in the first year of life in the developed
world.
MICROBIOLOGY• Manyotherrespiratoryvirusesmaycausebronchiolitis,includinghumanmetapneumovirus,
influenza,parainfluenza,adenovirus,coronavirus,andbocavirus.
DIAGNOSIS• DiagnosisisclinicallybasedonpresenceofRSVinthecommunity,initialepisodeofwheez-
ing,andevidenceofupperrespiratoryinfection.• Othercausesofwheezinginearlychildhoodshouldbeexcluded,suchascongenitalheart
diseasewithfailure,foreign-bodyaspiration,dysphagia,andasthma.• Apneamayoccurearlyinthecourseofviralbronchiolitis,usuallyininfantsyoungerthan
44weeks’postconceptionalage.
THERAPY• Therapyissupportiveandincludeshydration,oxygen,andrespiratorysupportasneeded.• Corticosteroidsandbronchodilatorsarenotgenerallybeneficial.• Hypertonicsalineaerosolsdeliveredthreetimesdailymayhastenrecoverybuthavenotbeen
widelyadopted.• Respiratorysupportbyhigh-flownasalcannulamaypreventordelayintubationinpatients
withapneaorrespiratoryfailure.
PREVENTION• CarefulattentiontohandsanitationisimportantinlimitingspreadofRSVinfectionduring
epidemics.• Monoclonalantibodyprophylaxismaypreventormitigateinfectioninhighriskinfants.
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14 Acute PneumoniaRichard T. Ellison III and Gerald R. Donowitz
EPIDEMIOLOGY AND ETIOLOGY• Pneumoniaisthemostcommoncauseofinfection-relateddeath.• Predominant pathogens of community-acquired pneumonia (CAP) in adults include
Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae,andChlamydia pneumoniae.
• Legionellaspecies,Staphylococcus aureus,andentericgram-negativebacilliarelessfrequentcausesthatcanproducemoreseveredisease.
• PredominantpathogensofpatientsrecentlyhospitalizedornursinghomeresidentsincludeS. aureus, aerobic gram-negative rods, including Pseudomonas aeruginosa, and mixedaerobic/anaerobicorganisms.
DIAGNOSIS• Typicalclinicalmanifestationsarecough—thesinequanonofpneumonia—sputumproduc-
tion,dyspnea,chestpain,fever,fatigue,sweats,headache,nausea,myalgia,andoccasionallyabdominalpainanddiarrhea.
• Gramstainandcultureofsputumsamplesremainvaluablediagnosticassays.• Bloodculturesshouldbeobtainedinallpatientswhoareimmunocompromised,havehealth
care–associated (HCAP)orhospital-acquiredpneumonia (HAP),orarehospitalizedwithsevereCAP.
• Chestradiographsshouldbeobtainedonallpatientswithsuspectedpneumonia.• Severalbiomarkers,includingprocalcitoninandC-reactiveprotein,areunderassessmentas
discriminatoryassays todefinepopulationswithahigher likelihoodofbacterial infectionthatcouldbenefitfromantibiotictherapy,buttheclinicalutilityofsuchassayshasnotyetbeenestablished.
THERAPY• Oneofthreeseverityindexscores(PSI,CURB-65,orCRB-65)canbeusedtoassesstheneed
forhospitalizationinimmunocompetentpatientswithCAP,andsimilarindicescanbeusedtodefinetheneedforintensivecareunitadmission.
• Antibiotictherapyforpneumoniashouldbestartedassoonasthediagnosisisconsideredlikely.
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TABLE 14-1 Guide to Empirical Choice of Antimicrobial Agent for Treating Adult Patients with Community-Acquired Pneumonia or Health Care–Acquired Pneumonia
PATIENT CHARACTERISTICS PREFERRED TREATMENT OPTIONS
OutpatientPreviously Healthy
No recent antibiotic therapy Macrolidea or doxycycline (100 mg 2 times/day)
Recent antibiotic therapyb A respiratory fluoroquinolonec alone, an advanced macrolided plus oral β-lactame
Comorbidities (COPD, Diabetes, Renal Failure or Congestive Heart Failure, or Malignancy)
No recent antibiotic therapy An advanced macrolide plus oral β-lactam or a respiratory fluoroquinolone
Recent antibiotic therapy A respiratory fluoroquinolone alone or an advanced macrolide plus a β-lactam
Suspected aspiration with infection Amoxicillin-clavulanate or clindamycin (600 mg IV q8h or 300 mg PO q6h)
Influenza with bacterial superinfection Vancomycin, linezolid, or other coverage for MRSA, including community-acquired MRSAf
InpatientMedical Ward
No recent antibiotic therapy A respiratory fluoroquinolone alone or an advanced macrolide plus an intravenous β-lactamg
Recent antibiotic therapy An advanced macrolide plus an intravenous β-lactam, or a respiratory fluoroquinolone alone (regimen selected will depend on nature of recent antibiotic therapy)
Intensive Care Unit (ICU)
Pseudomonas infection is not a concern A β-lactamg plus either an advanced macrolide or a respiratory fluoroquinolone
Pseudomonas infection is not a concern but patient has a β-lactam allergy
A respiratory fluoroquinolone, with or without clindamycin
Pseudomonas infection is a concernh (cystic fibrosis, impaired host defenses)
Either (1) an antipseudomonal β-lactami plus ciprofloxacin (400 mg IV q8h or 750 mg PO q12h), or (2) an antipseudomonal agent plus an aminoglycosidej plus a respiratory fluoroquinolone or a macrolide
Pseudomonas infection is a concern but the patient has a β-lactam allergy
Aztreonam (2 g IV q8h) plus aminoglycoside plus a respiratory fluoroquinolone
• Advancedmacrolides,respiratoryfluoroquinolones,andβ-lactamagentsare theprincipalantibioticsusedforthetreatmentofCAP.CoverageforS. aureusandmixedanaerobesshouldbeconsideredinselectsituations(seeTable14-1forsuggestedagentsanddosages).
• Antibiotic treatment for HCAP should include coverage for potentially drug-resistantS. aureus and aerobic gram-negative bacilli and in most settings includes coverage forPseudomonas aeruginosa(seeTable14-1forsuggestedagentsanddosages).
• Thedurationofintravenoustreatment,inpatienthospitalization,andtotalintravenousandoralantibiotictherapyforCAPshouldbeguidedbythepatient’sclinicalstability.
PREVENTION• Provideimmunizationasappropriatewithinfluenzaandpneumococcalvaccines.• Encouragecessationoftobaccosmoking.
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PATIENT CHARACTERISTICS PREFERRED TREATMENT OPTIONS
Health Care–Associated Pneumoniak
— Either (1) an antipseudomonal β-lactam plus ciprofloxacin or levofloxacin or (2) an antipseudomonal agent plus an aminoglycoside plus a respiratory fluoroquinolone or a macrolide plus vancomycin or linezolid (for MRSA coverage)
COPD, chronic obstructive pulmonary disease; MRSA, methicillin-resistant S. aureus.Note: All dosages are usual adult doses and may require adjustment in relation to renal or hepatic function, a
patient’s body mass index, or drug-drug interactions.aAzithromycin, clarithromycin, or erythromycin.bThat is, the patient was given a course of antibiotic(s) for treatment of any infection within the past 3 months,
excluding the current episode of infection. Such treatment is a risk factor for drug-resistant Streptococcus pneu-moniae and possibly for infection with gram-negative bacilli. Depending on the class of antibiotics recently given, one or another of the suggested options may be selected. Recent use of a fluoroquinolone should dictate selection of a nonfluoroquinolone regimen and vice versa.
cMoxifloxacin (400 mg once daily), gemifloxacin (320 mg once daily), or levofloxacin (750 mg once daily).dAzithromycin (500 mg once daily), clarithromycin (250-500 mg twice daily), erythromycin (250-500 mg four
times a day).eHigh-dose amoxicillin (1 g three times a day), high-dose amoxicillin-clavulanate (2 g twice daily), cefpodoxime
(200 mg twice daily), or cefuroxime (500 mg twice daily).fVancomycin dosing should target a vancomycin trough level of 15 to 20 µg/mL; linezolid (600 mg twice daily).gCefotaxime (1-2 g IV q4-8h), ceftriaxone (1 g IV daily), ampicillin (1-2 g IV q4-6h), ampicillin-sulbactam (1.5-3 g
IV q6h), or ertapenem (1 g IV daily).hRisk factors for Pseudomonas infection include severe structural lung disease (e.g., bronchiectasis) and recent
antibiotic therapy, health care–associated exposures or stay in hospital (especially in the ICU). For patients with community-acquired pneumonia in the ICU, coverage for S. pneumoniae and Legionella species must always be considered.
iPiperacillin (3 g IV q4h), piperacillin-tazobactam (3.375 g IV q6h), imipenem (500-1000 mg IV q6h), meropenem (1-2 g IV q8h), ceftazidime (2 g IV q6-8h), or cefepime (1-2 g IV q8h) are excellent β-lactams and are adequate for most S. pneumoniae and H. influenzae infections. They may be preferred when there is concern for relatively unusual pathogens of community-acquired pneumonia, such as P. aeruginosa, Klebsiella species, and other gram-negative bacteria.
jData suggest that older adults receiving aminoglycosides have worse outcomes. Traditionally dosed aminoglyco-sides should achieve peak levels of at least 8 µg/mL for gentamicin or tobramycin and 25-35 µg/mL for amikacin and troughs less than 2 µg/mL for gentamicin and tobramycin and less than 10 µg/mL for amikacin. Once-daily dosing for gentamicin or tobramycin is 7 mg/kg IV with trough target <1 µg/mL, and 20 mg/kg IV for amikacin with trough target <4 µg/mL.
kPneumonia developing in patients who have been hospitalized for 2 or more days within 90 days of developing infection; patients attending hospital or hemodialysis clinics; patients receiving intravenous antibiotic therapy, wound care, or chemotherapy at home within 30 days of developing infection; and residents of long-term care facilities or nursing homes.
Modified from Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72; and American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.
TABLE 14-1 Guide to Empirical Choice of Antimicrobial Agent for Treating Adult Patients with Community-Acquired Pneumonia or Health Care–Acquired Pneumonia—cont’d
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15 Pleural Effusion and EmpyemaEdward J. Septimus
DIAGNOSIS• Fluidinthepleuralspacemaybetransudativeorexudative(seeTable15-1).Anexudative
effusionwithpusinthepleuralspaceiscalledanempyema.Computedtomography(CT)isbetter than a chest radiograph for distinguishing pleural fluid from pneumonia and mayallowvisualizationofstrandingorloculationwithinanempyema.
THORACENTESIS• For pleural fluid suspected of empyema, send fluid in capped syringe for pH, inoculate
aerobic and anaerobic blood culture bottles directly at bedside, moisten syringe withpreservative-free heparin because clotting interferes with white blood cell count (WBC),cytology, and Gram stain. Laboratory studies: WBC, differential, protein, glucose, lactatedehydrogenase(LDH),Gramstain,cultureforbacteria,cytology,mycobacteriaandfungi.SendbloodforLDHandproteintodeterminepleuralfluid–to-serumratio.
• Specialstudiesonpleuralfluid:immunochromatographictestforStreptococcus pneumoniaeantigen,polymerasechainreaction(PCR)targeting16SribosomalDNA,modifiedacid-faststainforNocardia,PCR,ornucleicacidamplificationtestoradenosinedeaminaseorcultureofpleuralbiopsyforMycobacterium tuberculosis
• Sourceofempyemaaffectsthemostcommonorganisms:• Community-acquiredpneumonia:S. pneumoniae, Staphylococcus aureus• Community-acquiredempyema:Streptococcus anginosusgroup,Prevotella, Bacteroides• Post-traumaorpostoperativehemothorax:Staphylococcus aureus• Complicationofviralinfluenza:S. pneumoniae, S. aureus, Streptococcus pyogenes• Esophagealrupture:mixedaerobicandanaerobicbacteria,Candida• Hematogenousseedingofserouseffusion:gram-negativebacilli• Spreadacrossdiaphragm:amebiasis,mixedaerobic-anaerobic
TREATMENT• Systemicantibioticsplusadequatedrainageisnecessaryforempyema.Empiricalantibiotic
choices for a presumed bacterial empyema include ampicillin-sulbactam, piperacillin-tazobactam,imipenem,ertapenem,doripenem,meropenem,orcombinationofathird-orfourth-generationcephalosporinandeitherclindamycinormetronidazole.Indicationsfordrainage includecloudyfluid,pH<7.2,glucose<60mg/dL,protein>3g/dL,LDH>1000,orratioofpleuralfluidtoserumforprotein>0.5orLDH>0.6.
• Video-assisted thoracoscopy is being used earlier in empyema treatment, particularly inchildren,andinadultswithempyemanotrespondingtoCT-orultrasound-guidedcathetertubedrainage.Fibrinolytictherapystillhasadvocates,althoughitiscontraindicatedifbron-chopleuralfistulaispresent.
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TABLE 15-1 Features Differentiating Exudative from Transudative Pleural Effusion
FEATURE TRANSUDATE EXUDATEAppearance Serous Cloudy
Leukocyte count <10,000/mm3 >50,000/mm3
pH >7.2 <7.2
Protein <3.0 g/dL >3.0 g/dL
Ratio of pleural fluid protein to serum <0.5 >0.5
Lactate dehydrogenase (LDH) <200 IU/L >200 IU/L
Ratio of pleural fluid LDH to serum <0.6 >0.6
Glucose ≥60 mg/dL <60 mg/dL
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16 Bacterial Lung AbscessBennett Lorber
DEFINITION• Localizednecrosisoflungtissuecausedbymicrobialinfection.Oneormorecavities.
EPIDEMIOLOGY• Primary lung abscess: bad teeth, altered consciousness, aspiration. Secondary: airway
obstructionorimmunosuppression.
MICROBIOLOGY• Polymicrobial. Predominantly mouth anaerobes and streptococci. Klebsiella or Staphylo
coccus aureusuncommonly.
DIAGNOSIS• Radiographorcomputedtomography(CT):thick-walledcavitywithair-fluidlevel.Putrid
sputuminhalfofcases.
THERAPY• β-Lactam/β-lactamasecombinationorclindamycin.
PREVENTION• Maintainoralhygiene.Elevateheadofbedforthosewithalteredconsciousness.
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17 Chronic PneumoniaPeter G. Pappas
DEFINITION• Persistent or progressive cough, dyspnea, often with chronic sputum production, with or
withoutfever,lastingweeksormonthsratherthandays• Alwaysassociatedwithabnormalchestradiography• Constitutionalsymptoms,includingweightlossandanorexia,aretypical• Definitiondoesnotincludeasymptomaticsolitarypulmonarynodules• Maybeinfectiousornoninfectious
EPIDEMIOLOGY• Age,race/ethnicity,andgenderareimportantconsiderations• Underlyinghealthissuesandcomorbidconditions• Currentandpastresidence,occupation,travel,andrecreationhistorymaybeimportant• Recenthospitalizationorhistoryofimprisonment• Drugandalcoholhistory• Recentprescriptiondrugexposure
MICROBIOLOGY• Bacterial: anaerobes, microaerophilic and viridans streptococci; Staphylococcus aureus;
selected community-acquired and nosocomial gram-negative bacilli; Burkholderia pseudomallei
• Higher-orderbacteria:Mycobacterium tuberculosis, Mycobacterium kansasii,andothernon-tuberculousmycobacteria;Nocardiaspp.;Rhodococcus equi; Actinomycesspp.
• Fungi: Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis/posadasii, Paracoccidioides brasiliensis, Cryptococcus neoformans, and Cryptococcus gattii, Aspergillusspp.,Scedosporiumspp.
• Parasites:Dirofilaria, Echinococcus granulosus, Paragonimus westermani,filariasis• Noninfectiouscauses:vasculitides,neoplasia,druginduced,sarcoidosis,pulmonaryalveolar
proteinosis,andahostofotherconditions
DIAGNOSIS• Carefulclinicalassessment,includingdetailedhistory,isessential.• Clinicalfindingsaregenerallynonspecific;rash,osteoarticularfindings,andmucocutaneous
andneurologicfindingsmayprovidehelpfulclues.• Radiographicimaging,includingroutinechestradiographorchestcomputedtomography,
orboth,arecriticaltodiagnosis.• Routine microbiologic studies, including sputum examination by Gram stain, potassium
hydroxide,acid-faststain,andpreparationsforovaandparasites,areimportant.• Cultureforroutinebacteria,fungi,andacid-fastbacilliwhenpossible.• Biopsyandcultureofnonpulmonaryspecimens(e.g.,skin,bone,orbrainbiopsy)inclini-
callyrelevantsettings.PotentiallyimportantserologicstudiesincludethequantiFERONgold
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assayfortuberculosis;Histoplasmaantigen;cryptococcalantigen;andserumandbronchoal-veolarlavagegalactomannan.
• Bronchoalveolar lavage for acid-fast, modified acid-fast, and Gram stain; wet mount orcalcofluor stain; cultures forbacteria,mycobacteria, and fungi; galactomannanassay; andcytopathology.
THERAPY• Specifictherapyisentirelydependentonthemostlikelyetiologies,ofwhichtherearemany
possibilities,usuallyincludingantimicrobials.
PREVENTION• Inthisbroadcategoryofdisease,preventiongenerallyentailstherecognitionandavoidance
ofcircumstances,whichincreasethelikelihoodofdevelopingchronicpneumonia.Inselectedsettings,suchashigh-riskpatientsreceivingchemotherapy,prophylacticantimicrobialsmaybewarranted.
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18 Cystic FibrosisAhmet Uluer and Francisco M. Marty
DEFINITION• Cystic fibrosis (CF) is a genetically inherited autosomal-recessive disease resulting from
mutationstothecysticfibrosistransmembraneconductanceregulatorgene(CFTR,locatedonthe longarmofchromosome7),andalthoughit isamultisystemdisorder,respiratoryandgastrointestinalmanifestationspredominate.
EPIDEMIOLOGY• Staphylococcus aureusandPseudomonas aeruginosa(PA)arethemostcommonCF-associated
pathogens. The prevalence of other bacterial infections varies between countries and CFclinics.
MICROBIOLOGY• Chronicairwayinfectionandinflammation,mostcommonlyassociatedwithPA,arestrongly
associated with morbidity and mortality. Many other pathogens, including methicillin-resistantS. aureus, Burkholderia cepaciacomplexorganisms,andStenotrophomonas malto-philia,arealsoimplicatedinchronicprogressivelungdisease.
DIAGNOSIS• NewbornscreeningisnowavailableintheUnitedStatesandothercountries.• SweatchloridetestingandCFTRgenemutationanalysisarethemainstayfordiagnosingCF,
alongwithimmunoreactivetrypsinogenassociatedwithnewbornscreening.• Acutepulmonaryexacerbationsareusuallylinkedtoprogressionofdisease(seeTable18-1).
Respiratoryvirusesmaytriggerpulmonaryexacerbations.
THERAPY• Maintenance therapy includes mucolytics, airway hydrating agents, chest physiotherapy,
anti-inflammatories,andacombinationoforalandinhaledantibiotics(seeTable18-2).• Acutepulmonaryexacerbationmaybetreatedwithoralandnebulizedantibioticsasneeded,
whereasmoreseriousexacerbationsusuallyrequireintravenousantibiotics,intenseairwayclearanceaccompanyingmucolyticsandairwayhydratingagents,andaggressivenutritionalmanagementwhilemonitoringforcomplications(seeTable18-2)
• Selectionofantibioticsisguidedbycurrentandpreviouspatientrespiratorycultures.Severityofexacerbationwilldeterminewhetheroralorintravenousantibioticswillbeused.
• CFpatientsrequirehigherdosesofmanyhydrophilicantibioticsbecauseofCF-associatedincreasedvolumeofdistributionandclearance.Theseincludeaminoglycosides,penicillins,andcephalosporins.
• InadditiontotheCFTRmodulatorivacaftor—U.S.FoodandDrugAdministration[FDA]approved for those with at least one gating defect mutation (e.g., G551D)—and R117H,Orkambi,acombinationofivacaftorandlumacaftor,hasalsobeenapprovedbytheFDAfortherapyofpatientshomozygousfortheF508delmutation.
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TABLE 18-1 Summary of Recommendations for Chronic Pulmonary Therapies for Patients with Cystic Fibrosis, 2013
TREA
TMEN
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REC
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Inhaled tobramycin—moderate to severe disease*
For individuals with CF, 6 yr of age and older, with moderate to severe lung disease and Pseudomonas aeruginosa persistently present in culture of the airways, the CF Foundation strongly recommends the chronic use of inhaled tobramycin to improve lung function, improve quality of life, and reduce exacerbations.
High Substantial A
Dornase alfa—moderate to severe disease*
For individuals with CF, 6 yr of age and older, with moderate to severe lung disease, the CF Foundation strongly recommends the chronic use of dornase alfa to improve lung function, improve quality of life, and reduce exacerbations.
High Substantial A
Ivacaftor† For individuals with CF, 6 yr of age and older, with at least one G551D CFTR mutation, the Pulmonary Clinical Practice Guidelines Committee strongly recommends the chronic use of ivacaftor to improve lung function, improve quality of life, and reduce exacerbations.
High Substantial A
Inhaled aztreonam—moderate to severe disease*
For individuals with CF, 6 yr of age and older, with moderate to severe lung disease and P. aeruginosa persistently present in cultures of the airways, the CF Foundation strongly recommends the chronic use of inhaled aztreonam to improve lung function and quality of life.
High Substantial A
Dornase alfa—mild disease*
For individuals with CF, 6 yr of age and older, with asymptomatic or mild lung disease, the CF Foundation recommends the chronic use of dornase alfa to improve lung function and reduce exacerbations.
High Moderate B
Azithromycin with P. aeruginosa
For individuals with CF, 6 yr of age and older, with P. aeruginosa persistently present in cultures of the airways, the CF Foundation recommends the chronic use of azithromycin to improve lung function and reduce exacerbations.
High Moderate B
Inhaled tobramycin—mild disease*
For individuals with CF, 6 yr of age and older, with mild lung disease and P. aeruginosa persistently present in cultures of the airways, the CF Foundation recommends the chronic use of inhaled tobramycin to reduce exacerbations.
Moderate Moderate B
Inhaled hypertonic saline
For individuals with CF, 6 yr of age and older, the CF Foundation recommends the chronic use of inhaled hypertonic saline to improve lung function, improve quality of life, and reduce exacerbations.
Moderate Moderate B
Inhaled aztreonam—mild disease†
For individuals with CF, 6 yr of age and older, with mild lung disease and P. aeruginosa persistently present in cultures of the airways, the CF Foundation recommends the chronic use of inhaled aztreonam to improve lung function and quality of life.
Moderate Moderate B
Chronic use of ibuprofen (age < 18 yr)
For individuals with CF, between 6 and 17 yr of age, with an FEV1 ≥60% predicted, the CF Foundation recommends the chronic use of oral ibuprofen, at a peak plasma concentration of 50-100 µg/mL, to slow the loss of lung function.
Moderate Moderate B
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Azithromycin without P. aeruginosa
For individuals with CF, 6 yr of age and older, without P. aeruginosa persistently present in cultures of the airways, the CF Foundation recommends the chronic use of azithromycin should be considered to reduce exacerbations.
Moderate Small C
Inhaled corticosteroids For individuals with CF, 6 yr of age and older, without asthma or allergic bronchopulmonary aspergillosis, the CF Foundation recommends against the routine use of inhaled corticosteroids to improve lung function or quality of life and reduce pulmonary exacerbations.
High Zero D
Oral corticosteroids For individuals with CF, 6 yr of age and older, without asthma or allergic bronchopulmonary aspergillosis, the CF Foundation recommends against the chronic use of oral corticosteroids to improve lung function, quality of life, or reduce exacerbations.
High Negative D
Other inhaled antibiotics
For individuals with CF, 6 yr of age and older, with P. aeruginosa persistently present in cultures of the airways, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of other inhaled antibiotics (i.e., carbenicillin, ceftazidime, colistin, gentamicin) to improve lung function and quality of life or reduce exacerbations.
Low — I
Oral antipseudomonal antibiotics
For individuals with CF, 6 yr of age and older, with P. aeruginosa persistently present in the culture of the airways, the CF Foundation concludes that the evidence is insufficient to recommend for or against the routine use of chronic oral antipseudomonal antibiotics to improve lung function and quality of life or reduce exacerbations
Low — I
Leukotriene modifiers For individuals with CF, 6 yr of age and older, the CF Foundation concludes that the evidence is insufficient to recommend for or against the routine chronic use of leukotriene modifiers to improve lung function and quality of life or reduce exacerbations.
Low — I
Inhaled or oral N-acetylcysteine, or inhaled glutathione
For individuals with CF, 6 yr of age and older, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of inhaled or oral N-acetylcysteine or inhaled glutathione to improve lung function and quality of life or reduce exacerbations.
Low — I
Inhaled anticholinergics
For individuals with CF, 6 yr of age or older, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of inhaled anticholinergic bronchodilators to improve lung function and quality of life or reduce exacerbations.
Low — I
Chronic use of ibuprofen (age ≥ 18 yr)
For individuals with CF, 18 years of age and older, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of oral ibuprofen to slow the loss of lung function or reduce exacerbations.
Low — I
Continued
TABLE 18-1 Summary of Recommendations for Chronic Pulmonary Therapies for Patients with Cystic Fibrosis, 2013—cont’d
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Chronic inhaled β2-adrenergic receptor agonists
For individuals with CF, 6 yr of age and older, the CF Foundation concludes that the evidence is insufficient to recommend for or against chronic use of inhaled β2-adrenergic receptor agonists to improve lung function and quality of life or reduce exacerbations.
Low — I
Oral antistaphylococcal antibiotics, chronic use
For individuals with CF, 6 yr of age and older, with Staphylococcus aureus persistently present in cultures of the airways, the CF Foundation concludes that the evidence is insufficient to recommend for or against the chronic use of oral antistaphylococcal antibiotics to improve lung function and quality of life or reduce exacerbations.
Low — I
A, substantial; B, moderate; C, small; CF, cystic fibrosis; D, zero negative; FEV1, forced expiratory volume in 1 second; I, the committee concludes that the current evidence is insufficient to assess the balance of benefits, and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance and harms cannot be determined.
*Severity of lung disease is defined by FEV1% predicted as follows: normal, >90% predicted; mildly impaired, 70%-89% predicted; moderately impaired, 50%-69% predicted; and severely impaired, <40% predicted (1).
†CF Foundation personnel did not participate in any activity related to ivacaftor.From Mogayzel PJ, Naureckas ET, Robinson KA. Cystic fibrosis pulmonary guidelines. Am J Respir Crit Care Med.
2013;187:680-689.
TABLE 18-1 Summary of Recommendations for Chronic Pulmonary Therapies for Patients with Cystic Fibrosis, 2013—cont’d
PREVENTION• StrictlyadheretoinfectioncontrolmeasurestopreventtransmissionofCF-associatedpatho-
gensamongCFpatients.• EarlyeradicationwillpreventchronicairwayinfectionwithPAandotherpathogensassoci-
atedwithchronicprogressivelungdisease.
TABLE 18-2 Acute Pulmonary Exacerbations in Cystic Fibrosis*Increase in sputum volume or colorNew or increased hemoptysisIncreased coughIncreased dyspneaMalaiseFatigue or lethargyTemperature >38° CAnorexia or weight lossSinus pain or tendernessChange in sinus dischargeChange in physical examination of the chestDecrease in FEV1 by 10% or moreRadiographic changes in support of a pulmonary infection
FEV1, forced expiratory volume in 1 second.*Generally defined as the presence of four of the above.From Cystic Fibrosis Foundation. Treatment of pulmonary exacerbations of cystic fibrosis. In: Clinical Practice
Guidelines for Cystic Fibrosis. Bethesda, MD: Cystic Fibrosis Foundation; 1997.
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D Urinary Tract Infections
19 Urinary Tract InfectionsJack D. Sobel and Donald Kaye
PATHOLOGIC CHARACTERISTICS• Withacutepyelonephritisthereissuppurativenecrosisorabscessformation.• Withchronicpyelonephritisthereisunevenscarring.• Withpapillarynecrosisoneormorepyramidsmayslough.
PATHOGENESIS• Mosturinarytractinfections(UTIs)aretheresultofretrogradeascendinginfection,conse-
quenttonumerousbehavioralfactors.• Becauseofefficienthostdefensemechanisms,bacterialpathogenscapableofcausingUTIs
(uropathogens)areselectedbyvirtueofgeneticallydeterminedvirulencefactors.• Virulencefactorsfacilitatemicroorganismpersistenceintheurinarytract.• Virulence factors include adhesins, bacterial capsules, aerobactin, cytotoxic necrotizing
factors,hemolysins,andsiderophorereceptors.• Infunctionalandstructurallycompromisedurinarytracts,thereisreducedrequirementfor
virulencefactorsinordertoproduceinfection.
HOST DEFENSES• Nonimmunemechanisms,especiallyantibacterialactivityofurine,shearingforceofmicturi-
tion,andurineflow,arehighlyeffectiveinreducingUTIfrequency.• Adaptiveimmunity,bothantibody-andcell-mediatedmechanisms,hasalimitedprotective
role.• Innateimmunitybasedonuroepithelialcellsandresponsetoadherentmicrobesreflectsa
complexrecognitionandreactiveproinflammatoryresponseconsistingofmultiplecytokinesandinflammatorycells.
• Protective cytokine response is genetically determined and influences outcome spectrumfromasymptomaticbacteriuriatosuppurativerenaldisease.
• GeneticsusceptibilitytoUTIisstillminimallyrecognizedandunderstood.
EPIDEMIOLOGY AND NATURAL HISTORY• Escherichia coliisthemostcommoninfectingorganism.• ResistantE. coli andotherresistantbacteriaare increased inhealthcare–related infection
comparedwithcommunityinfection.• ResistantbacteriaareincreasedincomplicatedUTI.• Asymptomaticbacteriuriaiscommonandoflittleconsequenceexceptinafewgroups.• UTIsoccurin1%to2%ofinfants,about5%ofgirls,and0.5%orlessofboys.• Renaldamageisrelatedtovesicoureteralreflux,whichoccursin30%to50%ofpreschool
childrenwithinfection;structuralorfunctionalobstructionalsocausesdamage.• UTIsaremuchmorecommoninwomenthanmenandaremostoftenasymptomatic.• Upto60%ofwomenhavesymptomaticUTIsduringtheirlifespan,and10%ofwomenhave
UTIseachyear.• TwotofivepercentofwomenhaverecurrentUTIswithageneticpredisposition.
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• UTIinmenisuncommonbutoftenassociatedwithstructuralorfunctionalabnormality.• Renalinfectionrarelycausesend-stagerenaldiseasewithoutotherunderlyingdisease.
DIAGNOSIS• Urinedipsticksforpyuriaandbacteriuriaareusefulscreeningtests.• AnegativetestforpyuriamakesUTIunlikely.• NegativetestsforbacteriuriaarecommoninUTIbecauseoflowtitersofbacteria.• Twourinecultureswithgreaterthanorequalto105ofthesameuropathogen/mLurineare
requiredfordiagnosisofasymptomaticbacteriuria.• Oneculturewith102/mLormoreofagram-negativebacillaryuropathogenisdiagnosticin
symptomaticUTI.• Onethirdofyoungwomenwithcystitishavefewerthan105bacteria/mLurine.
MANAGEMENT AND TREATMENT (SEE TABLE 19-1)• AllsymptomaticUTIisusuallytreatedforreliefofsymptoms.• Mostasymptomaticinfectionshouldbeneithersoughtnortreatedbecauseoflackofbenefit;
exceptions are pregnancy and those who are to have traumatic urologic procedures.Controversialexceptionsaresomeyoungchildrenandafterrenaltransplantation.
• Nonantimicrobialpreventionmeasuresaredirectedatreinfectionsandreducingriskfactors.Theyincludeavoidanceofspermicidaljelliesandcatheterizationandinvestigationaluseofestrogens,cranberryproducts,andprobiotics.
• Treatment for infants younger than 3 months involves a β-lactam and aminoglycosideintravenously.
• Treatmentforinfantsolderthan3monthsisasmentionedaboveforthoseseriouslyillandoralβ-lactamortrimethoprim-sulfamethoxazole(TMP-SMX)forothers.
• Treatmentforacute,uncomplicatedpyelonephritisinnonpregnantwomenisaurinecultureandthenfluoroquinolone.
• Treatmentforuncomplicatedcystitisinwomenisshort-coursetherapywithnitrofurantoin,TMP-SMX,fosfomycin,pivmecillinam,orfluoroquinolone.
• TreatmentforcomplicatedUTIisurinecultureandthenfluoroquinolone.Cystitisnitrofu-rantoinandfosfomycinareoptions.
• Treatment of relapses is prolonged therapy or chronic suppression. Complicated UTI orprostatitisispossible.
• Reinfectionscanbeself-treatedperepisodeorpreventedusingsingle-doseprophylaxisforintercourseorlong-termprophylaxis.
PREGNANCY• Asymptomaticbacteriuriaofpregnancyrequirestherapyandpost-treatmentsurveillanceto
reducetheriskofmaternalpyelonephritis,hypertension,andpretermdelivery.• UTItreatmentoptionsarereducedgivenlackofavailabilityofquinolones,tetracyclines,and
sulfonamides(atterm)astreatmentoptions.
IMAGING• The ever-improving quality and availability of renal ultrasonography has facilitated the
diagnosisofrenalcomplicationsandunderlyingurologicabnormalities.Excretoryurogra-phy(intravenouspyelography)hasfastdisappeared,replacedbycomputedtomographyscanandmagneticresonanceimagingexaminations.
• The use of imaging studies in infants and preschool children with febrile UTIs remainscontroversialwithreducedrelianceoncystourethrographyandthepreferenceshiftingtoa“top-down”approachselectingchildrenwhowouldmostbenefitfrominvestigation.
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TABLE 19-1 Recommendations for Initial Therapy of Urinary Tract Infection in Adults
PARAMETER ORAL*PARENTERAL (SWITCH TO ORAL WHEN RESPONSE)
Uncomplicated PyelonephritisGNB or no urine Gram stain available
CP 7 days, LV 5 days; if cannot use FQ, TMP-SMX 14 days ± 1 dose CT or AM
FQ 7 days or extended spectrum β-lactam (e.g., CT), 14 days ± AM
GPC in chains Amoxicillin, 14 days Ampicillin, 14 days
GPC in clusters Linezolid or TMP-SMX, 14 days Vancomycin, 14 days
Complicated PyelonephritisNonpregnant women or men
As for uncomplicated pyelonephritis FQ, 7 days plus extended spectrum β-lactam initially ± AM
Pregnant women Extended spectrum β-lactam;TMP-SMX† only if known sensitive both for 14 days
Extended spectrum β-lactam ± AM for 14 days
Uncomplicated CystitisNonpregnant women Nitrofurantoin, 5 days or fosfomycin, 1
dose, or TMP-SMX, 3 days, or pivmecillinam, 3-7 days; FQ in reserve, 3 days
Complicated CystitisWomen or men FQ or nitrofurantoin, 7 days or fosfomycin,
1 dose
Pregnant women Cephalexin, 3-5 days or fosfomycin, 1 dose or nitrofurantoin, 7 days or TMP-SMX,† 3 days if sensitive
GNB, gram-negative bacilli; GPC, gram-positive cocci.Drugs and Doses:
CP, ciprofloxacin orally 500 mg twice/day or 1000 mg once/day.LV, levofloxacin orally 750 mg once/day.TMP-SMX, trimethoprim-sulfamethoxazole orally 160/800 mg twice/day.CT, ceftriaxone parenterally 1 g/day.FQ, fluoroquinolone parenterally—ciprofloxacin 500 mg twice/day or levofloxacin 750 mg once/day.FQ, fluoroquinolone orally—ciprofloxacin 500 mg twice/day or 1000 once/day or levofloxacin 750 mg
once/day.AM, aminoglycoside parenterally (e.g., gentamicin 5 mg/kg/day).Amoxicillin orally 875 mg twice/day.Ampicillin parenterally 2 g every 4 hr.Linezolid orally 600 mg twice/day.Vancomycin parenterally 15 mg/kg twice/day.Nitrofurantoin orally 100 mg twice/day.Fosfomycin orally 3 g once.Pivmecillinam orally 400 mg twice/day.Cephalexin orally 500 mg four times/day.
*Preferred if the patient is reliable, compliant, hemodynamically stable, and able to take oral therapy.†TMP-SMX should be avoided in the third trimester.
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E Sepsis
20 Sepsis, Severe Sepsis, and Septic ShockRobert S. Munford and Anthony F. Suffredini
DEFINITIONS• Sepsisisthebody’sharmfulsystemicreactiontomicrobialinfection.• Severesepsis isorgandysfunctioncomplicatinginfection; ifhypotensionispresent, itcan
bereversedwithintravenousfluids.• Septicshockissepsis-associatedhypotensionthatrequirespharmacologicreversal.
EPIDEMIOLOGY• Mostcommonlyaffectedpersonsaretheveryyoungandolderadults.• Majoroutcomedeterminantsareageandcomorbidity,especiallyimmunosuppressiveillness.
MICROBIOLOGY• Virtuallyanymicrobecantriggersepsis.• Most cases today occur in previously morbid individuals and are caused by opportunists
fromthepatient’sownmicrobiome.
DIAGNOSIS• Usualsigns:tachycardia,tachypnea,leukocytosisorleukopenia,feverorhypothermia• Frequent, suggestive: thrombocytopenia, lactatemia, delirium, respiratory alkalosis,
hyperbilirubinemia
THERAPY• Promptadministrationofantimicrobialdrugsthatcankillthepatient’soffendingmicrobe
(seeTable20-1)• Intravenousfluidsandpressorsupportasneeded• Source control: eliminating the local site of infection, usually with surgery or removal of
indwellingdevice• Supportivecare
PREVENTION• Hospitalinfectioncontrol• Vaccination
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TABLE 20-1 Empirical Antibiotic Options for Patients with Severe Sepsis or Septic Shock
SUSPECTED SOURCE
LUNG ABDOMENSKIN/SOFT TISSUE
URINARY TRACT
SOURCE UNCERTAIN
Major Community-Acquired Pathogens
Streptococcus pneumoniaeHaemophilus influenzaeLegionellaChlamydia pneumoniae
Escherichia coliBacteroides fragilis
Streptococcus pyogenesStaphylococcus aureusPolymicrobial
E. coliKlebsiella speciesEnterobacter speciesProteus spp.Enterococci
Empirical Antibiotic Therapy
Moxifloxacin or levofloxacin or azithromycin plus cefotaxime or ceftazidime or cefepime or piperacillin-tazobactam
Imipenem or meropenem or doripenem or piperacillin-tazobactam ± aminoglycosideIf biliary source: piperacillin-tazobactam, ampicillin-sulbactam, or ceftriaxone with metronidazole
Vancomycin or daptomycin plus either imipenem or meropenem or piperacillin-tazobactam; ± clindamycin
Ciprofloxacin or levofloxacin (if gram-positive cocci, use ampicillin or vancomycin ± gentamicin)
Vancomycin plus either doripenem or ertapenem or imipenem or meropenem
Major Commensal or Nosocomial Microorganisms
Aerobic gram-negative bacilli
Aerobic gram-negative rodsAnaerobesCandida spp.
Staphylococcus aureus (? MRSA)Aerobic gram-negative rods
Aerobic gram-negative rodsEnterococci
Consider MDRO if in area of high prevalenceConsider echinocandin if neutropenic or indwelling intravascular catheter
Empirical Antibiotic Therapy
Imipenem or meropenem or doripenem or cefepime (if Acinetobacter baumanii or carbapenem-resistant Klebsiella in ICU, add colistin)
Imipenem or meropenem ± aminoglycoside (consider echinocandin)
Vancomycin or daptomycin plus imipenem-cilastatin or meropenem or cefepime, ± clindamycin
Vancomycin plus imipenem or meropenem or cefepime
Cefepime plus vancomycin ± caspofungin
Dosages for intravenous administration (normal renal function):*Imipenem-cilastatin, 0.5-1.0 g q6-8h*Meropenem, 1-2 g q8h*Doripenem, 0.5 g q8hPiperacillin-tazobactam, 3.375 g q4h or 4.5 g q6hVancomycin, load 25-30 mg/kg, then 15-20 q8-12hCefepime, 1-2 g q8hLevofloxacin, 750 mg q24hCiprofloxacin, 400 mg q8-12hMoxifloxacin, 400 mg qdCeftriaxone, 2.0 g q24hCaspofungin, 70 mg, followed by 50 mg q24hColistin: loading dose = 5 mg/kg body weight. For maintenance dosing, see University of California, Los Angeles
Dosing Protocol: www.infectiousdiseases-ucla-affiliated.org/Intranet/FILES/ColistinDosing.pdfICU, intensive care unit; MDRO, multidrug-resistant organisms; MRSA, methicillin-resistant Staphylococcus aureus.For MDRO, resistance usually includes carbapenems.*Carbapenems are less susceptible to extended-spectrum β-lactamases; base choice on local resistance pattern.
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F Intra-abdominal Infections
21 Peritonitis and Intraperitoneal AbscessesMatthew E. Levison and Larry M. Bush
DEFINITION• Infectionintheabdominalcavityencompassesawidespectrumofentitiesandmayinvolve
anyintra-abdominalorganorspace.• Peritonitisisaninflammatoryresponsewithintheperitonealcavityastheresultofcontami-
nationwithmicroorganisms,chemicals,orboth.• Infectiveperitonitisisclassifiedaseitherdiffuseorlocalized,primary(spontaneous),second-
ary,ortertiaryandisfurthercharacterizedas“uncomplicated”or“complicated.”• Inprimaryperitonitis,thereisnointra-abdominalsource,whereasinsecondary,thereisan
intra-abdominalsourceofinfection.• Uncomplicatedinfectionsarecontainedwithinasingleorganwithoutanatomicdisruption,
whereas complicated infections involve extension beyond the organ, either localized orgeneralizedperitonitis,withspillageofmicroorganismsintothesterileperitonealspace.
• Peritonitisisacommoncomplicationoccurringinpatientsundergoingcontinuousambula-toryperitonealdialysis(CAPD).
• Intraperitonealabscessesarefocalcollectionsofpuscomplicatingeitherprimaryorsecond-aryperitonitis,withlocationsgenerallyrelatedtothesiteofprimarydiseaseandthedirectionofdependentperitonealdrainage.
• Themajorityofintra-abdominalinfections(80%)are“communityacquired”andaregradedfrom“mildtomoderate”to“moresevere”onthebasisofphysiologicscoringsystems(AcutePhysiologyandChronicHealthEvaluationII[APACHEII]),thepatient’scomorbidcondi-tions,underlyingimmunestatus,andaninabilitytoachieveadequatesourcecontrol.
• Healthcare–associatedintra-abdominalinfectionsaremostcommonlyacquiredascompli-cationsofpreviouselectiveoremergencyabdominalsurgeries.
EPIDEMIOLOGY• Primaryperitonitisaccountsforapproximately1%ofallperitonitiscases.• Adultpatientsusuallyhavecirrhosisandascitesandareatgreaterriskifthereisacoexisting
gastrointestinalhemorrhage,previousepisode,orlowasciticproteinconcentration.• Secondaryperitonitisisthemostcommonintra-abdominalinfection(80%to90%),caused
bymicrobialorchemicalcontaminationofthesterileperitonealcavityfrommultiplediseaseprocesses(seeTable21-1).
• Tertiaryperitonitisreferstoapersistentorrecurrentinfectionwithoutasurgicallytreatablefocus,maybeduetodisturbanceinthehost’simmuneresponse,andoftenisassociatedwithlessvirulentandpotentiallyresistantmicroorganisms.
• CAPDperitonitisisthemajorcomplicationofperitonealdialysisandmostoftenisduetotouchcontaminationorcatheter-relatedinfection.
• Itrecursin20%to30%andistheprimaryreasonforaswitchtohemodialysis.• Intraperitonealabscessesoccursecondarilyasaconsequenceofdiseasedorgans,penetrating
trauma,orasurgicalprocedure.
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MICROBIOLOGY• Primaryperitonitisisamonomicrobialinfectionwithmorethan60%ofepisodesincirrhotic
patientscausedbygram-negativeentericbacteria.• In children, hematogenous spread of Streptococcus pneumoniae and other streptococcal
speciesismorefrequent.• Staphylococcus aureusisrarelyisolatedinprimaryperitonitis.• Variantsofprimaryperitonitisincludeascitesthatgrowsasingletypeoforganismbuthas
fewerthan250polymorphonuclearwhitebloodcells(PMNWBCs)/mm3(monomicrobialnon-neutrocyticbacterascites)orhasmorethan250PMNWBCs/mm3withnegativecul-tures(culture-negativeneutrophilicascites).
• Secondaryperitonitisischaracteristicallypolymicrobial(seeTable21-2)anddependsuponthemicrofloraassociatedwiththeprimarydiseaseprocess,whichmaybealteredbypreviousantibiotictherapy,othermedications,andspecifichostfactors.
• Enterococci and Candida spp. can often be isolated, the significance of which iscontroversial.
TABLE 21-1 Causes of Secondary PeritonitisDistal esophagus Boerhaave syndrome
MalignancyTraumaIatrogenic*
Stomach Peptic ulcer perforationMalignancyTraumaIatrogenic*
Duodenum Peptic ulcer perforationTraumaIatrogenic*
Biliary tract CholecystitisStone perforation from gallbladder or common ductMalignancyTraumaIatrogenic*
Pancreas Pancreatitis (e.g., alcohol, drugs, gallstones)TraumaIatrogenic*
Small bowel Ischemic bowelIncarcerated herniaCrohn’s diseaseMalignancyMeckel’s diverticulumTrauma
Large bowel and appendix Ischemic bowelDiverticulitisMalignancyUlcerative colitis and Crohn’s diseaseAppendicitisVolvulusTrauma (mostly penetrating)Iatrogenic*
Uterus, salpinx, and ovaries Pelvic inflammatory disease (e.g., salpingo-oophoritis, tubo-ovarian abscess, ovarian cyst)TraumaMalignancyIatrogenic*
*Dehiscence of surgical anastomosis or inadvertent injury during a procedure (e.g., endoscopy).Modified from Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-
abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:133-164.
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• CAPD peritonitis is caused by gram-positive organisms (Staphylococcus epidermidis, S. aureus,andStreptococcusspp.)in60%to80%ofcases.
• Gram-negativebacteria(e.g.,Enterobacteriaceae,Pseudomonasspp.,andAcinetobacterspp.)makeup15%to30%ofcases,oftenderivedfromurinarytract,bowel,skin,orcontaminatedwater.
• Fungalandmycobacterialspeciesareoccasionallyinvolved.• PolymicrobialperitonitisinCAPDisassumedtobesecondarytoanintestinalprocess(e.g.,
bowelperforation).• Intraperitoneal abscesses are mostly polymicrobial and involve the same microorganisms
thatcausesecondaryperitonitis.• Pathogensincludeobligateanaerobicspecies(e.g.,Bacteroides fragilis,anaerobiccocci,and
Clostridia)alongwithfacultativegram-negativebacilli(e.g.,Escherichia coliandProteusandKlebsiellaspp.)
DIAGNOSIS• Primary peritonitis is diagnosed by excluding a primary source of intra-abdominal
infection.• AsciticfluidstudiesincludeWBCcountwithdifferential,proteinconcentration,Gramstain,
andculture.• Thedifferencebetweenserumandasciticfluidalbuminconcentrationisgreaterthan1.1g/
dL,whichiscorrelatedwithportalhypertension.• Asciticfluidglucose,amylase,andlactatedehydrogenasemeasurementsmayhelptodistin-
guishprimaryfromsecondaryperitonitis.• Patientssuspectedofhavingsecondaryperitonitisoranintraperitonealabscessonthebasis
of clinical findings or peritoneal fluid examination require radiologic evaluation with acomputedtomographyscanand/orultrasonography.
TABLE 21-2 Organisms Causing Complicated Intra-abdominal Infections
ORGANISM PATIENTS (%)
Facultative and Aerobic Gram-Negative BacilliEscherichia coli 71
Klebsiella spp. 14
Pseudomonas aeruginosa 14
Proteus mirabilis 5
Enterobacter spp. 5
AnaerobicBacterioides fragilis 35
Other Bacterioides spp. 71
Clostridium spp. 29
Prevotella spp. 12
Peptostreptococcus spp. 17
Fusobacterium spp. 9
Eubacterium spp. 17
Gram-Positive Aerobic CocciStreptococcus spp. 38
Enterococcus faecalis 12
Enterococcus faecium 3
Enterococcus spp. 8
Staphylococcus aureus 4
Modified from Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infec Dis. 2010;50:133-164.
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• When clinically suspected, CAPD peritonitis is confirmed by finding greater than 100WBCs/mm3(predominantlyPMNcells)inmostlycloudydialysate,togetherwiththeisola-tionofamicroorganism(90%to95%ofcases).
THERAPY• Pendingconfirmatorystudies,empiricalantibiotictherapyforsuspectedprimaryperitonitis
shouldbeinitiated(seeTable21-3)onthebasisofthemostlikelypathogens.• Fivedaysofantibiotictherapyissufficientinmostinstances,andoralantibiotictherapymay
beanoptioninselectedcases.• Thetreatmentofsecondaryperitonitisrequiresantibiotictherapy(seeTables21-4and21-5),
alongwithappropriatemedical support, sourcecontrol,andremovalofadiseasedorgan,
TABLE 21-3 Primary Peritonitis: Indications for Initiation of TherapyTemperature >37.8° C (100° F)Abdominal pain and/or tendernessAn unexplained change in mental statusLaboratory abnormalities suggestive of infection (e.g., renal failure, acidosis, or peripheral leukocytosis)Peritoneal fluid neutrophil count ≥250 cells/mm3
TABLE 21-4 Recommended Agents for Treatment of Complicated Intra-abdominal Infections
TYPE OF THERAPYa
FOR MILD TO MODERATELY SEVERE INFECTIONSb
FOR HIGHLY SEVERE COMMUNITY-ACQUIRED, HEALTH CARE–ASSOCIATED, AND TERTIARY INFECTIONSc
Single Agentβ-lactam/β-lactamase inhibitor combinations
Ticarcillin-clavulanic acid Piperacillin-tazobactamd
Fluoroquinolonee Moxifloxacinf Moxifloxacinf
Carbapenems Ertapenem Imipenem-cilastatind or meropenem or doripenem
Glycylcyclines Tigecyclinef Tigecyclinef
Combination TherapyCephalosporin based Cefazolin, cefuroxime, cefotaxime,
ceftriaxone plus metronidazoleThird- or fourth-generation cephalosporin (ceftazidime or cefepime) plus metronidazoleCeftazidime/avibactam plus metronidazoleg
Ceftolozane/tazobactam plus metronidazole
Fluoroquinolone basede
Ciprofloxacin or levofloxacin, each in combination with metronidazoleg
Ciprofloxacin in combination with metronidazoleh
Monobactam based Aztreonam plus vancomycinf or clindamycin plus metronidazole
aEmpirical antimicrobial regimens should be adjusted according to culture and susceptibility reports to ensure activity against the predominant pathogens isolated in culture.
bApplies mainly to community-acquired intra-abdominal infections.cApplies to health care–associated and tertiary peritonitis cases, as well as some severe community-acquired intra-
abdominal infections. However, tigecycline should NOT be used as empirical therapy for health care–associated or tertiary infection due to inactivity of tigecycline against Pseudomonas aeruginosa.
dIn vitro activity may be less, compared to alternative antibiotics.eFluoroquinolone-resistant Escherichia coli has become common in some communities, and fluoroquinolones
should not be used unless hospital surveys indicate at least 90% susceptibility of E. coli to fluoroquinolones.fRisk of mortality may be greater compared with alternative antimicrobials.gClinical cure rates were lower than those achieved with meropenem in a phase III trial, with baseline creatinine
clearance (CrCL) of 30 to 50 mL/min. However, patients treated with ceftazidime/avibactam received a 33% lower daily dose than is currently recommended for patients with this CrCL.
hBecause Bacteroides strains are resistant to these fluoroquinolones, addition of metronidazole is necessary.
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TABLE 21-5 Antibiotic Dosage for Peritonitis during Peritoneal Dialysis
DRUGINTERMITTENT (PER EXCHANGE, ONCE DAILY)
CONTINUOUS (ALL EXCHANGES)
AminoglycosidesGentamicin 0.6 mg/kg LD: 8 mg/L
MD: 4 mg/L
Tobramycin 0.6 mg/kg LD: 8 mg/LMD: 4 mg/L
CephalosporinsCefazolin 15 mg/kg LD: 500 mg/L
MD: 125 mg/L
Cefepime 1 g LD: 500 mg/LMD: 125 mg/L
Ceftazidime 1-1.5 g LD: 500 mg/LMD: 125 mg/L
Cefotaxime 1 g LD: 500 mg/LMD: 125 mg/L
PenicillinsAmpicillin ND MD: 125 mg/L
Oxacillin ND MD: 125 mg/L
Penicillin G ND LD: 50,000 UMD: 25,000 U
Piperacillin ND LD: 500 mg/LMD: 250 mg/L
QuinolonesCiprofloxacin ND LD: 50 mg/L
MD: 25 mg/L
OthersVancomycin 15-30 mg/kg every 5-7 days LD: 1000 mg/L
MD: 25 mg/L
Aztreonam ND LD: 1000 mg/LMD: 250 mg/L
Trimethoprim-sulfamethoxazole ND LD: 320/1600 mg/L POMD: 80/400 mg/L PO daily
CombinationsAmpicillin-sulbactam 2 g every 12 hr LD: 1000 mg/L
MD: 100 mg/L
Imipenem-cilastatin 1 g every 12 hr LD: 500 mg/LMD: 200 mg/L
AntifungalsAmphotericin B NA 1.5 mg/L
Fluconazole ND 200 mg/L IP or PO daily
IP, intraperitoneal; LD, loading dose; MD, maintenance dose; NA, not applicable; ND, no data; PO, orally.Modified from Piraino B, Bailie GR, Bernardini J, et al. Peritoneal dialysis-related infections recommendations: 2005
update. Perit Dial Int. 2005;25:107-131.
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TABLE 21-6 CAPD Peritonitis: Indications for Catheter RemovalPersistent infection at skin exit site or tunnelRelapsing peritonitis with same organism—within 4 wkRefractory peritonitis—failure to respond within 5 daysFungal, mycobacterial, Pseudomonas aeruginosa peritonitisIntraperitoneal abscessCatheter malfunction
CAPD, continuous ambulatory peritoneal dialysis.
necrotic tissue, purulence, blood, feces, and other intraperitoneal foreign material, whenpresent.
• CAPDperitonitis is treatedwithintraperitonealantibiotics(seeTable21-6)usuallyfor10to21days.
• Peritonealdialysiscatheterremovalisnecessaryin10%to20%ofpatients,particularlywithfungalandnontuberculousmycobacterialinfections(seeTable21-6).
• Intraperitoneal abscesses require drainage (percutaneous catheter or surgical), antibiotictherapy(seeTables21-4and21-5),andpossiblysourcecontrol.
PREVENTION• Primaryperitonitisprophylaxisisrecommendedincirrhoticpatientswithasciteswhoare
havingagastrointestinalhemorrhage.• Long-term antibiotic prophylaxis (e.g., norfloxacin or trimethoprim-sulfamethoxazole) is
indicatedinpatientswithoneormoreepisodesofprimaryperitonitis,aswellasincirrhoticpatientswithasciticfluidproteinconcentrationslessthan1.5g/dL.
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22 Infections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis)Costi D. Sifri and Lawrence C. Madoff
DEFINITION• Apyogenicliverabscessistheendresultofanumberofpathologicprocessesresultingina
focal,purulentbacterialcollectionintheliver.• Anamebicliverabscessisaninvasivecomplicationofintestinalamebiasisresultinginafocal
collectionofnonpurulentfluidintheliver.• Cholecystitis: Inflammation/bacterial infection of the gallbladder often resulting from
obstructing gallstones. Acalculous cholecystitis is a similar process in the absence ofgallstones.
• Cholangitisisinflammation/infectionofthebileducts.
EPIDEMIOLOGY• Anestimated10to20casesofpyogenicliverabscessoccurper100,000hospitaladmissions,
or11casespermillionpersonsperyear.• Amebicliverabscessesarerarer,about1permillionpersons,butmorecommoninendemic
regions.Theyaffectmenabout10timesmorefrequentlythanwomen.• Tens of millions in the United States have gallstones; 1% to 3% are complicated by acute
cholecystitis.• Approximately120,000cholecystectomiesoccureachyearintheUnitedStates.• Between 2% and 15% of cases occur without gallstones, known as “acalculous
cholecystitis.”• Inendemicregions,parasitessuchasAscarisandClonorchismaycausebiliarydisease.
MICROBIOLOGY• Pyogenicliverabscessesmaybemonomicrobial,especiallywhencausedbybacteremia,or
polymicrobialinvolvingaerobicgram-negativebacilliandanaerobes.• Klebsiella pneumoniae(typicallyK1andK2strains)arenowanimportantcauseofpyogenic
liverabscess,particularlyinpartsofAsia,butincreasinglyelsewhere.• AmebicliverabscessesarecausedbyinvasivestrainsofEntamoeba histolytica.
DIAGNOSIS• Symptomsareoftennonspecific,andahighindexofsuspicionisrequired.• Diagnostic imaging, especially by ultrasonography, radionuclide cholescintigraphy, or
computed tomography, is essential. For pyogenic liver abscesses, it is often coupled withdiagnostic/therapeuticaspiration.
THERAPY• Somepyogenicprocessesrequirepromptrecognitionandurgentimage-guideddrainageor
definitivesurgery.• Antibioticsdirectedatthesuspectedpathogensplayanimportantroleasadjunctstosurgery
or, in limited cases, may be the sole form of therapy (e.g., small pyogenic liver abscesses,amebicliverabscess).
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23 Pancreatic InfectionMiriam Baron Barshak
DEFINITION• Infectionofpancreatictissue.• Mostcommonlydevelopsasacomplicationofacutepancreatitis(AP),intissuethathasbeen
damagedbyinflammation(seeTable23-1).• Pancreaticabscessisacircumscribedcollectionofpususuallyinornearthepancreas,arising
asaconsequenceofAPorpancreatictrauma.
EPIDEMIOLOGY• Approximately185,000casesofAPperyear intheUnitedStates,20%ofwhichmayhave
significantpancreaticnecrosis.• Upto70%ofpatientswithpancreaticnecrosismaydeveloppancreaticinfection.
MICROBIOLOGY• Gastrointestinalbacterialfloramostcommon(aerobesandanaerobes,gram-positive,and
gram-negative).• Use of preemptive antibiotics may select for more resistant bacterial species and fungal
pathogens.
DIAGNOSIS• Mustbedistinguishedfromsterilepancreaticnecrosis,whichcanbeassociatedwithasepsis-
likesyndrome.• Tissuesamplingisrequiredtoidentifyinfection.
THERAPY• Antimicrobial therapy targeting organisms identified in cultures of the infected site, in
combination with catheter drainage and/or surgical removal of the infected material (seeTable23-2).
• Delayinsurgeryfor infectedpancreaticnecrosismayallowforamorestablepatientwithbetter-demarcatedareasofnecrotictissue.
• Newer surgical approaches include video-assisted retroperitoneal débridement and endo-scopictransgastricnecrosectomy.
PREVENTION• Avoidtoo-earlyenteralfeeding.• Aconsensus favoringuseofearly (preemptive) systemicantibioticsemerged in the1990s
and2000s,usingcarbapenemaloneorquinoloneplusmetronidazoleasfirst-choicetherapy.• Morerecentrandomizedcontrolledstudieshavenotdemonstratedabenefitfromthisprac-
tice,andsomeguidelinesnolongerrecommendpreemptiveantibioticsforpatientswithAP.
50Part
I M
ajo
r C
linic
al S
ynd
rom
es
TABLE 23-1 Definitions Derived from the International Symposium on Acute Pancreatitis, 1992
TERM DEFINITIONAcute pancreatitis Acute inflammatory process of the pancreas with variable involvement of other
regional tissues or remote organ systems
Severe acute pancreatitis Association with organ failure or local complications, or both, such as necrosis, abscess, or pseudocyst
Acute fluid collection Occurs early in the course of AP, located in or near the pancreas, always lacking a wall of granulation or fibrous tissue; bacteria variably present; occurs in 30%-50% of severe AP; most acute fluid collections regress, but some progress to pseudocyst or abscess
Pancreatic necrosis Diffuse or focal area(s) of nonviable pancreatic parenchyma, typically associated with peripancreatic fat necrosis, diagnosed by computed tomography scan with intravenous contrast enhancement
Acute pseudocyst Collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue that arises as a consequence of AP, pancreatic trauma, or chronic pancreatitis; formation requires 4 or more weeks from onset of AP
Pancreatic abscess Circumscribed intraabdominal collection of pus usually in or near the pancreas, containing little or no pancreatic necrosis, arises as a consequence of AP or pancreatic trauma
AP, acute pancreatitis.Note: The use of terms such as phlegmon, infected pseudocyst, hemorrhagic pancreatitis, and persistent acute
pancreatitis is explicitly discouraged.From Bradley EL. A clinically based classification system for acute pancreatitis. Arch Surg. 1993;128:586-590.
51C
hap
ter 23 Pancreatic In
fection
TAB
LE 2
3-2
Pan
creati
c In
fect
ion
In
cid
en
ce a
nd
Mo
rtali
ty R
ate
in
Co
ntr
oll
ed
Tri
als
wit
h A
nti
bio
tics
an
d M
eta
-An
aly
ses
AU
THO
RA
NTI
BIO
TIC
NO
. O
F PA
TIEN
TS
PAN
CR
EATI
C
INFE
CTI
ON
R
ATE
(%
) C
ON
TRO
L/C
ASE
MO
RTA
LITY
R
ATE
(%
) C
ON
TRO
L/C
ASE
CO
MM
ENTS
Luite
n et
al
SGD
: en
tera
l col
istin
, no
rflox
acin
, an
d am
phot
eric
in B
, un
til
clin
ical
rec
over
y pl
us IV
ce
fota
xim
e un
til g
ram
-ne
gativ
e ba
cter
ia a
re
elim
inat
ed f
rom
the
ora
l ca
vity
102
seve
re A
P38
/18*
35/2
2N
onbl
inde
d.N
ecro
sis
not
defin
ed.
Mor
talit
y di
ffer
ence
sta
tistic
ally
sig
nific
ant
whe
n di
seas
e se
verit
y di
ffer
ence
s be
twee
n th
e gr
oups
are
tak
en in
to
acco
unt.
Pre
dom
inan
t ef
fect
on
gram
-neg
ativ
e pa
ncre
atic
in
fect
ion
(8%
in S
GD
gro
up v
s. 3
3% in
con
vent
iona
l tre
atm
ent
grou
p).
Trea
tmen
t w
ith in
trav
enou
s ce
furo
xim
e as
wel
l as
ente
ral S
GD
obs
cure
s in
terp
reta
tion
of t
he e
ffec
t of
ent
eral
tr
eatm
ents
alo
ne.
Pede
rzol
i et
al
Imip
enem
, 50
0 m
g IV
tid
, 14
day
s74 ne
crot
izin
g pa
ncre
atiti
s,
mos
tly o
f bi
liary
orig
in
30/1
2*12
/7N
ot p
lace
bo-c
ontr
olle
d.N
onpa
ncre
atic
infe
ctio
ns a
lso
redu
ced
(15%
vs.
49%
, P <
.01)
. N
o ch
ange
in m
ultio
rgan
fai
lure
rat
e, n
eed
for
surg
ery,
or
surv
ival
com
pare
d w
ith n
o ea
rly a
ntib
iotic
tre
atm
ent.
Sain
io e
t al
Cef
urox
ime,
1.5
g IV
tid
, un
til c
linic
al r
ecov
ery
and
norm
aliz
atio
n of
CRP
leve
l
60 seve
re a
cute
alc
ohol
ic
panc
reat
itis
and
necr
osis
of
at le
ast
one
third
of
the
panc
reas
by
cont
rast
-enh
ance
d C
T
40/3
023
/3*
Not
pla
cebo
-con
trol
led.
Red
uctio
n in
tot
al in
fect
ions
, in
fect
ions
pe
r pa
tient
, an
d op
erat
ions
als
o st
atis
tical
ly s
igni
fican
t. R
ate
of
cultu
re-p
rove
n se
psis
not
sta
tistic
ally
sig
nific
ant.
Onl
y ur
inar
y tr
act
infe
ctio
ns w
ere
redu
ced
sign
ifica
ntly
.
Del
cens
erie
et
al
Cef
tazi
dim
e, a
mik
acin
, an
d m
etro
nida
zole
IV,
10 d
ays
23 alco
hol-i
nduc
ed s
ever
e A
P
58/0
*25
/9C
T w
ith t
wo
or m
ore
fluid
col
lect
ions
, ne
cros
is n
ot d
efine
d
Schw
arz
et a
lO
floxa
cin
and
met
roni
dazo
le IV
, 10
day
s26 C
T-co
nfirm
ed
panc
reat
ic n
ecro
sis
53/6
115
/0N
ot p
lace
bo-c
ontr
olle
d. F
NA
per
form
ed o
n da
ys 1
, 3,
5,
7, a
nd
10 in
all
patie
nts;
ant
ibio
tics
give
n to
con
trol
pat
ient
s w
ith
evid
ence
of
infe
ctio
n. B
ette
r cl
inic
al c
ours
e in
inte
rven
tion
grou
p, b
ut n
o ef
fect
on
deve
lopm
ent
of p
ancr
eatic
infe
ctio
ns.
Bass
i et
alPe
floxa
cin
(400
mg
bid)
vs.
im
ipen
em (
500
mg
tid),
14
days
60 seve
re n
ecro
tizin
g pa
ncre
atiti
s
Peflo
xaci
n: 3
3*
Imip
enem
: 10
*Pe
floxa
cin:
24
Imip
enem
: 10
Non
blin
ded.
CT
confi
rmed
at
leas
t 50
% n
ecro
sis.
Cont
inue
d
52Part
I M
ajo
r C
linic
al S
ynd
rom
es
AU
THO
RA
NTI
BIO
TIC
NO
. O
F PA
TIEN
TS
PAN
CR
EATI
C
INFE
CTI
ON
R
ATE
(%
) C
ON
TRO
L/C
ASE
MO
RTA
LITY
R
ATE
(%
) C
ON
TRO
L/C
ASE
CO
MM
ENTS
Isen
man
n et
al
Cip
roflo
xaci
n (4
00 m
g bi
d)
and
met
roni
dazo
le (
500
mg
bid)
IV,
or p
lace
bo,
14 o
r 21
day
s
114
AP
plus
ser
um C
RP
>150
mg/
L an
d/or
ne
cros
is o
n co
ntra
st-
enha
nced
CT
12/9
5/7
Rand
omiz
ed,
doub
le-b
linde
d, p
lace
bo-c
ontr
olle
d; 2
8% o
f C
IP/
MET
gro
up a
nd 4
6% o
f pl
aceb
o gr
oup
requ
ired
open
an
tibio
tic t
reat
men
t; m
ost
plac
ebo
grou
p sw
itche
s m
otiv
ated
by
ext
rapa
ncre
atic
infe
ctio
ns;
over
all m
orta
lity
and
rate
s of
pa
ncre
atic
infe
ctio
n lo
w,
num
ber
of p
atie
nts
with
pan
crea
tic
necr
osis
low
Gol
ub e
t al
Met
a-an
alys
is o
f ei
ght
cont
rolle
d tr
ials
, in
clud
ing
tria
ls f
rom
the
197
0s
Find
ings
: Ea
rly a
ntib
iotic
adm
inis
trat
ion
redu
ced
mor
talit
y fr
om
AP
but
only
for
pat
ient
s w
ith s
ever
e pa
ncre
atiti
s w
ho r
ecei
ved
broa
d-sp
ectr
um a
ntib
iotic
s re
achi
ng t
hera
peut
ic le
vels
in
panc
reat
ic t
issu
e
Shar
ma
et a
lM
eta-
anal
ysis
incl
udin
g on
ly r
ando
miz
ed,
cont
rolle
d, n
onbl
inde
d st
udie
s ev
alua
ting
patie
nts
with
nec
rotiz
ing
panc
reat
itis
who
rec
eive
d ei
ther
no
pree
mpt
ive
antib
iotic
s or
pre
empt
ive
trea
tmen
t w
ith a
ntib
iotic
s re
achi
ng t
hera
peut
ic le
vels
in
nec
rotic
pan
crea
tic t
issu
e
84 rece
ived
ant
ibio
tic
prop
hyla
xis;
76
did
not;
of
not
e, t
he t
otal
of
160
patie
nts
in t
he
pool
ed d
ata
set
is
inad
equa
te f
or
dete
ctio
n of
a 5
0%
redu
ctio
n in
the
rat
e of
in
fect
ions
Find
ings
: N
onsi
gnifi
cant
tre
nd t
owar
d de
crea
sed
loca
l inf
ectio
n in
pat
ient
s gi
ven
early
imip
enem
, ce
furo
xim
e, o
r ofl
oxac
in.
Inci
denc
e of
sep
sis
and
over
all m
orta
lity
sign
ifica
ntly
low
er
(abs
olut
e ris
k re
duct
ions
, 21
.1%
and
12.
3%,
resp
ectiv
ely,
for
a
rela
tive
risk
redu
ctio
n of
72%
) fo
r an
tibio
tic t
reat
men
t. O
n th
is
basi
s, t
he a
utho
rs r
ecom
men
d th
at “
all p
atie
nts
with
acu
te
necr
otiz
ing
panc
reat
itis…
be g
iven
pro
phyl
axis
with
an
antib
iotic
w
ith p
rove
n ef
ficac
y in
nec
rotic
pan
crea
tic t
issu
e.”
Vill
ator
o et
al
Coc
hran
e Re
view
incl
udin
g ra
ndom
ized
con
trol
led
tria
ls
com
parin
g an
tibio
tics
with
pl
aceb
o in
AP
with
C
T-pr
oven
nec
rosi
s
294
(fro
m 5
eva
luab
le
stud
ies)
Find
ings
: Si
gnifi
cant
ly le
ss m
orta
lity
with
the
rapy
(6%
) vs
. co
ntro
ls (
15.3
%).
No
diff
eren
ces
in r
ates
of
infe
cted
pan
crea
tic
necr
osis
, op
erat
ive
trea
tmen
t, n
onpa
ncre
atic
infe
ctio
n, a
nd
fung
al in
fect
ion.
Sub
grou
p an
alys
is o
f β-
lact
am t
reat
men
t:
Sign
ifica
ntly
less
mor
talit
y (6
.3%
vs.
16.
7%)
than
in c
ontr
ols,
w
ithou
t si
gnifi
cant
diff
eren
ces
in r
ates
of
oper
ativ
e tr
eatm
ent
or n
onpa
ncre
atic
infe
ctio
ns.
No
sign
ifica
nt d
iffer
ence
s w
ith
quin
olon
e pl
us im
idaz
ole
trea
tmen
t. β
-Lac
tam
s as
soci
ated
with
si
gnifi
cant
ly d
ecre
ased
mor
talit
y an
d in
fect
ed p
ancr
eatic
ne
cros
is.
Rokk
e et
al
Pros
pect
ive
rand
omiz
ed
cont
rolle
d tr
ial,
imip
enem
(5
00 m
g tid
for
5-7
day
s)
vs.
no a
ntib
iotic
s
73:
36 r
ecei
ved
imip
enem
; 37
rec
eive
d no
an
tibio
tics
43/1
4*11
/8U
nder
pow
ered
stu
dy (
slow
pat
ient
acc
rual
).N
o di
ffer
ence
s in
leng
th o
f ho
spita
l sta
y, n
eed
of in
tens
ive
care
, ne
ed o
f ac
ute
inte
rven
tions
, ne
ed f
or s
urge
ry,
or 3
0-da
y m
orta
lity
rate
s.A
utho
rs c
oncl
ude
that
“th
e st
udy,
alth
ough
und
erpo
wer
ed,
supp
orts
the
use
of
early
pro
phyl
actic
tre
atm
ent
with
imip
enem
in
ord
er t
o re
duce
the
rat
e of
sep
tic c
ompl
icat
ions
in p
atie
nts
with
sev
ere
panc
reat
itis.
”
Del
linge
r et
al
Mul
ticen
ter,
pros
pect
ive,
do
uble
-blin
d, p
lace
bo-
cont
rolle
d ra
ndom
ized
st
udy
set
in 3
2 ce
nter
s w
ithin
Nor
th A
mer
ica
and
Euro
pe
100
clin
ical
ly s
ever
e,
confi
rmed
nec
rotiz
ing
panc
reat
itis:
50 r
ecei
ved
mer
open
em
(1g
IV q
8h);
50 r
ecei
ved
plac
ebo
with
in 5
day
s of
sym
ptom
ons
et,
for
7 to
21
days
12/1
818
/20
No
stat
istic
ally
sig
nific
ant
diff
eren
ce b
etw
een
the
trea
tmen
t gr
oups
for
pan
crea
tic o
r pe
ripan
crea
tic in
fect
ion,
mor
talit
y, o
r re
quire
men
t fo
r su
rgic
al in
terv
entio
n.
Jafr
i et
alM
eta-
anal
ysis
ass
essi
ng t
he
clin
ical
out
com
e of
pat
ient
s w
ith s
ever
e A
P tr
eate
d w
ith
prop
hyla
ctic
ant
ibio
tics
com
pare
d w
ith t
hat
of
patie
nts
not
trea
ted
with
an
tibio
tics
502
(fro
m 8
stu
dies
)Fi
ndin
gs:
No
effe
ct o
f an
tibio
tics
on m
orta
lity,
rat
es o
f in
fect
ed
necr
osis
, or
fre
quen
cy o
f su
rgic
al in
terv
entio
n. A
ppar
ent
bene
fit r
egar
ding
non
panc
reat
ic in
fect
ions
(RR
, 0.
60;
95%
CI,
0.44
-0.8
2),
with
a R
R re
duct
ion
of 4
0% (
95%
CI,
18%
-56%
); ab
solu
te r
isk
redu
ctio
n of
15%
(95
% C
I, 6%
-23%
), an
d nu
mbe
r ne
eded
to
trea
t of
7 (
95%
CI,
4-17
).
Vill
ator
o et
al
Coc
hran
e Re
view
incl
udin
g ra
ndom
ized
con
trol
led
tria
ls
com
parin
g an
tibio
tics
with
pl
aceb
o in
AP
with
C
T-pr
oven
nec
rosi
s
404
(fro
m 7
eva
luab
le
stud
ies)
Find
ings
: N
o be
nefit
of
antib
iotic
s in
pre
vent
ing
infe
ctio
n of
pa
ncre
atic
nec
rosi
s or
mor
talit
y, e
xcep
t w
hen
imip
enem
was
co
nsid
ered
on
its o
wn,
in w
hich
cas
e a
sign
ifica
nt d
ecre
ase
in
panc
reat
ic in
fect
ion
was
fou
nd (
P =
.02;
RR,
0.3
4; 9
5% C
I, 0.
13-0
.84)
with
out
effe
ct o
n m
orta
lity.
“N
one
of t
he s
tudi
es
incl
uded
in t
his
revi
ew w
ere
adeq
uate
ly p
ower
ed.
Furt
her
bett
er d
esig
ned
stud
ies
are
need
ed if
the
use
of
antib
iotic
pr
ophy
laxi
s is
to
be r
ecom
men
ded.
”
AP,
acu
te p
ancr
eatit
is;
CI,
confi
denc
e in
terv
al;
CIP
/MET
, ci
profl
oxac
in/m
etro
nida
zole
; C
RP,
C-r
eact
ive
prot
ein;
CT,
com
pute
d to
mog
raph
y; F
NA
, fin
e-ne
edle
asp
iratio
n; IV
, in
trav
enou
s; R
R,
rela
tive
risk;
SG
D,
sele
ctiv
e gu
t de
cont
amin
atio
n.*P
< .
05.
Mod
ified
fro
m T
ooul
i J,
Broo
ke-S
mith
M,
Bass
i C,
et a
l. G
uide
lines
for
the
man
agem
ent
of a
cute
pan
crea
titis
. J
Gas
troe
nter
ol H
epat
ol.
2002
;17(
supp
l):S1
5-S3
9.
TAB
LE 2
3-2
Pan
creati
c In
fect
ion
In
cid
en
ce a
nd
Mo
rtali
ty R
ate
in
Co
ntr
oll
ed
Tri
als
wit
h A
nti
bio
tics
an
d
Meta
-An
aly
ses—
con
t’d
53C
hap
ter 23 Pancreatic In
fection
AU
THO
RA
NTI
BIO
TIC
NO
. O
F PA
TIEN
TS
PAN
CR
EATI
C
INFE
CTI
ON
R
ATE
(%
) C
ON
TRO
L/C
ASE
MO
RTA
LITY
R
ATE
(%
) C
ON
TRO
L/C
ASE
CO
MM
ENTS
Isen
man
n et
al
Cip
roflo
xaci
n (4
00 m
g bi
d)
and
met
roni
dazo
le (
500
mg
bid)
IV,
or p
lace
bo,
14 o
r 21
day
s
114
AP
plus
ser
um C
RP
>150
mg/
L an
d/or
ne
cros
is o
n co
ntra
st-
enha
nced
CT
12/9
5/7
Rand
omiz
ed,
doub
le-b
linde
d, p
lace
bo-c
ontr
olle
d; 2
8% o
f C
IP/
MET
gro
up a
nd 4
6% o
f pl
aceb
o gr
oup
requ
ired
open
an
tibio
tic t
reat
men
t; m
ost
plac
ebo
grou
p sw
itche
s m
otiv
ated
by
ext
rapa
ncre
atic
infe
ctio
ns;
over
all m
orta
lity
and
rate
s of
pa
ncre
atic
infe
ctio
n lo
w,
num
ber
of p
atie
nts
with
pan
crea
tic
necr
osis
low
Gol
ub e
t al
Met
a-an
alys
is o
f ei
ght
cont
rolle
d tr
ials
, in
clud
ing
tria
ls f
rom
the
197
0s
Find
ings
: Ea
rly a
ntib
iotic
adm
inis
trat
ion
redu
ced
mor
talit
y fr
om
AP
but
only
for
pat
ient
s w
ith s
ever
e pa
ncre
atiti
s w
ho r
ecei
ved
broa
d-sp
ectr
um a
ntib
iotic
s re
achi
ng t
hera
peut
ic le
vels
in
panc
reat
ic t
issu
e
Shar
ma
et a
lM
eta-
anal
ysis
incl
udin
g on
ly r
ando
miz
ed,
cont
rolle
d, n
onbl
inde
d st
udie
s ev
alua
ting
patie
nts
with
nec
rotiz
ing
panc
reat
itis
who
rec
eive
d ei
ther
no
pree
mpt
ive
antib
iotic
s or
pre
empt
ive
trea
tmen
t w
ith a
ntib
iotic
s re
achi
ng t
hera
peut
ic le
vels
in
nec
rotic
pan
crea
tic t
issu
e
84 rece
ived
ant
ibio
tic
prop
hyla
xis;
76
did
not;
of
not
e, t
he t
otal
of
160
patie
nts
in t
he
pool
ed d
ata
set
is
inad
equa
te f
or
dete
ctio
n of
a 5
0%
redu
ctio
n in
the
rat
e of
in
fect
ions
Find
ings
: N
onsi
gnifi
cant
tre
nd t
owar
d de
crea
sed
loca
l inf
ectio
n in
pat
ient
s gi
ven
early
imip
enem
, ce
furo
xim
e, o
r ofl
oxac
in.
Inci
denc
e of
sep
sis
and
over
all m
orta
lity
sign
ifica
ntly
low
er
(abs
olut
e ris
k re
duct
ions
, 21
.1%
and
12.
3%,
resp
ectiv
ely,
for
a
rela
tive
risk
redu
ctio
n of
72%
) fo
r an
tibio
tic t
reat
men
t. O
n th
is
basi
s, t
he a
utho
rs r
ecom
men
d th
at “
all p
atie
nts
with
acu
te
necr
otiz
ing
panc
reat
itis…
be g
iven
pro
phyl
axis
with
an
antib
iotic
w
ith p
rove
n ef
ficac
y in
nec
rotic
pan
crea
tic t
issu
e.”
Vill
ator
o et
al
Coc
hran
e Re
view
incl
udin
g ra
ndom
ized
con
trol
led
tria
ls
com
parin
g an
tibio
tics
with
pl
aceb
o in
AP
with
C
T-pr
oven
nec
rosi
s
294
(fro
m 5
eva
luab
le
stud
ies)
Find
ings
: Si
gnifi
cant
ly le
ss m
orta
lity
with
the
rapy
(6%
) vs
. co
ntro
ls (
15.3
%).
No
diff
eren
ces
in r
ates
of
infe
cted
pan
crea
tic
necr
osis
, op
erat
ive
trea
tmen
t, n
onpa
ncre
atic
infe
ctio
n, a
nd
fung
al in
fect
ion.
Sub
grou
p an
alys
is o
f β-
lact
am t
reat
men
t:
Sign
ifica
ntly
less
mor
talit
y (6
.3%
vs.
16.
7%)
than
in c
ontr
ols,
w
ithou
t si
gnifi
cant
diff
eren
ces
in r
ates
of
oper
ativ
e tr
eatm
ent
or n
onpa
ncre
atic
infe
ctio
ns.
No
sign
ifica
nt d
iffer
ence
s w
ith
quin
olon
e pl
us im
idaz
ole
trea
tmen
t. β
-Lac
tam
s as
soci
ated
with
si
gnifi
cant
ly d
ecre
ased
mor
talit
y an
d in
fect
ed p
ancr
eatic
ne
cros
is.
Rokk
e et
al
Pros
pect
ive
rand
omiz
ed
cont
rolle
d tr
ial,
imip
enem
(5
00 m
g tid
for
5-7
day
s)
vs.
no a
ntib
iotic
s
73:
36 r
ecei
ved
imip
enem
; 37
rec
eive
d no
an
tibio
tics
43/1
4*11
/8U
nder
pow
ered
stu
dy (
slow
pat
ient
acc
rual
).N
o di
ffer
ence
s in
leng
th o
f ho
spita
l sta
y, n
eed
of in
tens
ive
care
, ne
ed o
f ac
ute
inte
rven
tions
, ne
ed f
or s
urge
ry,
or 3
0-da
y m
orta
lity
rate
s.A
utho
rs c
oncl
ude
that
“th
e st
udy,
alth
ough
und
erpo
wer
ed,
supp
orts
the
use
of
early
pro
phyl
actic
tre
atm
ent
with
imip
enem
in
ord
er t
o re
duce
the
rat
e of
sep
tic c
ompl
icat
ions
in p
atie
nts
with
sev
ere
panc
reat
itis.
”
Del
linge
r et
al
Mul
ticen
ter,
pros
pect
ive,
do
uble
-blin
d, p
lace
bo-
cont
rolle
d ra
ndom
ized
st
udy
set
in 3
2 ce
nter
s w
ithin
Nor
th A
mer
ica
and
Euro
pe
100
clin
ical
ly s
ever
e,
confi
rmed
nec
rotiz
ing
panc
reat
itis:
50 r
ecei
ved
mer
open
em
(1g
IV q
8h);
50 r
ecei
ved
plac
ebo
with
in 5
day
s of
sym
ptom
ons
et,
for
7 to
21
days
12/1
818
/20
No
stat
istic
ally
sig
nific
ant
diff
eren
ce b
etw
een
the
trea
tmen
t gr
oups
for
pan
crea
tic o
r pe
ripan
crea
tic in
fect
ion,
mor
talit
y, o
r re
quire
men
t fo
r su
rgic
al in
terv
entio
n.
Jafr
i et
alM
eta-
anal
ysis
ass
essi
ng t
he
clin
ical
out
com
e of
pat
ient
s w
ith s
ever
e A
P tr
eate
d w
ith
prop
hyla
ctic
ant
ibio
tics
com
pare
d w
ith t
hat
of
patie
nts
not
trea
ted
with
an
tibio
tics
502
(fro
m 8
stu
dies
)Fi
ndin
gs:
No
effe
ct o
f an
tibio
tics
on m
orta
lity,
rat
es o
f in
fect
ed
necr
osis
, or
fre
quen
cy o
f su
rgic
al in
terv
entio
n. A
ppar
ent
bene
fit r
egar
ding
non
panc
reat
ic in
fect
ions
(RR
, 0.
60;
95%
CI,
0.44
-0.8
2),
with
a R
R re
duct
ion
of 4
0% (
95%
CI,
18%
-56%
); ab
solu
te r
isk
redu
ctio
n of
15%
(95
% C
I, 6%
-23%
), an
d nu
mbe
r ne
eded
to
trea
t of
7 (
95%
CI,
4-17
).
Vill
ator
o et
al
Coc
hran
e Re
view
incl
udin
g ra
ndom
ized
con
trol
led
tria
ls
com
parin
g an
tibio
tics
with
pl
aceb
o in
AP
with
C
T-pr
oven
nec
rosi
s
404
(fro
m 7
eva
luab
le
stud
ies)
Find
ings
: N
o be
nefit
of
antib
iotic
s in
pre
vent
ing
infe
ctio
n of
pa
ncre
atic
nec
rosi
s or
mor
talit
y, e
xcep
t w
hen
imip
enem
was
co
nsid
ered
on
its o
wn,
in w
hich
cas
e a
sign
ifica
nt d
ecre
ase
in
panc
reat
ic in
fect
ion
was
fou
nd (
P =
.02;
RR,
0.3
4; 9
5% C
I, 0.
13-0
.84)
with
out
effe
ct o
n m
orta
lity.
“N
one
of t
he s
tudi
es
incl
uded
in t
his
revi
ew w
ere
adeq
uate
ly p
ower
ed.
Furt
her
bett
er d
esig
ned
stud
ies
are
need
ed if
the
use
of
antib
iotic
pr
ophy
laxi
s is
to
be r
ecom
men
ded.
”
AP,
acu
te p
ancr
eatit
is;
CI,
confi
denc
e in
terv
al;
CIP
/MET
, ci
profl
oxac
in/m
etro
nida
zole
; C
RP,
C-r
eact
ive
prot
ein;
CT,
com
pute
d to
mog
raph
y; F
NA
, fin
e-ne
edle
asp
iratio
n; IV
, in
trav
enou
s; R
R,
rela
tive
risk;
SG
D,
sele
ctiv
e gu
t de
cont
amin
atio
n.*P
< .
05.
Mod
ified
fro
m T
ooul
i J,
Broo
ke-S
mith
M,
Bass
i C,
et a
l. G
uide
lines
for
the
man
agem
ent
of a
cute
pan
crea
titis
. J
Gas
troe
nter
ol H
epat
ol.
2002
;17(
supp
l):S1
5-S3
9.
54
24 Splenic AbscessLawrence C. Madoff
DEFINITION• Theabscessescompriseoneormorefocalcollectionsinducedbybacteria,mycobacteria,or
fungiinthespleen.• Predisposingconditionsincludeimmunosuppression,trauma,diabetes,hemoglobinopathy,
Felty’ssyndrome,intravenousdruguse,andendocarditis.
EPIDEMIOLOGY• Splenic abscesses are uncommon and have only been reported in small numbers in the
medicalliterature.• Splenicabscessesarepresentin0.2%to0.7%ingeneralautopsyseries.• Splenicabscessesarea frequentfinding inbacterialendocarditisandarepresent inup to
onethirdofpatientsatautopsy.• Thereisabimodalagedistribution,withpeaksinthethirdandsixthdecadesoflife.
MICROBIOLOGY• Streptococci,staphylococci,salmonellae,andEscherichia coliareimportantcausativeagents
and,alsoincreasingly,fungiandmycobacteria.• InspecificgeographicareasofAsia,Klebsiella pneumoniae andBurkholderia pseudomallei
areimportantcausativeagents.• Anaerobesarerare.
CLINICAL FINDINGS AND DIAGNOSIS• Feverispresent,withabdominalpaininleftupperquadrantbutapaucityofspecificsymp-
tomsandfindings.• Ultrasound, computed tomography, and magnetic resonance tomography are used for
diagnosis.
THERAPY• Splenectomy has been the gold standard of treatment, along with antibiotic treatment of
underlyinginfectionelsewhere.• Recentemphasisisontheuseofpercutaneousdrainagewithantibiotictreatmentor,insome
cases,antibiotictreatmentalone,inanattempttoreducemorbidityandpreservethespleen.
55
25 AppendicitisCosti D. Sifri and Lawrence C. Madoff
DEFINITION• Appendicitis is acute inflammation of the vermiform appendix that is often related to
obstructionandmaybecomplicatedbypolymicrobialinfection.• Complicationsincludeperforation,peritonitis,andintra-abdominalabscesses.
EPIDEMIOLOGY• Acuteappendicitisisarelativelycommondisease,oftenpresentinginadolescenceandearly
adulthood.• Lifetimeriskforappendicitisis8.6%inmenand6.7%inwomen.• Over300,000appendectomiesareperformedannuallyintheUnitedStates.
MICROBIOLOGY• Theinflammationisusuallypolymicrobial,frequentlyinvolvingaerobicandanaerobicgram-
negativebacilli.• Alargevarietyofmicrobeshavebeenisolatedfromacuteappendicitisandrelatedabscesses.• InfectionsbyYersiniaspp.,parasites,includingEntamoeba histolytica,andvirusesmaymimic
appendicitis(e.g.,mesentericadenitis)orcauseobstructionleadingtoacuteappendicitis.
DIAGNOSIS• Clinicaldiagnosisisenhancedbytheuseofimaging,especiallycomputedtomographyand
ultrasonography.• Diagnosis ismoredifficult inwomenof childbearingage inwhomgynecologicprocesses
maymimicappendicitis.
THERAPY• Surgicalremovaloftheappendix,oftendonelaparoscopically,iscurative.• Adjunctiveuseofbroad-spectrumantibiotics,suchaspiperacillin-tazobactam,ceftriaxone,
andmetronidazole,mayberequired.
56
26 Diverticulitis and TyphlitisCosti D. Sifri and Lawrence C. Madoff
DEFINITION• Diverticulitisisinflammationandinfectionofthebowelwall,leadingtomicroperforation
ofcolonicdiverticula.• Typhlitis (neutropenic enterocolitis) is characterized by abdominal pain and fever during
periodsofneutropeniaresultingfrommucosalinflammation,degeneration,andmicrobialinvasion.
EPIDEMIOLOGY• Diverticulitisoccursin10%to25%ofallindividualswithdiverticulosis,whichhasapreva-
lenceof30%to40%inWesternsociety.• Diverticulitisleadsto150,000hospitaladmissionsand24,000electiveoperationsannually
intheUnitedStates.• Theincidenceoftyphlitisisunknownbuthasbeenestimatedtobe5%inhospitalizedneu-
tropenicadultswithcancer.• Bacteremiaorfungemiaoccursin14%to44%ofpatientswithtyphlitis.
MICROBIOLOGY• Acutediverticulitisisapolymicrobialinfectioncausedbyendogenousanaerobicandfaculta-
tivebacteria,includingBacteroidesspp.,Peptostreptococcusspp.,Enterobacteriaceae,viridansstreptococci,andenterococci.
• Pseudomonas aeruginosa, Enterobacteriaceae, Bacteroides fragilis, viridans streptococci,enterococci,andCandidaspp.arecommoncausesofbloodstreaminfectionsinpatientswithtyphlitis.
DIAGNOSIS• Radiographic imaging (computed tomography and ultrasonography) is essential for the
evaluationofsuspecteddiverticulitisandtyphlitis.• More than half of patients with clinically suspected diverticulitis are diagnosed with an
alternativeconditionafterdiagnosticimaging.• Radiographicfindingsofdiverticulitisincludepericolicfatstranding,diverticula,bowelwall
thickening,andphlegmonorabscessformation.• Typhlitiscanbedefinedasbowelwallthickeninggreaterthan4mm,usuallyofthececum,
withneutropenia,fever,andabdominalpain.
THERAPY• Acute uncomplicated diverticulitis can be safely treated in select outpatients with a short
courseoforalantibiotics.• However,thenecessityofantibiotictherapyforthetreatmentofuncomplicateddiverticulitis
iscontroversial.• Complicateddiverticulitisorpatientswithcomorbiditiesorotherpredictorsofworseout-
comesshouldbehospitalized.
57C
hap
ter 26 Diverticu
litis and
Typh
litis
• Percutaneousdrainageoflargeabscesses(>5cmindiameter)canbetemporizinginacutelyillpatients.
• Management of typhlitis includes bowel rest, intravenous fluids, nutritional support, andbroad-spectrum parenteral antibiotics that cover enteric facultative and anaerobic flora,Pseudomonas aeruginosa,andperhapsyeast.
• Surgery may be required for patients with diverticulitis or typhlitis with intraperitonealperforation,uncontrolledsepsis,persistentgastrointestinalbleeding,obstruction,orwhofailtorespondtomedicaltherapy.
PREVENTION• Highdietaryfiberandphysicalactivitymaybeassociatedwithreducedsymptomaticdiver-
ticulardisease.
58
G Cardiovascular Infections
27 Endocarditis and Intravascular InfectionsVance G. Fowler, Jr., W. Michael Scheld, and Arnold S. Bayer
DEFINITION• Infective endocarditis(IE)isaninfectionoftheendocardialsurfaceoftheheart.
EPIDEMIOLOGY• Itistraditionallyassociatedwithheartvalvesdamagedbyrheumaticheartdisease.• Inthecurrentera,healthcarecontactandinjectiondrugusearetheprimaryriskfactors.
MICROBIOLOGY• Staphylococcus aureusisnowtheleadingcauseofIEinmostoftheindustrializedworld.• Historically,viridansgroupstreptococciwerethemostcommoncauseofendocarditis.• Bartonellaspp.arethemostcommoncauseofculture-negativeIEintheUnitedStates.Other
commoncausesofculture-negativeIEaresummarizedinTable27-1.
DIAGNOSIS• Resultsofbloodculturesremainthecornerstoneofdiagnosisofendocarditis.• Clinicalevaluationaloneisinsufficienttoexcludethepossibilityofendocarditis.• Echocardiography,particularlytransesophagealechocardiography,hasgreatlyimprovedthe
clinician’sabilitytoidentifyendocarditis.• Diagnosticschema,suchasthemodifiedDukeCriteria,areusefulinestablishingthepres-
enceofendocarditis.
THERAPY• Cardiacsurgeryisrequiredinuptohalfofpatientswithendocarditisandimprovespatient
outcome.• Cardiacsurgeryisespeciallyimportantinpatientswithendocarditiswhohaveheartfailure,
paravalvularabscess,recurrentembolicevents,orongoingsepsisorwhoareinfectedwithhighlyresistantorfungalpathogens.
• Althoughthetimingofcardiacsurgery,particularlyafteremboliceventsinvolvingthecentralnervoussystem,remainscontroversial,emergingevidencesupportsthebenefitofearlyvalvereplacementsurgeryforendocarditis.
• Antibiotic therapy involves extended courses of antibiotics. Treatment is highly pathogenspecificandissummarizedinTable27-2.GuidelinesfortreatmentofIEwerepublishedin2005andarecurrentlybeingupdated.
• Additionofadjunctivelow-dose,short-coursegentamicintostandardantibiotictreatmentofS. aureusnativevalveIEhasbeenshowntoconferhighriskfornephrotoxicitywithoutsignificantimprovementinclinicaloutcomesandisnotencouraged.
• Severalobservationalstudiessupporttheuseofhigh-doseceftriaxoneincombinationwithampicillinforthetreatmentofampicillin-susceptible,aminoglycoside-resistantenterococcalendocarditisorforpatientswithunderlyingrenaldisease.
http://internalmedicinebook.com
59C
hap
ter 27 End
ocard
itis and
Intravascu
lar Infectio
ns
PREVENTION• Prevention of endocarditis involves reduction of bloodstream infections, especially in the
healthcaresetting.• The role of antibiotic prophylaxis for the prevention of endocarditis is controversial.
GuidelineshavebeenpublishedfromtheAmericanHeartAssociation.
TABLE 27-1 Causes of Culture-Negative Endocarditis
ORGANISMEPIDEMIOLOGY AND EXPOSURES DIAGNOSTIC APPROACHES
Aspergillus and other noncandidal fungi
Prosthetic valve Lysis-centrifugation technique; also culture and histopathologic examination of any emboli
Bartonella spp. B. henselae: exposure to cats or cat fleasB. quintana: louse infestation; homelessness, alcohol abuse
Most common cause of culture-negative IE in United States; serologic testing (may cross-react with Chlamydia spp.); PCR assay of valve or emboli is best test; lysis-centrifugation technique may be useful
Brucella spp. Ingestion of unpasteurized milk or dairy products; livestock contact
Blood cultures ultimately become positive in 80% of cases with extended incubation time of 4-6 wk; lysis-centrifugation technique may expedite growth; serologic tests are available
Chlamydia psittaci Bird exposure Serologic tests available but exhibit cross-reactivity with Bartonella; monoclonal antibody direct stains on tissue may be useful; PCR assay now available
Coxiella burnetii(Q fever)
Global distribution; exposure to unpasteurized milk or agricultural areas
Serologic tests (high titers of antibody to both phase 1 and phase 2 antigens); also PCR assay on blood or valve tissue
HACEK spp. Periodontal disease or preceding dental work
Although traditionally a cause of culture-negative IE, HACEK species are now routinely isolated from most liquid broth continuous monitoring blood culture systems without prolonged incubation times
Legionella spp. Contaminated water distribution systems; prosthetic valves
Serology available; periodic subcultures onto buffered charcoal yeast extract medium; lysis-centrifugation technique; PCR assay available
Nutritionally variant streptococci
Slow and indolent course Supplemented culture media or growth as satellite colonies around Staphylococcus aureus streak; antimicrobial susceptibility testing often requires processing specialized microbiology laboratory
Tropheryma whipplei (Whipple’s disease)
Typical signs and symptoms include diarrhea, weight loss, arthralgias, abdominal pain, lymphadenopathy, central nervous system involvement; IE may be present without systemic symptoms
Histologic examination of valve with periodic acid–Schiff stain; valve cultures may be done using fibroblast cell lines; PCR assay on vegetation material
HACEK, Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp.; IE, infective endocarditis; PCR, polymerase chain reaction.
http://internalmedicinebook.com
60Part
I M
ajo
r C
linic
al S
ynd
rom
es
TABLE 27-2 Summary of Treatment Options for EndocarditisORGANISM/REGIMENa COMMENTS
Staphylococcus aureus
Native Valve
Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × 4-6 wkOptional: gentamicin, 1 mg/kg IV q8h × 3-5 daysb
Use of gentamicin in native valve S. aureus IE is associated with significant nephrotoxicity without clear clinical benefit and therefore is not encouraged
Cefazolin, 2 g IV q8h × 4-6 hrOptional: gentamicin, 1 mg/kg IV q8h × 3-5 daysb
Acceptable in setting of penicillin allergy other than immediate hypersensitivity. See above cautions about gentamicin use.
Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × 6 wkb
Also acceptable in setting of immediate hypersensitivity or anaphylaxis to penicillin; goal vancomycin trough level 15-20 µg/mL is recommended
Prosthetic Valve
Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × ≥6 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk, plus rifampin, 300 mg PO/IV q8h × ≥6 wk
Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × ≥6 wk plus gentamicin, 1 mg/kg IV q8h × 2 wk, plus rifampin, 300 mg PO/IV q8h × ≥6 wk
Goal vancomycin trough level 15-20 µg/mL is recommended
Injection Drug Use
Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × 2 wk; plus gentamicin, 1 mg/kg IV q8h × 2 wk
Two-week regimen only for use in injection drug users with infection limited to tricuspid valve, no renal insufficiency, and no extrapulmonary infection. Two weeks of monotherapy with antistaphylococcal penicillin has also been successfully used in these patients.
Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × 4 wk
Use of gentamicin in this setting is not recommended. Goal vancomycin trough level 15-20 µg/mL is recommended.
Daptomycin, 6 mg/kg IV qd × 4-6 wk Daptomycin is U.S. Food and Drug Administration–approved for treatment of right-sided S. aureus IE; for adults, some experts recommend 8-10 mg/kg IV
Coagulase-Negative Staphylococci
Native Valve
Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × 4-6 wkOptional: gentamicin, 1 mg/kg IV q8h × 3-5 days
Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × 6 wk
Also acceptable in setting of immediate hypersensitivity or anaphylaxis to penicillin. Goal vancomycin trough level 15-20 µg/mL is recommended.
Prosthetic Valve
Methicillin-susceptible Nafcillin or oxacillin, 2 g IV q4h × ≥6 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk, plus rifampin, 300 mg PO/IV q8h × ≥6 wk
Methicillin-resistant Vancomycin, 15-20 mg/kg IV q8-12h × ≥6 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk, plus rifampin, 300 mg PO/IV q8h × ≥6 wk
Goal vancomycin trough level 15-20 µg/mL is recommended
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Penicillin-Susceptible Viridans Streptococci (MIC ≤0.1 µg/mL) and Streptococcus bovis (S. gallolyticus)
Penicillin, 2-3 million units IV q4h × 4 wk, or ampicillin, 2 g IV q4h × 4wk
Also effective for other penicillin-susceptible nonviridans streptococci (e.g., group A streptococci)
Ceftriaxone, 2 g IV qd × 4 wk For penicillin allergy; patients with uncomplicated viridans streptococcal IE are candidates for outpatient therapy
Penicillin, 2-3 million units IV q4h × 2 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk
Uncomplicated native valve IE only; not acceptable for nutritionally variant streptococci
Nutritionally variant strain
Penicillin, 2-4 million units IV q4h × 4 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk
For prosthetic valve IE, give 6 wk of penicillin. Nutritionally variant streptococci are often penicillin tolerant.
Vancomycin, 15-20 mg/kg IV q8-12h × 4 wk
For penicillin allergy
Relatively Penicillin-Resistant Viridans Streptococci (MIC 0.12-<0.5 µg/mL)Penicillin, 4 million units IV q4h × 4 wk, plus gentamicin, 1 mg/kg IV q8h × 2 wk
Vancomycin, 15-20 mg/kg IV q8-12h × 4 wk
For penicillin allergy or to avoid gentamicin
Enterococcic and Penicillin-Resistant Viridans Streptococci (Penicillin MIC >0.5 µg/mL)Penicillin-susceptible, aminoglycoside-susceptible enterococci
Penicillind 3-5 g IV q4h × 4-6 wk, plus gentamicin, 1 mg/kg IV q8h × 4-6 wk; orAmpicillin, 2 g IV q4h, plus gentamicin, 1 mg/kg IV q8h × 4-6 wk
Increase duration of both drugs to 6 wk for prosthetic valve infection or for enterococcal IE with symptoms >3 mo. For older patients and those with underlying renal disease, can consider shortening the duration of gentamicin to 2 wk.
Penicillin-resistant, vancomycin-susceptible, aminoglycoside-susceptible enterococci
Vancomycin, 15-20 mg/kg IV q8-12h × 6 wk, plus gentamicin, 1 mg/kg q8h × 6 wke
Also for patients with penicillin allergy. This regimen is associated with enhanced risk of nephrotoxicity. Penicillin desensitization should be considered as an alternative to this regimen when possible.
Penicillin-susceptible, aminoglycoside-resistant enterococci
Ampicillin, 2 g IV q4h, plus ceftriaxone, 2 g IV q12h
Useful for patients with significant underlying renal disease
Penicillin-resistant, vancomycin-resistant enterococci
No standard therapy; daptomycin, linezolid, and quinupristin-dalfopristin have been used
Consult infectious diseases specialist
HACEK StrainsCeftriaxone, 2 g IV qd × 4 wk Increase duration to 6 wk for infections
involving prosthetic valves
Ampicillin-sulbactam, 3 g IV q6h × 4 wk (if β-lactamase producing strain)a
Increase duration to 6 wk for infections involving prosthetic valves
Non-HACEK Gram-Negative Bacillif
Enterobacteriaceae Extended-spectrum penicillin (e.g., piperacillin-tazobactam) or cephalosporin plus aminoglycosides for susceptible strains
Treat for a minimum of 6-8 wk. Some species exhibit inducible resistance to third-generation cephalosporins. Valve surgery is often required for patients with left-sided IE caused by gram-negative bacilli, especially for prosthetic valve IE. Consultation with an infectious diseases specialist is recommended.
TABLE 27-2 Summary of Treatment Options for Endocarditis—cont’d
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Pseudomonas aeruginosa
Antipseudomonal penicillin (e.g., piperacillin) plus high-dose tobramycin, 8 mg/kg/day IV or IM in once-daily doses; orHigh-dose ceftazidime, cefepime, or imipenem
Goal tobramycin peak and trough concentrations of 15-20 µg/mL and ≤2 µg/mL, respectively. Treat for a minimum of 6-8 wk. Early valve surgery usually required for left-sided Pseudomonas IE; consultation with a specialist in infectious diseases is recommended.
Fungif
Treatment with a parenteral antifungal agent (usually an amphotericin B–containing product) is usually recommended as initial therapy
Fungal endocarditis is usually an indication for valve replacement surgery. Long-term/lifelong suppressive therapy with oral antifungal agents is often required. Consultation with a specialist in infectious diseases is recommended.
HACEK, Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp.; IE, infective endocarditis; MIC, minimal inhibitory concentration.
aDosages assume normal renal function. For patients with renal insufficiency, adjustments must be made for all antibiotics except nafcillin, rifampin, and ceftriaxone. Gentamicin doses should be adjusted to achieve a peak serum concentration of approximately 3 µg/mL 30 minutes after dosing and a trough gentamicin level of <1 µg/mL.
bPrimarily relevant to left-sided IE.cEnterococci must undergo antimicrobial susceptibility testing. These recommendations are for enterococci sus-
ceptible to penicillin, gentamicin, and vancomycin except as indicated.dAmpicillin, 12 g/day, can be used instead of penicillin.eThe need to add an aminoglycoside has not been demonstrated for penicillin-resistant streptococci.fLimited data exist.Modified from Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis,
antimicrobial therapy, and management of complications. Circulation. 2005;111:e394-e433.
TABLE 27-2 Summary of Treatment Options for Endocarditis—cont’d
Non-HACEK Gram-Negative Bacillif—cont’d
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28 Prosthetic Valve EndocarditisRaj Palraj, Bettina M. Knoll, Larry M. Baddour, and Walter R. Wilson
DEFINITION• Prostheticvalveendocarditis(PVE)isapotentiallylife-threateninginfectionthatinvolvesa
valveprosthesisorannuloplastyring.
EPIDEMIOLOGY• Prosthetic valve endocarditis is an uncommon but well-recognized complication of valve
replacementorrepair.• Healthcare–associatedPVEisincreasinginincidence.• Staphylococcus aureusisthemostcommoncauseofPVE.
MICROBIOLOGY• Early-onset(illnessonsetwithin1yearofvalvesurgery)PVEisusuallycausedbymicroor-
ganisms acquired perioperatively, such as S. aureus and coagulase-negative staphylococci(CoNS).Nosocomialgram-negativepathogens,manyofwhicharemultidrugresistant,andfungirarelycauseearly-onsetPVE.
• Late-onsetPVEisusuallycausedbyorganismsrepresentativeof“normalmicrobiota”andincludeviridansgroupstreptococciandenterococci.
• S. aureusandCoNSarealsocommonpathogensoflate-onsetPVEdue,inpart,toanincreaseinfrequencyofhealthcare–associatedexposureinthelateperiod.
DIAGNOSIS• ModifiedDukecriteriahavebeenusedtodefinesuspectcasesofPVE.• Blood cultures are critical in both supporting a PVE diagnosis and directing selection of
antimicrobialtherapy.• Transesophageal echocardiography (TEE) is the preferred imaging modality to support a
diagnosisand to identifycomplications suchas severevalvedysfunctionandperivalvularextensionofinfection,whichmayrequiresurgicalintervention.
THERAPY• Parenteral antimicrobial therapydirectedagainst a specificpathogen foraminimumof6
weeksisrecommended(seeTable28-1).• TEEmayneed toberepeatedduringantimicrobial therapy to identifycomplications that
wouldpromptsurgicalintervention.• Early surgical intervention should be considered in complicated PVE with perivalvular
extension,severeheartfailure,severevalvedysfunction/dehiscence,multipleemboli,unre-sponsiveinfection,andPVEduetomultidrug-resistantorganismsorfungi(seeTable28-2).
PREVENTION• Perioperativeantibioticprophylaxis, strict infectioncontrolmeasures,good surgical tech-
nique,and limiting theuseofcentralvenouscathetersare important inpreventingearly-onsetPVE.
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• Maintenanceofgoodoralhygieneis importanttopreventlate-onsetcommunity-acquiredPVE.
• Althoughtherehasbeennorandomized,placebo-controlledtrialtodefinetheefficacyandsafetyofantibioticprophylaxis, it is recommended foranydentalprocedure that involvesmanipulationofthegingivalorperiapicalregionofteethorperforationoforalmucosa,aswellasforproceduresontherespiratorytract,infectedskin,skinstructures,and/ormuscu-loskeletaltissue.
TABLE 28-1 Therapy for Prosthetic Valve Endocarditis Caused by Staphylococci, Suggested by American Heart Association
REGIMEN DOSAGE AND ROUTE DURATION
Methicillin-Susceptible StaphylococciNafcillin or oxacillin*plus
2 g IV q4h ≥6 wk
Rifampin†
plus300 mg PO or IV q8h ≥6 wk
Gentamicin‡ 3 mg/kg IV/IM q24h in 2 or 3 equally divided doses 2 wk
Methicillin-Resistant StaphylococciVancomycin§
plus15 mg/kg IV q12h ≥6 wk
Rifampin†
plus300 mg PO or IV q8h ≥6 wk
Gentamicin‡ 3 mg/kg per IV/IM in 2 or 3 equally divided doses 2 wk
Dosages recommended are for patients with normal renal function.*Penicillin G, 24 million U/24 hr IV, may be used in place of nafcillin or oxacillin if the strain is penicillin susceptible
(MIC ≤0.1 µg/mL) and does not produce β-lactamase. Cefazolin 2 g IV q8h may be substituted for nafcillin or oxacillin. Cefazolin can be used in non–immediate-type allergic reaction to penicillin. Consider skin testing for patients with history of immediate-type allergy to penicillin. Vancomycin is recommended only in patients unable to tolerate penicillins and cephalosporins.
†It is recommended to initiate rifampin therapy only after susceptibility results are known and ideally after 2 days of effective combination therapy, in an attempt to reduce the risk of emergence of rifampin resistance.
‡Gentamicin should be administered in close proximity to vancomycin, nafcillin, or oxacillin to maximize synergy. Renal function and serum gentamicin concentrations should be closely monitored. Goal trough level is <1 µg/mL and peak level (1 hr postdose) is 3-4 µg/mL.
§Vancomycin dosage should be adjusted to a trough level of 10-15 µg/mL.From Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and man-
agement of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394-e434.
TABLE 28-2 Indications for Consideration of Surgical InterventionSevere heart failure; mild-moderate heart failure unresponsive to medical therapyValvular dehiscence, obstruction, or leaflet perforationPerivalvular extension of infection leading to myocardial abscess, fistula, or shuntNew severe conduction defects suggestive of perivalvular extensionMultiple (>1) systemic emboli despite appropriate antimicrobial therapyUncontrolled infection—persistent fever and positive blood cultures for >5 daysFungal, Pseudomonas spp., or other multidrug-resistant organisms
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29 Infections of Nonvalvular Cardiovascular DevicesM. Rizwan Sohail, Walter R. Wilson, and Larry M. Baddour
CARDIOVASCULAR IMPLANTABLE ELECTRONIC DEVICE (CIED) INFECTIONS• TheinfectionrateofCIEDinfectionisrisingdisproportionatetotherateofimplantation.• Mostearly-onset(within6monthsofimplantation)CIEDpocketinfectionsarecausedby
devicecontaminationatthetimeofimplantation,whereashematogenousseedingisafre-quentsourceoflate-onset(after6monthsofimplantation)CIEDleadinfections.
• HematogenousseedingofCIEDleadsisrarewithgram-negativebacteremiafromadistantsource.
• Bloodculturesshouldbeobtainedinallpatientsatinitialpresentation.Ifbloodculturesarepositive,thentransesophagealechocardiographyshouldbedonetoexcludeendocarditis.
• CompleteremovaloftheCIEDsystemisrequiredforeradicationofinfection.• Areplacementdevicecanbeimplantedoncebloodculturesarenegativefor72hoursand
perhapsearlierincasesinwhichadmissionbloodculturesarenegative.A2-weekdelayisrecommendedforpatientswithvalvularendocarditis.
• All patients should receive perioperative antibiotics as primary prevention of CIEDinfection.
LEFT VENTRICULAR ASSIST DEVICE (LVAD) INFECTIONS• In addition to being a bridge to transplantation, LVADs are increasingly being used as
destination therapy for patients with end-stage heart failure who are not transplantcandidates.
• Continuous-flowpumpsareatlowerriskofinfectioncomparedwithdeviceswithpulsatileflowpumps.
• Driveline exit-site infections are the most common type of LVAD-specific infections, fol-lowedbyLVAD-relatedbacteremiaandendocarditis.
• Staphylococcus aureusandcoagulase-negativestaphylococciareresponsibleforthemajorityofLVAD-specificinfections.
• MostLVADinfectionsaretreatedwiththeinfecteddeviceleftinsitubecausedeviceremovalisnotanoptioninmostcases.
• Suppressive antibiotics are continued lifelong or until the infected LVAD is removed andcardiactransplantationisperformed.
• Immobilizingthedrivelineattheskinexitsitetopreventrepeatedskintraumareducestheriskoflocalinfections.
PROSTHETIC VASCULAR GRAFT INFECTIONS (PVGIS)• StaphylococcalspeciesarethepredominantpathogensinPVGIs.• Microbialseedingofagraftatthetimeofimplantationorintheimmediatepostoperative
periodisoperativeingraftinfections.• Computedtomographic(CT)scanningisthebesttoolinthediagnosticevaluationofgraft
infection.CTfindingsofperigraftfluidaccumulation,fatstrandingorgasbubbles,lackof
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fat plane between graft and bowel, and anastomotic aneurysms are all suggestive of graftinfection.
• Surgical management of an infected graft includes complete excision of infected graftmaterial,débridementofallinfectedanddevitalizedtissues,andrevascularizationofdistaltissues.
• If complete excision of an infected graft is not feasible, patients should be prescribedlifelongoralsuppressiveantibioticsafteraninitial4-weekcourseofparenteralantimicrobialtherapy.
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30 Prophylaxis of Infective EndocarditisDavid T. Durack
DEFINITION OF THE ISSUEInfective endocarditis (IE) continues to cause serious morbidity and mortality; therefore, pre-vention of IE is a priority.
EPIDEMIOLOGY• The incidence of IE is increasing in developing countries.• Contributing factors include aging populations, the steadily increasing number of medical
procedures, implants and prostheses, and the rising frequency of health care–associated infections, especially catheter-related bloodstream infections.
MICROBIOLOGY• Staphylococci have superseded viridans streptococci as the predominant pathogens.• Methicillin-sensitive, methicillin-resistant, and coagulase-negative strains of staphylococci
all contribute to the increase in cases of staphylococcal IE.• Increasing resistance to β-lactams, aminoglycosides, and vancomycin among staphylococci,
streptococci, and enterococci presents new challenges for prevention and therapy of IE.
PREVENTION OF INFECTIVE ENDOCARDITIS• Many dental, medical, and diagnostic procedures cause bacteremias, which occasionally
result in IE.• Antibiotics can prevent IE in vivo in experimental animals.• For more than 50 years, administration of antibiotics before procedures known to cause
bacteremias was recommended to prevent IE, but there is no definitive evidence that this practice is effective or cost-effective in humans. Antibiotics can cause unwanted side effects, including profound and persistent alterations of the microbiome.
• Therefore, recent guidelines sharply restrict use of antibiotic prophylaxis for IE, limiting it to patients at highest risk of an adverse outcome of IE: those with prosthetic heart valves; with cyanotic congenital heart disease (CHD); with repaired CHD with implanted prosthetic material, for the first 6 months only; with a history of previous episode(s) of IE; with valvu-lopathy after a heart transplant (see Table 30-1).
• For this small group of high-risk patients, the standard regimen is a single 2-g dose of amoxicillin given orally 30 to 60 minutes before the dental procedure. Alternative regimens are recommended for penicillin-allergic patients and those unable to take oral medication, and dosages are adjusted for children (see Table 30-2).
• There is no evidence that this major change in prevention guidelines has resulted in any increase in the number of cases of IE.
• Continuing surveillance of epidemiologic trends and microbial resistance, together with education of patients at risk for IE and their health care providers, is recommended.
• Prevention and prompt treatment of health care–associated infections is important, to reduce the incidence of bacteremias that can cause IE.
• Because preventive measures may fail, early diagnosis and prompt therapy of IE are impor-tant, to reduce morbidity and mortality.
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TABLE 30-1 Preexisting Cardiac Conditions Associated with Highest Risk of Adverse Outcome from Infective Endocarditis• Prostheticcardiacvalve(s)orprostheticmaterialinsertedforcardiacvalverepair• Previousinfectiveendocarditis• Congenitalheartdisease(CHD)
• UnrepairedcyanoticCHD,includingpalliativeshuntsandconduits• CompletelyrepairedCHDwithprostheticmaterialordevice,whetherplacedbysurgeryorcatheter
intervention,duringthefirst6monthsaftertheprocedure• RepairedCHDwithresidualdefectsatsiteoradjacenttositeofprostheticpatchorprostheticdevice
(whichinhibitendothelialization)• Cardiactransplantrecipientswhodevelopcardiacvalvulopathy
ModifiedfromWilsonW,TaubertKA,GewitzM,etal.Preventionof infectiveendocarditis:guidelines fromtheAmericanHeartAssociation:aguidelinefromtheAmericanHeartAssociationRheumaticFever,Endocarditis,andKawasaki Disease Committee; Council on Cardiovascular Disease in the Young; and the Council on ClinicalCardiology;CouncilonCardiovascularSurgeryandAnesthesia;andtheQualityofCareandOutcomesResearchInterdisciplinaryWorkingGroup.Circulation.2007;116:1736-1754.
TABLE 30-2 Regimens for Antibiotic Prophylaxis of Infective Endocarditis during Dental Procedures*
CLINICAL SITUATION ANTIBIOTIC DOSAGE FOR ADULTS† DOSAGE FOR CHILDREN†,‡
Standardoralregimen—formostpatients
Amoxicillin 2.0gPO 50mg/kgPO
Ifunabletotakeoralmedication
Ampicillinorceftriaxone
2.0gIMorIV1.0gIMorIV
50mg/kgIMorIV50mg/kgIMorIV
Ifallergictopenicillins Clindamycinorazithromycinorclarithromycin
600mgPO500mgPO500mgPO
15mg/kgPO15mg/kgPO15mg/kgPO
Ifallergictopenicillinsandunabletotakeoralmedication
Clindamycin 600mgIMorIV 20mg/kgIMorIV
IM,intramuscular;IV,intravenous;PO,oral.*Onlyforpatientswithhighestriskofadverseoutcomeofinfectiveendocarditis;seeTable30-1.†Singledose,30to60minutesbeforeprocedure.‡Nottoexceedadultdose.ModifiedfromWilsonW,TaubertKA,GewitzM,etal.Preventionofinfectiveendocarditis:guidelinesfromthe
AmericanHeartAssociation:aguidelinefromtheAmericanHeartAssociationRheumaticFever,Endocarditis,andKawasaki Disease Committee; Council on Cardiovascular Disease in the Young; and the Council on ClinicalCardiology;CouncilonCardiovascularSurgeryandAnesthesia;andtheQualityofCareandOutcomesResearchInterdisciplinaryWorkingGroup.Circulation.2007;116:1736-1754.
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31 Myocarditis and PericarditisKirk U. Knowlton, Anna Narezkina, Maria C. Savoia, and Michael N. Oxman
MYOCARDITIS• Inflammationofthemyocardium,whichisclinicallymanifestedbychestpain,arrhythmias,
orcongestiveheartfailure(CHF)
Etiologic Agents• Most commonly associated with viral infections, particularly enteroviruses, adenoviruses,
parvovirusB19,humanherpesvirus6,anddengueviruses(seeTable31-1).• Occasionallycausedbybacteria,asaresultofbacteremia,directextensionfromacontiguous
focus,orabacterialtoxin.• CausedbyTrypanosoma cruzi,thecauseofChagas’disease,whichisprevalentinSouthand
CentralAmerica.
Diagnosis• In the setting of clinical suspicion, elevations of cardiac enzymes, electrocardiographic
changes (nonspecific), echocardiography, and cardiac magnetic resonance imaging arehelpful.
• Evidenceofcoincidentviralinfection,eitherbycultureorserology,iscircumstantial.• Endomyocardial biopsy can provide a definitive diagnosis, but sampling errors limit its
utility.
Treatment• SupportivecareandmanagementofCHFareessential.• Thebenefitofimmunosuppressivetherapyisnotestablished.• Theefficacyofintravenousimmunoglobulintherapyisalsonotestablished.
PERICARDITIS• Inflammationofthepericardiumisclinicallymanifestedbychestpain,pericardialfriction
rub, and pericardial effusion. These may be present individually or in combination.Monitoringforcardiactamponadeisimportant.
Etiologic Agents• Enterovirusesaremostcommon,butothervirusesmaysometimesberesponsible(seeTable
31-2).• Bacteriararelymaycausepurulentpericarditis,usuallyasacomplicationofpneumonia.• Mycobacterium tuberculosiscancausepericarditis,usuallyasacomplicationofpulmonary
tuberculosis.This isamajorprobleminAfrica inassociationwithacquired immunodefi-ciencysyndrome.
Diagnosis• Etiologyisoftenundeterminedinindividualcases.• Pericardiocentesismayyieldanetiologicagentbutisnegativeinthemajorityofpatients.
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• Evidenceofviralinfectionbydetectioninperipheralsamplesorbyserologyprovidesonlycircumstantialevidenceofpossibleetiology.
• Percutaneous pericardial biopsy or pericardiotomy with biopsy and drainage increase thediagnosticyield.
Treatment• For presumed viral or idiopathic pericarditis, analgesic treatment with nonsteroidal anti-
inflammatorydrugs(NSAIDs),togetherwithbedrest,isoftensuccessfulinrelievingsymp-toms.NSAIDsaregenerallycontinuedfor1to2weeks,oruntilsymptomsresolve.
• Colchicine given with NSAIDs has been found to improve rate of recovery and reducerecurrence.
• Purulentpericarditisusuallyrequiresdrainagetogetherwithappropriateantibiotics.• Tuberculouspericarditisrequiresappropriateantituberculoustherapy;concomitantadmin-
istrationofcorticosteroidsreducesdevelopmentofconstrictivepericarditisandtheneedforrepeatedpericardiocentesis.
TABLE 31-1 Infectious Causes of Myocarditis
VirusesCoxsackie B virusesCoxsackie A virusesAdenovirusesEchovirusesParvovirus B19Nonpolio enterovirusesPoliovirusesRabies virusMumps virusRubeola (measles) virusInfluenza A and B virusesRubellaDengue virusesChikungunya virusYellow fever virusArgentine hemorrhagic fever virus (Junin virus)Bolivian hemorrhagic fever virus (Machupo virus)Lymphocytic choriomeningitis virusLassa fever virusVaricella-zoster virusHuman cytomegalovirusEpstein-Barr virusHuman herpesvirus 6Herpes simplex virusVariola virusVaccinia virusHepatitis B virusHepatitis C virusRespiratory syncytial virusHuman immunodeficiency virus
Bacteria and RickettsiaeBrucellaCampylobacterCorynebacterium diphtheriaeClostridium perfringens
Francisella tularensisNeisseria meningitidisSalmonellaShigellaStreptococcus pyogenesStaphylococcus aureusListeria monocytogenesVibrio choleraeMycobacterium tuberculosisLegionella pneumophilaMycoplasma pneumoniaeChlamydia psittaciChlamydia pneumoniaeRickettsia rickettsiiRickettsia prowazekiiRickettsia (Orientia) tsutsugamushiCoxiella burnetiiEhrlichiaBorrelia burgdorferiTropheryma whippeliiUreaplasma spp.
FungiAspergillusCandida speciesBlastomycesCoccidioides immitisCryptococcus neoformansHistoplasma capsulatum
ParasitesTrypanosoma cruziTrypanosoma gambienseTrypanosoma rhodesienseTrichinella spiralisToxoplasma gondiiToxocara canis
Bacteria and Rickettsiae—cont’d
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TABLE 31-2 Infectious Causes of Pericarditis
VirusesCoxsackie A virusesCoxsackie B virusesEchovirusesAdenovirusesMumps virusInfluenza A and B virusesLymphocytic choriomeningitis virusLassa fever virusVaricella-zoster virusHuman cytomegalovirusEpstein-Barr virusHerpes simplex virusVariola (smallpox) virusVaccinia virusHepatitis B virusHuman immunodeficiency virus
Bacteria and RickettsiaStreptococcus pneumoniaeOther streptococcal speciesStaphylococcus aureusNeisseria meningitidisNeisseria gonorrhoeaeHaemophilus influenzaeSalmonellaYersiniaFrancisella tularensisPseudomonas
CampylobacterBrucellaListeria monocytogenesNocardiaActinomycesOther anaerobic bacteriaCorynebacterium diphtheriaeMycobacterium tuberculosisNontuberculous mycobacteriaLegionella pneumophilaMycoplasma pneumoniaeCoxiella burnetiiChlamydiaBorrelia burgdorferi
FungiAspergillusCandida speciesBlastomycesCoccidioides immitisCryptococcus neoformansHistoplasma capsulatum
ParasitesEntamoeba histolyticaToxoplasma gondiiToxocara canisSchistosoma
Bacteria and Rickettsia—cont’d
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32 MediastinitisTrevor C. Van Schooneveld and Mark E. Rupp
DEFINITION• Mediastinitisisaninfectioninvolvingthestructuresofthemediastinum(seeFig.32-1).
EPIDEMIOLOGY• Acutemediastinitisusuallyoccursviaoneofthreeroutes:esophagealperforation,extension
of a head and neck infection (descending necrotizing mediastinitis), and post–cardiacsurgery(seeTable32-1).
• Post–cardiacsurgerymediastinitisoccursin1%to2%ofcardiacsurgerycases,andimpor-tantriskfactorsformediastinitisincludeobesity,diabetes,Staphylococcus aureuscoloniza-tion,useofbilateralinternalthoracicarteries,needforreexploration,andreceiptofmultiplebloodproducts.
• Chronic/fibrosing mediastinitis is usually due to an excessive immune reaction to histo-plasma antigens in mediastinal lymph nodes, which results in fibrosis and narrowing ofmediastinalstructures.
MICROBIOLOGY• Oral flora, including streptococci, gram-negative bacilli, and anaerobes predominate in
mediastinitisduetoesophagealperforationanddescendingheadandneckinfections.• Poststernotomymediastinitisismostfrequentlyduetogram-positivecocci,especiallystaph-
ylococci,whereasgram-negativebacilliandcandidaarelesscommon.
DIAGNOSIS• Esophageal rupture is usually manifested by chest pain, shortness of breath, and
odynophagia.• Signsof the initiatingheadandneck infection (swelling,pain, erythema)predominate in
descendingnecrotizingmediastinitis.• Post–cardiacsurgerymediastinitisfindingsmayrangefromsubtletofulminantbutusually
presentwithin2weeksofsurgery.Fever,wounddrainage,cellulitis,andchestpainareusuallypresent.
• Laboratory findings often include leukocytosis and a rising procalcitonin in postmediansternotomypatients.
• Fibrosing mediastinitis manifestations include cough, dyspnea, chest pain, and exerciseintolerancebutdependonthestructuresbeingoccluded.
• Computedtomographyisthepreferreddiagnosticimagingforallformsofmediastinitis.
THERAPY• Broad-spectrumantimicrobialstargetedtoexpectedpathogensareessential.• Aggressivesurgicalinterventionisessentialinallformsofmediastinitiswithdébridement
ofanyinfectedornecrotictissues.• Early esophageal perforation may occasionally be managed with stenting, but most cases
requireurgentsurgicalrepair.• Post–cardiacsurgerymediastinitisrequiressternalandmediastinaldébridement.
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FIGURE 32-1 Anatomic boundaries and divisions of the mediastinum.
Superior
Posterior
Middle
Anterior
First rib
TABLE 32-1 Causes of Acute Mediastinitis
Esophageal PerforationIatrogenic
Esophagogastroduodenoscopy, esophageal dilation, esophageal variceal sclerotherapy, nasogastric tube, Sengstaken-Blakemore tube, endotracheal intubation, esophageal surgery including endoscopic resection, paraesophageal surgery, transesophageal echocardiography, anterior stabilization of cervical vertebral bodies, catheter ablation of atrial fibrillation
Swallowed Foreign Bodies
Bones, coins, can pull-tabs, drug-filled condoms, swords, ballpoint pens, button batteries
Trauma
Penetrating—gunshot wound, knife woundBlunt—steering wheel injury, seatbelt injury, cardiopulmonary resuscitation, whiplash injury, barotrauma
Spontaneous or Other
Emesis, cricoid pressure during anesthesia induction, heavy lifting, defecation, parturition, carcinoma, ingestion of caustic or corrosive liquids
Head and Neck InfectionsOdontogenic, Ludwig’s angina, pharyngitis, tonsillitis, parotitis, epiglottitis, Lemierre syndrome
Infection Originating at Another SitePneumonia; pleural space infection or empyema; subphrenic abscess; pancreatitis; cellulitis or soft tissue
infection of the chest wall; osteomyelitis of sternum, clavicle, ribs, or vertebrae; hematogenous spread from distant foci
Lymph nodes—necrosis and hemorrhage (anthrax) or caseous necrosis (tuberculosis)
Cardiothoracic Surgery (Median Sternotomy)Coronary artery bypass grafting, cardiac valve replacement, repair of congenital heart defect, heart
transplantation, heart-lung transplantation, cardiac assist devices, extracorporeal membrane oxygenation (ECMO), other types of cardiothoracic surgery
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• Multiple surgical techniques can be utilized for surgical treatment of poststernotomymediastinitis with increasing use of vacuum-assisted closure and soft tissue flaps forreconstruction.
• Therole,ifany,forantifungaltherapyinfibrosingmediastinitisisnotestablished.• In fibrosing mediastinitis, stenoses of vessels and other structures are often successfully
managedbyeithersurgicalbypassorstenting.
PREVENTION• Preventionofpost–cardiacsurgeryisamajorfocusofqualitymeasuresandguidelines.• Keyfactorsassociatedwithdecreasedpost–cardiacsurgeryinfectionratesincludeappropri-
ateantimicrobialprophylaxis(administrationwithin1hourbeforesurgeryandfornolongerthan24to48hoursanduseoftheappropriateagent),controlofpostoperativebloodglucose,anduseofnasalmupirocininpatientscolonizedwithS. aureus.
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33 Acute MeningitisAllan R. Tunkel, Diederik van de Beek, and W. Michael Scheld
DEFINITION• Meningitis, or inflammation of the meninges, is identified by an abnormal number of
white blood cells in cerebrospinal fluid (CSF). Acute meningitis is clinically defined as asyndromecharacterizedbytheonsetofmeningealsymptomsoverthecourseofhourstouptoseveraldays.
EPIDEMIOLOGY• EstimatesfromtheCentersforDiseaseControlandPrevention(CDC)indicatethat10to
15 million symptomatic enteroviral infections occur annually in the United States, whichincludes30,000to75,000casesofmeningitis.
• Inasurveillancestudyamongresidentsineightsurveillanceareasrepresenting17.4millionpersonsfrom1998to2007,theimpactoftheheptavalentpneumococcalconjugatevaccinewasappreciated,inwhichtheincidenceofbacterialmeningitiscausedbyvaccineserotypesdecreasedfrom0.61cases/100,000populationin1998to1999to0.05cases/100,000popula-tionin2006to2007.
• Inpatients16yearsoldorolder,therelativefrequencyofisolationofmeningealpathogensin patients with community-acquired bacterial meningitis is somewhat different than ininfantsandchildren,withmostcasescausedbyStreptococcus pneumoniae, Neisseria menin-gitidis,andListeria monocytogenes.
MICROBIOLOGY• Enteroviruses, currently the leading recognizable cause of aseptic meningitis syndrome,
accountfor85%to95%ofallcasesinwhichapathogenisidentified.• DNA of herpes simplex virus (HSV) has been detected in the CSF of published cases of
Mollaret’smeningitis(nowtermedrecurrent benign lymphocytic meningitis),almostallbeingHSV-2.
• Aprofoundreductionhasbeenseenintheincidenceofinvasiveinfections(includingbacte-rialmeningitis)causedbyHaemophilus influenzaetypebintheUnitedStatesandWesternEurope;thisdecreaseininfectionisattributed,inpart,tothewidespreaduseofconjugatevaccinesagainstH. influenzaetypebthathavebeenlicensedforroutineuseinallchildrenbeginningat2monthsofage.
• From1998to2007,atotalof2262casesofmeningococcaldiseasewerereportedtotheActiveBacterialCoresurveillancesites,withanannualincidenceof0.53cases/100,000population;theincidencedecreasedfrom0.92cases/100,000populationin1998to0.33cases/100,000population in 2007 before the introduction of the quadrivalent meningococcal conjugatevaccine.
• Patientswithpneumococcalmeningitisoftenhavecontiguousordistantfociofpneumococ-cal infection, such as pneumonia, otitis media, mastoiditis, sinusitis, and endocarditis;seriousinfectionmaybeobservedinpatientswithvariousunderlyingconditions(e.g.,sple-nectomyorasplenicstates,multiplemyeloma,hypogammaglobulinemia,alcoholism,mal-nutrition,chronicliverorrenaldisease,malignancy,anddiabetesmellitus).
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• OutbreaksofListeriainfectionhavebeenassociatedwiththeconsumptionofcontaminatedcoleslaw,rawvegetables,milk,andcheese,withsporadiccasestracedtocontaminatedturkeyfranks,alfalfatablets,cantaloupe,dicedcelery,hogheadcheese(ameatjellymadefromhogheadsandfeet),andprocessedmeats,thuspointingtotheintestinaltractastheusualportalofentry.
• GroupBstreptococcusisacommoncauseofmeningitisinneonates,with52%ofallcasesintheUnitedStatesreportedduringthefirstmonthoflife.
• Aerobic gram-negative bacilli (e.g., Klebsiella spp., Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter spp., Salmonella spp.) have become increasinglyimportant as etiologic agents in patients with bacterial meningitis; these agents may beisolatedfromtheCSFofpatientsafterheadtraumaorneurosurgicalproceduresandmayalsobefoundinneonates,olderadults,immunosuppressedpatients,andpatientswithgram-negativesepsis.
DIAGNOSIS• Nucleicacidamplificationtests,suchaspolymerasechainreaction(PCR)assay,arethemost
promisingalternativestoviralcultureforthediagnosisofenteroviralmeningitis.• CSFcultureisthegoldstandardindiagnosisofbacterialmeningitisandispositivein80%
to 90% of patients of community-acquired disease if CSF is obtained before the start ofantimicrobialtherapy.
• Broad-based bacterial PCR can be used to detect the most common microorganisms ofbacterialmeningitis inonlyonetestandhasadequatesensitivityandexcellentspecificity;thesetestscanbedonewithin2hoursinmostindustrializedcountries,buttheyarescarceinresource-poorcountries.
• ThediagnosticaccuracyofCSFlactateisbetterthanthatoftheCSFwhitebloodcellcount,glucose,andproteininthedifferentiationofbacterialfromasepticmeningitis,withsensitivi-tiesof93%and97%andspecificitiesof96%and94%,respectively.
THERAPY• The initial management of a patient with presumed bacterial meningitis includes perfor-
manceofalumbarpuncturetodeterminewhethertheCSFformulaisconsistentwiththatdiagnosis.
• Ifpurulentmeningitisispresent,institutionofantimicrobialtherapyshouldbebasedontheresultsofGramstaining;however,ifnoetiologicagentcanbeidentifiedbythismeansorifperformanceofthelumbarpunctureisdelayed,institutionofempiricalantimicrobialtherapyshouldbebasedonthepatient’sageandunderlyingdiseasestatus.
• Certainpatientswithbacterialmeningitisshouldalsobetreatedwithadjunctivedexametha-sone.InaCochraneDatabaseSystematicreviewof24studiesinvolving4041participants,adjunctivedexamethasonedidnotreduceoverallmortalitybuttherewasatrendtolowermortalityinadults;corticosteroidswereassociatedwithlowerratesofseverehearingloss,anyhearingloss,andneurologicsequelae,althoughthesebenefitswereonlyseeninstudiesfromhigh-incomecountries.
• Penicillincanneverberecommendedasempiricaltherapyinpatientswithsuspectedpneu-mococcalmeningitis;asanempiricalregimen,thecombinationofvancomycinplusathird-generationcephalosporin(eithercefotaximeorceftriaxone)isrecommended.
• Empiricaltreatmentofgram-negativemeningitiscouldbeginwithceftazidime,cefepime,ormeropenem.Iftheorganismis laterfoundtoberesistanttothesecephalosporinsandthecarbapenems,colistin(usuallyformulatedascolistimethatesodium)orpolymyxinBshouldbesubstitutedformeropenemandmayalsoneedtobeadministeredbytheintraventricularorintrathecalroute.
PREVENTION• Chemoprophylaxisisalsonecessaryforclosecontactsofpatientswithinvasivemeningococ-
caldisease;theCDCcurrentlyrecommendstheadministrationofrifampin,ciprofloxacin,or ceftriaxone,whichareall 90% to95%effectiveat eradicatingnasopharyngeal carriage,althoughcasesofciprofloxacin-resistantN. meningitidishavebeenreportedinNorthDakota
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andMinnesota,leadingtheCDCtonolongerrecommendciprofloxacinformeningococcalchemoprophylaxisinselectedcountiesofthesestates.
• Vaccinationtopreventinfectionwithspecificmeningealpathogensisaveryusefulmeasurefordecreasingtheincidenceofbacterialmeningitis.
• ForH. influenzaetypeb,theavailabilityofconjugatevaccineshasdecreasedthenumberofcasesofH. influenzaetypebmeningitismorethan90%.
• Thefirstmeningococcalconjugatevaccine(meningococcalpolysaccharide-diphtheriatoxoidconjugatevaccinecontainingserogroupsA,C,W135,andYpolysaccharides)waslicensedforuseintheUnitedStatesforroutinevaccinationofallpersonsaged11to18yearswithonedose;inupdatedguidelines,aboosterdoseisnowrecommendedatage16yearsandatwo-doseprimaryseriesisadministered2monthsapartforpersonsaged2through54yearswithpersistentcomplementcomponentdeficiencyorfunctionaloranatomicaspleniaandforadolescentswithhumanimmunodeficiencyvirusinfection;otherpersonswhoareatriskformeningococcaldisease(e.g.,microbiologistsortravelerstoanepidemicorhighlyendemiccountry)shouldreceiveasingledose.
• TheAdvisoryCommitteeonImmunizationPracticesnowrecommendsuseofthe13-valentpneumococcal conjugate vaccine to prevent pneumococcal disease in infants and youngchildrenagedyoungerthan6years;thisvaccinehasactivityagainsttheserotypesthatwerepresentintheheptavalentvaccine(4,6B,9V,14,18C,19F,and23F)alongwithsixadditionalserotypes(1,3,5,6A,7F,and19A).
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34 Chronic MeningitisJohn E. Bennett
DEFINITION• Chronicmeningitis,definedhereasatleast4weeksofsymptomswithsignsofinflammation
inthecerebrospinalfluid,mustbedistinguishedfromrecurrentasepticmeningitis,chronicmyeloradiculitis,andchronicencephalitis.
ETIOLOGY• Majorcausesarefungalinfections,tuberculosis,syphilis,andmalignancy(seeTable34-1)
DIAGNOSIS• Majordiagnostictoolsaregadolinium-enhancedmagneticresonanceimagingandcerebro-
spinalfluidstudies(seeTable34-2).Surgicalbiopsyhasalowyield.• Polymerase chain reaction assay has taken on an increasing role, including its use in the
diagnosis of Whipple’s disease, chronic enteroviral meningitis, lymphoma, toxoplasmosis,andtuberculosis.
THERAPY• Empirical therapy for suspected tuberculous meningitis is often done because of disease
severity,butadditionofprednisonemaycausedeteriorationofunsuspectedfungalmenin-gitis.Worseningofinfectionmaynotbedetectedinitiallybecausecorticosteroidscantem-porarily improve hypoglycorrhachia, fever, and cerebral edema on T2-weighted magneticresonanceimages.Thesameissueariseswithcorticosteroidtreatmentofsuspectedsarcoidorautoimmunemeningitis.Itisonlywhensubsequent,potentiallyirreversibledeteriorationoccursdespitecorticosteroidsthataninfectiouscauseisfound.Thebenefitofcorticosteroidsinempiricalregimensisusuallyoutweighedbytheharm.
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TABLE 34-1 Differential Diagnosis of Chronic Meningitis
MycosesCryptococcus (cryptococcosis)Coccidioides (coccidioidomycosis)Histoplasma (histoplasmosis)Candida (candidiasis)Sporothrix (sporotrichosis [rare])Blastomyces (blastomycosis [rare])Other molds (rare): Scedosporium, Aspergillus, Cladophialophora and other dark-walled molds
BacteriaMycobacterium tuberculosis (tuberculosis)Treponema pallidum (syphilis)Borrelia burgdorferi (Lyme disease)Tropheryma whipplei (Whipple’s disease)Actinomyces (actinomycosis [parameningeal, rare])Nocardia (nocardiosis [with brain abscess])Brucella (brucellosis [rare])
ParasitesAcanthamoeba (acanthamebiasis)Taenia solium (cysticercosis)Angiostrongylus cantonensis (angiostrongyliasis)
VirusesEchovirus (meningoencephalitis)
Postneurosurgical CausesInfected cerebrospinal fluid shuntInfected prosthetic material
TumorsDiffuse gliomatosisMetastatic meningeal malignancy, including lymphomatous meningitis
Other CausesSarcoidosisVogt-Koyanagi-Harada syndromeBehçet’s syndromeIgG4-related hypertrophic pachymeningitis
TABLE 34-2 Diagnostic Tests for Chronic Meningitis
Cerebrospinal Fluid TestsGlucose, blood, protein, and cell count and differential (including eosinophils)India ink on centrifuged sedimentFungal culture of 3 to 5 mL of cerebrospinal fluidCytopathology for malignant cells, including polymerase chain reaction assay or flow cytometry for
monoclonal B cellsPeriodic acid–Schiff stain of cytopathologic specimen for Whipple’s diseaseVenereal Disease Research Laboratory test (VDRL) for syphilisCryptococcal antigenHistoplasma antigenAspergillus galactomannan antigenComplement fixation for antibody to Coccidioides speciesMTB Direct (Gen-Probe, San Diego, CA)Polymerase chain reaction assay for tuberculosis, Whipple’s disease, enterovirus infection, toxoplasmosis,
lymphomaCulture for enterovirus, Acanthamoeba
Serum TestsRapid plasma reagin (RPR) test or antitreponemal antibody testAntibody to Coccidioides, Histoplasma, Toxoplasma, BrucellaHistoplasma antigen
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35 EncephalitisJ. David Beckham and Kenneth L. Tyler
DEFINITION• Encephalitis is an inflammatory process involving the brain parenchyma associated with
clinicalorlaboratoryevidenceofneurologicdysfunction.
EPIDEMIOLOGY• Itoccursmostfrequentlyininfantsyoungerthan1yearofageandinelderlypatientsolder
thantheageof65withintermediateincidenceinindividualsbetweentheseageextremes.
MICROBIOLOGY• Upto60%ofencephalitiscasesresultfromanunidentifiedetiologicagent.• Viruses,bacteria,andautoimmuneinflammationcausethemajorityofknownencephalitis
cases.
DIAGNOSIS• Acompatiblefebrilesyndromewithevidenceofcentralnervoussystemimpairmentexists
(seeTable35-1).• Standard cerebral spinal fluid (CSF) analysis and neuroimaging with magnetic resonance
imagingarepreferred.• SpecificCSForserumstudiesfordefinedetiologiesofencephalitis,orboth,arewarranted
(seeTable35-2).
THERAPY• Early, empirical use of high-dose acyclovir is warranted to treat possible herpes simplex
encephalitispendingdiagnosticstudies.• Antiviral therapy is indicated for the treatment of other herpes viruses that cause
encephalitis.• Empirical antiviral therapy is recommended for suspected encephalitis associated with
influenza.• There is currently no therapy of known benefit for patients with encephalitis due to
arboviruses.
PREVENTION• RoutinevaccinationforcommonpathogensandvaccinationforJapaneseencephalitisvirus
inselectedtravelersmaypreventsomecasesofencephalitis.• Procedures to decrease exposure to mosquito bites may decrease the risk for arbovirus-
relatedcasesofencephalitis.
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TABLE 35-1 Comparison of Encephalitis and Encephalopathy
ENCEPHALITIS ENCEPHALOPATHY
Clinical FeaturesFever Common Uncommon
Headache Common Uncommon
Depressed mental status May fluctuate Steady decline in mental status
Focal neurologic signs Common Uncommon
Seizures Common Uncommon
Types of seizures Generalized or focal Generalized
Laboratory ResultsComplete blood count Leukocytosis common Leukocytosis uncommon
Cerebrospinal fluid Pleocytosis common Pleocytosis uncommon
Electroencephalogram Diffuse slowing and occasional focal abnormalities or periodic patterns
Diffuse slowing
Magnetic resonance imaging May have focal abnormalities No focal abnormalities
Modified from Davis LE. Diagnosis and treatment of acute encephalitis. Neurologist. 2000;6:145-159.
TABLE 35-2 Other Important and Emerging Causes of Viral Encephalitis
VIRAL ETIOLOGY EPIDEMIOLOGY
CLINICAL FEATURES DIAGNOSIS TREATMENT
Adenovirus Children and immunocompromised patients
Associated pneumonia PCR or culture of brain biopsy specimen or CSF
Supportive
Chikungunya virus
Epidemic setting; India and Southeast Asia; mosquito vector
Febrile syndrome with rash and arthralgias
CSF and serum IgM and PCR
Supportive
Hendra virus Australia; fruit bat reservoir; humans infected by secretions of bats
Fever, drowsiness, seizures, and coma associated with a flulike prodrome
Contact Special Pathogens Branch at CDC
Supportive
HIV Worldwide epidemic; recent high-risk behavior
Fever, headache-associated acute retroviral syndrome; commonly associated with HIV dementia
HIV serology testing and HIV quantitative PCR of CSF; MRI may reveal T2 or FLAIR hyperintense lesions in periventricular regions and centrum semiovale
Combination antiretroviral therapy
Influenza Fall and winter seasonal predilection; worldwide distribution; rare complication in children
Associated febrile syndrome, myalgias, respiratory prodrome; may be associated with bilateral thalamic necrosis
Viral culture, antigen detection, and PCR in respiratory secretions
Oseltamivir (C-III); poor outcomes
Japanese encephalitis
Mosquito vector, swine and bird reservoirs; most common cause of epidemic viral encephalitis throughout Southeast Asia and Australia
Seizures and parkinsonian features common; acute flaccid paralysis; case-fatality rate of 20%-30%
Serum IgM or acute/convalescent IgG; CSF IgM or antigen; MRI can show T2 and FLAIR hyperintense lesions at basal ganglia, thalami, and midbrain
Supportive; formalin-inactivated mouse brain–derived vaccine available for prevention
Continued
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VIRAL ETIOLOGY EPIDEMIOLOGY
CLINICAL FEATURES DIAGNOSIS TREATMENT
JC virus Cell-mediated immunodeficiencies (AIDS) and immunomodulating therapy (natalizumab, rituximab, efalizumab)
Cognitive dysfunction, limb weakness, gait disturbance, visual loss, focal neurologic findings
CSF PCR (sensitivity 50%-70% for PML); MRI shows ≥1 nonenhancing, confluent subcortical white matter hyperintensity on T2 and FLAIR sequences
Combination antiretroviral therapy in AIDS patients or reversal of immunosuppression
Louping ill virus
Tick-borne disease; found in Ireland, Scotland, and England; associated with livestock
Usually mild febrile illness with associated confusion and stupor in some; deaths are rare
Serum IgM ELISA or a 4-fold increase in IgG antibody in paired acute and convalescent sera
Supportive
LCMV Rodent-borne virus infects humans with exposure to infected urine, feces, saliva, or blood; severe disease in immunocompromised patients
Fever, headache, leukopenia, and thrombocytopenia; encephalitis characterized by personality changes, increased ICP, paraplegia, and cranial nerve and sensory dysfunction
CSF and serum IgM ELISA
Supportive
Me Tri virus Mosquito-borne; Southeast Asia; transmitted among livestock
Fever, rash, seizures, lethargy, and meningismus
CSF PCR and IgM ELISA, serology
Supportive
Monkeypox Prairie dog exposure Vesiculopustular rash on head, extremities, palms, and soles; adenopathy; encephalitis is rare, with confusion, somnolence, and diminished reflexes
Skin biopsy, CSF, and serum IgM, serology; MRI showing T2 and FLAIR hyperintense lesions of the pons, thalamus, and subparietal cortex
Supportive care; consider cidofovir or vaccinia immune globulin (C-III)
Mumps virus Unvaccinated Previous parotitis followed by headaches, vomiting, seizures, altered consciousness, and sensorineural hearing loss
4-fold IgG increase in paired acute and convalescent sera, culture of saliva, CSF culture and PCR
Supportive
Murray Valley encephalitis virus
Mosquito vector; bird reservoir; Australia and New Guinea
Rapid onset in infants with case-fatality rate of 15%-30%
IgG antibody testing with 4-fold increase in paired acute and convalescent sera
Supportive
Nipah virus Exposure to infected pigs; pteropid bat reservoir; exposure to infected bats or bat roosting sites; close contact to infected humans; South Asia
Fever, headache, altered consciousness, dizziness, vomiting, myoclonus, dystonia, areflexia, hypotonia; pneumonitis
4-fold IgG increase in paired acute and convalescent sera; CSF culture; MRI may show T2 focal hyperintensity of subcortical and deep white matter of cerebral hemispheres; contact Special Pathogens Branch at CDC
Supportive; ribavirin (C-III)
TABLE 35-2 Other Important and Emerging Causes of Viral Encephalitis—cont’d
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TABLE 35-2 Other Important and Emerging Causes of Viral Encephalitis—cont’d
VIRAL ETIOLOGY EPIDEMIOLOGY
CLINICAL FEATURES DIAGNOSIS TREATMENT
Powassan virus
Tick vector; rodent reservoir; New England states, Canada, and Asia
Case-fatality rate of 10%-15% and focal neurologic findings in >50% of patients
Serum and CSF IgM; IgG antibody 4-fold increase in acute and convalescent paired sera
Supportive
Rift Valley fever virus
Sub-Saharan Africa, Egypt, Saudi Arabia, Yemen; mosquito vector and livestock reservoir; humans infected via exposure to infected animal secretions
1% of infected humans develop encephalitis with headache, meningismus, and altered consciousness
ELISA antigen detection or culture from serum and PCR; contact Special Pathogens Branch at CDC
Supportive
Rocio virus Cause of epidemic encephalitis in Brazil; mosquito vector
Fever, headache, confusion, motor impairment, and cerebellar syndrome; sequelae include ataxia, dysphagia, incontinence, and memory problems
4-fold IgG increase in acute and convalescent sera
Supportive
Rubella virus Unvaccinated adults Rash followed by headache, dizziness, behavioral changes, and seizures
CSF IgM; 4-fold IgG increase in paired acute and convalescent sera
Supportive
Snowshoe hare virus
Mosquito-borne; North America; children predominantly affected by encephalitis
Fever, headache, confusion, and lethargy; low mortality and rare long-term neurologic sequelae
CSF and serum IgM ELISA or 4-fold increase in IgG acute and convalescent sera
Supportive
Tick-borne encephalitis virus
Tick vector; rodent reservoir; unpasteurized milk; Eastern Russia, central Europe, Far East
Acute encephalitis; acute flaccid paralysis
Serum IgM or 4-fold increase in IgG antibody in paired acute and convalescent sera
Supportive
Toscana virus Sandfly vector; infection during summer months in Mediterranean countries
Fever, headache, meningismus, and meningoencephalitis with coma, lethargy, hydrocephalus, and hepatosplenomegaly
CSF PCR; serum and CSF IgM; 4-fold increase in IgG acute and convalescent sera
Supportive
Vaccinia Most cases are postinfectious; rare event after vaccination
Abrupt encephalopathy with focal neurologic signs 2-30 days postvaccination
CSF PCR or IgM Supportive; corticosteroids if postvaccination (C-III); consider cidofovir or vaccinia immune globulin
AIDS, acquired immunodeficiency syndrome; CDC, Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; FLAIR, fluid-attenuated inversion recovery; HIV, human immu-nodeficiency virus; ICP, intracranial pressure; LCMV, lymphocytic choriomeningitis virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy.
Modified from Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Disease Society of America. Clin Infect Dis. 2008;47:303-327.
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36 Brain AbscessAllan R. Tunkel
DEFINITION• Brainabscess isa focal, intracerebral infection thatbeginsasa localizedareaofcerebritis
anddevelopsintoacollectionofpussurroundedbyawell-vascularizedcapsule.
EPIDEMIOLOGY• Before the advent of human immunodeficiency virus (HIV) infection, brain abscess
accountedfor1500to2500casestreatedintheUnitedStateseachyear;theincidencewasestimatedat0.3to1.3casesper100,000peopleperyear.
• Inmostpediatricandadultseries,amalepredominanceexists(aratioof2:1to3:1)withamedianageof30to40years,althoughtheagedistributionvariesdependingonthepre-disposingconditionleadingtotheformationofbrainabscess.
• Theincidenceofbrainabscessisalsoaffectedbythegeneralhealthofthepopulation.Inonestudy of 973 patients from one tertiary hospital in South Africa from 1983 to 2002, theincidencedeclinedduringthestudyperiodasaresultof improvements insocioeconomicstandardsandavailabilityofhealthcareservices.
• Theincidenceofotogenicabscesseshasdecreased,whereastheincidenceofpost-traumaticandpostoperativebrainabscesseshasincreased.
MICROBIOLOGY• Streptococci(aerobic,anaerobic,andmicroaerophilic)arethebacteriamostcommonly(70%
ofcases)culturedfrompatientswithbacterialbrainabscess,andtheyarefrequentlyisolatedinmixedinfections(30%to60%ofcases).
• Staphylococcus aureusaccountsfor10%to20%ofisolates,usuallyinpatientswithcranialtrauma or infective endocarditis, and it is often isolated in pure culture; cases caused bycommunity-associatedmethicillin-resistantS. aureusstrainshavebeenreported.
• The attention to proper culture techniques has increased the isolation of anaerobes frombrainabscesseswithBacteroidesandPrevotellaspp.,isolatedin20%to40%ofpatients,ofteninmixedculture.
• Enteric gram-negative bacilli (e.g., Proteus spp., Escherichia coli, Klebsiella spp., andPseudomonasspp.)areisolatedin23%to33%ofpatients,ofteninpatientswithotiticfociof infection, with septicemia, who have had neurosurgical procedures, or who areimmunocompromised.
• Nocardialbrainabscessmayoccurasanisolatedcentralnervoussystem(CNS)lesionoraspartofadisseminatedinfectioninassociationwithpulmonaryorcutaneousdisease.
• Theincidenceoffungalbrainabscesshasincreasedasaresultoftheprevalentadministrationofimmunosuppressiveagents,broad-spectrumantimicrobialtherapy,andcorticosteroids.
DIAGNOSIS• Magneticresonanceimaging(MRI)hasbeenextensivelyevaluatedinthediagnosisofbrain
abscessandisthefirstimagingchoiceintheevaluationofapatientsuspectedtohavethisdisorder.
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• ThecombineduseofprotonMRspectroscopy,diffusion-weighted imaging, anddiffusiontensorimaginghasbeenshowntoimprovethespecificityofdiagnosisoffocalring-enhancinglesions and differentiating brain abscess from other cystic lesions of the brain, includingtumors.
• Amajoradvanceintheuseofcomputedtomography(CT)inpatientswithsuspectedbrainabscessistheabilitytoperformstereotacticCT-guidedaspirationtofacilitatemicrobiologicdiagnosisandtoguideantimicrobialtherapy;atthetimeofaspiration,specimensshouldbesentforGramstain,routineaerobicandanaerobiccultures,andculturesformycobacteriaandfungi.
THERAPY• When abscess material has been obtained for microbiologic and histopathologic studies,
empiricalantimicrobialtherapyshouldbeinitiatedonthebasisofthepatient’spredisposingconditionsandthepresumedpathogenesisofabscessformation(seeTable36-1).
• InHIV-infectedpatientswithCNSmasslesions,theinitialapproachtomanagementisdif-ferentbecauseofthehighlikelihoodofthediagnosisoftoxoplasmicencephalitis.
• Antimicrobial therapy with high-dose intravenous agents has traditionally been adminis-teredfor6to8weeksinpatientswithbacterialbrainabscesses.
• Mostpatientswithbacterialbrainabscessrequiresurgicalmanagementforoptimaltherapy.• The combination of surgical aspiration or removal of all abscesses larger than 2.5cm in
diameter,a6-weekorlongercourseofintravenousantimicrobialtherapy,andresponseonfollow-upneuroimagingshouldresultinacurerateofmorethan90%.
TABLE 36-1 Empirical Antimicrobial Therapy for Bacterial Brain Abscess
PREDISPOSING CONDITION ANTIMICROBIAL REGIMENOtitis media or mastoiditis Metronidazole + third-generation cephalosporin*
Sinusitis (frontoethmoid or sphenoid) Metronidazole + third-generation cephalosporin*†
Dental infection Penicillin + metronidazole
Penetrating trauma or postneurosurgical Vancomycin + third- or fourth-generation cephalosporin*‡
Lung abscess, empyema, bronchiectasis Penicillin + metronidazole + sulfonamide§
Bacterial endocarditis Vancomycin‖
Congenital heart disease Third-generation cephalosporin*
Unknown Vancomycin + metronidazole + third- or fourth-generation cephalosporin*‡
*Cefotaxime or ceftriaxone; the fourth-generation cephalosporin cefepime may also be used.†Add vancomycin when infection caused by methicillin-resistant Staphylococcus aureus is suspected.‡Use ceftazidime or cefepime as the cephalosporin if Pseudomonas aeruginosa is suspected.§Trimethoprim-sulfamethoxazole; include if a Nocardia spp. is suspected.‖Additional agents should be added based upon other likely microbiologic etiologies.
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37 Subdural Empyema, Epidural Abscess, and Suppurative Intracranial ThrombophlebitisAllan R. Tunkel
DEFINITION• Subduralempyemareferstoacollectionofpusbetweentheduraandarachnoid.• Epiduralabscessisalocalizedcollectionofpusbetweentheduramaterandoverlyingskull
orvertebralcolumn.• Suppurative intracranial thrombophlebitis includes dural venous sinus thrombosis and
suppuration.
EPIDEMIOLOGY• Themostcommonconditionspredisposingtocranialsubduralempyemaareotorhinologic
infections, especially of the paranasal sinuses, which are affected in 40% to 80% of cases.Spinalsubduralempyemaoriginateshematogenously.
• About 0.2 to 2/10,000 hospitalized patients have spinal epidural abscess, with most casesusuallysecondarytoextensionfromvertebralosteomyelitis.
• Suppurativeintracranialthrombophlebitismayoccurafterinfectionoftheparanasalsinuses,middleear,mastoid,face,ororopharynx.
MICROBIOLOGY• Anumberofbacterialspecieshavebeenisolatedinpatientswithcranialsubduralempyema,
includingaerobicstreptococci,staphylococci,aerobicgram-negativebacilli,andanaerobicstreptococciandotheranaerobes.
• Staphylococcus aureus isthemostcommonetiologicagentinpatientswithspinalepiduralabscess.
• The likely infecting pathogens in patients with suppurative intracranial thrombophlebitisdependonthepathogenesisofinfection.
DIAGNOSIS• Magneticresonanceimaging(MRI),withgadoliniumenhancement,isthediagnosticpro-
cedureofchoiceinpatientswithsubduralempyemaandepiduralabscess.• The noninvasive diagnostic procedure of choice in patients with suppurative intracranial
thrombophlebitis is MRI and magnetic resonance venography; computed tomographyvenographyisdoneinpatientsunabletoundergoMRI.
THERAPY• Subduralempyemaisamedicalandsurgicalemergency.Thegoalsofsurgeryaretoachieve
adequatedecompressionofthebrainandcompletelyevacuatetheempyema;basedonret-rospectiveoutcomedata,craniotomyisthesurgicalprocedureofchoice.
• Theprinciplesoftherapyforspinalepiduralabscessarepromptlaminectomyandsurgicaldecompressioninpatientswithneurologicdysfunction,drainageoftheabscess,andlong-termantimicrobialtherapy.Antimicrobialtherapyalonecanbeconsideredinpatientswithlocalizedpainandradicularsymptomswithoutlong-tractfindings,butfrequentneurologic
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examinationsandserialMRIstudiesshouldbeperformedtodemonstrateresolutionoftheabscess.
• Empirical antimicrobial therapy for suppurative intracranial thrombophlebitis is usuallyvancomycin,metronidazole,andathird-orfourth-generationcephalosporin;anticoagula-tionshouldalsobeusedinpatientswithsepticcavernoussinusthrombosisunlesstherearecontraindications.
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38 Cerebrospinal Fluid Shunt and Drain InfectionsAdarsh Bhimraj, James M. Drake, and Allan R. Tunkel
DEFINITION• Ventriculoperitoneal(VP)shuntinfectionscanbeeithersuperficial,involvingtheskinand
softtissueadjacenttotheshuntvalveorreservoir,oritcanbeadeeperinfection,involvingthecerebralventricles,proximallyortheperitoneumdistally.
• Cerebrospinalfluid(CSF)draininfectionscanbetunnelinfections,catheterexitsiteinfec-tions,orventriculitis.
EPIDEMIOLOGY• The case incidence of CSF shunt infection (i.e., the occurrence of infection in any given
patient)hasrangedfrom5%to41%,althoughusuallyitis4%to17%.• Theoperative incidence (i.e., theoccurrenceof infectionperprocedure)has ranged from
2.8%to14%,althoughusuallyitislessthan4%.• InpatientswithCSFdrains,theincidenceofventriculitishasrangedfromzeroto22%.
MICROBIOLOGY• StaphylococcalspeciesaccountforthemajorityofisolatesinpatientswithCSFshuntinfec-
tions,withStaphylococcus epidermidismostfrequentlyisolated(47%to64%ofinfections),followedbyStaphylococcus aureus(12%to29%ofinfections).
• The most common isolated gram-negative species are Escherichia coli, Klebsiella, Proteus,andPseudomonas;casesofAcinetobactermeningitishavealsobeenreportedinpatientswithVPshunts.
• Inrecentyears,anincreasingprevalenceofdiphtheroids(includingPropionibacterium acnes)hasbeenfoundinCSFshuntinfections.
DIAGNOSIS• ThediagnosisisestablishedbyeitherdirectcultureoftheCSFobtainedbyshuntaspiration
orbycultureoftheproximalshuntcomponentsiftheshuntisexplanted.• CSFculture fromtheshunt, reservoir,ordrain is themost important test toestablish the
diagnosisofinfection.• Inpatientswithlumbardrainsorexternalizedventriculardrains,definiteinfectionisdefined
asapositiveCSFculture(obtainedfromtheventricularorlumbarcatheter)associatedwithCSFpleocytosis.
THERAPY• TheprinciplesofantimicrobialtherapyforCSFshuntinfectionsaregenerallythesameas
thoseforacutebacterialmeningitis; theagentselectedmustpenetratethecentralnervoussystem,attainadequateCSFconcentrations,andhavebactericidalactivityagainsttheinfect-ingpathogen.
• Empirical therapy with intravenous vancomycin plus either cefepime, ceftazidime, ormeropenemisappropriate.
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• OptimaltherapyofaninfectedCSFshuntisaninitial intravenousantimicrobial,followedbyremovalofallcomponentsoftheinfectedshunt,insertionofafreshventricularcatheter,andaperiodofexternaldrainage.Later,thedrainisremovedandanewshuntisplaced.
• Directinstillationofantimicrobialagentsintothelateralventricleor,inthecaseoflumbarshunts, intothe lumbarthecalsacmaybenecessary inpatientswithshunt infectionsthataredifficulttoeradicatewithintravenousantimicrobialtherapyandshuntremovalorwhenthepatientisunabletoundergoshuntreplacement.
PREVENTION• Thereisevidencetosupporttheuseofperiproceduralprophylacticantimicrobialadminis-
trationforpatientsundergoingCSFshuntinsertionandplacementofexternalventriculardrains.
• Useofantimicrobial-impregnatedCSFshuntsandCSFdrainsappearstobesafeandeffectiveinpreventionofventriculitis,althoughprospective,randomizedcontrolledtrialsareneededtofirmlyconfirmtheirbenefits.
• UseofastandardizedprotocolandreducingvariationbyadherencetoacommonprotocolareeffectiveatreducingCSFshuntinfectionrates.
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I Skin and Soft Tissue Infections
39 Cellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue InfectionsMark S. Pasternack and Morton N. Swartz*
DEFINITION• Skin and soft tissue infections are characterized by location, depth of infection, etiologic
agent,andclinicalsettingandmayresultfromeitherprimarycutaneousinoculationor,lesscommonly,hematogenousseeding.
• Impetigoisasuperficialcrustingandattimesbullousinfectionoftheskin;localizedprogres-sionintothedermisleadstoecthyma.
• Folliculitisisalocalizedinfectionofhairfollicles,whichcanextendintosubcutaneoustissue,resultinginfuruncles.These,inturn,maycoalesce,leadingtocarbuncleformation.
• Erysipelasisarapidlyprogressiveinfectionofthesuperficialdermis,withsharperythema-tousborders;cellulitisreflectsdeeperdermalinvolvement.
• Necrotizing skin and soft tissue infections, including necrotizing fasciitis, are rare life-threateninginfections,occurinavarietyofclinicalsettings,andrequirepromptdiagnosisandsurgicalintervention.
EPIDEMIOLOGY• Significant skin and soft tissue infection may occur throughout the age spectrum. Minor
localtraumaastheinitialpathogeniceventisacommonfeatureoftheseprocesses.Althoughinvasive infections may occur in previously healthy individuals, a variety of systemic riskfactorspredisposesindividualstotheseinfections.
MICROBIOLOGY• HemolyticstreptococciandStaphylococcus aureus,includingmethicillin-resistantS. aureus
(MRSA),arethemostcommoncausesofsuperficialcutaneousinfection.• Mixedinfectionoffacultativegram-negativebacilli,anaerobes,andgram-positiveorganisms
mostfrequentlycausenecrotizinginfection,butgroupAstreptococci,clostridia,andVibriospeciescanalsocausenecrotizingfasciitis.
• Abroaddifferentialdiagnosismostbeconsideredinconfrontinginfectionsinimmunocom-promisedpatients.
DIAGNOSIS• Mostcutaneousinfectionsarenotassociatedwithbacteremia,anddiagnosisandempirical
therapyarebasedonphysicalfindingsandclinicalsetting.• Incompromisedhosts,tissuebiopsyformicrobiologicandhistologicstudyiscriticaltoplan
definitivetherapy.
*MortonN.Swartz,a long-timecontributor tochapters inpreviouseditionsofPrinciples and Practice of Infectious Diseases,diedonSeptember9,2013.
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THERAPY• Oraltherapytargetedagainstgram-positivepathogensisappropriateformilddisease,with
closefollow-upandrevisionoftherapyforinadequateresponse.Parenteraltherapytargetedmore broadly against gram-positive organisms, including S. aureus and MRSA, gram-negativepathogens,andanaerobesisrequiredinmanysettingsofsevereinfection,particu-larlyincompromisedhosts.
• Necrotizinginfectionsrequireurgentsurgicaldébridement.• Infectionsassociatedwithtoxicshocksyndromearetreatedwithprotein-synthesisinhibitors
such as clindamycin and with intravenous immune globulin to neutralize streptococcaltoxins.
PREVENTION• Good hygienic practices and attention to early therapy for superficial processes such as
dermatophyteinfectionreducetheriskforcutaneousandsofttissueinfection.• Individualswithrecurrentcellulitismaybenefitfromchronicantibioticsuppression.
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40 Myositis and MyonecrosisMark S. Pasternack and Morton N. Swartz*
DEFINITION• Myositisisaninflammatoryandgenerallynecrotizingprocessprimarilyduetohematoge-
nousseedingofmusclewithsubsequentbacterialinvasion.Directinoculationofmuscleasthe result of penetrating trauma is also an important mechanism of infection (associatedwithclostridialmyonecrosis).Moregeneralizedmuscleinflammationmayalsoaccompanyavarietyofacuteandchronicviralandparasiticdisorders.
EPIDEMIOLOGY• Pyomyositisoccursacrosstheagespectrumintemperateregionsandmayoccurinprevi-
ouslyhealthyaswellasimmunocompromisedindividuals; inwarmclimates, infectionsinchildrenpredominate(i.e., tropicalpyomyositis).Clostridialmyonecrosismostcommonlycomplicatespenetratingtrauma(e.g.,vehicularaccidents,war,naturaldisasters),especiallyinresource-limitedsettings.
MICROBIOLOGY• Staphylococcus aureus is the classic cause of pyomyositis, but similar illnesses have been
associated with a wide variety of bacterial pathogens, particularly in compromised hosts.Clostridium perfringensmyonecrosiscomplicatespenetratingtrauma,butnontraumaticclos-tridial myonecrosis may develop after hematogenous dissemination of more aerotolerantspecies(e.g.,C. septicum, C. sordellii).GroupAstreptococcicanalsocauseseveremyone-croticinfection,whichisatruemedicalemergency.Acutegeneralizedmuscleinflammationoccursafterinfluenzaanddenguevirusinfections,butawidevarietyofviralpathogenshavesporadicallyledtosignificantmuscleinjuryandevensevererhabdomyolysis.
DIAGNOSIS• Considerationof theseuncommonprocesses is thefirststeptowardtheproperdiagnosis,
becausethefocalprogressivepainofpyomyositismimicsavarietyofdisorders.Bloodcul-turesand(percutaneous)drainagebasedonthefindingsofcross-sectionalimagingconfirmthediagnosisandguidetherapy.Pyomyositismayaccompanytoxicshock,andinvestigationofafocalprocessresponsibleforfulminantsystemicillnessisessential.Gasproductioninmuscle and soft tissue in the setting of a rapidly progressive illness occurs in clostridialmyonecrosisandrelatedinfections;thisisasurgicalemergencyandexplorationfordébride-mentofnonviabletissueandappropriateculturesiscritical.
THERAPY• Ideally, after expedited imaging and drainage, empirical broad-spectrum antibacterial
therapy effective against S. aureus (including methicillin-resistant S. aureus) and
*MortonN.Swartz,a long-timecontributor tochapters inpreviouseditionsofPrinciples and Practice of Infectious Diseases,diedonSeptember9,2013.
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gram-negativebacilliaswellasanaerobesshouldbeadministered.Thefindingsofassociatedtoxic shock mandate the addition of a protein synthesis inhibitor (e.g., clindamycin) andpossiblyintravenousimmunoglobulintherapy.Narrow-spectrumtherapyisappropriateafteridentificationandsensitivity testingof the isolatedpathogen.Patientspresentingwith theclinical findings of gas gangrene (clostridial myonecrosis) require immediate high-dosepenicillinandclindamycinandurgentsurgicalexploration.
PREVENTION• Becausemostepisodesofpyomyositisdevelopaftertransientbacteremia,preventionisnot
practical.Promptdébridementofdevitalizedtissueafterpenetratinginjuryishighlyeffectiveatpreventingclostridialmyonecrosis.
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41 Lymphadenitis and LymphangitisMark S. Pasternack and Morton N. Swartz*
DEFINITION: LYMPHADENITIS• Acute(suppurative)orchronic(oftengranulomatous)inflammationofthelymphnodes
EPIDEMIOLOGY• Suppurativelymphadenitismostcommonamongyoungchildren;granulomatouslymphad-
enitismayoccurinindividualsofallages.
MICROBIOLOGY (SEE TABLE 41-1)
• SuppurativelymphadenitisprimarilyduetoStaphylococcus aureus(methicillinsensitiveandmethicillinresistant)andgroupAstreptococciinnormalhosts;avarietyofpathogensmaycausesuppurativelymphadenitisinimmunocompromisedindividuals.
• Granulomatouslymphadenitisisdueprimarilytonontuberculousmycobacteriainhealthychildren. Mycobacterium tuberculosis is the most important etiology in older patients butmaybeduetoavarietyofpathogensincompromisedhosts.
DIAGNOSIS• Needleaspiration,incisionalbiopsy,orexcisionalbiopsy,dependingonthetempoandsever-
ityoftheillnessandpossibleimmunodeficiency
THERAPY• Drainage of established abscesses and conventional antimicrobial therapy against gram-
positivepathogensforacutesuppurativelymphadenitis• Targetedtherapybasedonmicrobiologic/histopathologicinvestigationforchronicgranulo-
matouslymphadenitis
PREVENTION• Earlytherapyofprimarysuperficialinfectionsandearlytherapyofacuteadenitisepisodes
mayreducetheriskofsuppurationandneedforsurgicaldrainage.
DEFINITION: LYMPHANGITIS• Lymphangitisisaninflammationoflymphaticchannels,usuallyinsubcutaneoustissues.It
iscausedbyanacuteprocessofbacterialoriginorasachronicprocessofmycotic,myco-bacterial,orfilarialetiology(seeTable41-2).
*MortonSwartz,along-termcontributortopreviouseditionsofPrinciples and Practice of Infectious Diseases,diedonSeptember9,2013.
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TABLE 41-1 Forms of Lymphadenitis
DIS
EASE
INFE
CTI
NG
OR
GA
NIS
M
REG
ION
AL
REG
ION
AL
WIT
H
SUPP
UR
ATI
ON
(O
R
CA
SEA
TIO
N)
ING
UIN
AL
BU
BO
FO
RM
ATI
ON
ULC
ERO
GLA
ND
ULA
R
OC
ULO
GLA
ND
ULA
R
GEN
ERA
L
BacterialPyogenic Group A or B streptococci,
Staphylococcus aureus+ +
Scarlet fever Group A streptococci + + +Diphtheria Corynebacterium diphtheriae +Fusospirochetal angina Prevotella melaninogenica,
peptostreptococci, etc.+
Scrofula Mycobacterium tuberculosis + +Mycobacterium scrofulaceum + +Mycobacterium avium-intracellulare
+ +
Miliary tuberculosis M. tuberculosis + +Brucellosis Brucella + +Leptospirosis Leptospira + +Syphilis Treponema pallidum + +Chancroid Haemophilus ducreyi +Plague Yersinia pestis + + +Tularemia Francisella tularensis + + + + +Rat-bite fever Streptobacillus moniliformis +
Spirillum minus + +Anthrax Bacillus anthracis + + +Listeriosis Listeria monocytogenes +Melioidosis Burkholderia pseudomallei + + +Glanders Burkholderia mallei + + +Cat-scratch disease Bartonella henselae + + ± ± +Typhoid fever Salmonella typhi +
MycoticHistoplasmosis Histoplasma capsulatum +
H. capsulatum var. duboisii +Coccidioidomycosis Coccidioides immitis +Paracoccidioidomycosis Paracoccidioides brasiliensis +Cryptococcosis Cryptococcus neoformans + +
RickettsiaeBoutonneuse fever, etc. Rickettsia conorii +Scrub typhus Rickettsia tsutsugamushi +Rickettsialpox Rickettsia akari +
ChlamydialLymphogranuloma venereum
Chlamydia trachomatis + + +
Continued
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DIS
EASE
INFE
CTI
NG
OR
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REG
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AL
REG
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(O
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ULC
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ERA
L
ViralMeasles Measles virus +Rubella Rubella virus +Infectious mononucleosis
Epstein-Barr virus +
Cytomegalovirus mononucleosis
Cytomegalovirus +
Dengue fever Dengue virus +West Nile fever West Nile virus +Lassa fever Lassa fever virus +Oropharyngeal herpes infection
Herpes simplex virus type 1 + ± +
Genital herpes infection Herpes simplex virus type 2 +Primary HHV-6 infection
Human herpesvirus 6 +
Primary HHV-7 infection
Human herpesvirus 7 +
Cowpox Cowpox virus + ±Pharyngoconjunctival fever
Adenovirus (types 3 and 7) + +
Epidemic keratoconjunctivitis
Adenovirus (types 8 and 19) +
AIDS, AIDS-related complex
Human immunodeficiency virus +
ProtozoanKala azar Leishmania donovani +African trypanosomiasis Trypanosoma brucei + +Chagas’ disease Trypanosoma cruzi + +Toxoplasmosis Toxoplasma gondii + + +
HelminthicFilariasis Wuchereria bancrofti + +
Brugia malayi + +Loiasis Loa loa +Onchocerciasis Onchocerca volvulus +
AIDS, acquired immunodeficiency syndrome; HHV, human herpesvirus; +, present; ±, rare.
TABLE 41-1 Forms of Lymphadenitis—cont’d
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TABLE 41-2 Causes of Lymphangitis
CLINICAL FORM ETIOLOGIC AGENT
RELATIVE FREQUENCY AS CAUSE OF LYMPHANGITIS
Acute Group A streptococci CommonStaphylococcus aureus OccasionalPasteurella multocida OccasionalStreptobacillus moniliformis (rat-bite fever) RareWuchereria bancrofti; Brugia malayi (filariasis) Rare (only in immigrants from endemic areas)
Chronic Sporothrix schenckii (sporotrichosis) OccasionalMycobacterium marinum (swimming pool granuloma)
Occasional
Mycobacterium kansasii RareNocardia brasiliensis RareW. bancrofti; B. malayi Rare (only in immigrants from endemic areas)Nocardia asteroides Very rareMycobacterium chelonae Very rareS. aureus (botryomycosis) Very rareLeishmania brasiliensis or Leishmania mexicana Very rareFrancisella tularensis Very rare
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J Gastrointestinal Infections and Food Poisoning
42 EsophagitisPaul S. Graman
DEFINITION• Inflammationoftheesophagus,ofnoninfectiousorinfectiousetiology
EPIDEMIOLOGY• Gastroesophageal reflux disease is the most common cause. Esophageal infections occur
predominantlyinpatientswithimpairedimmunity,particularlythosewithacquiredimmu-nodeficiencysyndromeorreceivingcancerchemotherapy.Immunocompetentpersonsareoccasionallyaffected.
MICROBIOLOGY• Candidaspecies,herpessimplexvirus(HSV),andcytomegalovirusaremostcommon.
DIAGNOSIS• Endoscopyandbiopsyforimmunohistopathologyandculture,polymerasechainreaction
THERAPY (SEE TABLE 42-1)• Candida: fluconazole, itraconazole, amphotericin lipid formulations, voriconazole,
echinocandins• Herpessimplexvirus:acyclovirorvalacyclovir,famciclovir;foscarnetforacyclovir-resistant
HSV• Cytomegalovirus:ganciclovir,valganciclovir,orfoscarnet• Aphthousulceration(inacquiredimmunodeficiencysyndrome):prednisone,thalidomide
PREVENTION• Recipientsofallogeneichematologicstemcelltransplantswhoareneutropeniccommonly
receiveantiviralandantifungalprophylaxis.
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TABLE 42-1 Treatment of Esophagitis
CAUSEUSUAL TREATMENT (ADULT DOSE) ALTERNATIVE DRUGS
Candida Fluconazole, 100-200 mg/day PO or IV for 14-21 days; maintenance suppressive therapy may be necessary in AIDS (fluconazole, 100-200 mg/day PO)
Itraconazole oral suspension, 100-200 mg bid POVoriconazole, 200 mg bid PO*Amphotericin B, 0.3-0.7 mg/kg/day IV for 7 daysCaspofungin, 50 mg/day IV after 70-mg loading dose*Micafungin, 150 mg/day IVAnidulafungin, 100 mg on day 1, then 50 mg/day IV
Herpes simplex virus
Acyclovir, 5 mg/kg IV q8h for 7-14 days or 400 mg 5 times daily PO for 14-21 daysOr valacyclovir, 1 g PO tid for 14-21 days†; maintenance suppressive therapy may be necessary in AIDS
Famciclovir, 500 mg bid PO for 14-21 days (not for acyclovir-resistant infection)Foscarnet, 90 mg/kg q12h IV for 7-14 days (used for acyclovir-resistant infection)
Cytomegalovirus Ganciclovir, 5 mg/kg IV q12h for 14-21 days; maintenance suppressive therapy usually is necessary in AIDS (ganciclovir, 5 mg/kg/day IV 7 days/wk or 6 mg/kg/day IV 5 days/wk)
Foscarnet, 90 mg/kg q12h IV for 14-21 days; suppression with foscarnet, 90-120 mg/kg/day IVValganciclovir, 900 mg bid PO for treatment, and 900 mg qd for maintenance/suppression†
Aphthous ulceration (in AIDS)
Prednisone, 40 mg/day PO for 14 days, then taper
Thalidomide, 200 mg/day PO†
AIDS, acquired immunodeficiency syndrome.*Amphotericin, echinocandins, and voriconazole are indicated for severe or refractory esophageal candidiasis.†Not approved by the U.S. Food and Drug Administration for this indication.
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43 Nausea, Vomiting, and Noninflammatory DiarrheaDavid A. Bobak and Richard L. Guerrant
DEFINITION• A disease group consisting of acute and chronic forms of gastroenteritis occurs in both
pediatric and adult patients, and these diseases have the unifying characteristic of beingpredominantlynoninflammatoryinnature.
EPIDEMIOLOGY• Noninflammatorygastroenteritidesareamongthemostcommoninfectionsofhumans.As
agroup,theyaresecondinincidenceonlytoviralupperrespiratoryinfections.• Mostcasesofthesediseasesarenottrackedorreportedbutareestimatedtoaffecttensof
millionsofpeopleworldwideeachyear.• Therearebaselineendemicandseasonalratesaswellasepidemicoutbreaksofmostforms
oftheseinfections.• Theratesofinfectionaswellasetiologicagentsvaryaccordingtoage,climate,andgeography.
Inaddition,therearedifferencesintheseparametersobservedforplaceofacquisition(e.g.,community-vs.healthcarefacility–acquiredinfections).
MICROBIOLOGY• Viruses,includingmembersoftherotavirus,norovirus,adenovirus,andastrovirusgenera,
arethecauseofmostcasesofnoninflammatorygastroenteritis.• Amongthebacterialcausesofthissyndrome,certainpathogenicstrainsofEscherichia coli
andsomeserotypesofcholeraandnoncholeraVibrioareparticularlynoteworthy.• Certainprotozoan typesofparasitescancauseapredominantlynoninflammatory typeof
gastroenteritis and include members of the Giardia, Cryptosporidium, Cystoisospora, andCyclosporagenera.
• Althoughmanyoftheetiologicagentsaresimilar,therearealsosomeimportantdifferencesbetweentheendemicandepidemiccausesofnoninflammatorygastroenteritisindeveloping,newly industrialized, and developed countries. Newborn nursery–associated and noso-comial outbreaks of this syndrome have differences from those cases acquired in thecommunity.
• Thenumberofpotential infectiousagents ismuchgreater in immunocompromisedcom-paredwithimmunocompetenthosts.
DIAGNOSIS• Thetypicalclinical syndromeconsistsofvaryingdegreesofnausea,vomiting,andwatery
diarrhea,oftenincombinationwithfever,myalgias,andarthralgias.• Mostcasesofthissyndromeareself-limited,andnospecificetiologyisidentified.• Incertaininstances,suchasepidemic,nosocomial,andfoodbornecases,anetiologicagent
canbeidentifiedbyeithercultureormoleculardiagnosticassay.
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iarrhea
THERAPY• Adequatereplacementoffluidsandelectrolytesremainsthemainstayofallformsofgastro-
enteritis,includingthenoninflammatorygastroenteritidesdiscussedinthischapter.• Inmostcasesofnoninflammatorygastroenteritis,specificantimicrobialtherapyisnotused.
However,inmoresevereorspecificformsofthisinfection,specificantiviral,antibacterial,orantiparasitictreatmentmaybebeneficial.
PREVENTION• Adequate sanitation for the local water supply and food processing and distribution
systems helps to prevent many forms of endemic, community-acquired noninflammatorygastroenteritis.
• Althoughtherehasbeentremendousinterestindevelopingeffectivevaccinationorimmu-nizationschemesformanyoftheseinfectiousagents,onlyvaccinesforrotavirusarecurrentlyavailableforgeneraluse.
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44 Bacterial Inflammatory EnteritidesAldo A. M. Lima, Cirle A. Warren, and Richard L. Guerrant
DEFINITION• Acuteandchronicinflammatoryenteritidesarecausedbyseveralspecificinfectiousagents.
EPIDEMIOLOGY• Acute dysenteric syndromes are influenced by the unusually low inoculum required for
infectionbyorganismssuchasshigellae.• Thebacterial entericpathogensmostassociatedwith illnesses inchildrenyounger than5
years intheUnitedStatesarenontyphoidSalmonella, followedbyCampylobacter, Yersinia enterocolitica,andEscherichia coliO157.
• Venerealexposure,particularlyamongmenwhohavesexwithmen,mayimplicategono-cocci, herpes simplex virus, Chlamydia trachomatis, or Treponema pallidum as a cause ofproctitis, or Campylobacter, Shigella, C. trachomatis (lymphogranuloma venereum sero-types),orClostridium difficileasacauseofcolitis.
• Ahistoryofantibioticintakeand/orrecentadmissiontoahealthcarefacilitywouldstronglysuggestC. difficileinfection.
MICROBIOLOGY• GenomicstudiesofShigellaspecieshaveindicatedthatShigellaandenteroinvasiveE. coliare
derivedfrommultipleoriginsofE. coliandformasinglepathovar.• Thecauseofarecentoutbreakofbloodydiarrheaandseverehemolytic-uremicsyndrome,
unlike prior enterohemorrhagic E. coli strains that had exhibited enteropathogenic E. colitraitsofattachmentandeffacement,wasaShigatoxin–producingenteroaggregativeE. colistrain.
• Campylobacterspp.haveasmallgenome(1.6to2.0Mb)andcancauseintestinalandsys-temicinfections.
• TheprimaryvirulencefactorsthatareknowntocauseclinicaldiseaseinC. difficileinfectionarethetwolargetoxins:C. difficiletoxin(Tcd)A,ortoxinA(308kDa),andTcdB,ortoxinB(270kDa).
• Vibrio parahaemolyticushasbeenrecognizedsince1950inJapanandisacauseofseafoodpoisoning.
• SalmonellaflagellinisregulatedbythefliCgene,whichisthemajorligandfortheToll-likereceptor5,nucleotideoligomerizationdomain–likereceptors,andICEprotease-activatingfactor(Ipaf)protein.
DIAGNOSIS• Anyoftheabovemicroorganismsmaycauseanacutedysenterysyndromewithbloodand
pusinthestool.• Examinationforleukocytesorforfecallactoferrinmaysuggestintestinalinflammation,even
ifbloodisnotpresentinthestoolongrossexamination.
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• Recent approaches using a laboratory-developed TaqMan Array Card for simultaneousdetection of several enteropathogens hold promise, with high accuracy, sensitivity, andspecificityaswellasbeingpotentiallysuitedforsurveillanceorclinicalpurposes.
THERAPY AND PREVENTION• Becausetherearemanyetiologicagents,thetreatmentandpreventionrelyoneachspecific
causeofacuteandchronicinflammatoryenteritides
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45 Enteric Fever and Other Causes of Fever and Abdominal SymptomsJason B. Harris and Edward T. Ryan
DEFINITION• Enteric fever is a nonspecific febrile illness caused by typhoidal Salmonella; the diagnosis
shouldbeconsideredinanypatientwithotherwiseunexplainedprolongedfever.• Thetermtyphoidal feverissometimesusedmorebroadlytorefertoasyndromeofpersistent
high-gradefevers,oftenwithnolocalizingfeatures.
EPIDEMIOLOGY• Tensofmillionsofcasesofentericfeveroccureachyear, largely in impoverishedareasof
AsiaandAfrica.• Entericfeverisfecally/orallytransmitted,withcontaminatedmunicipalwatersuppliesbeing
commonlyinvolvedintransmission.• Multidrug-resistantstrainsofthemajorcausativeagentsofentericfever(Salmonella enterica
serotypeTyphiandParatyphiA)arenowcommonworldwide.
CLINICAL MANIFESTATIONS• Commonlife-threateningcomplicationsofentericfeverincludeintestinalhemorrhage,per-
foration,encephalopathy,andshock.• Untreated,patientswithentericfevermaybefebrilefor3to4weeksorlonger,withmortality
ratesexceeding10%,andprolongedastheniaandfatiguearecommonamongsurvivors.• Chronic biliary carriage of typhoidal Salmonella may occur after resolution of the acute
illness.
DIAGNOSIS• Currentdiagnostictestsforentericfeverareimperfect:bloodculturesare30%to70%sensi-
tive,bonemarrowculturesaremoresensitivebutareimpractical,serologicassayslackbothsensitivityandspecificity,especiallyinentericfeverendemicareas,andnucleicacidampli-ficationassayswithsensitivityarenotavailable.
THERAPY• Given the morbidity of typhoid fever, the risk of complications, and the lack of optimal
diagnostic tests, the initiationofantibiotics fortreating individualswithsuspectedentericfevermaybebasedonapresumptivediagnosis,particularlyinresource-limitedsettings.
• The most commonly used agents for treating individuals with enteric fever are fluoro-quinolones, azithromycin, and cefixime or ceftriaxone. Chloramphenicol, trimethoprim-sulfamethoxazole,andamoxicillinmaybeusedtotreatpatientswithsusceptiblestrains.
• Anoral-attenuatedtyphoidvaccineandinjectablepolysaccharidevaccineareinternationallycommerciallyavailableandprovide50%to75%protectionfor5and2years,respectively.Injectable typhoid conjugate vaccines are in late-stage development. No vaccine effectiveagainstparatyphoidAiscurrentlycommerciallyavailable.
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46 Foodborne DiseaseRajal K. Mody and Patricia M. Griffin
DEFINITION• Foodbornediseasesareillnessesthatareacquiredthroughingestionoffoodcontaminated
withpathogenicmicroorganisms,bacterialandnonbacterialtoxins,orothersubstances.
EPIDEMIOLOGY• Anestimated48millionfoodborneillnessescausedbypathogensortheirtoxinsareacquired
annuallyintheUnitedStates.• Manyagentsthatcausefoodborneinfectioncanalsobeacquiredinotherways,including
ingestionofcontaminateddrinkingorrecreationalwater,throughcontactwithanimalsortheirenvironment,andfromonepersontoanotherdirectlyorthroughfomites.
• Somefoodbornediseasescanleadtolong-termsequelae,suchasimpairedkidneyfunctionafter Shiga toxin–producing Escherichia coli infection, Guillain-Barré syndrome afterCampylobacterinfection,andreactivearthritisandirritablebowelsyndromeafteravarietyofinfections.
• Groups at higher risk of acquiring or experiencing more severe foodborne diseaseincludeinfants,youngchildren,pregnantwomen,olderadults,andimmunocompromisedpersons.
• Afoodbornediseaseoutbreakshouldbeconsideredwhenanacuteillness,especiallywithgastrointestinalorneurologicmanifestations,affectstwoormorepeoplewhosharedameal.However,mostfoodbornediseasesdonotoccurinthecontextofanoutbreak.
MICROBIOLOGY• Many pathogens, including bacteria, viruses, and parasites, can cause foodborne
disease.• Someillnessesarecausedbyingestionofchemicals(e.g.,heavymetals,mushroomtoxins)
orpreformedmicrobialtoxins(e.g.,staphylococcaltoxin,botulinumtoxin).
DIAGNOSIS• Detection of pathogens has mostly relied on isolating bacterial pathogens in culture, by
visualizingparasitesbymicroscopy,andbyenzyme-linkedimmunosorbentassays.• Newermoleculartestsposeopportunitiesandchallengestobothclinicalpracticeandpublic
healthsurveillance.• Manyintoxicationsmustbediagnosedbasedonclinicalsuspicionalone.
THERAPY• Therapyformostfoodbornediseasesissupportive;replacingfluidandelectrolytelossesis
importantindiarrhealillnesses.• Antimicrobialagentsareusedtotreatparasiticinfectionsandselectedbacterialinfections.• Resistancetoantimicrobialagentscomplicatestreatmentandcanincreasethelikelihoodof
clinicallyapparentinfection.
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PREVENTION
• Toreducecontamination, foodproducers identifypointswhere theriskofcontaminationcanbecontrolledanduseproductionsystemsthatdecreasethehazards.
• Outbreak investigation is important to identify foodsafetygaps thatmaybepresentany-whereinthefoodproductionchain,fromthefarmtothetable.
• Individualscanreducetheirriskofillnessbyadheringtosafefoodhandlingpractices.
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47 Tropical Sprue: EnteropathyChristine A. Wanke
DEFINITION• Syndromeofdiarrhea,malabsorptionofatleasttwodistinctnutrients,abnormalduodenal
histopathology,andweightloss.
EPIDEMIOLOGY• Most frequent in Asia and the Caribbean islands, more frequent in adults than children;
occursinlong-termtravelerstoendemicregions.
MICROBIOLOGY• Nosingleagentassociatedwithcausality,smallbowelovergrowthcommon.
DIAGNOSIS• Appropriate clinical syndrome (persistent diarrhea, malabsorption of at least two distinct
nutrients,weightloss)withconsistentsmallbowelseriesorupperendoscopy.Responsetofolateandtetracyclineultimatelyconfirmsdiagnosis.
THERAPY• Removalfromareaofrisk,treatmentwithfolateandtetracycline.
PREVENTION• Goodhygienepractices.
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48 Infectious Arthritis of Native JointsChristopher A. Ohl and Derek Forster
DEFINITION• Infectious arthritis is an infection of one or more joints that can be caused by bacteria,
viruses,fungi,andparasites.
CLINICAL CATEGORIESAcute Bacterial Arthritis• Overall incidence in native joints is 2 to 10/100,000 per year, increased in rheumatoid
arthritis.• Infectioncanbeacquiredfromhematogenousdissemination,directjointinoculation,ora
contiguousfocus.Mostinfectionsaremonarticular;10%to20%arepolyarticular.Thekneeismostofteninvolved.
• Microbiology• Gram-positive organisms, including Staphylococcus aureus and Streptococcus spp.
predominate.• Gram-negativebacilliin5%to20%aremainlyinneonates,theelderly,intravenousdrug
users,andimmunocompromised.• Prevalence rates of gonococcal arthritis have markedly decreased. There are two syn-
dromes of joint involvement: monarticular arthritis and disseminated gonorrhea withfebriletenosynovitisandskinlesions.
Viral Arthritis• It may occur sporadically or in community outbreaks that may be small (e.g., parvovirus
B19)orexplosive(e.g.,chikungunyavirus).• Itiscausedbyinfectionofthejointspaceorbyimmune-mediatedinflammation.• Itisusuallyanacutepolyarticulararthritisthatoccurssimultaneouslywithothersystemic
symptomsofviralinfection.• Causes include parvovirus B19, rubella (which may follow immunization), hepatitis B,
hepatitisC,andalphaviruses,includingchikungunyavirus,RossRivervirus,ando’nyong-nyongvirus.
• Itmayoccasionallycauseprolongedorchronicarthritisafteracuteinfection.
CLINICAL EVALUATION• Bacterial arthritis is an emergency and should be considered in any patient with acute
monoarticularorpolyarticulararthritis.• Themostusefuldemographic risk factorsarepresenceorabsenceof recent joint surgery,
rheumatoidarthritis,advancedage,concomitantskininfection,ordiabetesmellitus.• Themosthelpfullaboratoryparametersarethesynovialfluidleukocytecountanddifferen-
tial,andexaminationforcrystalstoruleoutgoutorpseudogout.• Diagnosticimagingshouldincludeplainfilmradiography.Forprolongedoratypicalsymp-
toms, or for deep joints, computed tomography or magnetic resonance imaging isrecommended.
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• Identificationof the infectingorganismonsynovialfluidGramstainandcultureremainsthedefinitivediagnostictest.Thepolymerasechainreaction(PCR)assaycontinuestoshowpromise.
THERAPYAcute Bacterial Arthritis• Jointdrainagebyrepeataspiration,arthroscopy,orarthrotomyisrequired.• EmpiricalselectionshouldbebasedonsynovialfluidGramstain(seeTable48-1).• Intravenous therapy, in some instanceswithanoral transition, isusuallyprescribed fora
totalof2to4weeks.
Chronic Infectious Arthritis• Itisusuallymonarticular,involvingthelargeperipheraljoints.• Itisrelativelyuncommoncomparedwithacutebacterialarthritisbutisincreasinglyseenin
immunocompromisedorchronicallyillhosts.EtiologyincludesMycobacterium tuberculosisandnontuberculosismycobacteria.Fungal causes includeCandida,dimorphic fungi (e.g.,Blastomyces, Coccidioides, Histoplasma, and Sporothrix), Cryptococcus, and Aspergillus,amongothers.
• TherapyofM. tuberculosisarthritisissimilartopulmonarytuberculosis.• Manyfungalarthritidesaredifficulttotreatandresultinchronicjointdisability.Treatment
variesbyinfectingorganism.Experienceusingtheazoles(includingnewtriazoles)andtheechinocandinsisgrowing,andinmanycases,thesedrugsarereplacingamphotericin.
• ExceptforCryptococcusandperhapsSporothrix,fungalarthritisrequiressurgicaldrainageanddébridement.
TABLE 48-1 Recommended Empirical Therapy for Adult Native Joint Bacterial Arthritis
GRAM STAIN PREFERRED ANTIBIOTICa ALTERNATIVE ANTIBIOTICGram-positive cocci Vancomycin, 15-20 mg/kg (ABW) daily
every 8-12 hrbDaptomycin, 6-8 mg/kg dailyc or linezolid, 600 mg IV or PO every 12 hrc
Gram-negative coccid Ceftriaxone, 1 g every 24 hr Cefotaxime, 1 g every 8 hre
Gram-negative rodsf Ceftazidime, 2 g every 8 hr orCefepime, 2 g every 8 hr orPiperacillin-tazobactam, 4.5 g every 6 hr
Aztreonam, 2 g every 8 hr orFluoroquinoloneg orCarbapenemh,i
Gram-stain negativef VancomycinplusCeftazidime orCefepime
Daptomycinc or linezolidc
plusPiperacillin-tazobactam orAztreonam orFluoroquinoloneg orCarbapenemh,i
ABW, actual body weight; IgE, immunoglobulin E; IV, intravenous; PO, by mouth.aUnless noted otherwise, dosages are IV for persons with normal renal function.bTherapeutic monitoring should target a serum trough of 15-20 mg/L.cFor patients allergic to, or intolerant of, vancomycin.dEquivocal gram-negative morphology should be considered as gram-negative rods.eGram-negative cocci with epidemiology or history suggestive of gonococcal infection should be initially treated
per Centers for Disease Control and Prevention Sexually Transmitted Disease Guidelines. Alternative therapies have not been suggested for patients with a history of a Stevens-Johnson syndrome or severe IgE-mediated allergy to β-lactam antibiotics. Possible empirical options for penicillin-allergic patients, pending culture sensitivities, include azithromycin, ciprofloxacin, tobramycin, gentamicin, and spectinomycin (not available in United States).
fFor patients with risk factors for resistant gram-negative pathogens (significant health care exposure, immunosup-pression, or history of extended-spectrum β-lactamase gram-negative infection or colonization), drug selection should consider regional or local antibiograms.
gCiprofloxacin, 400 mg IV every 8 hr or 750 mg PO every 12 hr or levofloxacin, 750 mg IV or PO every 24 hr.hDoripenem, 500 mg every 8 hr; imipenem, 500 mg every 6 hr; or meropenem, 1 g every 8 hr.iUsually reserved for patients with risk factors for resistant gram-negative pathogens (significant health care
exposure, immunosuppression, or history of extended-spectrum β-lactamase gram-negative infection or colonization).
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SEPTIC BURSITIS• Itpredominantlyinvolvestheprepatellar,olecranon,andtrochantericbursa.• Itcanbecausedbydirectinoculation,contiguousinfection,orlesscommonly,fromahema-
togenoussource.• Morethan80%ofcasesareduetoStaphylococcus aureus.• Diagnosisismadefromtheclinicalpresentationandbyaspiratingthebursaforfluidanalysis,
Gramstain,andculture.• Treatmentincludesantibiotics(usually14to21days)anddailyaspirationofthebursauntil
sterile fluid is obtained. Except for severe cases, oral antistaphylococcal agents that haveactivityagainstcommunity-acquiredmethicillin-resistantS. aureus(CA-MRSA)arerecom-mended pending culture and sensitivity. For moderate-to-severe cases or patients withimmunosuppression,intravenousantibioticsshouldbeselected.
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49 OsteomyelitisElie F. Berbari, James M. Steckelberg, and Douglas R. Osmon
CLASSIFICATION• Osteomyelitiscandevelopastheresultofcontiguousspreadfromadjacentsofttissuesand
joints,hematogenousseeding,ordirect inoculationofmicroorganisms into theboneasaresultoftraumaorsurgery.
• TheCiernyandMaderclassificationisbasedontheaffectedportionofthebone,thephysi-ologicstatusofthehost,andthelocalenvironment.
• The Lew and Waldvogel classification is based on the duration of illness (acute versuschronic), themechanismof infection(hematogenousvs.contiguous),andthepresenceofvascularinsufficiency.
GENERAL PRINCIPLES• Thediagnosisofosteomyelitisissuspectedonclinicalgrounds.Confirmationusuallyentails
acombinationofradiologic,microbiologic,andpathologictests.• Cross-sectionalimagingmodalities,suchascomputedtomographyormagneticresonance
imaging(MRI),areconsideredstandardofcareinthediagnosisofosteomyelitis.• Repeatedswabculturesofthesameorganismfromdrainingwoundsandsinustractsmay
beofdiagnosticbenefit,althoughfailuretorecoverthetruepathogeniscommon,exceptforStaphylococcus aureus.
• Bonebiopsyorneedleaspirationisbestfororganismidentification.• Therapy is typically a combinationof complete surgicaldébridementand4 to6weeksof
antimicrobialtherapy(seeTable49-1).
OSTEOMYELITIS AFTER A CONTAMINATED OPEN FRACTURE• Contaminatedopenfracturescanleadtothedevelopmentofosteomyelitisofthefractured
bone,typicallyatthefracturesitein3%to25%ofcases.• Staphylococciandaerobicgram-negativebacilliarethetwomostcommongroupsofmicro-
organismsinthissetting.• Thehallmarkofosteomyelitisafteropen fracture isnonunionof the fracture siteorpoor
woundhealingafterwoundclosureorsofttissuecoverage.• Managementofopencontaminatedfracturesentailsearlyaggressivewoundirrigationand
débridement, administration of parenteral and local antimicrobials, fracture fixation, andsofttissuecoverageofexposedbone.
VERTEBRAL OSTEOMYELITIS AND SPONDYLODISKITIS• The origin is hematogenous in most native cases; it may also occur postoperatively or
postprocedurally.• S. aureus, coagulase-negative staphylococci,Mycobacterium tuberculosis, andBrucella spp.
arethemostcommonmicroorganismsencounteredinvertebralosteomyelitis.• MRIofthespineishighlyaccurateinthediagnosisofvertebralosteomyelitis.• Image-guidedaspirationandbiopsyishighlyspecificbutlackssensitivity.• Mostcasescanbetreatedwitha6-weekcourseofparenteralantimicrobialtherapywithout
surgery.
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OSTEOMYELITIS IN PATIENTS WITH DIABETES MELLITUS OR VASCULAR INSUFFICIENCY• Patientstypicallyhaveosteomyelitiscontiguoustoanulcerofthelowerextremity.• The sensitivity of exposed bone or a probe-to-bone test was 60%, and the specificity
was91%.• Thiscategoryofosteomyelitisisoftenpolymicrobial.• Therapy requires a combination of broad-spectrum antimicrobial regimen and surgical
débridement.
ACUTE HEMATOGENOUS OSTEOMYELITIS• Acute hematogenous osteomyelitis of long bones occurs mainly in prepubertal children,
elderlypatients,intravenousdrugabusers,andpatientswithindwellingcentralcatheters.• ThemostcommonrecoveredmicroorganismisS. aureus.• Acutehematogenousosteomyelitisoflongbonesinprepubertalchildrenistypicallytreated
witha2-to3-weekcourseofantimicrobialtherapy.
TABLE 49-1 Antimicrobial Therapy of Chronic Osteomyelitis in Adults for Selected Microorganisms
MICROORGANISMS FIRST CHOICE* ALTERNATIVE CHOICE*Staphylococci
Oxacillin sensitive Nafcillin sodium or oxacillin sodium, 1.5-2 g IV q4h for 4-6 wk, or cefazolin, 1-2 g IV q8h for 4-6 wk
Vancomycin, 15 mg/kg IV q12h for 4-6 wk; some add rifampin, 600 mg PO qd, to nafcillin/oxacillin
Oxacillin resistant (MRSA)
Vancomycin,† 15 mg/kg IV q12h for 4-6 wk
Linezolid, 600 mg PO/IV q12h for 6 wk, or levofloxacin,†
500-750 mg PO/IV daily, plus rifampin, 600-900 mg/day PO for 6 wk if susceptible to both drugs
orDaptomycin 6 mg/kg IV q24h
Penicillin-sensitive streptococci
Aqueous crystalline penicillin G, 20 × 106 U/24 hr IV either continuously or in six equally divided daily doses for 4-6 wk, or ceftriaxone, 1-2 g IV or IM q24h for 4-6 wk or cefazolin, 1-2 g IV q8h for 4-6 wk
Vancomycin, 15 mg/kg IV q12h for 4-6 wk
Enterococci or streptococci with MIC ≥0.5 µg/mL, or Abiotrophia or Granulicatella spp.
Aqueous crystalline penicillin G, 20 × 106 U/24 hr IV either continuously or in six equally divided daily doses for 4-6 wk, or ampicillin sodium, 12 g/24 hr IV either continuously or in 6 equally divided daily doses; the addition of gentamicin sulfate, 1 mg/kg IV or IM q8h for 1-2 wk is optional
Vancomycin,† 15 mg/kg IV q12h for 4-6 wk; the addition of gentamicin sulfate, 1 mg/kg IV or IM q8h for 1-2 wk is optional
Enterobacteriaceae Ceftriaxone, 1-2 g IV q24h for 4-6 wk, or ertapenem 1 g IV q24h
Ciprofloxacin,† 500-750 mg PO q12h for 4-6 wk, or levofloxacin 500-750 mg PO q24h
Pseudomonas aeruginosa Cefepime, 2 g IV q12h, meropenem, 1 g IV q8h or imipenem, 500 mg IV q6h for 4-6 wk
Ciprofloxacin,† 750 mg PO q12h for 4-6 wk, or ceftazidime, 2 g IV q8h
MIC, minimal inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus.*Antimicrobial selection should be based on in vitro sensitivity data.†Should be avoided, if possible, in pediatric patients and in osteomyelitis associated with fractures.
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50 Orthopedic Implant–Associated InfectionsWerner Zimmerli and Parham Sendi
PERIPROSTHETIC JOINT INFECTION (PJI)Diagnosis• Determinationthataprostheticjointisinfecteddependsonrecoveryofanorganismfrom
ajointaspirateorsurgicallyobtainedmaterialfromthejoint,althoughinflammation,wounddehiscence,adrainingsinustract,jointeffusion,andlooseningoftheprosthesiscanpointtowardthisdiagnosis.
Microbiology• Mostfrequentmicroorganisms:Staphylococcus aureus,coagulase-negativestaphylococciand
streptococci• Propionibacterium acnes: Most important microorganism in periprosthetic shoulder
infection• Microorganismsestablishabiofilmonthesurfaceoftheimplant
Pathogenesis• Foreigndevicesarecoveredbyhostproteins(e.g.,fibronectin)after implantationfavoring
bacterialadherence.• Minimalinfectingdoseisgreaterthan10,000-foldlowerinthepresencethanabsenceofan
implant.• Granulocytefunctionaroundtheimplantisimpaired(activationanddegranulation).
Clinical Manifestations• Acute exogenous PJI: Local signs of inflammation (wound dehiscence, secretion,
erythema)• AcutehematogenousPJI:New-onsetpainatany timeafter implantation, initiallywithout
localsignsofinfection,new-onsetarticulareffusion• ChronicPJI:Painbecauseofearlyloosening,localinflammation,sinustract,chronicarticu-
lareffusion
Treatment• Cornerstoneofsuccessfultreatmentisearlydiagnosis.• Cureisonlypossiblewithadequatesurgerycombinedwithlong-termantibiotictherapy.• Atreatmentalgorithm(seeFig.50-1)allowschoosingthemostappropriatesurgicalinter-
vention: Débridement with retention, one-stage exchange, two-stage exchange, removalwithoutreplacement,orsuppressivetherapy.
• Guidelines:www.idsociety.org/Organ_System/#Skeletal%20%28Bones%20&%20Joints%29
INTERNAL FIXATION–ASSOCIATED INFECTIONDiagnosis• Diagnosis of infection associated with implanted devices used to stabilize bone fractures,
suchaspinsandrods,requirescultureofthedevice,usuallyfollowingsurgicalremoval.Pain,
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inflammation, wound dehiscence, or loosening of the fixation device often indicatesinfection.
Microbiology• Microbiology is comparable with that of PJI. Staphylococci are the most important
pathogens.• Inopenfractureswithenvironmentalexposureandpreemptivetherapy,considerselection
ofβ-lactam–resistantgram-negativebacillisuchasEnterobacterspp.,nonfermenters.
Pathogenesis• Theexogenousrouteplaysamoreimportantrolethanthehematogenous.• Infectionmayalsooccurviaanadjacentfocus(contiguous).
FIGURE 50-1 Surgical treatment algorithm for prosthetic joint infections. *Difficult-to-treat microorganisms include microorganisms resistant to antibiotics with good oral bioavailability, rifampin-resistant staphylococci, enterococci, and quinolone-resistant gram-negative bacilli and fungi. (Modified from Trampuz A, Zimmerli W. Prosthetic joint infections: update in diagnosis and treatment. Swiss Med Wkly. 2005;135:243-251.)
Otherwise
Allyes
Condition Surgical Procedure
Duration of symptoms 3 weeks orinfection within 4 weeks after implantation+ stable implant+ absence of sinus tract+ susceptibility to antibiotics with
activity against surface-adheringmicroorganisms
Intact or only slightlydamaged soft tissue
Damaged soft tissue,abcess, or sinus tract
Microorganism resistant ordifficult to treat*
No functional improvementby exchange of the implant
Inoperable, debilitated, orbedridden
Two-stage exchange with shortinterval (2-4 weeks)
Two-stage exchange with longinterval (8 weeks)
Implant removal withoutreplacement
Long-term suppressiveantimicrobial treatment
One-stage exchange
Débridement with retention
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Clinical Manifestations• Acuteearlypostoperativeinfections:Woundhealingdisturbances,discharge,erythema• Acute symptoms after an uneventful postoperative period: Systemic infection signs are
dominating, pain is the most important local sign. Other local features are absent in thebeginningandbecomeapparentinthecourseofdisease.
• Acutesymptomsmayalsobeduetoreactivationofchronicpost-traumaticosteomyelitisthathasbeensilentformanyyears:Painwithoutprominentsystemicinflammatorysigns.
• Chronicsymptoms:Sinustract,pain,implantloosening.
Treatment• Bonefracturesarelesssusceptibletoinfectionifstabilized.• Inacuteinfections:Retainimplantwithdébridementandantimicrobialtherapy,untilfrac-
tureisconsolidated.• Indelayedinfections,implantmustberemovedafterhealingofbonefracture.
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L Diseases of the Reproductive Organs and Sexually Transmitted Diseases
51 Genital Skin and Mucous Membrane LesionsMichael H. Augenbraun
DEFINITION• Infectiousgenitalskinandmucousmembranelesionscoverawidespectrumofpathologic
etiologiesandclinicalmanifestations,mostlypresentingasinflammatoryreactionsordefectsintheepitheliumofthegenitaltractinmenandwomen.
EPIDEMIOLOGY• Infectious genital skin and mucous membrane lesions are seen globally without
seasonality.• Theselesionsoccurprimarilyamongindividualswhoaresexuallyactive.• Incubationperiodsmayvaryaccordingtoetiology,thatis,humanpapillomaviruspotentially
weeks,months,oryearsafterexposure;primarysyphilisweekstomonths;herpessimplexoutbreaksyears.
• Diseasemaybemodifiedinpopulationsthatareimmunocompromised.• Someconditionsarecurrentlybeingseenmorefrequentlyinmenwhohavesexwithmen
(early-stagesyphilis,lymphogranulomavenereum[LGV]).
MICROBIOLOGY• Bacteria:Treponema pallidum (spirochete),Haemophilus ducreyi (gram-negativediplococ-
cus), Chlamydia trachomatis L serovars (obligate intracellular pathogen), Klebsiella granulomatis/donovanosis(gram-negativerod)
• Viruses:Herpessimplexvirus,molluscumcontagiosumvirus,humanpapillomavirus• Fungi:Candida albicans
DIAGNOSIS• Clinicalassessmentalonemaybemisleading.• Laboratoryexaminationusingmicroscopyandserologictestingisoftenhelpful.• GramstainingandlightmicroscopyhelptoidentifyH. ducreyiandCandida.• DarkfieldmicroscopyisusedtoidentifyTreponema pallidum.• SerologyhelpstodiagnoseT. pallidumandherpessimplexvirus.• Cellcultureisusedtodiagnoseherpessimplexvirus.• NucleicacidamplificationtestsareusedtoidentifyC. trachomatis.
THERAPY• Therapyisbestchosenbasedonthelikelyorspecificetiologicagent.• Syphilisistreatedwithpenicillinandtetracyclines.• Herpessimplexvirusinfectionistreatedwithacyclovir,valacyclovir,andfamciclovir.• C. trachomatiscausingLGVshouldbetreatedwithtetracyclines.
PREVENTION• Safesex• Partnercontacttracing• Preemptivetreatmentbasedoncontactandrisk
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52 UrethritisMichael H. Augenbraun and William M. McCormack
DEFINITION• Urethritisisaninflammatoryconditioninvolvingthemaleurethrausuallycausedbysexually
transmittedinfectiouspathogens.
EPIDEMIOLOGY• Urethritisoccursworldwide.
MICROBIOLOGY• CommonetiologicagentsincludeChlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas
vaginalis,andMycoplasma genitalium.
DIAGNOSIS• Lightmicroscopyofurethraldischargecanbehelpful.Thepresenceofpolymorphonuclear
leukocytes is highly suggestive of inflammation. Gram stain of this material that revealsintracellular gram-negative diplococci suggests Neisseria gonorrhoeae, which can also becultured using standard agar-based techniques. Nucleic acid amplification techniques arepreferredfordiagnosingtheotheretiologicagentsofthiscondition(seeTable52-1).
THERAPY• Treatment is directed toward the known or suspected pathogen. Infection with Neisseria
gonorrhoeae isgenerally treatedwith third-generationcephalosporins,butresistance isanemerging concern. Infection with Chlamydia trachomatis responds to azalides andtetracyclines.
PREVENTION• Condomuseorabstainingfromhigh-risksexualactivityreducestheriskforurethritis.
TABLE 52-1 Evaluation of Men Who Have Urethral Symptoms
DIAGNOSTIC STUDIES COMMENTSGram-stained urethral smear
Examination of first-void urine specimen for leukocytes
Endourethral cultures or nonculture tests Neisseria gonorrhoeae Culture and NAATs are equally appropriate. Culture
can provide option for susceptibility testing. Chlamydia trachomatis NAATs preferred Trichomonas vaginalis Culture or NAATs Mycoplasma genitalium No currently available commercial test
NAATs, nucleic acid amplification tests.
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53 Vulvovaginitis and CervicitisWilliam M. McCormack and Michael H. Augenbraun
DEFINITION• Vulvovaginitisandcervicitisincludeinfectiousandnoninfectiousconditionsinvolvingthe
vulva,vagina,andcervix.
EPIDEMIOLOGY• Trichomoniasisisasexuallytransmittedcondition.• Bacterialvaginosisandvulvovaginalcandidiasisarenotclassicsexuallytransmitteddiseases
butseldomoccurinsexuallyinexperiencedwomen.• Vulvitisanddesquamativeinflammatoryvaginitisarenotsexuallytransmitted.• Cervicitismaybesexuallytransmittedoridiopathic.
MICROBIOLOGY• TrichomoniasisiscausedbyTrichomonas vaginalis.• CandidiasisiscausedbyCandida albicansandotherfungalspecies.• Bacterialvaginosisisassociatedwithacomplexbacterialmicrobiota.• Infectiouscervicitis isusuallycausedbyNeisseria gonorrhoeae, Mycoplasma genitalium,or
Chlamydia trachomatis.
DIAGNOSIS• TrichomoniasisandcervicalinfectionsduetoN. gonorrhoeae, M. genitalium,andC. tracho-
matiscanbediagnosedbyidentifyingthecausativeorganismswithuseofcultureornon-culturemethodsofwhichnucleicacidamplificationtestingisthemostaccurate.
• Bacterialvaginosisisdiagnosedusingclinicalcriteria,includingvaginalpH,odorproducedwhen potassium hydroxide is added to vaginal fluid, and detection of “clue cells” whenvaginalfluidisexaminedmicroscopically.
• Vulvovaginalcandidiasis isdiagnosedclinicallyandby the identificationofC. albicansorotherfungalspeciesinculturesofvaginalfluid.
• Desquamativeinflammatoryvaginitisisdiagnosedbytheclinicalappearanceofthevaginaandtheidentificationofleukocytesandparabasalcellsinwetpreparationsofvaginalfluid.
THERAPY• Trichomoniasisistreatedwiththeoraladministrationofmetronidazoleortinidazole.• Bacterialvaginosisistreatedwitha7-daycourseoforalmetronidazoleorwithpreparations
forintravaginalusethatcontainmetronidazoleorclindamycin.• Vulvovaginalcandidiasisistreatedwithoralfluconazoleorwithpreparationsforvaginaluse
thatcontainnystatin,miconazole,orotherantifungalagents.• Desquamativeinflammatoryvaginitisisbesttreatedwithintravaginalclindamycin.• Intravaginaladministrationofboricacidorcorticosteroidsprovidessymptomaticrelief.
PREVENTION• Judiciouschoiceofsexualpartnersandregularuseofcondomsispreventative.
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54 Infections of the Female PelvisDavid E. Soper
DEFINITION• Anacuteinflammationoftheepitheliumand/orsofttissueofthepelvicorgans
MICROBIOLOGY• Microorganismsfoundintheendocervixandvagina• Bacterialvaginosismicroorganisms,predominantlyanaerobes• GroupBStreptococcusandEscherichia coli• Sexually transmitted microorganisms, such as Neisseria gonorrhoeae and Chlamydia
trachomatis
DIAGNOSIS• Clinicaldiagnosisbasedonfever,erythema,andtendernessinthepostoperativesetting• Clinicaldiagnosisbasedonriskassessmentforsexuallytransmitteddiseaseandanevalua-
tionforlowergenitaltractinflammationinthecaseofpelvicinflammatorydisease
THERAPY FOR POSTOPERATIVE INFECTIONS• Broad-spectrumantibiotictherapy• Includecoverageofpenicillinase-producinganaerobes• Useantibioticregimenseffectiveinananaerobicenvironment
THERAPY FOR PELVIC INFLAMMATORY DISEASE• BeawareoftheemergingresistanceofN. gonorrhoeaetoquinolones,azithromycin,and,to
somedegree,cephalosporins• Treatconcurrentlyforbacterialvaginosisifthediagnosisismadeconcurrently
PREVENTION• Preoperativeantibioticprophylaxis• Screeningforsexuallytransmittedmicroorganisms
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55 Prostatitis, Epididymitis, and OrchitisCatherine C. McGowan and John Krieger
DEFINITION AND CLASSIFICATION• FortheNationalInstitutesofHealthclassificationofprostatitissyndromes,seeTable55-1.• Acutebacterialprostatitisisassociatedwithlowerurinarytractinfectionandsepsis.• Chronic bacterial prostatitis is associated with recurrent lower urinary tract infections
causedbythesamebacterialclade.• Chronicprostatitis/chronicpelvicpainsyndrome(CP/CPPS)occursinabsenceofuropatho-
genicbacteria.• Acuteepididymitisandorchitisareusuallyduetoinfectiousagentsorlocaltrauma.
EPIDEMIOLOGY• Prostatitis represents the most common urologic diagnosis in healthy young men. Fifty
percentofmenmayexperiencesymptomsintheirlifetimes.Prevalenceis2%to16%.• Nearly90%ofmenevaluatedforgenitourinarysymptomshaveCP/CPPS.• Sexually transmitted epididymitis is most common in young men. Men with bacterial
epididymitis may have underlying urologic pathology or recent genitourinary tractmanipulation.
• Isolatedorchitisisrare.
MICROBIOLOGY• Gram-negativeEnterobacteriaceaecausemostepisodesofbacterialprostatitis.Enterococci
accountforasmallpercentage.• Etiologyofepididymitisandorchitisreflectspatientage.Chlamydia trachomatisandNeisseria
gonorrhoeaepredominateinyoungmen,andcoliformorPseudomonasspeciespredominateinoldermen.
• Mostorchitisiscausedbyviralinfections.
DIAGNOSIS• Carefulhistory,physicalexamination,urinalysis,andurinecultureareessential.• Thelowerurinarytractlocalizationtest(seeTable55-2)isthegoldstandard.• EpididymitisandorchitisshouldbeevaluatedwithaurethralswabforC. trachomatisand
N. gonorrhoeae.AurethralsmearforGramstainandmidstreamurinecultureisusefulforestablishingotheretiologies.
THERAPY• Fluoroquinolonesarepreferredoraltreatment.Quinoloneresistanceisincreasinglycommon,
especiallyaftergenitourinarytractinstrumentation.• Septicpatientsshouldreceiveempiricalbroad-spectrumparenteraltherapy.• Combinationsofantibiotics,α-blockers,anti-inflammatoryagents,andpainmanagement
therapiesrepresentthemosteffectivetreatmentforCP/CPPS.• Combination therapy with intramuscular ceftriaxone plus either azithromycin or doxycy-
clineisrecommendedforN. gonorrhoeaeinfections.
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TABLE 55-1 Classification of Prostatitis Syndromes on the Basis of Lower Urinary Tract Localization Studies
CO
ND
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a
INFE
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LO
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Acute bacterial prostatitis + + + + +Chronic bacterial prostatitis + + + − −Chronic prostatitis/chronic pelvic pain syndrome − Inflammatory subtypee − − + − − Noninflammatory subtypef − − − − −Asymptomatic inflammatory prostatitis − − + ± −
aDocumented with an identical organism that is shown to localize to a prostatic focus when the midstream urine culture is negative.
bIn expressed prostatic secretions, semen, postmassage urine, or prostate tissue.cAbnormal findings include exquisite tenderness and swelling that may be associated with signs of lower urinary
tract obstruction.dSystemic findings frequently include fever and rigors and may include signs of bacteremia.eFormerly termed nonbacterial prostatitis.fFormerly termed prostatodynia.From Krieger JN, Nyberg L Jr, Nickel JC. NIH consensus definition and classification of prostatitis. JAMA.
1999;282:236-237.
TABLE 55-2 Lower Urinary Tract Localization Using Sequential Urine Cultures*
SPECIMEN SYMBOL DESCRIPTIONVoided bladder 1 VB1 Initial 5-10 mL of urinary stream
Voided bladder 2 VB2 Midstream specimen
Expressed prostatic secretions EPS Secretions expressed from prostate by digital massage
Voided bladder 3 VB3 First 5-10 mL of urinary stream immediately after prostatic massage
*Unequivocal diagnosis of bacterial prostatitis requires that the colony count in the VB3 specimen greatly exceed the count in the VB1 specimen, preferably by at least 10-fold. Many patients who have chronic bacterial prostatitis harbor only small numbers of bacteria in the prostate. In these patients, direct culture of prostatic secretions is particularly useful. Microscopic examination of the EPS is useful for identifying white blood cells and oval fat bodies—large lipid-laden macrophages characteristic of the prostatic inflammatory response.
From Stamey T. Pathogenesis and Treatment of Urinary Tract Infections. Baltimore: Williams & Wilkins; 1980.
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56 Microbial ConjunctivitisScott D. Barnes, Nalin M. Kumar, Deborah Pavan-Langston, and Dimitri T. Azar
DEFINITION• Microbialconjunctivitisinvolvesinflammationofthethinliningoftheinnereyelidandfront
oftheeyeball,causedbybacteria,viruses,fungi,orparasites.
EPIDEMIOLOGY• Conjunctivitisaffectsmalesandfemalesofallages.• Bacterialconjunctivitisismoreprevalentinchildren;viralconjunctivitisismoreprevalent
inadults.• Risk factors include contact lens wear, contaminated ocular medications, exposure to an
infectedperson,vaginalversuscesareandelivery,andvisitstocampsandswimmingpools.
MICROBIOLOGY• Common causes of bacterial conjunctivitis include Staphylococcus aureus, Streptococcus
pneumoniae, Haemophilus species, Moraxella, Corynebacterium diphtheriae, Neisseriaspecies,andentericgram-negativerods.
• Themostcommoncauseofviralconjunctivitisisinfectionwithadenovirus,butotherviralcausesincludeherpessimplexvirus(HSV),picornavirus,andherpeszostervirus.
• Neonatal conjunctivitis is commonly due to transmission from the mother during child-birth of sexually transmitted bacteria, including Chlamydia trachomatis and Neisseria gonorrhoeae.
DIAGNOSIS• Symptoms of conjunctivitis include itching, increased ocular secretions, swelling of the
conjunctivaand/oreyelids,pinkcolorinthewhiteoftheeyes,andlightsensitivity.• Clinicalpresentationofacutebacterialconjunctivitis involvesrapidonsetofunilateral lid
edema,conjunctivalinjection,amucopurulentdischarge,andinvolvementofthesecondeyewithin1to2days.Itchingisuncommon.Unlikeviralandchlamydialconjunctivitis,thereisnopreauricularlymphadenopathy.
• Clinicalpresentationofviralconjunctivitis isacute,unilateralconjunctivitiswith involve-ment of the second eye occurring often within 1 week. It is associated with a watery tomucousdischargeandenlargementofpreauricularlymphnodes.
• Routine laboratory evaluation is not usually required except in the first month of lifewhere cultures and smears for bacterial, chlamydial, and herpetic causes need to beperformed.
• Ifbacterial conjunctivitis is suspected, conjunctival scraping for identificationofbacterialspecies by further analysis is recommended for guidance of appropriate antibiotictherapy.
• Viral conjunctivitis can often be diagnosed from signs (e.g., common cold); symptoms(e.g., watery, rather than mucus, discharge); and patient history (e.g., work environmentsuch as if person is a veterinarian or poultry worker). Laboratory tests are not usuallynecessary.
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THERAPY• Acutebacterialconjunctivitisistreatedwithabroad-spectrumtopicalagentsuchassulfa-
cetamide, trimethoprim-polymyxin, or a fluoroquinolone (ciprofloxacin, levofloxacin, ormoxifloxacin) as eyedrops, usually every 3 hours when awake for 7 to 10 days. Topicalazithromycinhasbeenshowntobeeffectiveintreatingbacterialconjunctivitiswitha3-daycourse.
• Viral conjunctivitis spontaneously resolves within days to weeks, usually without adversesequelae to the conjunctiva, but associated keratitis may have long-term sequelae. HSVconjunctivitisinnewbornsshouldbetreatedwithintravenousacyclovir.
• Adult inclusion conjunctivitis involves systemic treatment for 3 weeks with tetracycline,doxycycline,orerythromycin,withthecautiontoavoidtetracyclineinchildrenyoungerthanage8andinpregnantorlactatingwomen.Theuseoforalazithromycinhasalsobeenfoundtobeeffective.
• Forhyperacutebacterialconjunctivitis,theprevalenceofpenicillin-resistantorganismshasmadeceftriaxonethetreatmentofchoice.
• Whentreatingneonatalchlamydialconjunctivitis,iferythromycinortetracyclineointmentisappliedtotheconjunctivalsurfacewithin1hourafterdelivery,thechanceofdevelopingchlamydialconjunctivitisisreportedlyalmostzero.Twoweeksoforalerythromycintherapyisgiventothenewbornwithlaboratory-provenchlamydialconjunctivitis;asecondcoursemaybegivenifadequateresolutionisnotachievedwiththeinitialtreatment.
• Limit spread of conjunctivitis by following good hygiene steps, including washing handsoften,washinganydischargefromaroundtheeyesmultipletimesduringtheday,andusingfreshwashcloths,cottonballs,ortissueseachtime.
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57 Microbial KeratitisScott D. Barnes, Joelle Hallak, Deborah Pavan-Langston, and Dimitri T. Azar
DEFINITION• Microbialkeratitisisavision-threateningcornealinflammatorycondition,causedbybacte-
ria,viruses,fungi,orparasites.
EPIDEMIOLOGY• Diseaseburdenishigherindevelopingthandevelopedcountries.• Riskfactorsincludecontactlenswear,trauma(surgicalandnonsurgical),contaminatedocular
medications,alteredstructureofthecornealsurface,andcontributingsystemicdiseases.• ContactlensuseisthemaincauseforkeratitisintheUnitedStates:poorlensstorageand
hygieneandovernightlensuse.• Nonsurgicaloculartraumaisthemaincauseofkeratitisindevelopingcountries.• Trachomaisencounteredmorecommonlyindevelopingcountries.
MICROBIOLOGY• Pathogenscanbegram-negativeorganisms,suchasPseudomonas aeruginosa.• Pathogenscanbegram-positiveorganisms,suchasStaphylococcusandStreptococcusspp.• Viralpathogensincludeherpessimplexvirus,varicella-zostervirus,adenovirus.• RecentoutbreaksofmicrobialkeratitisincontactlenswearershaveinvolvedAcanthamoeba
andFusariumspp.
DIAGNOSIS• Symptoms include severepainanddiscomfort, tearing,photophobia,blepharospasm,and
decreasedvision.• Clinicalpresentationincludesconjunctivalinjectionanddischarge,decreasedcornealtrans-
parency, corneal infiltrate, epithelial defect and/or stromal inflammation, corneal edema,cornealneovascularization,stromalmelting,lossofvision.
• Knowingthenatureofthestromalinflammation(suppurativeornonsuppurative),anditslocation(focal,multifocal,ordiffuse)ishelpful.
THERAPY• Cornealscrapingsandculturesshouldbeperformedonallsuspectedcaseswithinfectious
keratitis.• Aggressiveantimicrobialtherapyshouldbeinitiatedafterscrapingsandculturesofinfectious
keratitis.• Fortified topical administration is the most common route of antimicrobial therapy.
Subconjunctival injections, parenteral and oral routes, and antibiotic-soaked collagenshields/softlensesareusedinfrequently.
• Fortifiedcefazolinandaminoglycosideshouldbeusedformoreseverebacterialkeratitis.• Monotherapywithafourth-generationfluoroquinoloneisusedforbacterialkeratitis.• Antifungaltherapeuticagentsincludetopicalnatamycin,amphotericinB,flucytosine,fluco-
nazole,anditraconazole.Oralitraconazoleorvoriconazolehavealsoshownfavorableout-comeswhenaddedtotopicaltherapy.
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58 EndophthalmitisMarlene L. Durand
DEFINITION• Endophthalmitisisabacterialorfungalinfectioninsidetheeye,involvingthevitreousand/
oraqueous.Itiseitherexogenous,inwhichinfectionisintroducedfromtheoutsidein,orendogenous,inwhichtheeyeisseededfromthebloodstream.
CLINICAL MANIFESTATIONS• Decreasedvisionandeyepainareusuallypresent.Hypopyon(layerofwhitebloodcellsin
aqueoushumor)iscommonlyseen.Nofeverorleukocytosisispresentinexogenouscasesandmayalsobeabsentinendogenouscasesonpresentation.
CATEGORIES AND MICROBIOLOGY (SEE TABLE 58-1)• Acute postcataract endophthalmitis.Incidenceis0.1%to0.2%ofcataractsurgeries,withonset
within 1 week postoperatively in 75%. Etiology is contamination of aqueous from ocularsurfaceflora.Gram-positivecoccicause95%ofcases,withcoagulase-negativestaphylococcithemajorpathogens(70%ofallcases).
• Chronic postcataract endophthalmitis.Rare,thiscategorypresentsaslow-gradeinflammationinaqueouspostoperativelythatpersistsformonths.Itmayrespondtotopicalcorticosteroidsinitiallybut recursas thedrugdosage is tapered.Thecause isPropionibacterium acnes inmostcases.
• Postinjection endophthalmitis. Incidence is 0.1% after each intravitreal injection of anti–vascularendothelialgrowthfactoragents(treatmentofwetmaculardegeneration).Injectionsaretypicallygivenoncemonthly.Majorpathogensarecoagulase-negativestaphylococciandstreptococci(25%ofcases),thelatterusuallycausingsevereendophthalmitis.
• Bleb-related endophthalmitis.Afilteringblebisa“bleb”ofconjunctivaoverlyingasurgicallycreated defect in the sclera. Endophthalmitis typically occurs suddenly, months to yearspostoperatively; incidence is 1.3% per patient-year. Infection is often fulminant becausestreptococci, including Streptococcus pneumoniae, and Haemophilus influenzae are majorpathogens.
• Post-traumatic endophthalmitis.Incidenceis3%to10%afterpenetratingeyetrauma(“openglobe”)butmaybemuchlowerafterprotocolthatincludes48hoursofprophylacticantibiot-ics.Coagulase-negativestaphylococciandBacillus cereusaremajorpathogens;B. cereus ismostfearedandcausesfulminantinfection.
• Endogenous bacterial endophthalmitis.Sourcesincludeendocarditis(Staphylococcus aureusandstreptococciaremajorpathogens),intraabdominalabscess(liverabscessduetoKlebsiella pneumoniaeinEastAsiannations),transientbacteremia(e.g.,endoscopy,intravenousdrugabuse).
• Candidaendophthalmitis.Thiscategoryisusuallyendogenous,andchorioretinitis,theearli-estmanifestation,isoftenasymptomatic.Chorioretinitisusuallyrespondstosystemicanti-fungaltreatmentalone,butcaseswithendophthalmitis(markedvitreousinflammation)alsorequireintravitrealantifungalinjectionandoftenvitrectomy.
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• Mold endophthalmitis.Usuallyexogenous,thisinfectionoccursaftereyesurgery,eyetrauma,orasanextensionofkeratomycosis(fungalcornealinfection).AspergillusandFusariumarethemostcommonpathogens.
DIAGNOSIS• Exogenous cases, and some endogenous cases, require vitreous aspirate or vitrectomy for
culture(aqueousmayalsobecultured).Endogenouscaseswithpositivebloodculturesareusuallypresumedtobeduetothesameorganism.
THERAPY• Intravitreal antibiotics and often vitrectomy (surgical débridement of the vitreous) are
requiredinallcases.Systemicantibioticsalonearenotusedtotreatendophthalmitis,exceptincasesofCandidachorioretinitis.
TABLE 58-1 Endophthalmitis Categories and the Most Common Pathogens in Each
CATEGORY PATHOGENAcute postcataract Coagulase-negative staphylococci
Chronic postcataract Propionibacterium acnes
Postinjection Viridans streptococci, coagulase-negative staphylococci
Bleb-related Streptococci, Haemophilus influenzae
Post-traumatic Bacillus cereus
Endogenous Staphylococcus aureus, streptococci, gram-negative bacilli
Fungal Candida, Aspergillus, Fusarium
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59 Infectious Causes of UveitisMarlene L. Durand
DEFINITION AND CATEGORIES• Uveitismeansinflammationoftheuvea(iris,ciliarybody,choroid)orretina.• Dividedintocategoriesbysiteofgreatestinflammation:
• Anterior(iritis,iridocyclitis)• Intermediate(parsplanitis)• Posterior(choroiditis,retinitis,chorioretinitis)• Panuveitis
• Noninfectiouscausesofuveitis(idiopathic,autoimmune)aremorecommonthaninfectiouscauses,butthefrequencyofeachvariesdependingoncategory.
• Approximately10%ofanterioruveitiscaseshaveaninfectiousetiology.• Approximately50%ofposterioruveitiscaseshaveaninfectiousetiology.
EPIDEMIOLOGY AND ETIOLOGY• Themost likely infectiousetiologiesvarybyuveitiscategoryandby location in theworld
(seeTable59-1).• Infectiouscausesofanteriorincludeherpessimplexvirus(HSV)(90%ofinfectiousetiolo-
gies),varicella-zostervirus(VZV),syphilis,tuberculosis(TB),andLymedisease.• InfectiouscausesofintermediateuveitisarerareandincludeLymedisease.• Infectious causes of posterior uveitis include ocular toxoplasmosis, acute retinal necrosis
(HSV, VZV, sometimes cytomegalovirus [CMV]), CMV retinitis (severely immuno-compromised patients), ocular Toxocara, syphilis, cat-scratch disease, and Candidaendophthalmitis.
• Infectiouscausesofpanuveitisincludesyphilis,TB,andCandidaendophthalmitis.• Otherinfectiousetiologiesofuveitisseenprimarilyintropicalregionsordevelopingcoun-
triesincludeleptospirosis(panuveitiswithoutretinalorchoroidallesions),leprosy(anterioruveitis),Brucella(chronicrelapsinguveitis),andChikungunyavirus(anterioruveitis,reti-nitis,oropticneuritis).
DIAGNOSIS• Varies by etiology. Ocular syphilis is presumed in cases of uveitis with positive specific
treponemalserology.PolymerasechainreactionofaqueousorvitreousforHSV,VZV,andCMVmaybehelpful in somechronicanterioruveitis cases (aqueous)and in somecasesofacuteretinalnecrosis(vitreoushigheryieldthanaqueous,butvitreoussamplingcarriesmorerisk).
THERAPY• Variesbyetiology.Acuteretinalnecrosisisamedicalemergencyandrequiresantiviraltreat-
ment directed against HSV and VZV and against CMV as well in immunocompromisedpatients.OculartoxoplasmosisisdiscussedinChapter280ofMandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th Edition. Ocular TB and ocular syphilisshouldbetreatedthesamewayasTBmeningitisandneurosyphilis,respectively.
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TABLE 59-1 Classification of Uveitis and Major Infectious Etiologies in Each Category
CATEGORY OCULAR FINDINGS MAJOR INFECTIOUS ETIOLOGIES (%)*Anterior (iritis, cyclitis, iridocyclitis)
WBCs in aqueous, keratic precipitates, iris nodules, synechiae
Herpes simplex (10%); syphilis (<1%); TB (<1%); Lyme disease (<1%); leprosy (<1%)
Intermediate WBCs or snowballs in the vitreous, pars plana snow bank
Lyme disease (<1%)
Posterior (choroiditis, chorioretinitis, retinitis)
Lesions in choroid, retina, or both; vitritis in some
Toxoplasma (25%); CMV (12%)†; ARN (6%); Toxocara (3%); syphilis (2%); Candida (<1%)
Panuveitis WBCs in aqueous and vitreous Syphilis (6%); TB (2%); Candida (2%)
ARN, acute retinal necrosis; CMV, cytomegalovirus; TB, tuberculosis; WBCs, white blood cells.*Percentage of uveitis cases in each category (not of total uveitis cases), based on 1237 cases of uveitis seen at
Massachusetts Eye & Ear Infirmary, Boston, 1982-1992, by Foster’s group (Rodriguez A, Calonge M, Pedoza-Seres M, et al. Referral patterns of uveitis in a tertiary eye care center. Arch Ophthalmol. 1996;114:593-599).
†Series was before use of highly active antiretroviral therapy, and rate for CMV retinitis would be lower now.
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60 Periocular InfectionsMarlene L. Durand
DEFINITION• Periocularinfectionsincludeinfectionsoftheeyelids,lacrimalsystem,andorbit.• Eyelidinfectionsincludepreseptalcellulitis,infectionsofthemeibomianglandsofthelids
(hordeolum, stye), sterile inflammatory granulomatous nodule in the lid (chalazion), andmarginalblepharitis(inflammationatthelidmargins).
• Lacrimal system infections includedacryoadenitis (infectionof the lacrimalgland),canaliculitis(infectionofthecanaliculithatcollecttearsinthemedialcanthusanddrainintothelacrimalsac),anddacryocystitis(infectionofthelacrimalsac).
• Orbital infections includeorbital cellulitis, subperiosteal abscess,orbital abscess, andcavernous sinus thrombophlebitis. Acute sinusitis is the most common cause of orbitalinfections.
MICROBIOLOGY• Lidinfections: Staphylococcus aureus,streptococci• Canaliculitis:Actinomyces israelii,alsostaphylococci,streptococci• Dacryocystitis:S. aureus,streptococci;alsogramnegativebacilli• Orbitalinfections: S. aureusincludingmethicillinresistantS. aureus, Streptococcus anginosus
(milleri), other streptococci (including Streptococcus pneumoniae), gramnegative bacilli,anaerobes.Mixedinfectionscommon.
DIAGNOSIS• Clinicalexaminationinlidinfections,lacrimalsysteminfections,supportedbyculture.• Preseptalcellulitismustbedistinguishedfromorbitalinfections(orbitalcellulitis,subperi
osteal and orbital abscess). Orbital infections usually have one or more of the followingfindings: proptosis (which may not be grossly apparent but can be measured as 2mm ormoredifferenceinHertel’sexophthalmometermeasurements),ophthalmoplegia,andvisionloss.Preseptalcellulitishasnoneofthesefeatures—onlylidedemaanderythema.Computedtomography(CT)scanshouldbeperformedonanypatientwithorbitalfindings.CTshouldbe considered in children who present with what appears to be severe preseptal cellulitisbecausetheymayhavesubperiostealabscess.
THERAPY• Variesbydiagnosis• Orbitalinfectionsaremuchmoreseriousthanpreseptalcellulitis,andallorbitalinfections
mustbetreatedwithintravenousantibiotics.Subperiostealabscessesusuallyrequiresurgicaldrainage,andorbitalabscessesalmostalwaysdo.Drainageofanadjacentinfectedsinusmaybeindicated.
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61 Viral HepatitisJules L. Dienstag and Andrew S. Delemos
ACUTE HEPATITIS• Acuteclinicalillnessescausedbythefivehepatitisviruses(HAV,HBV,HCV,HDV,andHEV)
aresimilar.• Illnessrangesfromasymptomatictofulminant.• Asymptomaticinfectionsare10to30timesmorecommonthansymptomaticones.
CHRONIC HEPATITIS• Chronichepatitisaffectsmorethan500millionpeopleworldwide.• HBV,HCV,andHDVcausechronichepatitis.• HEVcausesprotractedandchronichepatitisonlyinimmunosuppressedpatients.
INDIVIDUAL HEPATITIS VIRUSES (SEE TABLE 61-1)Hepatitis A Virus (HAV)• HAVisanRNAvirusthatisamemberoftheHepatovirusgenus.• HAVistransmittedviathefecal-oralroute.• It typically causesanacute, self-limited illness,moreoften symptomatic inadults than in
children.• HAVismoresevereinpatientswithpreexistingchronichepatitisBorC.• Relapsingandcholestatichepatitismayoccur.• Diagnosisisbyserology(IgManti-HAV)(seeTable61-2).• Treatmentisusuallynotnecessarybeyondsupportivecare.• Prevention—highly effective HAV vaccines that have markedly reduced incidence where
usedareavailable.• Passive immunization with immune globulin intramuscularly is effective in postexposure
prophylaxis.
Hepatitis B Virus (HBV)Virology/Epidemiology• HBVisadouble-strandedDNAvirusintheOrthohepadnavirusgenusandtheHepadnavirus
family;10genotypeshavebeenidentified.• Worldwide,350millionpeopleareinfectedchronicallywithHBV.• Onemilliondeathsannuallyresultfromcomplicationsofchronicinfection—cirrhosis,hepa-
tocellularcarcinoma(HCC).• PrevalenceinAsiaisestimatedatgreaterthan10%,resultingprimarilyfromperinataltrans-
mission,afterwhichthelikelihoodofacquiringchronicinfectionis90%.• Inadults,transmissionofhepatitisBoccursprimarilyfollowinghigh-riskbehaviors(injec-
tion drug use, sexual activity) or after occupational exposure but resolves in greater than95%ofotherwisehealthypersons.
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TABLE 61-1 Hepatitis Viruses and Characteristics of Infection
CHARACTERISTIC A B C D EVirus family Picornaviridae Hepadnaviridae Flaviviridae Unassigned Hepeviridae
Genus Hepatovirus Orthohepadnavirus Hepacivirus Deltavirus Hepevirus
Nucleic acid RNA DNA RNA RNA RNA
Incubation period (days) 15-48 (mean 30)
30-180 (mean 60-90)
15-160 (mean 50)
30-180 (mean 60-90)
14-60 (mean 40)
Mode of transmission: Fecal-oral Yes No No No Yes Sexual Possible Yes Rare Yes No Blood Rare Yes Yes Yes No*
Chronic infection No Yes Yes Yes Yes†
Cirrhosis and hepatocellular carcinoma
No Yes Yes With hepatitis B No‡
*Can be bloodborne in endemic areas.†Acute hepatitis in normal hosts, protracted and chronic infection only in immunosuppressed patients.‡Cirrhosis can occur after chronic infection, which is confined to immunosuppressed patients.
TABLE 61-2 Simplified Diagnostic Approach in Patients Presenting with Acute Hepatitis
DIAGNOSTIC INTERPRETATION
SEROLOGIC TESTS OF PATIENT’S SERUM
HBsAg IgM Anti-HAV IgM Anti-HBc Anti-HCVAcute hepatitis B + − + −Chronic hepatitis B + − − −Acute hepatitis A superimposed on chronic hepatitis B
+ + − −
Acute hepatitis A and B + + + −Acute hepatitis A − + − −Acute hepatitis A and B (HBsAg below detection threshold)
− + + −
Acute hepatitis B (HBsAg below detection threshold)
− − + −
Acute hepatitis C − − − +
HAV, hepatitis A virus; HBc, hepatitis B core; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.Modified from Longo D, Fauci A, Kasper D, et al. Harrison’s Principles of Internal Medicine. 18th ed. New York:
McGraw Hill; 2011.
Diagnosis• AcutehepatitisBisasymptomaticinfectiontypifiedbyrightupperquadrantpain,nausea,
malaise,jaundice,elevatedalanineaminotransferase(ALT)andaspartateaminotransferase(AST),andIgMantibodytohepatitisBcoreantigen.
• DifferentcategoriesofchronicinfectionarediagnosedonthebasisofserologictestingandHBVDNAlevel(seeTable61-3).
• Liver biopsy is not required for diagnosis but may inform treatment decisions in chronicinfection.
Treatment• Indications(seeTable61-4):
• Hepatitis B e antigen (HBeAg)-positive or HBeAg-negative patients with ALT>2×upperlimitofnormalormoderatetoseverehepatitisonliverbiopsyandHBVDNA>20,000IU/mL
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TABLE 61-3 Viral and Laboratory Markers of Hepatitis B Virus Infection
DIA
GN
OSI
S
HB
sAg
An
ti-H
Bs
IgM
An
ti-H
Bc
IgG
An
ti-H
Bc
HB
eAg
An
ti-H
Be
ALT
Acute hepatitis + − + − + − Elevated
Recovered (immune) − + − + − + Normal
HBeAg-positive chronic hepatitis B + − − + + − Elevated
HBeAg-negative chronic hepatitis B + − − + − + Elevated (may be intermittent)
Vaccinated (immune) − + − − − − Normal
Inactive carrier + − − + − + Normal
ALT, alanine aminotransferase; HBc, hepatitis B core (antigen); HBe, HBeAg, hepatitis B e antigen; HBs, HBsAg, hepatitis B surface antigen; IgG, immunoglobulin G; IgM, immunoglobulin M.
TABLE 61-4 Recommendations/Guidelines of the American Association for the Study of Liver Diseases for the Treatment of Chronic Hepatitis B
HBeAg HBV DNA (IU/mL) ALT TREATMENT FIRST-LINE AGENTS
Chronic Hepatitis B without Cirrhosis+ >2 × 104 >2 × ULN Recommended PEG IFN, ETV, TDF
+ >2 × 104 ≤2 × ULN Not recommended
− >2 × 104 >2 × ULN Recommended PEG IFN, ETV, TDF
− >2 × 103 1 to >2 × ULN Histology determines*
− ≤2 × 103 Normal Not recommended†
Cirrhosis± Detectable (PCR‡) Normal or ↑ Recommended Compensated: treat with ETV
or TDF for HBV DNA >2 × 103; for HBV DNA <2 × 103, treat if ALT ↑Decompensated§: treat with ETV or combination nucleoside/nucleotide
± Undetectable (PCR‡) Normal or ↑ Not recommended §
ALT, alanine aminotransferase; ETV, entecavir; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IU, international units; PCR, polymerase chain reaction; PEG IFN, pegylated interferon; TDF, tenofovir; ULN, upper limit of normal.
Table is updated to reflect supplanting of the less effective drugs by the best available antiviral drugs.*If liver biopsy reveals advanced necroinflammatory activity or fibrosis, consider treatment.†Inactive carrier.‡>102 to 103 IU/mL.§If decompensated, coordinate care with a liver transplantation center.
• HBeAg-negativepatientswithlow-levelHBVDNAbutevidenceoffibrosisormoderatetoseverehepatitisonliverbiopsy
• CirrhosisassociatedwithchronicHBVirrespectiveofHBVDNAlevel• Inactivecarrier(hepatitisBsurfaceantigen[HBsAg]positive)preemptivelywhenstarting
chemotherapy or other immunosuppressive therapy (including anti–tumor necrosisfactor)
• Therapy(seeTable61-5):• Tenofovir300mgdailyorentecavir0.5mgdaily(1mgdoseapprovedforpriorlamivu-
dineresistancebutnotaviablealternativetoaddingtenofovir)
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TAB
LE 6
1-5
A
pp
roved
An
tivir
al
Dru
gs
for
Ch
ron
ic H
ep
ati
tis
B
IFN
PEG
IFN
LAM
AD
VET
VTB
VTD
FD
ose
5 M
U/d
ay*
180 µg
/wk
100
mg/
day
10 m
g/da
y0.
5 m
g/da
y60
0 m
g/da
y30
0 m
g/da
y
Rout
eSu
bcut
aneo
usSu
bcut
aneo
usO
ral
Ora
lO
ral
Ora
lO
ral
Dur
atio
n in
tria
ls4
mo
48 w
k48
-52
wk
48 w
k48
wk
52 w
k48
wk
Tole
rabi
lity
Poor
Poor
Exce
llent
Exce
llent
†Ex
celle
ntEx
celle
ntEx
celle
nt†
HBe
Ag
sero
conv
ersi
on18
%-2
0%27
%‡
16%
-21%
12%
21%
22%
21%
Log 1
0 H
BV D
NA
red
uctio
n
HBe
Ag-
posi
tive
?§4.
55.
53.
56.
96.
56.
2
HBe
Ag-
nega
tive
?§4.
14.
73.
95.
05.
24.
6
HBV
DN
A P
CR-
nega
tive
H
BeA
g-po
sitiv
e?
25%
44%
21%
67%
60%
76%
H
BeA
g-ne
gativ
e?
63%
73%
64%
90%
88%
93%
ALT
nor
mal
izat
ion
H
BeA
g-po
sitiv
e?‖
39%
75%
61%
68%
77%
68%
H
BeA
g-ne
gativ
e?‖
38%
79%
77%
78%
74%
76%
HBs
Ag
loss
dur
ing
trea
tmen
tup
to
8%3%
-4%
≤1%
0%2%
<1%
3%
Vira
l res
ista
nce
Non
eN
one
15%
-30%
Non
eN
one
2%-5
%0%
> 1 y
rN
one
Non
e5
yr:
70%
5 yr
: 29
%≤1
%2
yr:
9%-2
2%0%
Cos
t (U
.S.
$)56
00*
18,5
0025
0066
0087
0060
0060
00
AD
V, a
defo
vir;
ALT
, al
anin
e am
inot
rans
fera
se;
ETV,
ent
ecav
ir; H
BeA
g, h
epat
itis
B e
antig
en;
HBs
Ag,
hep
atiti
s B
viru
s su
rfac
e an
tigen
; H
BV,
hepa
titis
B v
irus;
IFN
, in
terf
eron
; LA
M,
lam
i-vu
dine
; PC
R, p
olym
eras
e ch
ain
reac
tion;
PEG
IFN
, pe
gyla
ted
IFN
; M
U,
mill
ion
units
; TB
V, t
elbi
vudi
ne;
TDF,
ten
ofov
ir.D
ata
show
n ar
e m
axim
um r
epor
ted
valu
es f
or u
p to
1 y
r (4
8-52
wk)
of
trea
tmen
t in
reg
istr
atio
n tr
ials
. Th
ese
com
paris
ons
are
head
to
head
onl
y fo
r PE
G I
FN v
s. L
AM
, ET
V v
s. L
AM
, TB
V v
s. L
MV,
and
TD
F vs
. A
DV.
*5 M
U d
aily
to
10 M
U t
hree
tim
es a
wk
for
16 t
o 24
wk;
the
cos
t is
tha
t of
a c
ompl
ete
cour
se,
not
of a
yr
of t
hera
py.
† Cre
atin
ine
mon
itorin
g re
com
men
ded.
‡ At
32%
24
wk
afte
r th
erap
y.§ W
hen
thes
e st
udie
s w
ere
cond
ucte
d, H
BV D
NA
was
mea
sure
d w
ith in
sens
itive
hyb
ridiz
atio
n as
says
.‖ A
LT is
gen
eral
ly n
orm
al in
tho
se w
ith a
dequ
ate
sero
logi
c/vi
rolo
gic
resp
onse
; rep
orts
rar
ely
incl
ude
ALT
leve
ls a
t th
e en
d of
tre
atm
ent.
In H
BeA
g-re
activ
e pa
tient
s, a
met
a-an
alys
is s
how
ed
a 23
% a
dvan
tage
in A
LT n
orm
aliz
atio
n (a
fter
the
rapy
) in
tre
ated
vs.
unt
reat
ed p
atie
nts.
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• 48weeksofpegylatedinterferon(PEGIFN)innoncirrhoticHBeAg-positivepatientsalsoanoption
• ConsiderstoppingoraltherapyinHBeAg-positivepatients6to12monthsafterHBeAgseroconversion (HBeAg-negative and anti-HBe-positive);≥40% chance of seroconver-sionafter5yearsoftherapy
• IndefinitetreatmentforchronicHBeAg-negativehepatitisB;considerstoppingtherapyforHBsAgseroconversion
Prevention• Universalvaccinationofinfantsbeginningatbirth(≥3intramusculardoses)• Prenatal maternal HBsAg screening and if HBsAg positive, hepatitis B immune globulin
0.5mLatbirthalongwithvaccination• Tenofovir 300mg starting in the third trimester in women with HBV DNA
>108IU/mL (some authorities recommend antiviral therapy for mothers with HBVDNA>106IU/mL)
Hepatitis D Virus (HDV)• HDVisapercutaneouslytransmitted,circularRNAvirus(genus:Deltavirus)thatrequires
HBV(orotherhepadnaviruses)toreplicateandpersist.• AcutecoinfectioncanoccurandfollowstheclinicalcourseofacuteHBVinfection.• HDVsuperinfectionresults inchronic infectioninpatientswithpriorchronichepatitisB
and has clinical features similar to chronic hepatitis B infection, although with increasedseverityandriskofprogressiontocirrhosis.
• Thediagnosis ismadebyserologictestingforantibodiestoHDVorbypolymerasechainreaction(PCR)forHDVRNA.
• OralantiviralsforhepatitisBarenotactiveagainstHDV,butprolongedtreatmentwithPEGIFNmaybenefitaproportionofpatients.
Hepatitis C Virus (HCV)Virology/Epidemiology• HCVisasingle-strandedRNAvirus(genus:Hepacivirus)withsixmaingenotypes(1to6);
itexistsasquasi-speciesbecauseofitshighmutationrate.• HCVrequireshostlipidmembraneassembly/secretionapparatusforreplication.• Worldwide,185millionpatientshavechronicHCV,withmorethan4millionresidinginthe
UnitedStates.• Transmission occurs predominantly through injection drug use, but other modes include
bloodtransfusionbeforetheavailabilityofscreeningornonsterilepracticesinwhichblood/body fluids are exchanged [note—the risk of hepatitis C is not increased in people withtattoosorinhealthworkers].
• ChronicHCVinfectiondevelopsinatleast85%ofpatientswithacuteinfectionand,intheabsenceoftreatment,resultsincirrhosisinapproximately20%ofpatientsafter20yearsofinfection.
• TheannualincidenceofHCCinpersonswithHCV-associatedcirrhosisis1%to4%.• HCVistheleadingindicationforlivertransplantationintheUnitedStates.
Diagnosis• Symptomatichepatitisandjaundicedevelopinfewerthan10%to20%ofpatientswithacute
hepatitisC,whichoftenportendsviralclearance.• Chronic hepatitis C tends to be asymptomatic, although patients often complain of
fatigue.• Patients with HCV-associated cirrhosis may present clinically with complications of end-
stageliverdiseasesuchasvaricealbleeding,hepaticencephalopathy,orascites.• Thedetectionofantibody toHCV is the initialdiagnostic test,butPCR testing forHCV
RNAdistinguishesongoingchronicinfection(commonly)frompriorexposurewithsubse-quentclearance(rare).
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Treatment• ThegoaloftherapyinchronichepatitisCistoachieveasustainedvirologicresponse(SVR),
whichisdefinedasundetectableHCVRNA24weeksfollowingcompletionoftherapy(12weekshasbeenadoptedastheSVRendpointinrecentclinicaltrials).
• Standard of care 2011-2013:forgenotypes2and3,24weeksofPEGIFN-α2aor-α2bandribavirin (RBV) 800mg daily; for genotype 1, PEG IFN, weight-based RBV, and eitherboceprevir (BOC) or telaprevir (TVR) (see Fig. 61-1). In prior treatment-naïve patients,treatmentregimensareeither24weeks(TVR),28weeks(BOC,after4weeksofPEGIFN/RBVlead-in),orupto48weeks(withtriple-drugtherapyfor12weeksandPEGIFN/RBVthereafterforTVRorBOC-basedtriple-drugtherapyforuptoweek36andPEGIFN/RBVthereafter)andarebasedonHCVRNAresponsemilestones(i.e.,response-guidedtherapy;see Figs. 61-1 and 61-2), except in cirrhotics, in whom treatment for a full 48 weeks isrecommended. In treatment-experienced patients, relapsers are treated the same way astreatment-naïve patients, while prior nonresponders are treated for up to 48 weeks (withtriple-drug therapy for 12 weeks and PEG IFN/RBV thereafter for TVR or triple-drugtherapyupto44weeksfollowing4weeksofPEGIFN/RBVlead-inforBOC).
• Standard of care 2014• Treatment-naïvepatients:
• Genotype1:sofosbuvir(SOF)400mgdailywithPEGIFN/RBV(weight-based,1000to1200mgdaily)for12weeksorsimeprevir(SMV)150mgwithPEGIFN/RBVfor12 weeks followed by another 12 weeks of PEG IFN/RBV; an alternative for IFN-ineligiblepatientsiscombinationSOF,SMV,andRBVfor12weeks.
• Genotype2:SOF400mgdailywithRBV(weight-based,1000to1200mgdaily)for12weeks.
• Genotype3:SOF400mgdailywithRBV(weight-based,1000to1200mgdaily)for24weeks(analternativeisSOFwithPEGIFN/RBVfor12weeks).
• Genotypes 4 to 6: similar to genotype 1 with minor modifications (seewww.hcvguidelines.org).
FIGURE 61-1 Recommended approach to treating patients with chronic hepatitis C virus (HCV), genotype 1, with telaprevir (TVR)-based therapy. eRVR, extended rapid virologic response; IU, international units; PEG IFN, pegylated interferon; RBV, ribavirin; RNA, ribonucleic acid. As of January 2015, telaprevir is no longer recommended for treatment of hepatitis C (see Table 61-6).
750 mg (two 375-mg tablets) q8h with food (not low fat)eRVR = HCV negative weeks 4 and 12
Treatment Naïve and Previous Relapsers
TVR + PEG IFN + RBV PEG IFN + RBV
TVR + PEG IFN + RBV PEG IFN + RBV
No eRVR; PEG IFN + RBV
0 4 12
*Treatment-naïve patients with compensated cirrhosis and eRVR may benefit from continuing PEG IFN + RBV to week 48.
24 48
eRVR; stop at week 24*
Previous Partial or Null Responders
Time Point
Week 24
Any
Week 4 or 12 Discontinue all therapyHCV RNA >1000 IU/mLDiscontinue PEG IFN/RBV
Discontinue TVR Discontinuation of PEG IFN/RBV for anyreason
Detectable HCV RNA
Criterion Stopping Rule
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FIGURE 61-2 Recommended approach to treating patients with chronic hepatitis C virus (HCV), genotype 1, with boceprevir (BOC)-based therapy. EU, European Union; IU, international units; LI, lead-in; PEG IFN, pegylated interferon; PR, pegylated; RBV, ribavirin; RGT, response-guided therapy; RNA, ribonucleic acid. As of January 2015, boceprevir is no longer recommended for treat-ment of hepatitis C (see Table 61-6).
800 mg (four 200-mg capsules) q8h with foodEarly response = HCV RNA negative at weeks 8 and 24
Treatment Naïve and Previous RelapsersPEGIFN +RBV
PEGIFN +RBV
PEG IFN + RBV
PEG IFN + RBVBOC + PEG IFN + RBV
BOC + PEG IFN + RBV
BOC + PEG IFN + RBV
BOC + PEG IFN + RBV
0 4 128
Cirrhotics and null responders should receive lead-in and then PEG IFN/RBV + BOC for 44 weeks (no RGT).Week 4 <1 log10 HCV RNA reduction: consider PEG IFN/RBV + BOC for 44 weeks after lead-in (no RGT).EU label: fixed-duration therapy for all treatment-experienced patients: LI + 32 weeks triple + 12 weeks PR (no RGT).
24Weeks
28 36 48
Early response; stop at week 28
Previous Relapsers or Partial Responders (noncirrhotic)
Additional recommendations:
Week 24Any
Week 12 Discontinue all therapyHCV RNA 100 IU/mLDiscontinue all therapy
Discontinue BOCDiscontinuation of PEG/RBV for any reasonDetectable HCV RNA
Time Point Criterion Stopping Rule
• PatientswithpriorPEGIFN/RBVtreatmentfailure:• Genotype1:SOF400mgdaily,SMV150mgdaily,andRBV(1000to1200mgdaily)
for12weeks(analternativeisSOFfor12weekswithPEGIFN/RBVfor12to24weeksorSMV150mgfor12weekswithPEGIFN/RBVfor48weeks).
• Genotype2:SOF400mgdailywithRBV(weight-based,1000to1200mgdaily)for12weeks(analternativeisSOF400mgdailywithPEGIFN/RBV[weight-based,1000to1200mgdaily]for12weeks).
• Genotype3:SOF400mgdailywithRBV(weight-based,1000to1200mgdaily)for24weeks(analternativeisSOF400mgdailywithPEGIFN/RBV[weight-based,1000to1200mgdaily]for12weeks).
• Genotypes 4 to 6: SOF 400mg daily with PEG IFN/RBV (weight-based, 1000 to1200mgdaily)for12weeks.
• Patientswithgenotype1andpriorTVRorBOCproteaseinhibitorfailure:SOFfor12weekswithPEGIFN/RBVfor12to24weeks.
• Standard of care: January 2015• The approval of new direct-acting antivirals in October and December 2014 has led
to IFN-free regimens of shorter duration and extraordinarily high efficacy, both intreatment-naïveandtreatment-experiencedpatients(seeTable61-6).
• Newlyrecommendedtreatmentregimens:• Ledipasvir/sofosbuvir(Harvoni):fixed-dosedailycombinationforgenotypes1a,1b,
4,and6• Paritaprevir/ritonavir/ombitasvir plus dasabuvir ± ribavirin for genotypes 1a, 1b,
and4
Hepatitis E (HEV)• HEVisanRNAvirus(genus:Hepevirus).• Itspreadsbyfecallycontaminatedwaterinendemicareas.• HEVcausesacute,self-limitedhepatitis,similartoHAV,innormalhosts.
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• Casefatalityratesare0.9%to2.8%inmenand20%inpregnantwomen,particularlyinthethirdtrimester.
• In immunosuppressed patients, particularly solid organ transplants, HEV can cause pro-tractedinfection,chronichepatitis,andcirrhosis.
• Diagnosisisbyserologictests(IgMantibodytoHEV)orPCRinbloodorstool.• Treatment:acutehepatitisEisusuallyself-limited;chronichepatitisErespondstoribavirin
therapy.• Highlyeffectivevaccinesconsistingofrecombinantcapsidproteinshavebeendevelopedfor
useinendemicareas.One(Hecolin)hasbeenrecentlylicensedinChina.
TABLE 61-6 AASLD and IDSA Recommendations for HCV Treatment-Naïve Patients: January 2015
GENOTYPE RECOMMENDATION*1a Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily–dosed dasabuvir (250 mg) and weight-based RBV for 12 wk (no cirrhosis) or 24 wk (cirrhosis)Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV for 12 wk (no cirrhosis) or 24 wk (cirrhosis)
1b Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wkDaily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily–dosed dasabuvir (250 mg) for 12 wk; weight-based RBV recommended for patients with cirrhosisDaily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 wk (no cirrhosis) or 24 wk (cirrhosis)
2 Daily sofosbuvir (400 mg) and weight-based RBV for 12 wk (no cirrhosis) or 16 wk (cirrhosis)
3 Daily sofosbuvir (400 mg) and weight-based RBV for 24 wk
4 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wkDaily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV for 12 wkDaily sofosbuvir (400 mg) and weight-based RBV for 24 wk
5 Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG IFN for 12 wk
6 Daily ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk
AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; PEG IFN, pegylated interferon; RBV, ribavirin.
*Listed alphabetically—see www.hcvguidelines.org for alternative treatments, treatments in experienced patients, and special populations.
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O Acquired Immunodeficiency Syndrome
62 Diagnosis of Human Immunodeficiency Virus InfectionFrancesco R. Simonetti, Robin Dewar, and Frank Maldarelli
DEFINITION• Human immunodeficiency virus (HIV) detection is the cornerstone of the medical and
publichealthresponse to theHIVepidemic.HIVdetection isaccurateandsensitive,andpreciseassayshavebeendesignedforthreegeneralpurposes:patientdiagnosisandclinicalmanagement, epidemiologic surveillance, and donor screening for blood and tissueproducts.
EPIDEMIOLOGY• Bytheendof2011,morethan34millionindividualswerelivingwithHIVinfectionthrough-
outtheworld.IntheUnitedStates,thepercentofindividualsevertestedforHIVincreasedfrom36%to45%in2000-2011,buttheyearlytestingratehasremainedrelativelystableat9.6%to10.4%despite thepromotionof rapid testingmodalitiesandexpansionof testingresources.AlthoughtheproportionofpeoplewithHIVawareoftheirstatusisabout80%in the United States, the United Nations estimates that only 30% of infected individualsworldwideareawareoftheirstatus.
MICROBIOLOGY• The genetic diversity of HIV-1 during early infection period is limited, and it is likely
that the majority of individuals are infected with a single variant, with slow, predictableaccumulationingeneticdiversityreflectingboththe intrinsicmutationrateofHIV-1andstrong selection pressure, likely including immune responses. At present, useful tools todetect HIV infection in vivo include viral components (HIV RNA and p24 antigen) andhumoralresponses(detectedbyenzyme-linkedimmunosorbentassay–,Westernblot–,andimmunofluorescence-basedstudies).
DIAGNOSIS• Diagnosisproceedsfromhistory,physicalexamination,andlaboratorystudies.Laboratory
detectionofHIVisatwo-stepsequentialprocessusingahighlysensitivescreeningtestfol-lowedbyahighlyspecificconfirmatoryassay(seeTable62-1).
• Avarietyofformatsareavailable,andrapidtestsarenowU.S.FoodandDrugAdministrationapprovedforHIVscreeningandconfirmation(seeTable62-2).Inmanycircumstances,itisnowpossibletoscreenandconfirmHIVinfectionusingrapidtestswithouthavingpatientsreturnforresults.
• HIVtestingisundergoingexpansionintheUnitedStates;CentersforDiseaseControlandPrevention (CDC) recommendations for opt-out testing for all individuals from 15 to 65yearshavebeenadoptedbytheU.S.PreventiveServicesTaskForce,andthecostforopt-outtestingwillbesubstantiallyunderwrittenthroughtheAffordableCareAct.
• In2014,theCDCissuedupdatedrecommendationsforthediagnosisofHIVinfection(seeTable 62-1). Initial tests are fourth-generation antigen/antibody combination assays, andconfirmatorytestsareHIV-1/HIV-2antibodydifferentiationassays,followedbyanHIV-1nucleicacidtestifneeded.
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irus In
fection
TABLE 62-1 CDC-Recommended Laboratory HIV Testing Algorithm for Serum or Plasma Specimens*Step 1: HIV-1/2 antigen/antibody combination immunoassay. If positive, proceed to Step 2.†
Step 2: HIV-1/HIV-2 antibody differentiation immunoassay. If negative or indeterminate for HIV-1 and negative for HIV-2, proceed to Step 3.‡
Step 3: HIV-1 nucleic acid test (NAT). Positive NAT indicates acute HIV-1 infection.§
*This algorithm, starting with the HIV-1/2 antigen/antibody combination immunoassay, should also be used after a reactive result from any rapid HIV test.
†No further testing is required for specimens that are nonreactive on the initial immunoassay.‡Reactive results on the initial antigen/antibody combination immunoassay and the HIV-1/HIV-2 antibody differ-
entiation immunoassay should be interpreted as positive for HIV-1 antibodies, HIV-2 antibodies, or, in the case where both HIV-1 and HIV-2 test results are reactive on the antibody differentiation assay, HIV antibodies, undifferentiated.
§A negative HIV-1 NAT result and nonreactive or indeterminate HIV-1/HIV-2 antibody differentiation immunoassay result indicates a false-positive result on the initial immunoassay.
CDC, Centers for Disease Control and Prevention; HIV, human immunodeficiency virus.
TABLE 62-2 FDA-Approved Formats for HIV Testing
Source for HIV Testing
FDA-APPROVED TESTING MODALITY*
ELISARapid EIA
Western Blot IFA
p24 Antigen Capture
HIV-1 TMA/HPA
Whole blood X X
Dried blood X
Plasma X X X X X X
Serum X X X X X
Oral fluid X X X
Urine X X
Mini-pools (donor screen) X X
Cadaveric serum X X
EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; FDA, U.S. Food and Drug Administration; HIV, human immunodeficiency virus; IFA, indirect immunofluorescence assay; TMA/HPA, transcription-mediated amplification/hybridization protection assay.
*Names and manufacturers of individual testing kits are available at www.fda.gov.
• Noassayorteststrategyisperfect,andfamiliaritywithassaylimitationsisessentialtoensureaccurateidentificationofHIVinfection.
THERAPY• HIVdiagnosisisessentialtointroducespecificantiretroviraltherapyfortreatmentofdisease
andnowaspartofpreexposureprophylaxisstrategies.• Screeningtestsarenecessary,butnotsufficient,tointroducetherapyforHIVinfection,and
confirmationofHIVinfectionisessentialbeforeintroductionofantiretroviraltherapy.• AnonreactiveHIVscreeningtestresulthasbeenusefulinidentifyingpatientsathighrisk
of HIV infection who may undergo preexposure prophylaxis. Regimens for preexposureprophylaxisaredistinctfromandlesspotentthanroutinecombinationantiretroviraltherapy,anditisessentialtoevaluatepatientscarefullyforHIVinfection.
• Specificguidelinesareavailablefortestingfortreatmentandprophylaxispurposes.
PREVENTION• Preexposureprophylaxisrepresentsastrategytotreathigh-riskindividualswithantiretro-
viral therapy to prevent HIV infection. Careful evaluation to rule out HIV infection isnecessary.
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63
General Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases)Timothy R. Sterling and Richard E. Chaisson
ACUTE RETROVIRAL SYNDROME• This syndrome is the initial manifestation of human immunodeficiency virus (HIV)
infection.• One half to two thirdsofpatientspresentwithanacute “mononucleosis-like” illness (see
Table63-1),oftenwithatruncalexanthem.• Symptomsgenerallyresolvewithin10to15days.
PERSISTENT GENERALIZED LYMPHADENOPATHY• Thisdisorderoccursin50%to70%ofHIV-infectedindividualsandusuallyaffectsthecervi-
cal,submandibular,occipital,andaxillaryregions.• Inpatientstreatedwithantiretroviraltherapy,previouslyinvolutednodesmayenlarge.
METABOLIC AND ENDOCRINE ABNORMALITIES• Hypogonadism,constitutionalwasting,lipidabnormalities,insulinresistance,andlipodys-
trophyhavebeenreported.
ORAL DISEASE• Oralcandidiasis,oralhairyleukoplakia,gingivitis,andperiodontitismayoccur.
CUTANEOUS DISEASE• Dermatologicconsequences includecutaneous infections (herpes simplexvirus,varicella-
zostervirus,molluscumcontagiosum,scabies,bacillaryangiomatosis,andKaposisarcoma).
RENAL DISEASE• MultiplecausesofrenaldiseasemayafflictpatientswithHIVinfection,aswellasaspecific
HIV-relatednephropathy,whichincludesproteinuria,mildlyelevatedserumcreatininecon-centration,reflectingglomerularinjury,mesangialproliferation,andtubulardegeneration.
CARDIAC DISEASE• AcceleratedatherosclerosiswithmyocardialinfarctionisseeninHIV-infectedpatientswho
havebeentreatedwithantiretroviraltherapyandappearstobeassociatedwithelevationsinproinflammatorycytokinesandprothromboticmarkers.
• Myocarditisandpericarditisarealsofound.
IMMUNE RECONSTITUTION SYNDROMES• Immune reconstitution syndromes are seen after antiretroviral therapy and can involve
Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus, hepatitis BandC,andotheropportunisticinfections.
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TABLE 63-1 Symptoms and Signs of the Acute Retroviral Syndrome in 209 Patients
SYMPTOM OR SIGN NO. WITH FINDING FREQUENCY (%)Fever 200 96
Adenopathy 154 74
Pharyngitis 146 70
Rash 146 70
Myalgia or arthralgia 112 54
Thrombocytopenia 94 45
Leukopenia 80 38
Diarrhea 67 32
Headache 66 32
Nausea, vomiting 56 27
Elevated aminotransferase levels* 38 21
Hepatosplenomegaly 30 14
Thrush 24 12
Neuropathy 13 6
Encephalopathy 12 6
*Based on 178 subjects.Modified from Niu MT, Stein DS, Schnittman SM. Primary human immunodeficiency virus type 1 infection: review
of pathogenesis and early treatment intervention in human and animal retrovirus infections. J Infect Dis. 1993;168:1490-1501.
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64 Pulmonary Manifestations of Human Immunodeficiency Virus InfectionPaul E. Sax and Kevin L. Ard
EPIDEMIOLOGY• Humanimmunodeficiencyvirus(HIV)infectionincreasestheriskofinfectiousandnonin-
fectiousrespiratoryconditions.• Mostcomplicationsoccurinthosenotreceivingantiretroviraltherapy(ART).• EffectiveARThasreduced,butnoteliminated,theexcessriskofpulmonaryinfectionssuch
asPneumocystis jiroveciipneumonia(PCP)andtoalesserextentbacterialpneumonia.• Noninfectiousconditions,suchaschronicobstructivepulmonarydiseaseandlungcancer,
areassuminggreaterimportanceasHIV-infectedindividualslivelonger.
APPROACH TO THE PATIENT• Thedifferentialdiagnosisisinfluencedbythestageofimmunosuppression,ART,prophylaxis
foropportunisticinfections,andthelocalepidemiologyofconditionssuchastuberculosisandendemicfungalinfections.
• LowerCD4cell counts increase the riskofallpulmonary infections, including those thatalsooccurathigherCD4cellcounts.
• Findingsonchestradiographycanhelpguidethedifferentialdiagnosis(seeTable64-1).
PNEUMOCYSTIS JIROVECII PNEUMONIA• Most cases of PCP occur at CD4 cell counts of fewer than 200 cells/mm3 in patients not
receivingART.• PatientswithPCPtypicallyreportcoughandfeverofatleastseveralweeks’duration.• Radiographic findings include diffuse interstitial infiltrates most commonly, but cavities,
pneumothoraces,pleuraleffusions,andnormalradiographscanoccur.• Diagnosis relieson identificationof theorganism in respiratory secretions,often through
inducedsputumorbronchoalveolarlavage,whichismoresensitive.• Serum(1→3)-β-D-glucanisalsohighlysensitiveforthediagnosisofPCP.
BACTERIAL PNEUMONIA• Streptococcus pneumoniae and Haemophilus influenzae are the most commonly isolated
pathogens.• Withworseningimmunosuppression,pneumoniasduetoStaphylococcus aureus, Pseudomo
nas aeruginosa (especially in the setting of neutropenia), Nocardia spp., and Rhodococcus equicanoccur.
MYCOBACTERIAL PNEUMONIA• ThefeaturesofMycobacterium tuberculosispulmonaryinfectionvarybasedonthedegreeof
immunosuppression.• HIV-infectedpatientswithrespiratorysymptomswhoarefromtuberculosis-endemicareas
orhaveother risk factors for tuberculosis,whohaveapositive test for latent tuberculosiswithout a history of prophylactic therapy, or who have a personal history of tuberculosis
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withoutdocumentationofappropriatetreatmentshouldbeplacedinnegativeairpressureroomsuntilthediagnosisofpulmonarytuberculosisisexcluded.
• Sputumnucleicacidamplificationtestscanhastendiagnosis,particularlyinsmear-negativecases.
FUNGAL PNEUMONIA• FungalpneumoniatendstooccurwithCD4cellcountfewerthan100cells/mm3,oftenasa
componentofdisseminated fungal infection (cryptococcosis,histoplasmosis, coccidioido-mycosis,blastomycosis).
• Histoplasmosis andcoccidioidomycosis are important causesofpneumonia in thosewhohaveresidedinortraveledtoendemicareas;BlastomycesrarelycausespulmonaryinfectioninpatientswithHIV.
• Pulmonaryaspergillosisisusuallyinseverelyimmunocompromisedindividualswithneu-tropeniaorcorticosteroiduse.
VIRAL PNEUMONIA• During the influenza season, influenza is the most common diagnosis in HIV-infected
patients with fever and respiratory symptoms, although adenovirus, respiratory syncytialvirus,andparainfluenzaviruscancauseasimilarpresentation.
NONINFECTIOUS RESPIRATORY DISORDERS• PulmonaryKaposisarcomausuallyoccurswithcutaneousormucosaldisease.• Pulmonarylymphomacausesnodules,masses,orpleuraleffusionsandisusuallydiagnosed
viavideo-assistedthorascopicsurgery(VATS).• Lymphocyticinterstitialpneumonitis,ararecauseofinterstitialinfiltrates,istypicallydiag-
nosedonbiopsy.Itprimarilyoccursinchildrenbutmaydevelopinadults,particularlythosewithhigherCD4countsthanareseenwithmanyopportunisticinfections.
TABLE 64-1 Radiographic Appearance of Pulmonary Diseases in Human Immunodeficiency Virus Infection
Diffuse Interstitial InfiltratesPneumocystis jiroveciiMycobacterium tuberculosis, especially with advanced
human immunodeficiency virus diseaseHistoplasma capsulatumCoccidioides spp.Cryptococcus neoformansToxoplasma gondiiCytomegalovirusInfluenzaLymphocytic interstitial pneumonitisAbacavir hypersensitivity
Focal ConsolidationPyogenic bacterial pneumonia from Streptococcus
pneumoniae, Haemophilus influenzaeM. tuberculosisLegionella spp.Rhodococcus equi
Hilar AdenopathyM. tuberculosisH. capsulatumCoccidioides spp.Non-Hodgkin’s or Hodgkin’s lymphomaMycobacterium avium complex
Cavitary DiseasePyogenic bacterial pneumonia from Pseudomonas
aeruginosa, Staphylococcus aureus, Enterobacteriaceae
M. tuberculosisC. neoformansR. equiAspergillus spp.Nocardia spp.Mycobacterium avium complexP. jirovecii
Nodules or MassesM. tuberculosisC. neoformansAspergillus spp.H. capsulatumNocardia spp.Non-Hodgkin’s lymphomaKaposi sarcomaLung cancer
Normal RadiographP. jiroveciiM. tuberculosis
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65 Gastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus InfectionCharles Haines and Mark S. Sulkowski
DEFINITION• Gastrointestinalandhepatobiliarydiseasesareacommoncauseofmorbidityinpersonswith
humanimmunodeficiencyvirus(HIV)infectionandoftenresultfrombothhostfactorsandexposures.
DISORDERS OF THE ESOPHAGUS• Disordersoftheesophagustypicallymanifestasdysphagiaorodynophagiaandaffectupto
onethirdofpatientswithacquiredimmunodeficiencysyndrome(AIDS).• InfectiouscausesincludeCandida,cytomegalovirus(CMV),herpessimplexvirus,varicella-
zostervirus,mycobacteria,Histoplasma,andPneumocystis jirovecii.• Noninfectiouscausesincluderefluxesophagitisandpillesophagitis.• Malignantcausesincludeesophagealcarcinoma,lymphoma,andKaposisarcoma.• Presumptivediagnosescanoftenbemadewithacarefulhistoryandphysicalexamination.• Upperendoscopywithbiopsyoflesionsishighlysensitiveinmanycases.
DISORDERS OF THE STOMACH• Gastric disorders can result from opportunistic infections but more commonly are not
relatedtoHIV-inducedimmunosuppression.• Helicobacter pylori,CMV,andKaposisarcomaarecommoncausesofgastricdisorders.• Upperendoscopyandgastricbiopsiesareoftenneededfordefinitivediagnosis.
DISORDERS OF THE LIVER• Becauseofsharedmodesoftransmission,hepatitiscausedbyacuteorchronicinfectionwith
hepatitisBandCvirusesiscommon.• NewlyavailabledirectlyactingantiviralsagainsthepatitisCvirus(HCV)arerecommended
fortreatmentofpatientscoinfectedwithHIVandHCV.• Drug-inducedliverinjuryhasbeenobservedwithsomeantiretroviralagentsandotherdrugs
usedinpersonswithHIVinfection.
DISORDERS OF THE BILIARY TREE, GALLBLADDER, AND PANCREAS• Acalculous cholecystitis and cholangitis are found primarily in advanced AIDS and may
involvethepancreas.• CMV,Cryptosporidium,andmicrosporidiaaremostcommonlyimplicated.• AIDS-relatedacalculouscholecystitisandcholangitisarerareinsettingswhereantiretroviral
therapy(ART)iswidelyused,andnon–AIDS-relatedgallbladderandbiliarydiseasesmaybemorecommoninsuchsettings.
• Endoscopic retrograde cholangiopancreatography can be used for both diagnosis andtreatment.
• Didanosineandsystemicpentamidinecancausepancreatitis.
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• Pancreatic infectionswithmycobacteria,Cryptococcus,Toxoplasma gondii,P. jirovecii, andCMVhavebeendescribed,oftenindisseminateddisease.
DISORDERS OF THE SMALL AND LARGE INTESTINE• Causesofenterocolitisincludebacterial,protozoal,andviralpathogens(seeTable65-1).• Clostridium difficileisthemostcommoncauseofdiarrheainHIV-infectedpatients.• CMV,Cryptosporidium,andMycobacterium aviumcomplexinfectionsaremorecommonin
thesettingofsevereimmunocompromise.• HIV-associatedenteropathycausesculture-negativediarrheaandmay improvewithART.
Humanpapillomavirus (HPV)andhigh-gradeanaldysplasiaareelevated inHIV,but theutilityofanalHPVscreeningisnotclear.
TABLE 65-1 Causes of Lower Gastrointestinal Tract Disease in Patients with Human Immunodeficiency Virus
Causes of Enterocolitis
Bacteria
Campylobacter jejuni and other spp.Salmonella spp.Shigella flexneriAeromonas hydrophilaPlesiomonas shigelloidesYersinia enterocoliticaVibrio spp.Mycobacterium avium complexMycobacterium tuberculosisEscherichia coli (enterotoxigenic, enteroadherent)Bacterial overgrowthClostridium difficile (toxin)
Parasites
Cryptosporidium parvumMicrosporidia (Enterocytozoon bieneusi, Septata intestinalis)Cystoisospora belliEntamoeba histolyticaGiardia lambliaCyclospora cayetanensis
Viruses
CytomegalovirusAdenovirusCalicivirusAstrovirusPicobirnavirusHuman immunodeficiency virus
Fungi
Histoplasma capsulatum
Causes of Proctitis
Bacteria
Chlamydia trachomatisNeisseria gonorrhoeaeTreponema pallidum
Viruses
Herpes simplexCytomegalovirus
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66 Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic InfectionsOmar K. Siddiqi and Igor J. Koralnik
DEFINITION• Human immunodeficiencyvirus (HIV)andassociated infections canadversely affect any
aspectofthecentralandperipheralnervoussystem.
EPIDEMIOLOGY• TenpercentofHIV-positivepatientsinitiallypresentwithneurologicdisease.• ThirtytofiftypercentofHIV-positivepatientshaveneurologiccomplications.• EightypercentofHIV-positivepatientshavenervoussysteminvolvementatautopsy.
COGNITIVE MANIFESTATIONS• HIV-associatedneurocognitivedisorderoccursin15%ofpatientswithAIDSandcanbethe
firstmanifestationofdiseasein3%to10%ofpatients.
CENTRAL NERVOUS SYSTEM (CNS) MASS LESIONS• Toxoplasmosisisthemostfrequentcerebralmasslesion.Incidencedependsontheseroposi-
tivityofthepopulation.Empiricaltreatmentwithpyrimethamineandsulfadiazineisusefulwhenclinicalandradiologicfindingsareconsistentwiththediagnosis.
• Primary CNS lymphoma is the most common HIV-associated brain malignancy and isassociatedwithEpstein-Barrvirusinfection.
• Progressivemultifocal leukoencephalopathy is causedby JCpolyomavirus,which induceslyticinfectionofoligodendrocytescausingmultifocalCNSdemyelination.
SPINAL CORD• Vacuolarmyelopathyispresentatautopsyin17%to46%ofpatientswithacquiredimmu-
nodeficiencysyndrome.• Presenting symptoms are gait disturbance, weakness, sensory changes, and urinary
dysfunction.• Diagnosisisoneofexclusion.• Etiologyisunclear.
PERIPHERAL NERVOUS SYSTEM• HIV-associateddistalsensorypolyneuropathyisthemostcommonperipheralneuropathy
seen in HIV. Symmetrical paresthesia, numbness, and painful dysesthesia of the lowerextremitiescanoccur.
• Nucleosideneuropathyisassociatedwithnucleosideanaloguereverse-transcriptaseinhibi-torszalcitabine,didanosine,andstavudine.
• ClinicalandelectrophysiologicmanifestationsareindistinguishablefromDSNP.Symptomscanimproveupondiscontinuationofoffendingmedication.
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67 Pediatric Human Immunodeficiency Virus InfectionGeoffrey A. Weinberg and George K. Siberry
EPIDEMIOLOGY• AremarkabledeclineinU.S.pediatrichumanimmunodeficiencyvirus(HIV)infectionhas
occurredasaresultofboththemajorityofcurrentlyinfectedchildrensurvivingintoyoungadulthood and the tremendous success in interrupting new mother-to-child transmission(MTCT). Such success may be achieved globally wherever effective HIV screening andtherapyforpregnantwomenisaccomplished.
• Asmall influxofHIV-infected immigrants,refugees,andadoptees,aswellasuncommondomesticMTCT,will continue tocontribute toaminorbutdefinitepresenceofpediatricHIVinfectionintheUnitedStates.
• AnalarmingincreaseinadolescentacquisitionofHIVinfectionisoccurringamongyoungmenwhohavesexwithmen,especiallyAfrican-AmericanandHispanicmen.
ELIMINATION OF NEW PEDIATRIC HIV INFECTION IN THE UNITED STATES• PreventionofpediatricHIVinfectioncriticallydependsonpreventionofHIVMTCT,which
inturndependsonprimarypreventionofHIVinfectioninwomen,universalHIVtestingofpregnantwomentoidentifythosewhoareHIVinfected,andappropriateantiretroviraltherapyinHIV-infectedwomenandtheirinfants.
• EachepisodeofperinatalHIVinfectionintheUnitedStatesshouldbeviewedasasentinelpublichealtheventindicatingawomanwhoseHIVinfectionwaseitherundiagnosedbeforeor during pregnancy or a woman with a known diagnosis who did not receive adequateprenatalcareincludingappropriateinterventionstopreventMTCT.
• PreventionofadolescentHIVinfectioninvolvessimilarstrategiestothoseusedforadults(safersex,avoidanceofintravenousorinjectiondruguse)butwithspecialattentiontotheadolescent’s unique developmental and biopsychosocial challenges. Additional challengesmaybeposedbyinterruptedhealthinsurance,homelessness,andstigmaamongyoungmenwhohavesexwithmen.
THERAPY FOR AGING HIV-INFECTED YOUTH• DisclosureofthediagnosisofperinatalHIVinfectiontotheagingchildrequiresdiscussion
andplanningand isaprocess thatmay takeplaceovermonths toyearsbasedonseveralfactors,includingthedevelopmentallevelofthechildandtheparent’sorcaretaker’sreadinesstodisclose.Disclosureisbestaccomplishedbyearlyadolescencetomorefullyengageyouthintheirowncare,preferablybeforetheageofsexualdebut.
• Adherence with medical care may suffer during adolescence because of issues revolvingaround psychosocial developmental, confidentiality, peer pressure, and socioeconomicfactors.ThiscontributestothesubstantialpresenceofantiretroviralresistanceofHIVstrainsinagingadolescents.
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• Transition from the pediatric care model to the adult care model is a multifacetedprocessthatrequirestimeandplanningtokeeptheagingadolescentsuccessfullyengagedincare.
• Complications of long-standing perinatal HIV infection and its therapy among maturingyouthincludeimpairedgrowthandbonemineralaccrual,possiblyincreasedcardiovascularriskfactors,increasedincidenceofbehavioralandpsychiatricdisorders,andincreasedriskforcervicaldysplasiaandpretermbirthamongyoungwomen.
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68 Antiretroviral Therapy for Human Immunodeficiency Virus InfectionAthe M. N. Tsibris and Martin S. Hirsch
DEFINITION• Treatmentofhumanimmunodeficiencyvirus(HIV)infectionusesacombinationofatleast
threedrugstoarrestvirusreplicationanddiseaseprogression.
THERAPY CHOICES• AntiretroviraltherapytargetsandinhibitsHIV-specificenzymes.
• Nucleosideandnucleotidereverse-transcriptaseinhibitors(seeTable68-1)• Non-nucleosidereverse-transcriptaseinhibitors(seeTable68-2)• Proteaseinhibitors(seeTable68-3)• Integraseinhibitor(seeTable68-4)
• CCR5antagonistsaretheonlydrugclasstotargetahostprotein.• Entryinhibitors(seeTable68-4)
THERAPY STRATEGIES• Preferredregimenswillusetwonucleosidereverse-transcriptaseinhibitorsincombination
witheitheranon-nucleosidereverse-transcriptaseinhibitor,aproteaseinhibitor,oraninte-grasestrandtransferinhibitor.
THERAPY GOALS• Thegoalofantiretroviraltherapy,inallpatients,isdurablesuppressionofvirusloadtolevels
undetectableincommercialassays.
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TABLE 68-1 Approved Nucleoside and Nucleotide Reverse-Transcriptase Inhibitors
AG
ENT
TRA
DE
NA
ME
OR
AL
BIO
AV
AIL
AB
ILIT
Y
(%)
SER
UM
HA
LF-L
IFE
(hr)
INTR
AC
ELLU
LAR
HA
LF-L
IFE
OF
TRIP
HO
SPH
ATE
(h
r)
ELIM
INA
TIO
N
AD
ULT
DO
SE
DO
SAG
E FO
RM
S
Zidovudine Retrovir 64 1.1 3-4 Hepatic glucuronidationRenal excretion
300 mg PO q12h or 200 mg PO q8h2 mg/kg IV loading dose, followed by 1 mg/kg/hr until umbilical cord is clamped
300-mg tablets100-mg capsules50-mg/5 mL syrup10-mg/mL solution for IV infusion
Didanosine VidexVidex EC
40 fasted
1.5 25-40 Cellular metabolism
≥60 kg: 400 mg PO qd25 kg < weight < 60 kg: 250 mg PO qd
125-, 200-, 250-, and 400-mg capsules2- and 4-g powder packets (makes 10-mg/mL solution)
Stavudine Zerit 86 1.1 3 Renal excretion ≥60 kg: capsules or solution, 40 mg PO q12h;<60 kg: capsules or solution, 30 mg PO q12h
15-, 20-, 30-, and 40-mg capsules1-mg/mL oral solution
Lamivudine Epivir 86 2.5 12-18 Renal excretion 300 mg PO qd or 150 mg PO q12h
150- and 300-mg tablets10-mg/mL solution
Abacavir Ziagen 83 1.5 3.3 Hepatic glucuronidation and carboxylation
600 mg PO qd or 300 mg PO q12h
300-mg tablets20-mg/mL solution
Tenofovir Viread 39 with meal
12-14 >11* Renal excretion 300 mg PO qd
150-, 200-, 250-, and 300-mg tabletOral powder 40 mg/g
Emtricitabine Emtriva 93 8-10 >24 Renal excretion 200 mg PO qdsolution, 240 mg PO qd
200-mg capsules10-mg/mL solution
Zidovudine + lamivudine
Combivir† One tablet PO q12h
300-mg zidovudine/150-mg lamivudine tablets
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AG
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TRA
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BIO
AV
AIL
AB
ILIT
Y
(%)
SER
UM
HA
LF-L
IFE
(hr)
INTR
AC
ELLU
LAR
HA
LF-L
IFE
OF
TRIP
HO
SPH
ATE
(h
r)
ELIM
INA
TIO
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AD
ULT
DO
SE
DO
SAG
E FO
RM
S
Abacavir + lamivudine
Epzicom†
KivexaOne tablet PO qd
Abacavir 600-mg/lamivudine 300-mg tablet
Tenofovir + emtricitabine
Truvada† One tablet PO qd
Tenofovir 300-mg/emtricitabine 200-mg tablet
Zidovudine + lamivudine + abacavir
Trizivir† One tablet PO q12h
300-mg zidovudine/ 150-mg lamivudine/300-mg abacavir tablets
Tenofovir + emtricitabine + efavirenz
Atripla† One tablet PO qd on an empty stomach
Tenofovir 300-mg/emtricitabine 200-mg/efavirenz 600-mg tablet
Tenofovir + emtricitabine + rilpivirine
CompleraEviplera†
One tablet PO qd with a meal
Tenofovir 300-mg/emtricitabine 200-mg/rilpivirine 27.5-mg tablet
Tenofovir + emtricitabine + elvitegravir + cobicistat
Stribild† One tablet PO qd with food
Tenofovir 300-mg/emtricitabine 200-mg/elvitegravir 150-mg/cobicistat 150-mg tablet
Abacavir + lamivudine + dolutegravir
Triumeq† One tablet PO qd with or without food
Abacavir 600-mg/lamivudine 300-mg/dolutegravir 50-mg tablet
*Diphosphate form in activated cells.†Pharmacokinetic properties are similar to those of the component drugs used separately.
TABLE 68-1 Approved Nucleoside and Nucleotide Reverse-Transcriptase Inhibitors—cont’d
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TABLE 68-2 Approved Non-Nucleoside Reverse-Transcriptase Inhibitors
AG
ENT
TRA
DE
NA
ME
OR
AL
BIO
AV
AIL
AB
ILIT
Y (
%)
SER
UM
HA
LF-L
IFE
(hr)
ELIM
INA
TIO
N
AD
ULT
DO
SE
DO
SAG
E FO
RM
S
Nevirapine Viramune >90 45 after first dose25-30 after 2 wk
Hepatic cytochrome P-450, CYP3A4 and CYP2B6
200 mg PO qd for 14 days, then, if no rash develops, 200 mg PO q12h or 400 mg XR PO qd
200-mg tablets50 mg/5-mL solution
Delavirdine Rescriptor 85 5.8 Hepatic cytochrome P-450, CYP3A4
400 mg PO q8h 100- and 200-mg tablets
Efavirenz SustivaStocrin
40-45 40-55 Hepatic cytochrome P-450, CYP2B6, and CYP3A4
600 mg PO qd 50- and 200-mg capsules600-mg tablet
Etravirine Intelence Unknown 41 ± 20 Hepatic cytochrome P-450, CYP3A4, 2C9, and 2C19
200 mg PO q12h after meals
25-, 100-, and 200-mg tablets
Rilpivirine Edurant Unknown 50 Hepatic cytochrome P-450, CYP3A
25 mg PO qd with a meal
25-mg tablet
TABLE 68-3 Approved Protease Inhibitors
AG
ENT
TRA
DE
NA
ME
OR
AL
BIO
AV
AIL
AB
ILIT
Y
(%)
SER
UM
HA
LF-L
IFE
(hr)
ELIM
INA
TIO
N
AD
ULT
DO
SE*
DO
SAG
E FO
RM
S
Saquinavir Invirase 4 1-2 Hepatic and intestinal cytochrome P-450, CYP3A4
1000 mg PO q12h with ritonavir 100 mg PO q12h
200-mg capsules500-mg tablets
Ritonavir Norvir 70 3-5 Hepatic cytochrome P-450, CYP3A4, and 2D6
300 mg PO q12h with escalation over 6-9 days to 600 mg PO q12h; rarely used as single agent
100-mg capsules and tablets80 mg/mL solution
Indinavir Crixivan 60-65 1.8 Hepatic cytochrome P-450, CYP3A4
800 mg PO q8hDrink ≥1.5L of water daily
200- and 400-mg capsules
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AG
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TRA
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OR
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BIO
AV
AIL
AB
ILIT
Y
(%)
SER
UM
HA
LF-L
IFE
(hr)
ELIM
INA
TIO
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AD
ULT
DO
SE*
DO
SAG
E FO
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S
Nelfinavir Viracept 70-80 3.5-5 Hepatic cytochrome P-450, CYP2C19, CYP3A4, and CYP2D6
1250 mg PO q12h or 750 mg PO q8h
250- and 625-mg tablets50-mg/g powder
Fosamprenavir LexivaTelzir
— 7-11 Hepatic cytochrome P-450, CYP3A4Biliary excretion
Treatment-naïve: 1400 mg PO q12h without food, or 1400 mg PO qd with ritonavir 200 mg PO qd, or 1400 mg PO qd with ritonavir 100 mg PO qd, or 700 mg PO q12h with ritonavir 100 mg PO q12hPI-experienced: 700 mg PO q12h with ritonavir 100 mg PO q12h
700-mg tablets50-mg/mL suspension
Lopinavir + ritonavir
Kaletra — 5-6 Hepatic cytochrome P-450, CYP3A4
Two tablets PO q12h Lopinavir/ritonavir 100-mg/ 25-mg and 200-mg/50-mg tabletsLopinavir/ritonavir 80-mg/ 20-mg per mL solution
Atazanavir Reyataz — 7 Hepatic cytochrome P-450, CYP3A4
Treatment-naïve: 400 mg PO qd with food or300 mg PO qd with ritonavir 100 mg PO qd with food.Treatment-experienced or with tenofovir: 300 mg PO qd with ritonavir 100 mg PO qd
100-, 150-, 200-, and 300-mg capsules
Tipranavir Aptivus — 5-6 Hepatic cytochrome P-450, CYP3A4
500 mg PO q12h with ritonavir 200 mg PO q12h
250-mg capsules100-mg/mL solution
Darunavir Prezista — 15 (with ritonavir)
Hepatic cytochrome P-450, CYP3A4
Treatment-naïve: 800 mg PO qd with ritonavir 100 mg qd and with food.Treatment-experienced: 800 mg PO qd with ritonavir 100 mg PO qd and with food, or 600 mg PO q12h with ritonavir 100 mg PO q12h and with food
75-, 150-, 400-, 600-, and 800-mg tablets100-mg/mL suspension
PI, protease inhibitor.*Consult product monograph for appropriate dose when low-dose ritonavir is used for pharmacokinetic
enhancement.
TABLE 68-3 Approved Protease Inhibitors—cont’d
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TABLE 68-4 Approved Entry Inhibitors and Integrase InhibitorA
GEN
T
TRA
DE
NA
ME
BIO
AV
AIL
AB
ILIT
Y (
%)
SER
UM
HA
LF-L
IFE
(hr)
ELIM
INA
TIO
N
AD
ULT
DO
SE*
AV
AIL
AB
ILIT
Y
Enfuvirtide Fuzeon 84 3.8 Catabolism to constituent amino acids
90 mg SC q12h 108-mg single-use vials, for reconstitution with 1.1 mL sterile water
Maraviroc SelzentryCelsentri
33 14-18 Hepatic cytochrome P-450, CYP3A
300 mg PO q12h 150- and 300-mg tablets
Raltegravir Isentress Not established
9 UGT1A1-mediated glucuronidation
400 mg PO q12h 400-mg tabletChewable 25- and 100-mg tablets
Dolutegravir Tivicay Not established
14 UGT1A1-mediated glucuronidationHepatic cytochrome P-450, CYP3A
Treatment- or INSTI-naïve: 50 mg PO qdINSTI-experienced or when co-administered with UGT1A/CYP3A inducers: 50 mg PO bid
50-mg tablet
INSTI, integrase strand transfer inhibitor.*Elvitegravir is not available as a single drug.
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69 Management of Opportunistic Infections Associated with Human Immunodeficiency Virus InfectionHenry Masur
DEFINITION• Acquiredimmunodeficiencysyndrome(AIDS)-relatedopportunisticinfectionsaredefined
asthoseinfectionsthatoccurwithincreasedfrequencyorseverityinpatientswithhumanimmunodeficiencyvirus(HIV)infectionorAIDS.
EPIDEMIOLOGY• TheincidenceofHIV-relatedopportunisticinfectionsdependsonthedegreeofimmunosup-
pressionandenvironmentalexposure.• Theoccurrenceofspecificinfectionsinsomecasesisduetoprimaryinfection;inothercases,
diseaseistheresultofreactivationoflatentinfection.
MICROBIOLOGY• TheconstellationofinfectionsthatcharacterizeAIDSisunique:Pneumocystispneumonia,
Toxoplasmaencephalitis,cytomegaloviralretinitis,pneumococcalpneumonia,disseminatedMycobacterium avium complex, cryptosporidiosis, cryptococcal meningitis, and Mycobacterium tuberculosis infection. The occurrence of these infections individually or in acluster should prompt consideration of underlying HIV infection/AIDS in any patientwithoutaclearpredisposingimmunodeficiency.
• The organisms that cause HIV-related opportunistic infections include bacteria, fungi,viruses,andprotozoa.Somearetransmittedpersontoperson,whereasothersarepresentincertainenvironmentalniches.
DIAGNOSIS• Given thebroadrangeofpathogens that cancause infectious syndromes inpatientswith
HIVinfection/AIDS,andthepotentialtoxicitiesoftherapeuticagents,specificmicrobiologicdiagnoses should be established when possible. AIDS-related opportunistic infections arediagnosedbyawidevarietyoftechniques,includingbacterialandfungalandviralculture,serumorbodyfluidantigenassaysorpolymerasechainreactionassays, colorimetricandimmunofluorescentstainofsecretionsortissue,andhistology.
THERAPY• TherearespecificagentsthatcansuccessfullytreatmostHIV-relatedopportunisticinfections
(seeTable69-1).Prognosisdependsontheseverityoftheacuteillnessaswellasprognosisforcomorbiditiesandavailabilityofeffectiveandwell-tolerated therapies.For someHIV-related opportunistic infections, such as cryptosporidiosis, microsporidiosis, and JC virusencephalitis, thereisnoeffectivespecifictherapy;clinicalresponsedependsonimprovingimmuneresponsebyinitiatingeffectiveantiretroviraltherapy.
PREVENTION• BecausepatientswithHIVinfectionhaveanextraordinarilyhighrateofopportunisticinfec-
tions, and because these opportunistic infections characteristically recur unless patients
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either are reconstituted with antiretroviral therapy (ART) or administered chemoprophy-laxis,bothARTandchemoprophylaxisarebothimportantpreventivestrategies(seeTable69-2).ForsomeinfectionssuchasPneumocystispneumonia,Toxoplasmaencephalitis,anddisseminatedMycobacterium aviumcomplex,primarypreventioniseffective,safe,andwelltolerated and should be part of standard patient management. Immunization is also animportantpartofroutineinfectionpreventionstrategy.
• Recommendationsfordiscontinuingorrestartingprophylacticmedicationsareavailable.
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections
OPPORTUNISTIC INFECTION PREFERRED THERAPY
ALTERNATIVE THERAPY OTHER COMMENTS
Pneumocystis pneumonia (PCP)
Patients who develop PCP despite TMP-SMX prophylaxis can usually be treated with standard doses of TMP-SMX.Duration of PCP treatment: 21 days
Indications for adjunctive corticosteroids:PaO2 <70 mm Hg at room air, orAlveolar-arterial O2 gradient >35 mm HgPrednisone doses (beginning as early as possible and within 72 hr of PCP therapy):Days 1-5: 40 mg PO bidDays 6-10: 40 mg PO dailyDays 11-21: 20 mg PO dailyIV methylprednisolone can be administered as 75% of prednisone dose.Benefit of corticosteroid if started after 72 hr of treatment is unknown, but some clinicians will use it for moderate-to-severe PCP.Whenever possible, patients should be tested for G6PD before use of dapsone or primaquine. Alternative therapy should be used in patients found to have G6PD deficiency.Patients who are receiving pyrimethamine-sulfadiazine for treatment or suppression of toxoplasmosis do not require additional PCP prophylaxis.If TMP-SMX is discontinued because of a mild adverse reaction, reinstitution should be considered after the reaction resolves. The dose can be increased gradually (desensitization), reduced, or the frequency modified.TMP-SMX should be permanently discontinued in patients with possible or definite Stevens-Johnson syndrome or toxic epidermal necrosis.
For moderate-to-severe PCP:TMP-SMX: (TMP 15-20 mg and SMX 75-100 mg)/kg/day IV given q6h or q8h; may switch to PO after clinical improvement
For moderate-to-severe PCP:Pentamidine 4 mg/kg IV daily infused over ≥60 min; can reduce dose to 3 mg/kg IV daily because of toxicities, orPrimaquine 30 mg (base) PO daily + clindamycin 600 mg q6h IV, or 900 mg IV q8h, or clindamycin 300 mg PO q6h, or 450 mg PO q8h
For mild-to-moderate PCP:TMP-SMX: (TMP 15-20 mg and SMX 75-100 mg)/kg/day, given PO in three divided doses, orTMP-SMX: (160 mg/800 mg or DS) 2 tablets PO tid
For mild-to-moderate PCP:Dapsone 100 mg PO daily + TMP 5 mg/kg PO tid, orPrimaquine 30 mg (base) PO daily + clindamycin 300 mg PO q6h, or 450 mg PO q8h, orAtovaquone 750 mg PO bid with food
Secondary prophylaxis, after completion of PCP treatment:TMP-SMX DS: 1 tablet PO daily orTMP-SMX (80 mg/400 mg or SS): 1 tablet PO daily
Secondary prophylaxis, after completion of PCP treatment:TMP-SMX DS: 1 tablet PO three times a week, orDapsone 100 mg PO daily, orDapsone 50 mg PO daily + pyrimethamine 50 mg + leucovorin 25 mg PO weekly, orDapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg PO weekly, orAerosolized pentamidine 300 mg monthly via Respirgard II nebulizer, orAtovaquone 1500 mg PO daily, orAtovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily
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Toxoplasma gondii encephalitis
Treatment of acute infection:Pyrimethamine 200 mg PO 1 time, followed by weight-based therapy:If <60 kg, pyrimethamine 50 mg PO once daily + sulfadiazine 1000 mg PO q6h + leucovorin 10-25 mg PO once dailyIf ≥60 kg, pyrimethamine 75 mg PO once daily + sulfadiazine 1500 mg PO q6h + leucovorin 10-25 mg PO once dailyLeucovorin dose can be increased to 50 mg daily or bid.Duration for acute therapy:At least 6 wk; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 wk
Treatment of acute infection:Pyrimethamine (leucovorin)* + clindamycin 600 mg IV or PO q6h, orTMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) IV or PO bid, orAtovaquone 1500 mg PO bid with food + pyrimethamine (leucovorin), orAtovaquone 1500 mg PO bid with food + sulfadiazine 1000-1500 mg PO q6h (weight-based dosing, as in preferred therapy), orAtovaquone 1500 mg PO bid with food, orPyrimethamine (leucovorin)* + azithromycin 900-1200 mg PO daily
Adjunctive corticosteroids (e.g., dexamethasone) should only be administered when clinically indicated to treat mass effect associated with focal lesions or associated edema; discontinue as soon as clinically feasible.Anticonvulsants should be administered to patients with a history of seizures and continued through acute treatment but should not be used as seizure prophylaxis.If clindamycin is used in place of sulfadiazine, additional therapy must be added to prevent PCP.
Chronic maintenance therapy:Pyrimethamine 25-50 mg PO daily + sulfadiazine 2000-4000 mg PO daily (in two to four divided doses) + leucovorin 10-25 mg PO daily
Chronic maintenance therapy:Clindamycin 600 mg PO q8h + (pyrimethamine 25-50 mg + leucovorin 10-25 mg) PO daily, orTMP-SMX DS 1 tablet bid, orAtovaquone 750-1500 mg PO bid + (pyrimethamine 25 mg + leucovorin 10 mg) PO daily, orAtovaquone 750-1500 mg PO bid + sulfadiazine 2000-4000 mg PO daily (in two to four divided doses), orAtovaquone 750-1500 mg PO bid with food
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections—cont’d
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OPPORTUNISTIC INFECTION PREFERRED THERAPY
ALTERNATIVE THERAPY OTHER COMMENTS
Mycobacterium tuberculosis disease
After collecting specimen for culture and molecular diagnostic tests, empirical TB treatment should be started in individuals with clinical and radiographic presentation suggestive of TB.Initial phase (2 mo, given daily, 5-7 times/wk by DOT):INH + [RIF or RFB] + PZA + EMBContinuation phase:INH + (RIF or RFB) daily (5-7 times/wk) or three times a weekTotal duration of therapy (for drug-susceptible TB):Pulmonary TB: 6 moPulmonary TB and culture positive after 2 mo of TB treatment: 9 moExtrapulmonary TB with CNS infection: 9-12 moExtrapulmonary TB with bone or joint involvement: 6 to 9 moExtrapulmonary TB in other sites: 6 moTotal duration of therapy should be based on number of doses received, not on calendar time.
Treatment of drug-resistant TBResistant to INH:(RIF or RFB) + EMB + PZA + (moxifloxacin or levofloxacin) for 2 mo; followed by (RIF or RFB) + EMB + (moxifloxacin or levofloxacin) for 7 moResistant to rifamycins ± other drugs:Regimen and duration of treatment should be individualized based on resistance pattern, clinical and microbiologic responses, and in close consultation with experienced specialists.
Adjunctive corticosteroid improves survival for TB meningitis and pericarditis. RIF is not recommended for patients receiving HIV PI because of its induction of PI metabolism.RFB is a less potent CYP3A4 inducer than RIF and is preferred in patients receiving PIs.Once-weekly rifapentine can result in development of rifamycin resistance in HIV-infected patients and is not recommended.Therapeutic drug monitoring should be considered in patients receiving rifamycin and interacting ART.Paradoxical IRIS that is not severe can be treated with NSAIDs without a change in TB or HIV therapy.For severe IRIS reaction, consider prednisone and taper over 4 wk based on clinical symptoms.For example:If receiving RIF: prednisone 1.5 mg/kg/day for 2 wk, then 0.75 mg/kg/day for 2 wkIf receiving RFB: prednisone 1.0 mg/kg/day for 2 wk, then 0.5 mg/kg/day for 2 wkA more gradual tapering schedule over a few months may be necessary for some patients.
Disseminated Mycobacterium avium complex (MAC) disease
At least two drugs as initial therapy with:Clarithromycin 500 mg PO bid + ethambutol 15 mg/kg PO daily, orAzithromycin 500-600 mg + ethambutol 15 mg/kg PO daily if drug interaction or intolerance precludes the use of clarithromycinDuration:At least 12 mo of therapy, can discontinue if no signs and symptoms of MAC disease and sustained (>6 mo) CD4 count >100 cells/mm3 in response to ART
Addition of a third or fourth drug should be considered for patients with advanced immunosuppression (CD4 counts <50 cells/mm3), high mycobacterial loads (>2 log CFU/mL of blood), or in the absence of effective ART.Third or fourth drug options may include:RFB 300 mg PO daily (dosage adjustment may be necessary based on drug interactions),Amikacin 10-15 mg/kg IV daily or streptomycin 1 g IV or IM daily, orMoxifloxacin 400 mg PO daily or levofloxacin 500 mg PO daily
Testing of susceptibility to clarithromycin and azithromycin is recommended.NSAIDs can be used for patients who experience moderate to severe symptoms attributed to IRIS.If IRIS symptoms persist, short-term (4-8 wk) systemic corticosteroids (equivalent to 20-40 mg prednisone) can be used.
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections—cont’d
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Bacterial respiratory diseases (with focus on pneumonia)
Empirical antibiotic therapy should be initiated promptly for patients presenting with clinical and radiographic evidence consistent with bacterial pneumonia. The recommendations listed are suggested empirical therapy. The regimen should be modified as needed once microbiologic results are available.
Fluoroquinolones should be used with caution in patients in whom TB is suspected but is not being treated.Empirical therapy with a macrolide alone is not routinely recommended, because of increasing pneumococcal resistance.Patients receiving a macrolide for MAC prophylaxis should not receive macrolide monotherapy for empirical treatment of bacterial pneumonia.For patients begun on IV antibiotic therapy, switching to PO should be considered when they are clinically improved and able to tolerate oral medications.Chemoprophylaxis can be considered for patients with frequent recurrences of serious bacterial pneumonia.Clinicians should be cautious about using antibiotics to prevent recurrences because of the potential for developing drug resistance and drug toxicities.
Empirical outpatient therapy:A PO β-lactam + a PO macrolide (azithromycin or clarithromycin)Preferred β-lactams: High-dose amoxicillin or amoxicillin/clavulanateAlternative β-lactams: Cefpodoxime or cefuroxime, orFor penicillin-allergic patients: Levofloxacin 750 mg PO once daily, or moxifloxacin 400 mg PO once dailyDuration: 7-10 days (a minimum of 5 days). Patients should be afebrile for 48-72 hr and clinically stable before stopping antibiotics.
Empirical outpatient therapy:A PO β-lactam + PO doxycyclinePreferred β-lactams: High-dose amoxicillin or amoxicillin-clavulanateAlternative β-lactams: Cefpodoxime or cefuroxime
Empirical therapy for non-ICU hospitalized patients:An IV β-lactam + a macrolide (azithromycin or clarithromycin)Preferred β-lactams: ceftriaxone, cefotaxime, or ampicillin-sulbactamFor penicillin-allergic patients:Levofloxacin, 750 mg IV once daily, or moxifloxacin, 400 mg IV once daily
Empirical therapy for non-ICU hospitalized patients:An IV β-lactam + doxycycline
Empirical therapy for ICU patients:An IV β-lactam + IV azithromycin, orAn IV β-lactam + (levofloxacin 750 mg IV once daily or moxifloxacin 400 mg IV once daily)Preferred β-lactams: Ceftriaxone, cefotaxime, or ampicillin-sulbactam
Empirical therapy for ICU patients:For penicillin-allergic patients: Aztreonam IV + (levofloxacin 750 mg IV once daily or moxifloxacin 400 mg IV once daily)
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Empirical therapy for patients at risk for Pseudomonas pneumonia:An IV antipneumococcal, antipseudomonal β-lactam + (ciprofloxacin 400 mg IV q8-12h or levofloxacin 750 mg IV once daily)Preferred β-lactams: Piperacillin-tazobactam, cefepime, imipenem, or meropenem
Empirical therapy for patients at risk for Pseudomonas pneumonia:An IV antipneumococcal, antipseudomonal β-lactam + an aminoglycoside + azithromycin, orAbove β-lactam + an aminoglycoside + (levofloxacin 750 mg IV once daily or moxifloxacin 400 mg IV once daily), orFor penicillin-allergic patients: Replace the β-lactam with aztreonam
Empirical therapy for patients at risk for methicillin-resistant Staphylococcus aureus pneumonia:Add vancomycin IV or linezolid (IV or PO) to the baseline regimen.Addition of clindamycin to vancomycin (but not to linezolid) can be considered for severe necrotizing pneumonia to minimize bacterial toxin production.
Salmonellosis Ciprofloxacin 500-750 mg PO (or 400 mg IV) q12h, if susceptibleDuration of therapy:For gastroenteritis without bacteremia:If CD4 count ≥ 200 cells/mm3: 7-14 daysIf CD4 count < 200 cells/mm3: 2-6 wkFor gastroenteritis with bacteremia:If CD4 count ≥ 200/mm3: 14 days; longer duration if bacteremia persists or if the infection is complicated (e.g., if metastatic foci of infection are present)If CD4 count < 200 cells/mm3: 2-6 wkSecondary prophylaxis should be considered for:Patients with recurrent Salmonella gastroenteritis ± bacteremia, orPatients with CD4 <200 cells/mm3 with severe diarrhea
Levofloxacin 750 mg (PO or IV) q24h, orMoxifloxacin 400 mg (PO or IV) q24h, orTMP-SMX (160 mg/800 mg) (PO or IV) q12h, orCeftriaxone 1 g IV q24h, orCefotaxime 1 g IV q8h
Oral or IV rehydration if indicated.Antimotility agents should be avoided.The role of long-term secondary prophylaxis in patients with recurrent Salmonella bacteremia is not well established. Must weigh benefit against risks of long-term antibiotic exposure.Effective ART may reduce the frequency, severity, and recurrence of Salmonella infections.
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections—cont’d
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Mucocutaneous candidiasis
For oropharyngeal candidiasis; initial episodes (for 7-14 days):Oral therapy:Fluconazole 100 mg PO daily, orTopical therapy:Clotrimazole troches, 10 mg PO five times daily, orMiconazole mucoadhesive buccal 50-mg tablet—apply to mucosal surface over the canine fossa once daily (do not swallow, chew, or crush)
For oropharyngeal candidiasis; initial episodes (for 7-14 days):Oral therapy:Itraconazole oral solution 200 mg PO daily, orPosaconazole oral solution 400 mg PO bid for 1 day, then 400 mg dailyTopical therapy:Nystatin suspension 4-6 mL qid or one to two flavored pastilles four to five times daily
Chronic or prolonged use of azoles may promote development of resistance.Higher relapse rate for esophageal candidiasis seen with echinocandins than with fluconazole use.Suppressive therapy usually not recommended unless patients have frequent or severe recurrences.If decision is to use suppressive therapy:Oropharyngeal candidiasis:Fluconazole 100 mg PO daily or three times a weekItraconazole oral solution 200 mg PO dailyEsophageal candidiasis:Fluconazole 100-200 mg PO dailyPosaconazole 400 mg PO bidVulvovaginal candidiasis:Fluconazole 150 mg PO once weekly
For esophageal candidiasis (for 14-21 days):Fluconazole 100 mg (up to 400 mg) PO or IV daily, orItraconazole oral solution 200 mg PO daily
For esophageal candidiasis (for 14-21 days):Voriconazole 200 mg PO or IV bid, orPosaconazole 400 mg PO bid, orAnidulafungin 100 mg IV one time, then 50 mg IV daily orCaspofungin 50 mg IV daily, orMicafungin 150 mg IV daily, orAmphotericin B deoxycholate 0.6 mg/kg IV daily orLipid formulation of amphotericin B 3-4 mg/kg IV daily
For uncomplicated vulvovaginal candidiasis:Oral fluconazole 150 mg for one dose, orTopical azoles (clotrimazole, butoconazole, miconazole, tioconazole, or terconazole) for 3-7 days
For uncomplicated vulvovaginal candidiasis:Itraconazole oral solution 200 mg PO daily for 3-7 days
For severe or recurrent vulvovaginal candidiasis:Fluconazole 100-200 mg PO daily for ≥7 days, orTopical antifungal ≥7 days
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Cryptococcosis Cryptococcal meningitis:Induction therapy (for at least 2 wk, followed by consolidation therapy):Liposomal amphotericin B 3-4 mg/kg IV daily + flucytosine 25 mg/kg PO qid (Note: flucytosine dose should be adjusted in patients with renal dysfunction.)
Cryptococcal meningitis:Induction therapy (for at least 2 wk, followed by consolidation therapy):Amphotericin B deoxycholate 0.7 mg/kg IV daily + flucytosine 25 mg/kg PO qid, orAmphotericin B lipid complex 5 mg/kg IV daily + flucytosine 25 mg/kg PO qid, orLiposomal amphotericin B 3-4 mg/kg IV daily + fluconazole 800 mg PO or IV daily, orAmphotericin B deoxycholate 0.7 mg/kg IV daily + fluconazole 800 mg PO or IV daily, orFluconazole 400-800 mg PO or IV daily + flucytosine 25 mg/kg PO qid, orFluconazole 1200 mg PO or IV daily
Addition of flucytosine to amphotericin B has been associated with more rapid sterilization of CSF and decreased risk for subsequent relapse.Patients receiving flucytosine should have either blood levels monitored (peak level 2 hr after dose should be 30-80 µg/mL) or close monitoring of blood cell counts for development of cytopenia. Dosage should be adjusted in patients with renal insufficiency.Opening pressure should always be measured when an LP is performed. Repeated LPs or CSF shunting are essential to effectively manage increased intracranial pressure.Corticosteroids and mannitol are ineffective in reducing ICP and are not recommended.Some specialists recommend a brief course of corticosteroid for management of severe IRIS symptoms.
Consolidation therapy (for at least 8 wk followed by maintenance therapy):Fluconazole 400 mg PO (or IV) daily
Consolidation therapy (for at least 8 wk followed by maintenance therapy):Itraconazole 200 mg PO bid for 8 wk—less effective than fluconazole
Maintenance therapy:Fluconazole 200 mg PO daily for at least 12 mo
Maintenance therapy:No alternative therapy recommendation
For non-CNS, extrapulmonary cryptococcosis and diffuse pulmonary disease:Treatment same as for cryptococcal meningitisNon-CNS cryptococcosis with mild-to-moderate symptoms and focal pulmonary infiltrates:Fluconazole, 400 mg PO daily for 12 mo
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections—cont’d
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Histoplasmosis Moderately severe to severe disseminated disease:Induction therapy (for at least 2 wk or until clinically improved):Liposomal amphotericin B 3 mg/kg IV dailyMaintenance therapy:Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bid
Moderately severe to severe disseminated disease:Induction therapy (for at least 2 wk, or until clinically improved):Amphotericin B lipid complex 3 mg/kg IV daily, orAmphotericin B cholesteryl sulfate complete 3 mg/kg IV daily
Itraconazole, posaconazole, and voriconazole may have significant interactions with certain ARV agents. These interactions are complex and can be bidirectional.Therapeutic drug monitoring and dosage adjustment may be necessary to ensure triazole antifungal and ARV efficacy and reduce concentration-related toxicities.Random serum concentration of itraconazole + hydroitraconazole should be >1 µg/mL.Clinical experience with voriconazole or posaconazole in the treatment of histoplasmosis is limited.Acute pulmonary histoplasmosis in HIV-infected patients with CD4 counts >300 cells/mm3 should be managed as nonimmunocompromised host.
Less severe disseminated disease:Induction and maintenance therapy:Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bidDuration of therapy:At least 12 mo
Alternatives to itraconazole for maintenance therapy or treatment of less severe disease:Voriconazole 400 mg PO bid for 1 day, then 200 mg bid, orPosaconazole 400 mg PO bid, orFluconazole 800 mg PO daily
Meningitis:Induction therapy (4-6 wk):Liposomal amphotericin B 5 mg/kg/dayMaintenance therapy:Itraconazole 200 mg PO bid to tid for ≥1 year and until resolution of abnormal CSF findings
Meningitis:No alternative therapy recommendation
Long-term suppression therapy:For patients with severe disseminated or CNS infection after completion of at least 12 mo of therapy; and those who relapse despite appropriate therapy:Itraconazole 200 mg PO daily
Long-term suppression therapy:Fluconazole 400 mg PO daily
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Coccidioidomycosis Clinically mild infections (e.g., focal pneumonia):Fluconazole 400 mg PO daily, orItraconazole 200 mg PO bid
Mild infections (focal pneumonia):For patients who failed to respond to fluconazole or itraconazole:Posaconazole 200 mg PO bid, orVoriconazole 200 mg PO bid)
Some patients with meningitis may develop hydrocephalus and require CSF shunting.Therapy should be continued indefinitely in patients with diffuse pulmonary or disseminated diseases because relapse can occur in 25%-33% of HIV-negative patients. It can also occur in HIV-infected patients with CD4 counts >250 cells/mm3.Therapy should be lifelong in patients with meningeal infections because relapse occurs in 80% of HIV-infected patients after discontinuation of triazole therapy.Itraconazole, posaconazole, and voriconazole may have significant interactions with certain ARV agents. These interactions are complex and can be bidirectional. Therapeutic drug monitoring and dosage adjustment may be necessary to ensure triazole antifungal and antiretroviral efficacy and reduce concentration-related toxicities.Intrathecal amphotericin B should only be given in consultation with a specialist and administered by an individual with experience with the technique.
Severe, nonmeningeal infection (diffuse pulmonary infection or severely ill patients with extrathoracic, disseminated disease):Amphotericin B deoxycholate 0.7-1.0 mg/kg IV dailyLipid formulation amphotericin B 4-6 mg/kg IV dailyDuration of therapy: Continue until clinical improvement, then switch to an azole.
Severe, nonmeningeal infection (diffuse pulmonary infection or severely ill patients with extrathoracic, disseminated disease):Some specialists will add a triazole (fluconazole or itraconazole, with itraconazole preferred for bone disease) 400 mg/day to amphotericin B therapy and continue triazole once amphotericin B is stopped.
Meningeal infections:Fluconazole 400-800 mg IV or PO daily
Meningeal infections:Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bid, orPosaconazole 200 mg PO bid, orVoriconazole 200-400 mg PO bid, orIntrathecal amphotericin B deoxycholate, when triazole antifungal agents are ineffective
Chronic suppressive therapy:Fluconazole 400 mg PO daily, orItraconazole 200 mg PO bid
Chronic suppressive therapy:Posaconazole 200 mg PO bid, orVoriconazole 200 mg PO bid
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections—cont’d
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Cytomegalovirus (CMV) disease
CMV retinitis:Induction therapy for immediate sight-threatening lesions (adjacent to the optic nerve or fovea):Consult ophthalmologist because ganciclovir implant no longer available:Ganciclovir 5 mg/kg IV q12h for 14-21 days followed by valganciclovir 900 mg PO bidFor small peripheral lesions:Valganciclovir 900 mg PO bid for 14-21 daysOne dose of intravitreal ganciclovir can be administered immediately after diagnosis until steady-state plasma ganciclovir concentration is achieved with oral valganciclovir.
CMV retinitis:Induction therapy:Ganciclovir 5 mg/kg IV q12h for 14-21 days, orFoscarnet 90 mg/kg IV q12h or 60 mg q8h for 14-21 days, orCidofovir 5 mg/kg/wk IV for 2 wk; saline hydration before and after therapy and probenecid, 2 g PO 3 hr before dose, followed by 1 g PO 2 hr and 8 hr after the dose (total of 4 g). (Note: This regimen should be avoided in patients with sulfa allergy because of cross-hypersensitivity with probenecid.)
The choice of therapy for CMV retinitis should be individualized, based on location and severity of the lesions, level of immunosuppression, and other factors (e.g., concomitant medications and ability to adhere to treatment).The choice of chronic maintenance therapy (route of administration and drug choices) should be made in consultation with an ophthalmologist. Considerations should include the anatomic location of the retinal lesion, vision in the contralateral eye, the patients’ immunologic and virologic status and response to ART.Patients with CMV retinitis who discontinue maintenance therapy should undergo regular eye examinations (optimally every 3 mo) for early detection of relapse IRU, and then annually after immune reconstitution.IRU may develop in the setting of immune reconstitution.Treatment of IRU:Periocular corticosteroid or short courses of systemic corticosteroid.Initial therapy in patients with CMV retinitis, esophagitis, colitis, and pneumonitis should include initiation or optimization of ART.
Chronic maintenance (secondary prophylaxis):Valganciclovir 900 mg PO daily (for small peripheral lesion)
Chronic maintenance (secondary prophylaxis):Ganciclovir 5 mg/kg IV five to seven times weekly, orFoscarnet 90-120 mg/kg IV once daily, orCidofovir 5 mg/kg IV every other week with saline hydration and probenecid as above
CMV esophagitis or colitis:Ganciclovir 5 mg/kg IV q12h; may switch to valganciclovir 900 mg PO q12h once the patient can tolerate oral therapyDuration: 21-42 days or until symptoms have resolvedMaintenance therapy is usually not necessary, but should be considered after relapses.
CMV esophagitis or colitis:Foscarnet 90 mg/kg IV q12h or 60 mg/kg q8h for patients with treatment-limiting toxicities to ganciclovir or with ganciclovir resistance, orValganciclovir 900 mg PO q12h in milder disease and if able to tolerate PO therapy, orFor mild cases, if ART can be initiated without delay, consider withholding CMV therapy.Duration: 21-42 days or until symptoms have resolved.
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OPPORTUNISTIC INFECTION PREFERRED THERAPY
ALTERNATIVE THERAPY OTHER COMMENTS
Well-documented, histologically confirmed CMV pneumonia:Experience for treating CMV pneumonitis in HIV patients is limited. Use of IV ganciclovir or IV foscarnet is reasonable (doses same as for CMV retinitis)The optimal duration of therapy and the role of oral valganciclovir have not been established.
Herpes simplex virus (HSV) disease
Orolabial lesions (for 5-10 days):Valacyclovir 1 g PO bid, orFamciclovir 500 mg PO bid, orAcyclovir 400 mg PO tidInitial or recurrent genital HSV (for 5-14 days):Valacyclovir 1 g PO bid, orFamciclovir 500 mg PO bid, orAcyclovir 400 mg PO tidSevere mucocutaneous HSV:Initial therapy, acyclovir 5 mg/kg IV q8hAfter lesions begin to regress, change to PO therapy as above. Continue until lesions are completely healed.Chronic suppressive therapy:For patients with severe recurrences of genital herpes or patients who want to minimize frequency of recurrences:Valacyclovir 500 mg PO bid, orFamciclovir 500 mg PO bid, orAcyclovir 400 mg PO bidContinue indefinitely regardless of CD4 cell count.
For acyclovir-resistant HSV:Preferred therapy:Foscarnet 80-120 mg/kg/day IV in two to three divided doses until clinical responseAlternative therapy:IV cidofovir (dosage as in CMV retinitis), orTopical trifluridine, orTopical cidofovir, orTopical imiquimodDuration of therapy:21-28 days or longer
Patients with HSV infections can be treated with episodic therapy when symptomatic lesions occur or with daily suppressive therapy to prevent recurrences.Topical formulations of trifluridine and cidofovir are not commercially available.Extemporaneous compounding of topical products can be prepared using trifluridine ophthalmic solution and the IV formulation of cidofovir.
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections—cont’d
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OPPORTUNISTIC INFECTION PREFERRED THERAPY
ALTERNATIVE THERAPY OTHER COMMENTS
Varicella-zoster virus (VZV) disease
Primary varicella infection (chickenpox):Uncomplicated cases (for 5-7 days):Valacyclovir 1 g PO tid, orFamciclovir 500 mg PO tidSevere or complicated cases:Acyclovir 10-15 mg/kg IV q8h for 7-10 daysMay switch to oral valacyclovir, famciclovir, or acyclovir after defervescence if no evidence of visceral involvement
Primary varicella infection (chickenpox)Uncomplicated cases (for 5-7 days):Acyclovir 800 mg PO five times a day
In managing VZV retinitis consultation with an ophthalmologist experienced in management of VZV retinitis is strongly recommended.Duration of therapy for VZV retinitis is not well defined and should be determined based on clinical, virologic, and immunologic responses and ophthalmologic responses.Optimization of ART is recommended for serious and difficult-to-treat VZV infections (e.g., retinitis, encephalitis).
Herpes zoster (shingles):Acute localized dermatomal:For 7-10 days consider longer duration if lesions are slow to resolve.Valacyclovir 1 g PO tid, orFamciclovir 500 mg tid
Herpes zoster (shingles):Acute localized dermatomal:For 7-10 days consider longer duration if lesions are slow to resolve.Acyclovir 800 mg PO five times a day
Extensive cutaneous lesion or visceral involvement:Acyclovir 10-15 mg/kg IV q8h until clinical improvement is evidentMay switch to PO therapy (valacyclovir, famciclovir, or acyclovir) after clinical improvement (i.e., when no new vesicle formation or improvement of signs and symptoms of visceral VZV), to complete a 10-14 day course.
Progressive outer retinal necrosis (PORN):(Ganciclovir 5 mg/kg + foscarnet 90 mg/kg) IV q12h + (ganciclovir 2 mg/0.05 mL ± foscarnet 1.2 mg/0.05 mL) intravitreal injection twice weekly, orInitiate or optimize ART.
Acute retinal necrosis (ARN):Acyclovir 10 mg/kg IV q8h for 10-14 days, followed by valacyclovir 1 g PO tid for 6 wk
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections—cont’d
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OPPORTUNISTIC INFECTION PREFERRED THERAPY
ALTERNATIVE THERAPY OTHER COMMENTS
Progressive multifocal leukoencephalopathy (PML) (JC virus infections)
There is no specific antiviral therapy for JC virus infection. The main treatment approach is to reverse the immunosuppression caused by HIV.Initiate ART immediately in ART-naïve patients.Optimize ART in patients who develop PML in phase of HIV viremia on ART.
None Corticosteroids may be used for PML-IRIS characterized by contrast enhancement, edema, or mass effect, and with clinical deterioration.
AIDS, acquired immunodeficiency syndrome; ART, antiretroviral therapy; ARV, antiretroviral; bid, twice daily; CD4, CD4+ lymphocyte cells; CFU, colony-forming unit; CNS, central nervous system; CSF, cerebrospinal fluid; CYP3A4, cytochrome P-450 3A4; DOT, directly observed therapy; DS, double strength; EMB, ethambutol; G6PD, glucose-6-phosphate dehydrogenase; HIV, human immunodeficiency virus; ICP, intracranial pressure; ICU, intensive care unit; IM, intramuscular; INH, isoniazid; IRIS, immune reconstitution inflammatory syndrome; IRU, immune recovery uveitis; IV, intravenous; LP, lumbar puncture; NSAIDs, nonsteroidal anti-inflammatory drugs; PI, protease inhibitor; PO, oral; PZA, pyrazinamide; q(n)h, every “n” hours; RFB, rifabutin; RIF, rifampin; SS, single strength; TB, tubercu-losis; tid, thrice daily; TVR, telaprevir; TMP-SMX, trimethoprim-sulfamethoxazole; ZDV, zidovudine.
*Pyrimethamine and leucovorin doses are the same as for preferred therapy.From Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents:
Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/guidelines. Accessed May 5, 2014.
TABLE 69-2 Prophylaxis to Prevent First Episode of Opportunistic Disease
OPPORTUNISTIC INFECTIONS INDICATION PREFERRED ALTERNATIVEPneumocystis pneumonia (PCP)
CD4 count <200 cells/mm3, or oropharyngeal candidiasis,or CD4 <14%, or history of AIDS-defining illness, orCD4 count >200 but <250 cells/mm3 if monitoring CD4 cell count every 3 mo is not possibleNote: Patients who are receiving pyrimethamine-sulfadiazine for treatment or suppression of toxoplasmosis do not require additional PCP prophylaxis.
TMP-SMX 1 DS tablet PO daily, orTMP-SMX 1 SS tablet PO daily
TMP-SMX 1 DS tablet PO three times a week, orDapsone 100 mg PO daily or 50 mg PO bid, orDapsone 50 mg PO daily + pyrimethamine 50 mg + leucovorin 25 mg PO weekly, orDapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg PO weekly; orAerosolized pentamidine 300 mg via Respirgard II nebulizer every month, orAtovaquone 1500 mg PO daily, or Atovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily
TABLE 69-1 Treatment of AIDS-Associated Opportunistic Infections—cont’d
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TABLE 69-2 Prophylaxis to Prevent First Episode of Opportunistic Disease—cont’d
OPPORTUNISTIC INFECTIONS INDICATION PREFERRED ALTERNATIVEToxoplasma gondii encephalitis
Toxoplasma IgG-positive patients with CD4 count <100 cells/mm3
Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have Toxoplasma serology retested if CD4 count declines to <100 cells/mm3.Prophylaxis should be initiated if seroconversion occurred.Note: All regimens recommended for primary prophylaxis against toxoplasmosis are also effective as PCP prophylaxis.
TMP-SMX 1 DS tablet PO daily
TMP-SMX 1 DS tablet PO three times a week, orTMP-SMX 1 SS tablet PO daily, orDapsone 50 mg PO daily + pyrimethamine 50 mg + leucovorin 25 mg PO weekly, orDapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg PO weekly; orAtovaquone 1500 mg PO daily; orAtovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily
Mycobacterium tuberculosis infection (i.e., treatment of LTBI)
Positive screening test for LTBI, with no evidence of active TB, and no prior treatment for active TB or LTBI, orClose contact with a person with infectious TB, with no evidence of active TB, regardless of screening test results.
INH 300 mg + pyridoxine 25 mg PO daily × 9 mo, orINH 900 mg PO twice weekly (by DOT) + pyridoxine 25 mg PO daily × 9 mo.
Rifampin 600 mg PO daily × 4 mo, orRifabutin (dose adjusted based on concomitant ART) × 4 mo.For persons exposed to drug-resistant TB, select anti-TB drugs after consultation with experts or public health authorities.
Disseminated Mycobacterium avium complex (MAC) disease
CD4 count <50 cells/mm3 after ruling out active disseminated MAC disease based on clinical assessment.
Azithromycin 1200 mg PO once weekly, orClarithromycin 500 mg PO bid, orAzithromycin 600 mg PO twice weekly
Rifabutin (dose adjusted based on concomitant ART); rule out active TB before starting rifabutin.
Streptococcus pneumoniae infection
For individuals who have not received any pneumococcal vaccine, regardless of CD4 count, followed by:if CD4 count ≥ 200 cells/mm3
if CD4 count < 200 cells/mm3
PCV13 0.5 mL IM × 1.PPV23 0.5 mL IM at least 8 wk after the PCV13 vaccine.PPV23 can be offered at least 8 wk after receiving PCV13 or can wait until CD4 count increased to >200 cells/mm3.
PPV23 0.5 mL IM × 1
For individuals who have previously received PPV23
One dose of PCV13 should be given at least 1 yr after the last receipt of PPV23.
Revaccination:If age 19-64 yr and ≥5 yr since the first PPV23 doseIf age ≥ 65 yr, and if ≥5 yr since the previous PPV23 dose
PPV23 0.5 mL IM × 1PPV23 0.5 mL IM × 1
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OPPORTUNISTIC INFECTIONS INDICATION PREFERRED ALTERNATIVEInfluenza A and B virus infection
All HIV-infected patients Inactivated influenza vaccine annually (per recommendation for the season).Live-attenuated influenza vaccine is contraindicated in HIV-infected patients.
Syphilis For individuals exposed to a sex partner with a diagnosis of primary, secondary, or early latent syphilis within past 90 days, orFor individuals exposed to a sex partner >90 days before syphilis diagnosis in the partner, if serologic test results are not available immediately after and the opportunity for follow-up is uncertain (AIII)
Benzathine penicillin G 2.4 million units IM for 1 dose
For pencillin-allergic patients:Doxycycline 100 mg PO bid for 14 days, orCeftriaxone 1 g IM or IV daily for 8-10 days, orAzithromycin 2 g PO for 1 dose: not recommended for MSM or pregnant women
Histoplasma capsulatum infection
CD4 count ≤150 cells/mm3and at high risk because of occupational exposure or live in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years)
Itraconazole 200 mg PO daily
Coccidioidomycosis A new positive IgM or IgG serologic test in patients who live in a disease-endemic area and with CD4 count <250 cells/mm3
Fluconazole 400 mg PO daily
Varicella-zoster virus Preexposure prevention:Patients with CD4 counts ≥200 cells/mm3 who have not been vaccinated, have no history of varicella or herpes zoster, or who are seronegative for VZVNote: Routine VZV serologic testing in HIV-infected adults and adolescents is not recommended.
Preexposure prevention:Primary varicella vaccination (Varivax), two doses (0.5 mL SQ each) administered 3 mo apart.If vaccination results in disease because of vaccine virus, treatment with acyclovir is recommended.
Preexposure prevention:VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent potential transmission of VZV to their HIV-infected contacts.
TABLE 69-2 Prophylaxis to Prevent First Episode of Opportunistic Disease—cont’d
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TABLE 69-2 Prophylaxis to Prevent First Episode of Opportunistic Disease—cont’d
OPPORTUNISTIC INFECTIONS INDICATION PREFERRED ALTERNATIVE
Postexposure prevention:Close contact with a person with chickenpox or herpes zoster and is susceptible (i.e., no history of vaccination or of either condition, or known to be VZV seronegative)
Postexposure prevention:Varicella-zoster immune globulin (VariZIG) 125 IU/10 kg (maximum 625 IU) IM, administered as soon as possible and within 10 days after exposure.Note: VariZIG is available through Cangene, Canada.Individuals receiving monthly high-dose IVIG (>400 mg/kg) are likely to be protected if the last dose of IVIG was administered <3 wk before exposure.
Alternative postexposure prevention:Acyclovir 800 mg PO five times a day for 5-7 days, orValacyclovir 1 g PO tid for 5-7 daysThese alternatives have not been studied in the HIV population.If antiviral therapy is used, varicella vaccines should not be given until at least 72 hr after the last dose of the antiviral drug.
Hepatitis A virus (HAV) infection
HAV-susceptible patients with chronic liver disease or who are injection drug users or MSM.
Hepatitis A vaccine 1 mL IM × two doses at 0 and 6-12 mo.IgG antibody response should be assessed 1 mo after vaccination; nonresponders should be revaccinated when CD4 count > 200 cells/mm3.
For patients susceptible to both HAV and hepatitis B virus (HBV) infection (see below):Combined HAV and HBV vaccine (Twinrix), 1 mL IM as a three-dose (0, 1, and 6 mo) or four-dose series (days 0, 7, 21 to 30 and at 12 mo)
Hepatitis B virus (HBV) infection
Vaccine nonresponders:Anti-HBs <10 IU/mL 1 mo after vaccination series.For patients with low CD4 counts at time of first vaccine series, some specialists might delay revaccination until after sustained increase in CD4 count with ART.
Revaccinate with a second vaccine series.
Some experts recommend revaccinating with 40-µg doses of either HBV vaccine.
ART, antiretroviral therapy; CD4, CD4+ lymphocyte count; DOT, directly observed treatment; DS, double strength; HBs, hepatitis B surface antibody; HIV, human immunodeficiency virus; IM, intramuscular; INH, isoniazid; IVIG, intravenous immune globulin; LTBI, latent tuberculosis infection; MSM, men who have sex with men; PCV13, 13-valent pneumococcal conjugate vaccine; PO, oral; PPV23, 23-valent pneumococcal polysaccharide vaccine; SQ, subcutaneous; SS, single strength; TB, tuberculosis; TMP-SMX, trimethoprim-sulfamethoxazole; VZV, varicella-zoster virus.
From Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/guidelines. Accessed May 5, 2014.
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P Miscellaneous Syndromes
70 Chronic Fatigue SyndromeN. Cary Engleberg
DEFINITION• As defined in a 1994 Centers for Disease Control and Prevention/National Institutes of
Healthconsensusconference,chronicfatiguesyndrome(CFS)isadisorderinvolving6ormoremonthsofunexplained,profoundfatiguewithat least fourofeightassociatedsymp-toms(seeTable70-1).
• A new name, “systemic exertion intolerance disease” was proposed by the Institute ofMedicinein2015,alongwithsomewhatmodifieddiagnosticcriteria(seeTable70-2).
• Othernamesusedforthisdisorderinclude“postinfectiousfatigue,”“chronicmononucleosis,”“myalgicencephalomyelitis”(UnitedKingdom/Canada),and“chronicfatigueandimmunedysfunctionsyndrome”(UnitedStates).
EPIDEMIOLOGY• Prevalenceisestimatedat0.2%to1%ofthepopulation,dependingonthedefinitionsused.• CFSoccursinwomenthreetoseventimesmorefrequentlythaninmen.• Itoccursinallsocioeconomicstrataandamongallraces.
ETIOLOGY• CFSmaybeasequelofvariousinfectiousdiseases(e.g.,herpesvirusinfections,influenza,Q
fever, brucellosis, Lyme disease, giardiasis) but is not known to be directly related to anyongoingchronicinfection(seeTable70-3).
• Subtledisturbancesofimmunefunctionarenotconsistentandnotknowntobecausativeofsymptoms.
• Hypothalamus-pituitary-adrenalaxisorautonomicdisturbancesmayoccur,butcorrectingthesesubtleanomaliesdoesnotimprovesymptomsofCFS.
• Priororconcurrenthistoryofpsychiatricdisordersiscommon.
DIAGNOSIS• Diagnosisisclinicalandusuallybasedonthe1994consensusdefinition(seeTable70-1).• ModifieddiagnosticcriteriahavealsobeenproposedbytheInstituteofMedicinein2015
(seeTable70-2).• ThereisnovalidlaboratorytesttoruleinortoruleoutCFS.
THERAPY• Pharmacologic therapiesaredirectedatrelievingsymptomsofpain,sleepdisruption,and
depression.• Noantimicrobialandimmunetherapieshavebeenproventobehelpful.• Nonpharmacologic therapies (cognitive-behavioral therapy and graded exercise therapy)
havebeenrepeatedlyshowntobehelpfulinmostpatients.
PREVENTION• Therearenoknownpreventivemeasures.
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TABLE 70-1 CDC/NIH Consensus Conference Definition of Chronic Fatigue SyndromeClinically evaluated, unexplained chronic fatigue for >6 mo duration, which is not lifelong or the result of
ongoing exertion and is not alleviated substantially by rest. Fatigue is associated with a significant reduction in occupational, educational, social, or personal activities plus ≥4 of the following concurrent symptoms:Impaired memory or concentrationSore throatTender cervical or axillary lymph nodesMuscle painMultijoint painNew headachesUnrefreshing sleepPostexertion malaise
CDC, Centers for Disease Control and Prevention; NIH, National Institutes of Health.Modified from Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach
to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-959.
TABLE 70-2 IOM Diagnostic Criteria for Systemic Exertion Intolerance DiseaseDiagnosis requires that the patient have the following three symptoms:
1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and
2. Postexertional malaise,* and3. Unrefreshing sleep*
At least one of the following manifestations is also required:1. Cognitive impairment* or2. Orthostatic intolerance
*Frequency and severity of symptoms should be assessed. The diagnosis of systemic intolerance disease (myalgic encephalomyelitis/chronic fatigue syndrome) should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
TABLE 70-3 Proposed Infectious Causes of Chronic Fatigue Syndrome
Proposed Etiologic Agent
REFERENCES
Suggestive Studies Negative StudiesEpstein-Barr virus 6, 7, 173 13, 14, 15, 16, 174-176
Cytomegalovirus 177, 178 13, 14, 174-176
Human herpesvirus 6 45, 46, 179, 180 13, 14, 175, 176, 181, 182
Human herpesvirus 7 183 46, 175, 179, 182
Human herpesvirus 8 — 46, 175, 184
Enteroviruses 185-187 13, 14, 188-191
Parvovirus 39, 192 175, 193, 194
GB virus-C 195
Human spumavirus 196 —
Bornavirus 197, 198 199
Human retrovirus 200 201-203
Xenotropic murine retrovirus (XMRV)
49, 50 54, 56-5859 (retraction of 49)60 (retraction of 50)
Borrelia burgdorferi 204 205, 206
Brucella spp. 207 3
Mycoplasma spp. 208, 209 210
Candida albicans 211, 212 213
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PART II
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A Viral Diseases
71 Orthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and CowpoxBrett W. Petersen and Inger K. Damon*
DEFINITION• Orthopoxvirus infections can cause a spectrum of febrile rash illnesses in humans, from
fairlybenign,localizedskininfectionstoseveresystemicinfections.• Vaccinia(smallpoxvaccine),variola(smallpox),monkeypox,andcowpoxarethefourortho-
poxvirusspeciesknowntocausehumandisease.
EPIDEMIOLOGY• Mostorthopoxvirusinfectionsarezoonotic,withhumansservingasaccidentalhosts.• Vacciniaviruscontinuestobeusedasavaccine,aswellasasubjectandtoolforbiomedical
research,anditcausessporadicdiseaseinvaccinees,contactsofvaccinees,andlaboratoryworkers.
• Variola,thecausativeagentofsmallpox,causedsignificantmorbidityandmortalityworld-widebeforeitseradicationin1980.
• Monkeypox virus causes intermittent human infections, primarily in Central and WestAfrica,althoughisolatedoutbreakshavebeenidentifiedintheUnitedStatesandSudan.
• Humancowpoxvirusinfectionisclassicallyassociatedwithoccupationalexposuretocattle;however, other animals, including rats, pet cats, and zoo and circus elephants, have beenimplicated.
MICROBIOLOGY• Orthopoxvirusesareagroupoflarge,complex,double-strandedDNAvirusesthatreplicate
inthecytoplasmofthehostcell.
DIAGNOSIS• Diagnostic laboratory testing for orthopoxvirus infections can include polymerase chain
reaction,viralculture,andelectronmicroscopyofrashlesionmaterial,aswellasserologictestingofserum.
THERAPY• Vaccinia Immune Globulin Intravenous (VIGIV) is licensed for the treatment of certain
complicationsofvacciniavaccineadministrationand is available through theCenters forDiseaseControlandPrevention.
• Noantiviraldrugsarecurrentlylicensedforuseinthetreatmentoforthopoxvirusorotherpoxviralillnesses.
• Thedevelopmentandevaluationfor therapeutics fororthopoxvirus infections isanactiveareaofresearch.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
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orthopoxvirusspecies.• Vaccinationwithsmallpoxvaccine(i.e.,vacciniavirus)canbeusedtoprotectindividualsat
highriskoforthopoxvirusdisease.• Othercontrolmeasures focusoneducationaloutreachtodecreasetheriskofexposureto
likelyzoonoticvectors.
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72 Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and YatapoxvirusesBrett W. Petersen and Inger K. Damon*
DEFINITION• Parapoxviruses,molluscumcontagiosum,andyatapoxvirusesareamongthenonorthopox-
virusinfectionsofhumans.
EPIDEMIOLOGY• Parapoxvirusinfectionsmostcommonlyoccurinindividualswithoccupationalexposures
toinfectedsheep,cattle,orgoats.• Molluscum contagiosum infection occurs worldwide and is spread through mild skin
trauma,fomites,andsexualtransmission.• Yatapoxvirus infections are rarely reported; infections are acquired through exposure to
infectedanimalsandpotentiallyarthropodvectorsandareusuallygeographicallyrestrictedtoCentralandEastAfrica.
MICROBIOLOGY• Poxvirusesareadiversegroupoflarge,complexdouble-strandedDNAvirusesthatreplicate
inthecytoplasmofthehostcell.
DIAGNOSIS• Parapoxvirus, molluscum contagiosum, and yatapoxvirus infections are often diagnosed
clinically based on their characteristic clinical features in combination with appropriateexposureandtravelhistories.
• Diagnostic laboratorytestingforpoxvirusesmayincludepolymerasechainreactionassay,electronmicroscopy,viralculture,andserology.
THERAPY• Parapoxvirus infections are usually self-limited; treatment with topical and intralesional
cidofovir,aswellasimiquimod,hasbeenanecdotallyreported.• Multiplemodalitiesfortreatmentofmolluscumcontagiosumhavebeendescribed,including
cryotherapy, mechanical curettage, and chemical treatments with podophyllin/podofilox,cantharidin,iodine,andtretinoin.
PREVENTION• Transmissionofparapoxviruses,molluscumcontagiosum,andyatapoxvirusescanbepre-
ventedbyavoidingexposures toanimalvectors,properly covering lesions, andobservinggoodhandhygienepractices.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
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73 Herpes Simplex VirusJoshua T. Schiffer and Lawrence Corey
DEFINITION• Herpessimplexvirus(HSV)isahumanα-herpesvirusoftwotypes,HSV-1andHSV-2.• Bothtypescausecommoninfectionswithvariedclinicalmanifestationsinotherwisehealthy
childrenandadultsthataregenerallymoresevereinpatientswithimmunosuppression.
EPIDEMIOLOGY• HSV-1andHSV-2haveaworldwidedistributionandhavenoknownanimalreservoirs.• HSV-1isacquiredmorefrequentlyandearlierthanHSV-2.Morethan90%ofadultshave
antibodiestoHSV-1bythefifthdecadeoflife.• HSV-2seroprevalencecorrelateswithonsetofsexualactivityandisconsistentlyhigherin
womenthanmen.• GlobalincidenceofHSV-2hasbeenestimatedat23millionnewcasesperyear.
MICROBIOLOGY• HSVisanonenvelopedvirusthatis160nmindiameterandhasalinear,double-stranded
DNAgenome.• HSV-1andHSV-2haveapproximately50%homology,andhomologoussequencesaredis-
tributedthroughoutthegenomemap.• HSVinfectionoccursthroughattachmenttocellsviaubiquitousreceptors,reflectingawide
tissuerangeofinfectionsinthehost,includingsensoryneurons,whichcanresultinlatency.• Viralreplicationoccursthroughnuclearandcytoplasmicphases.• Latency is associated with transcription of only a limited number of virus-encoded ribo-
nucleicacids.
CLINICAL MANIFESTATIONS• HSV has been isolated from nearly all visceral and mucosal sites. Clinical manifestations
dependontheanatomicsite,age,andimmunestatusofthehostandantigenictype(1or2)ofthevirus.
• Initial (primary) infectionsaremoresevere thanrecurrentones,butreactivationof latentinfectioncanresultinfrequentclinicalmanifestations.
• Orofacial infection(gingivostomatitisandpharyngitis) is themost frequent initialclinicalmanifestation of HSV-1 infection. Recurrent lesions on the vermilion border of the lip(herpeslabialis)arethemostfrequentmanifestationoflatentinfection.
• ClinicalaspectsofprimarygenitalinfectionsareclinicallysimilarwithHSV-1orHSV-2,butrecurrencesaremorefrequentwithHSV-2.Complicationsincludeasepticmeningitis,trans-versemyelitis,andsacralradiculopathy.Extragenitallesionsmayoccurduringthecourseofprimarygenitalinfection.
• HSV can cause various eye infections such as keratitis, blepharitis, conjunctivitis, andretinitis.
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TABLE 73-1 Antiviral Chemotherapy for Herpes Simplex Virus Infection
DOSAGE/REGIMEN COMMENT
Mucocutaneous HSV Infections
Infections in Immunosuppressed Patients
Acute symptomatic first or recurrent episodes
IV acyclovir, 5 mg/kg q8h, and oral acyclovir, 400 mg qid, famciclovir, 500 mg PO tid, or valacyclovir, 1 mg PO bid, for 7-10 days are effective
Treatment duration may vary from 7-14 days
Suppression of reactivation disease
IV acyclovir, 5 mg/kg q8h, valacyclovir, 500 mg PO bid, or oral acyclovir, 400-800 mg two to three times per day, prevents recurrences during the immediate 30-day post-transplantation period
Longer-term suppression is often used for persons with continued immunosuppression. In bone marrow and renal transplant recipients, valacyclovir, 2 g four times daily, is also effective in preventing CMV infection. Valacyclovir, 4 g four times daily, has been associated with TTP after extended use in HIV-positive persons. In HIV-infected persons, oral famciclovir, 500 mg bid, is effective in reducing clinical and subclinical reactivations of HSV-1 and HSV-2. If using acyclovir in HIV-infected patients, we generally start with the lower dose of 400 mg twice daily and increase to 800 mg twice daily if breakthrough recurrences occur. Note: Once-daily dosing of valacyclovir, 500 mg to 1 g, should be avoided in HIV-infected patients owing to concerns regarding lower efficacy.
Symptomatic recurrent genital herpes in HIV-1–infected patients
Oral acyclovir, 400 mg tid × 5-10 daysValacyclovir, 1000 mg bid × 5-10 daysFamciclovir, 500 mg PO bid × 5-10 days
• Herpessimplexencephalitisisthemostcommonlyidentifiedcauseofacute,sporadicviralencephalitisintheUnitedStates.Magneticresonanceimagingistheneuroimagingtechniqueofchoicetoidentifyabnormalities.
• EsophagitisandpulmonaryinfectionsmaybecausedbyHSV,mostcommonlyinimmuno-compromisedpatients.
• NeonatalinfectionsmayoccurthroughcontactwithHSVsecretions.Infantsyoungerthan6weekshavethehighestfrequencyofvisualandcentralnervoussysteminvolvement.
DIAGNOSIS• ClinicalcriteriaareutilizedforconsiderationofthediagnosisofHSVinfection,butlabora-
torytestsareneededtoconfirmthediagnosis.• Diagnosis canbemadebydetectionofHSVDNAbypolymerasechain reactionassay in
lesionscrapings,fluids,ortissue.Viralisolationcanalsobemadeintissueculture,butthisisthreetofourtimeslesssensitivethanbyDNAmoleculartechniques.
TREATMENT• Acyclovir,valacyclovir,orfamciclovirisusedtotreatmucocutaneousandvisceralinfections
(seeTable73-1).• Genital infectionsmaybetreatedasaprimary infectionwhenrecognizedorasadiscrete
recurrence.Individualswithfrequentrecurrencesmaybetreatedwithsuppressivetherapy.• Herpessimplexencephalitisistreatedwithhigh-doseacyclovir(10mg/kgIVevery8hours
for14to21days).• Acyclovir-resistantHSVstrainscanbetreatedwithfoscarnetorcidofovir.
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DOSAGE/REGIMEN COMMENT
Infections in Immunocompetent Patients
Genital Herpes
First episodes Oral acyclovir, 400 mg tid (V) or 200 mg five times per day (I) × 7-10 daysOral valacyclovir, 1000 mg bid × 7-10 days (I)Famciclovir, 250 mg tid × 5-10 days (I)IV acyclovir, 5 mg/kg q8h for 5 days, is given for severe disease or neurologic complications such as aseptic meningitis
Symptomatic recurrent genital herpes
Oral acyclovir, 400 mg tid × 5 days (V), 800 mg PO tid × 2 days or bid × 5 days (II)
All these therapies are effective in shortening lesion duration. Short-course options (1, 2, or 3 days of therapy) should be considered based on increased convenience, likelihood of adherence and reduced cost and are listed in bold. Given the brief period of viral replication and rapid evolution of lesions, patients should be given drugs for self-administration when prodromal symptoms occur.
Valacyclovir, 500 mg bid × 3 days (I) or 1 g daily × 5 days (I)
Famciclovir, 125 mg bid for 5 days (I), 1 g bid for 1 day (I), or 500 mg once then 250 mg PO bid × 3 doses (I)
Suppression of recurrent genital herpes
Oral acyclovir, 400 mg bid (I)
Valacyclovir, 500 mg daily (I) or 1000 mg daily (I) or 250-500 mg bid (I) prevents symptomatic reactivation. Persons with frequent reactivation (<9 episodes/yr) can take valacyclovir 500 mg daily; those with >9 episodes/yr should take valacyclovir 1000 mg/daily or 500 mg bid.
Consider for patients with frequent (>6 episodes) or severe recurrences, in immunocompromised patients, or as an adjunct to prevent transmission
Famciclovir, 250 mg bid (I)
Orolabial HSV Infections
First episode Oral acyclovir, 15 mg/kg (up to 200 mg) five times per day (II) or 400 mg tid (V) × 7 daysFamciclovir, 500 mg bid (V)Valacyclovir, 1000 mg bid (V) × 7 days
Recurrent episodes
Oral acyclovir, 400 mg five times per day × 5 days (II)
Self-initiated therapy with topical 1% penciclovir cream q2h during waking hours (I); topical acyclovir cream, 5% five times per day × 4 days (I). Short-course options should be considered based on increased convenience and likelihood of adherence and are listed in bold. Given the brief period of viral replication and rapid evolution of lesions, patients should be given drugs for self-administration when prodromal symptoms occur.
Valacyclovir, 2000 mg bid × 1 day (I)
Famciclovir, 1500 mg once (I)
Suppression of reactivation of orolabial HSV
Oral acyclovir, 400 mg bid (II), or valacyclovir, 500 mg or 1000 mg daily (II), or famciclovir, 500 mg bid (V)
Consider for patients with frequent (>6 episodes) or severe recurrences, in immunocompromised patients, or as an adjunct to prevent transmission
Herpetic Whitlow
Oral acyclovir, 200 mg five times daily for 7-10 days
HSV Proctitis
Oral acyclovir, 400 mg five times per day is useful in shortening the course of infection
In immunosuppressed patients or in patients with severe infection, IV acyclovir, 5 mg/kg q8h, may be useful
TABLE 73-1 Antiviral Chemotherapy for Herpes Simplex Virus Infection—cont’d
Continued
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DOSAGE/REGIMEN COMMENT
Herpetic Eye Infections
In acute keratitis, topical trifluorothymidine, vidarabine, idoxuridine, acyclovir, penciclovir, and interferon are all beneficial. Débridement may be required; topical corticosteroids may worsen disease.
CNS HSV InfectionsHSV encephalitis IV acyclovir, 10 mg/kg q8h (30 mg/kg/
day) for 14-21 days
HSV aseptic meningitis
IV acyclovir, 30 mg/kg/day for 7-10 days No studies of systemic antiviral chemotherapy exist
Autonomic radiculopathy
No studies are available
Neonatal HSV Infections
Acyclovir, 60 mg/kg/day (divided into three doses) × 21 days
Monitoring for relapse should be undertaken; most authorities recommend continued suppression with oral acyclovir suspension for 3-4 mo
Visceral HSV Infections
HSV esophagitis IV acyclovir, 15 mg/kg per day In some patients with milder forms of immunosuppression, oral therapy with valacyclovir or famciclovir is effective
HSV pneumonitis
No controlled studies exist. IV acyclovir, 15 mg/kg/day, should be considered.
Disseminated HSV Infections
No controlled studies exist. IV acyclovir, 10 mg/kg q8h, nevertheless should be given. No definite evidence indicates that therapy decreases the risk of death.
Erythema Multiforme–Associated HSV
Anecdotal observations suggest that oral acyclovir, 400 mg bid or tid, or valacyclovir, 500 mg bid, suppresses erythema multiforme
Surgical Prophylaxis
Several surgical procedures such as laser skin resurfacing, trigeminal nerve root decompression, and lumbar disk surgery have been associated with HSV reactivation. IV acyclovir, 3 mg/kg, and oral acyclovir, 800 bid, valacyclovir, 500 bid, or famciclovir, 250 bid, is effective in reducing reactivation. Therapy should be initiated 48 hr before surgery and continued for 3-7 days.
Infections with Acyclovir-Resistant HSV
Foscarnet, 40 mg/kg IV q8h, should be given until lesions heal. IV cidofovir, 5 mg/kg once weekly, might also be effective.
Imiquimod is a topical alternative, as is topical cidofovir gel 1%, which is not commercially available and must be compounded at a pharmacy. These topical preparations should be applied to the lesions once daily for 5 consecutive days.
CMV, cytomegalovirus; CNS, central nervous system; HIV, human immunodeficiency virus; HSV, herpes simplex virus; TTP, thrombotic thrombocytopenic purpura.
Note: I, II, III, IV, and V represent level of evidence.Modified from Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based
review. Arch Intern Med. 2008;168:1137-1144; and Spruance S, Aoki FY, Tyring S, et al. Short-course therapy for recurrent genital herpes and herpes labialis: entering an era of greater convenience, better treatment adherence, and reduced cost. J Fam Pract. 2007;56:30-36.
TABLE 73-1 Antiviral Chemotherapy for Herpes Simplex Virus Infection—cont’d
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74 Chickenpox and Herpes Zoster (Varicella-Zoster Virus)Richard J. Whitley
DEFINITION• Varicella-zoster virus (VZV) is an alpha herpesvirus that causes chickenpox and herpes
zoster.
EPIDEMIOLOGY• Chickenpoxistheprimaryinfectionoccurringprimarilyinchildhood.• Chickenpoxisusuallyabenigninfectionbutcancauselife-threateningdiseaseintheimmu-
nocompromisedhost.• Diseaseismorelikelytooccurinlatewinterandearlyspring.• Herpes zoster is the consequence of reactivation of latent virus, occurring mainly in the
elderly.• Herpeszostercausessignificantpaininmanyindividuals.• Thereisnoseasonalpredilectionforoccurrenceofherpeszoster.
MICROBIOLOGY• Varicella-zostervirusisadouble-strandedDNAvirus.Followingprimaryinfection,latency
isestablishedinsensoryganglia.
DIAGNOSIS• Thediagnosisofchickenpoxandherpeszosterisusuallyclinical.• Chickenpoxischaracterizedbyamaculopapular,vesicular,andpapularrashinallstagesof
evolution.• Herpes zoster isusuallyaunilateralvesicular rash.Disseminationcanoccur in immuno-
compromisedpatients.• Tzanck smears of lesion scrapings may demonstrate intranuclear inclusions; however, the
sensitivityislow.• Polymerasechainreaction(PCR)canbeappliedtolesionscrapinginordertodetectVZV
DNAandisthediagnosticprocedureofchoice.• Viralculturecanbeusedtomakeadiagnosis,butitislesssensitivethanPCR.
THERAPY• ThreedrugsarelicensedforthetreatmentofVZVinfections.• Chickenpox in children 2 to 16 years of age can be treated with acyclovir at a dosage of
20mg/kg4timesperdayfor5days.Forolderpatients,thedosageofacycloviris800mg5timesaday.
• Byclasseffect,theprodrugsvalacyclovirandfamciclovirareusedbysomeexpertstotreatchickenpox.
• Herpeszostercanbetreatedwithacyclovirat800mgfivetimesdailyfor7to10days.• Herpeszostercanbetreatedwithvalacyclovirat1gthreetimesdailyfor7to10days.• Herpeszostercanbetreatedwithfamciclovirat500mgthreetimesdailyfor7to10days.
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• Herpes zoster will likely require control of pain with analgesics and medications such aspregabalin.
PREVENTION• High-titeredvaricella-zosterimmuneglobulin(VariZIG)canbeadministeredtohigh-risk
patientstoattempttopreventinfection.• A VZV vaccine is available to prevent chickenpox. It is a two-dose series with the first
administeredat12to15monthsofageandthesecondbetween4and6years.Thistwo-doseseries has dramatically decreased the incidence of chickenpox and its associatedcomplications.
• Ahigh-titeredVZVvaccineisavailableforadultsolderthan50yearsofagethatwillreducetheincidenceofherpeszoster,theburdenofillness,andpostherpeticneuralgia.
185
75 Cytomegalovirus (CMV)Clyde S. Crumpacker II
DEFINITION• Human cytomegalovirus (HCMV) is a double-stranded DNA virus, a member of the
Herpesviridaefamily,andinfectsahighpercentageofhumansworldwide.Recentevidencepointstogreatgenomicvariabilityduringreplicationinasinglepatient.HCMVinfectionisusually asymptomatic, but may cause severe congenital infection and severe disease inimmunocompromised transplant and acquired immunodeficiency syndrome (AIDS)patients.
EPIDEMIOLOGY• Infantsinfectedinuteroasaresultofprimarycytomegalovirus(CMV)infectioninapreg-
nantwomanareatriskforseverecongenitalabnormalitiesandsensorineuralhearingloss.Healthy young adults can develop CMV mononucleosis. In immunocompromised AIDSpatients, CMV retinitis leads to vision loss. In solid-organ and hematopoietic stem celltransplant patients, life-threatening CMV pneumonia and hepatitis, meningoencephalitis,colitis, and esophageal ulcers can occur. The potential role of HCMV in cardiovasculardiseaseisbeingincreasinglyinvestigated.
MICROBIOLOGY• HCMVgrowsonlyinhumanepithelial,endothelial,smoothmuscle,neurologic,andfibro-
blastcells.Genomicanalysisusinghigh-throughputdeepsequencingincongenitallyinfectedinfantsrevealsextensivegenomicvariabilityanddiversity.
DIAGNOSIS• TheWorldHealthOrganizationhasstandardizedaCMVDNApolymerasechainreaction
assay(COBASAmplicor/COBASTagmanCMVtest)todetectCMVinbloodandinfectedtissue. This assay uses international units and permits comparison among clinical trials.DetectionofCMVpp65antigenininfectedneutrophilsremainsavaluablediagnostictool.
THERAPY• Ganciclovir(GCV)andvalganciclovir(VGC)are themainstaysof treatment.Foscarnet is
mainly useful for GCV-resistant CMV infection and disease. Cidofovir may be used fortreatment of failures with other anti-CMV drugs. A lipid-coated version of cidofovir(CMX001),maribavir,andletermovirareexperimentaldrugsforCMVundergoingclinicaldevelopment.
PREVENTION• GCVandVGCareusedasprophylaxis in the transplantationsetting.GCVandVGCare
alsousedaspreemptivetherapy.AneffectiveCMVvaccinehasnotyetbeendeveloped.
186
76 Epstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases)Eric C. Johannsen and Kenneth M. Kaye
DEFINITION• Infectiousmononucleosisisaclinicalsyndromecharacterizedbypharyngitis,fever,lymph-
adenopathy,andthepresenceofatypicallymphocytesonaperipheralbloodsmear.PrimaryEpstein-Barrvirus(EBV)infectionisthemostcommoncauseofthissyndrome.
VIROLOGY AND EPIDEMIOLOGY• EBVisaherpesvirusthatestablisheslifelonglatentinfectioninBlymphocytes.• Replicationoccursinoralepithelium,andinfectiousEBVisfrequentlypresentinthesaliva
ofasymptomaticseropositiveindividuals.• EBVistransmittedpredominantlythroughexposuretoinfectedsaliva,frequentlyasaresult
ofkissing.• Seroprevalenceapproaches95%inadults,andEBVisdistributedthroughouttheworld.• Inchildhood,primaryEBVinfectionisusuallyasymptomaticoranonspecificillness.• Frequencyofpresentationasinfectiousmononucleosisincreaseswithagetoabout50%of
primaryinfectionsbyadolescence.• EBV is tightly linked with several malignancies, including endemic Burkitt’s lymphoma,
nasopharyngealcarcinoma,andlymphoproliferativedisease.
MICROBIOLOGY• EBVisagamma-1herpesvirus,genusLymphocryptovirus.• EBVisadouble-strandedDNAvirusthatisenveloped.• EBVisalsoknownashumanherpesvirus4.
CLINICAL MANIFESTATIONS• Infectiousmononucleosisisgenerallyaself-limited,spontaneouslyremittingsyndrome.• Complications may occur, including splenic rupture, neurologic manifestations such as
encephalitis,autoimmunehemolyticanemia,andmildhepatocellularenzymeelevations.
DIAGNOSIS• Theappearanceofnonspecific,heterophileantibodies(IgMreactingwithsheeporhorsered
blood cells) can distinguish primary EBV infection from other causes of infectiousmononucleosis.
• ThepresenceofIgMviralcapsidantigen(VCA)antibodiesiscloselycorrelatedwithacuteEBVinfection.Heterophileantibodiesinapersonwithclinicalinfectiousmononucleosisissufficienttoestablishthediagnosis.
• EBVserologymaybehelpfulinatypicalcasesandinchildren(whoarefrequentlyhetero-philenegative).
• Primaryhumanimmunodeficiencyvirusinfectionisthemostimportantdifferentialdiag-nosticconsideration.
• Serial measurement of EBV viral loads may be useful in the detection of EBV-associatedmalignanciesinimmunosuppressedindividuals,especiallyforlymphoproliferativedisease.
187C
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-Barr V
irus (In
fectiou
s Mo
no
nu
cleosis, Ep
stein-B
arr Viru
s–Asso
ciated M
align
ant D
iseases, and
Oth
er Diseases)
THERAPY• Treatmentofmononucleosisisprimarilysupportive.• Corticosteroidsmaybehelpful inmanagingmononucleosis complications suchasairway
impingementfromtonsillarenlargement.• Antiviraltherapyisofnoprovenbenefitininfectiousmononucleosis.
PREVENTION• ThereiscurrentlynoEBVvaccine.
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77 Human Herpesvirus Types 6 and 7 (Exanthem Subitum)Jeffrey I. Cohen*
DEFINITION• Human herpesviruses 6 and 7 (HHV-6 and HHV-7) cause exanthem subitum or febrile
seizuresinyoungchildrenandreactivatefrequentlyinhighlyimmunocompromisedhosts.Theycanalsocauseencephalitisinimmunocompromisedhosts.
EPIDEMIOLOGY• MostadultsareseropositiveforHHV-6andHHV-7.• TheaverageageforinfectionwithHHV-6isabout1yearoldandforHHV-7is2yearsold.• About 50% of hematopoietic transplant recipients and 20% to 33% of organ transplant
recipientshaveHHV-6andHHV-7DNAintheblood.• HHV-6DNAisintegratedinthechromosomesof1%to2%ofpersonsandistransmitted
inthegermlineDNA.
MICROBIOLOGY• HHV-6andHHV-7,likecytomegalovirus,arebetaherpesviruses.
DIAGNOSIS• Exanthemsubitumisusuallydiagnosedclinically,butseroconversiontoHHV-6orHHV-7
antibodypositivitycanbeused.• DiagnosisofHHV-6orHHV-7diseaseinimmunocompromisedpersonsisdifficultdueto
thehighfrequencyofasymptomaticreactivationandthefindingthatupto2%ofpersonshaveHHV-6DNAintegratedintheirchromosomes.
• HHV-6limbicencephalitisisdiagnosedbasedonclinicalsignsandsymptomsandHHV-6DNAinthecerebrospinalfluid.
• DetectionofHHV-6proteinorRNAintissuesismorespecificthanHHV-6DNAfordiag-nosingvirus-associateddiseaseinimmunocompromisedpersons.
THERAPY• No therapy has been shown to be effective for treatment of HHV-6 or HHV-7, but both
virusesaresensitivetoganciclovir,foscarnet,andcidofovirinvitro.• Ganciclovir or foscarnet, or both, have been used to treat immunocompromised persons
withHHV-6orHHV-7disease,especiallywithlimbicencephalitis.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
189
78 Kaposi’s Sarcoma–Associated Herpesvirus (Human Herpesvirus 8)Kenneth M. Kaye
DEFINITION• Kaposi’ssarcoma–associatedherpesvirus(KSHV),orhumanherpesvirus8(HHV-8),isthe
etiologicagentofKaposi’ssarcoma,primaryeffusionlymphoma,andisalsotightlylinkedwithmulticentricCastleman’sdisease.
VIROLOGY AND EPIDEMIOLOGY• KSHV is a herpesvirus that establishes lifelong infection, primarily persisting in latently
infectedBlymphocytes.• Replicationoccursinoralepithelium,andinfectiousKSHVispresentinthesalivaofasymp-
tomaticseropositiveindividuals.• Transmissionispredominantlytheresultofexposuretoinfectedsaliva.• Primaryinfectionisusuallyasymptomaticandrarelyrecognized.• Incontrasttootherherpesviruses,seroprevalencevariessignificantlythroughouttheworld
andishighestinsub-SaharanAfrica,theMediterraneanregion,andinmenwhohavesexwithmenintheUnitedStates.
• KSHVmalignancyusuallyoccursinthesettingofimmunesuppression.
MICROBIOLOGY• KSHVisagamma-2herpesvirus,genusRhadinovirus.• KSHVisanenveloped,double-strandedDNAvirus.• KSHVisalsoknownasHHV-8.
DIAGNOSIS• KScanbediagnosedbyitsclinicalappearanceandconfirmedbybiopsy.• PrimaryeffusionlymphomaandmulticentricCastleman’sdiseasearediagnosedbybiopsy.• KSHVcanbedetectedserologically,althoughassaysarenotstandardized.
THERAPY• AntiviraltherapyisofnoprovenbenefitinthetreatmentofKSHVmalignancies,andtherapy
generallyreliesoncytotoxicapproaches.
PREVENTION• ThereiscurrentlynoKSHVvaccine.
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79 Herpes B VirusJeffrey I. Cohen*
DEFINITION• HerpesBvirusisamacaquevirusthatcancausefatalencephalitisinhumans.
EPIDEMIOLOGY• Herpes B virus naturally infects Old World macaques, including rhesus and pig-tailed
macaquesandcynomolgusmonkeys.• Humans are infected with herpes B virus after bites, scratches, needlesticks, or mucosal
splasheswithfluidsfromOldWorldmacaques.
MICROBIOLOGY• Herpes B virus is an alphaherpesvirus and is the homolog of herpes simplex virus in
macaques.
DIAGNOSIS• Apositivepolymerasechain reaction (PCR)orculture forherpesBvirus in skin lesions,
conjunctival swabs, or cerebrospinal fluid in the presence of symptoms is diagnostic forherpesBvirusinfection.
• ApositivePCRorcultureforherpesBvirusofwoundsormucosashortlyafterinjuryindi-catesexposuretothevirusbutnotnecessarilyinfection.
• Humanspecimens forPCR,culture,orantibody testing shouldbe sent to theNationalBVirusResourceCenterinAtlanta,Georgia(www2.gsu.edu/~wwwvir/index.html).
THERAPY• PersonswithsignsorsymptomsofBvirus,orpositiveculturesorPCR(otherthanwound
orpostcleansingPCRorculture)andexposuretoOldWorldmacaquesshouldbetreated.• Intravenousacyclovir(12.5to15mg/kgq8h)organciclovir(5mg/kgq12h)isrecommended
forpersonswithoutcentralnervoussystem(CNS)disease.• Intravenousganciclovir(5mg/kgq12h)isrecommendedforpersonswithCNSdisease.• Treatmentiscontinueduntilsymptomsresolveandtwoculturesovera2-weekperiodare
negative;oralvalacycloviroracyclovirareoftengivenafterintravenoustherapyisdiscon-tinuedtopreventreactivationoflatentvirus.
PREVENTION• Firstaid,withthoroughcleansingofwoundsorexposedmucosa,isimportantafterinjuries
ormucosalsplasheswithmacaquefluids.• PersonswhohavehighriskofexposuretoBvirus(seeTable79-1)shouldreceivepostex-
posureprophylaxiswithin5daysofexposurewithvalacyclovir,1gtid,oracyclovir,800mg5timesdailyfor14days.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
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irus
TABLE 79-1 Recommendations for Postexposure Prophylaxis for Persons Exposed to Herpes B Virus
Prophylaxis RecommendedSkin exposure* (with loss of skin integrity) or mucosal exposure (with or without injury) to a high-risk source
(e.g., a macaque that is ill, immunocompromised, or known to be shedding virus or that has lesions compatible with herpes B virus disease)
Inadequately cleaned skin exposure (with loss of skin integrity) or mucosal exposure (with or without injury)
Laceration of the head, neck, or torso
Deep puncture bite
Needlestick associated with tissue or fluid from the nervous system, lesions suspicious for herpes B virus, eyelids, or mucosa
Puncture or laceration after exposure to objects (a) contaminated either with fluid from monkey oral or genital lesions or with nervous system tissues, or (b) known to contain herpes B virus
A postcleansing culture is positive for herpes B virus
Prophylaxis ConsideredMucosal splash that has been adequately cleaned
Laceration (with loss of skin integrity) that has been adequately cleaned
Needlestick involving blood from an ill or immunocompromised macaque
Puncture or laceration occurring after exposure to (a) objects contaminated with body fluid (other than that from a lesion), or (b) potentially infected cell culture
Regimen for ProphylaxisValacyclovir, 1 g PO tid, or acyclovir, 800 mg PO 5 times daily × 14 days
Prophylaxis Not RecommendedSkin exposure in which the skin remains intact
Exposure associated with nonmacaque species of nonhuman primates
*Exposures include macaque bites or scratches, or contact with ocular, oral, or genital secretions, nervous system tissues, or materials contaminated by macaques (e.g., cages or equipment).
From Cohen JI, Davenport DS, Stewart JA, et al. Recommendations for prevention and therapy of persons exposed to B virus (Cercopithecine herpesvirus 1). Clin Infect Dis. 2002;35:1191-1203.
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80 AdenovirusesElizabeth G. Rhee and Dan H. Barouch
DEFINITION• Human adenoviruses (HAdVs) are DNA viruses that can cause a broad range of clinical
syndromes, including respiratory tract infections, ocular disease, gastroenteritis, diarrhea,andcystitis.
EPIDEMIOLOGY• HAdVs are ubiquitous; most humans have serologic evidence of prior infection by age
10years.• Transmission is via respiratory droplets or fecal-oral transmission. Virus secretion may
persistforprolongedperiodsafteracuteinfectionresolves.• Typically,thediseaseissubclinicalormildlysymptomaticandself-limited.• HAdVsareacommoncauseoffebrileillness,respiratorytractinfections(types1to7),and
gastroenteritis(types2to5)inyoungchildren;sporadicpediatricoutbreaksassociatedwithdaycarecentersandsummercamps.
• Acute respiratory disease, including pneumonia, is uncommon; sporadic outbreaks asso-ciated with military recruits (types 4 and 7); recent outbreak occurred in healthy adults(type14).
• Epidemickeratoconjunctivitis(types8,19,and37)hasbeenlinkedtonosocomialtransmis-sionbyinfectedinstruments.
• HAdV is an emerging opportunistic pathogen in immunocompromised hosts, primarilyhematopoieticstemcell transplant(HSCT)andsolidorgantransplant(SOT)recipients; itcanresultindisseminateddiseaseortargetgraftedorgan.
• There is interest inusingHAdVasvectors forgene therapy,asvaccinesbeingstudied forinfectiousdiseases(humanimmunodeficiencyvirus[HIV],malaria);andasimmunomodu-latorytreatmentsforsolidtumors.
MICROBIOLOGY• HAdVsarenonenveloped,lyticDNAviruses,characterizedbyserologicresponsestomajor
capsidproteinsandwhole-genomeanalysis.• HAdVs are classified into 7 groups (A to F); 60 types isolated from clinical specimens
sofar.• HAdVswereoriginallyisolatedfromadenoidtissues,leadingtothevirusname.
DIAGNOSIS• Diagnosisisnotroutinelypursuedbecausemostinfectionsaremildandself-limited.• HAdVs are detected by routine viral tissue culture (except types 40 and 41) and can be
recoveredfromswabs,samples,andtissues;immunofluorescenceassay(IFA),enzyme-linkedimmunosorbentassay,acute/convalescentserumtiterscanestablishdiagnosis.
• Polymerasechainreactionishighlysensitiveandspecific(96%to100%)inimmunocompe-tentadults.
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THERAPY• Therearenoapprovedtherapiesavailable.• CaseseriesreportpartialclinicalresponsebutsubstantialtoxicitiestocidofovirinHSCT/
SOT.Clinicaltrialofbrincidofovirintransplantpatientsisunderway.
PREVENTION• Liveoralvaccines(type4and7)areadministeredtomilitarypersonnelandarehighlyeffec-
tiveinpreventingadenovirus-associatedfebrilerespiratorydiseases.
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81 PapillomavirusesWilliam Bonnez
DEFINITION• Human papillomavirus (HPV) infects the squamous stratified epithelia of the body and
causestumorsthatcanbebenign(warts,condylomas,papillomas)ormalignant(squamouscellcarcinomas,uterinecervicaladenocarcinoma).
• Theycausetwomaingroupsofdiseases:(1)cutaneous(hand,foot,flat)wartsand(2)lesionsof the mucosal or genital surfaces, such as genital warts, laryngeal papillomas, as well ascancersofthecervix,vagina,vulva,anus,penis,andoropharynx,andtheirrespectiveprecur-sorlesions,calledintraepithelialneoplasias(dysplasias).
EPIDEMIOLOGY• Cutaneous warts are predominantly a disease of school-aged children. They are acquired
fromclosecontacts,predominantlyinthefamilyenvironment.• Genital (ormucosal)HPVinfectionsaremostlysexually transmitted,andtheir incidence
peaksinlateadolescenceandearlyadulthood.• MostofthesexuallyactivepopulationwillhavebeenexposedtogenitalHPVinalifetime.• GenitalHPVinfections inmalesandfemalesareeasilyacquired,butmostalsodisappear
quickly.Persistenceisariskfactorforthedevelopmentofcancer.
MICROBIOLOGY• HPVsaresmall,nonenvelopedDNAviruses,classifiedaccordingtothenucleotidesequence
of the gene coding for the major capsid protein. These viruses are not routinelycultivatable.
• Atleast184typeshavebeenidentified,butonlyasmallnumbercarrythebulkofthehealthburden.
• HPVtypes1,2,and4arethemostcommontypesfoundincutaneouswarts.• HPVtypes6and11accountformostgenitalwarts.• HPVtypes16and18cause thegreatmajorityofcancersof theanogenital tractandoro-
pharynxandaredefinedashigh-riskoncogenic.• The more severe the grade of intraepithelial neoplasia, the more prevalent are high-risk
oncogenicHPVsinthelesion.
DIAGNOSIS• Thediagnosisofcutaneouswartsandofgenitalwartsistypicallyclinical.Abiopsyisindi-
catedwhenthediagnosisisindoubtoramalignancyoritsprecursorisaconsideration.• For the screening of cervical cancer, cytology (Pap smear) is the primary diagnostic
approach.• HPVDNAtestingsupplementsscreeningcytology.
THERAPY• ManytherapeuticmodalitiesexistforthetreatmentofHPV-inducedlesions,noneofthem
fullysatisfactory.Theycanbedividedintomedicalandphysicalapproaches.
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ses
• Thechemicalmethodsincludesalicylicacidsolutionsforcutaneouswartsorpodofiloxorimiquimodforgenitalwarts.
• The physical methods include cryotherapy, cold-blade excision, electrosurgery, and lasertherapy,andtheycanbeappliedtomostlesions.
PREVENTION• Malecondomshavesomeeffectivenessinprotectingagainstgenitalinfections.• Papsmearsareessentialforthepreventionofcervicalcancer.• Vaccination is very effective and safe in preventing genital warts as well as intraepithelial
neoplasiasofthecervix,vagina,vulva,andtheanusinmalesandfemales.• Two highly effective vaccines are available. Gardasil is quadrivalent and protects against
HPV-6,HPV-11,HPV-16,andHPV-18;Cervarixisbivalent,anditonlycoversHPV-16andHPV-18.Thevaccinesaregivenintramuscularlyinthreedoses.
• A9-valentvaccine(Gardasil9)hasbeenapprovedbytheU.S.FoodandDrugAdministrationinDecember2014.ItcoversHPV-31,HPV-33,HPV-45,HPV-52,andHPV-58,inadditiontothefourlistedearlier.
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82 JC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML)C. Sabrina Tan and Igor J. Koralnik
JC VIRUSDefinition• JC virus (JCV) is a ubiquitous human polyomavirus that causes central nervous system
diseasesinimmunocompromisedpatients,includingprogressivemultifocalleukoencepha-lopathy(PML),JCVgranulecellneuronopathy,andJCVencephalopathy.
Epidemiology• JCVinfects40%to86%ofthegeneralpopulationworldwide.• JCV can be detected in the urine of one third of healthy and immunosuppressed
individuals.• PML can occur in up to 5% of untreated patients with acquired immunodeficiency
syndrome.• Upto82%ofPMLpatientsareinfectedwithhumanimmunodeficiencyvirus.
Microbiology• JCVisamemberofthePolyomaviridae.• Itisadouble-strandedDNAviruswithoutanenvelope.• Afterprimaryinfection,JCVremainslatentinthekidneyepithelialcells.• Reactivation of JCV causes a lytic infection of oligodendrocytes in the brain, leading
toPML.
Diagnosis• Definitive diagnosis of PML:JCVisdetectedincerebrospinalfluidbypolymerasechainreac-
tion(PCR)assayorJCVproteinsaredetectedinbraintissues.• Possible diagnosis of PML:Magneticresonanceimagingfindingsandclinicalpresentationare
consistentwithPMLintheabsenceofJCVdetectionincerebrospinalfluid.
Therapy• Therearenoeffectiveantiviralmedications.• ImmunereconstitutioncanboosthostcellularimmuneresponsetobettercontrolJCviral
replication.
Prevention• Measuresshouldbetakentopreventimmunosuppression.
BK VIRUSDefinition• BK virus (BKV) is a ubiquitous human polyomavirus that causes hemorrhagic cystitis in
hematopoieticstemcelltransplantationpatientsandnephropathyinkidneytransplantationrecipients.
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Epidemiology• BKVinfects82%to90%ofthegeneralpopulationworldwide.• BKVcanbedetectedintheurineofasymptomatichealthyindividuals.• BKVnephropathyoccursinupto10%ofkidneytransplantpatients.• BKV-associated disease can occur in up to 15.9% of allogeneic stem cell transplant
recipients.
Microbiology• BKVisamemberofthePolyomaviridae.• Itisadouble-strandedDNAviruswithoutanenvelope• Afterprimaryinfection,BKVremainslatentinthekidneyepithelialcells.• ReactivationofBKVcauseshemorrhagiccystitisandnephropathy.
Diagnosis• BKVisdetectedbyPCRassayinbloodandsustainedviruriainurine.• Cytopathologicchangesmaybedetectedonakidneybiopsyspecimen.
Therapy• Thereisnoeffectiveantiviralmedication.• Reductioninimmunosuppressioncanboosthostcellularimmuneresponsetobettercontrol
BKVreplication.
Prevention• EarlydetectionofviralreactivationinurineandbloodbyPCRassaycanbeanindicatorfor
apreemptivereductioninimmunosuppressiontohelpreduceoccurrenceofrenaldisease.
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83 Hepatitis B Virus and Hepatitis Delta VirusChloe Lynne Thio and Claudia Hawkins
DEFINITION• Hepatitis B virus (HBV) causes chronic hepatitis B, which can lead to progressive liver
disease,includingcirrhosisandhepatocellularcarcinoma.• Hepatitisdeltavirus(HDV)occursasacoinfectionorsuperinfectionwithHBVestablishing
achronicinfectioninhepatocytes.
EPIDEMIOLOGY• Fivepercentoftheworld’spopulationhaschronichepatitisB,butprevalencevarieswidely
(seeTable83-1).• ThehighestHBVprevalenceisinAsia,Africa,andpartsoftheMiddleEast.• ChronichepatitisBistheleadingcauseofend-stageliverdiseaseworldwide.• Transmission of HBV is through percutaneous or sexual routes. Perinatal transmission is
alsocommon.• About5%ofpeoplewithchronichepatitisBhaveevidenceofexposuretoHDV.• HDVhasaworldwideprevalencethatgenerallymirrorsHBVprevalence,althoughthereare
exceptions.• HDVisprimarilytransmittedviatheparenteralroute,butthereissomesexualtransmission.
Perinataltransmissionisuncommon.
MICROBIOLOGY• HBV is apartiallydouble-strandedDNAvirus in theHepadnavirus family thatprimarily
infectshepatocytes.• HBVreplicationisthroughanRNAintermediate,soithasareversetranscriptase.• HDVisasmall,defectiveRNAvirusthatreliesonhostcellmachineryforreplication.• HDVrequirestheenvelopeofHBVforviralassemblyandtransmission.
CLINICAL PRESENTATION AND DIAGNOSIS• Clinical presentation of HBV varies from asymptomatic to fulminant hepatitis with liver
failure.• TheriskofdevelopingchronichepatitisBisinverselyproportionaltoageofacquisitionof
infection.ChronichepatitisBisalsomorelikelyinhigh-riskpatientgroupssuchasinjectiondrug users, men who have sex with men, and human immunodeficiency virus–infectedindividuals.
• LaboratorydiagnosisofHBVisbyenzymeimmunoassays,whichdetectvariousHBVanti-gensandantibodies,andbyreal-timepolymerasechainreaction(PCR)todetectHBVDNA(seeTable83-2).
• ClinicalpresentationofHDVisalsovariablebutcanpresentasacuteseverehepatitis.• LaboratorydiagnosisofHDViswithenzymeimmunoassayforHDVantibodiesandHDV
RNAbyreal-timePCR.
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THERAPY• Anti-HBVagentssignificantlyreducecomplicationsofchronichepatitisB, including liver
cirrhosis and hepatocellular carcinoma. These therapies are also effective in reducing therecurrenceofHBVinfectionintransplantrecipientsandotherimmunocompromisedhosts.
• HBVistreatedwith180µgofpegylatedinterferon-α(PEGIFN-α)weeklyfor48weeksorwithnucleos(t)ideanaloguesoftenindefinitely(seeTable83-3).
• Thefirst-linenucleos(t)ideagentsareentecavir0.5mgdailyortenofovir300mgdaily.• HDVistreatedwith180µgPEGIFN-αweeklyforaminumumof48weeks.
PREVENTION• VaccinationwiththehepatitisBvaccineisrecommendedinallinfantsandchildrenandfor
nonimmuneadultsathighriskforinfection(seeTable83-4).• InfantsborntomotherswithchronichepatitisBshouldreceivethehepatitisBvaccineand
hepatitisBimmuneglobulin(HBIG)atbirth.• Nonimmune individuals who have percutaneous, sexual, ocular, or mucous membrane
exposure toHBV-infectedfluids shouldreceivepostexposureprophylaxiswithHBIGandhepatitisBvaccine.
TABLE 83-1 Global Seroprevalence Rates and Modes of Transmission of Hepatitis B
CHARACTERISTIC HIGH INTERMEDIATE LOWCarrier rate (%) >8 2-7 <2
Distribution Southeast Asia, China, Alaskan Eskimos, sub-Saharan Africa, Middle East except Israel, Haiti, Dominican Republic
Eastern and southern Europe, Mediterranean, central Asia, Latin and South America, Israel
United States, Canada, western Europe, Australia, New Zealand
Age at infection Perinatal and early childhood Childhood Adult
Mode of transmission Maternal and perinatal Percutaneous Sexual, percutaneous
TABLE 83-2 Interpretation of Serologic Tests in Hepatitis B
TESTACUTE HEPATITIS B
IMMUNITY THROUGH INFECTION*
IMMUNITY THROUGH VACCINATION
ACTIVE CHRONIC HEPATITIS B†
INACTIVE CHRONIC HEPATITIS B
HBsAg + – – + +Anti-HBs – + + – –
HBeAg + – – ± –
Anti-HBe – ± – ± +Anti-HBc + + – + +IgM anti-HBc + – – – –
HBV DNA + – – + ± (low)
ALT Elevated Normal Normal Elevated Normal
ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis B e antigen; anti-HBs, antibody to hepatitis B surface antigen; DNA, deoxyribonucleic acid; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgM, immunoglobulin M.
*Occasionally individuals with past infection have isolated anti-HBc only. The presence of an isolated immuno-globulin G anti-HBc may indicate a window period during acute infection or remote prior infection with loss of HBsAg or anti-HBs. In such cases, an HBV DNA test may prove useful.
†Chronic hepatitis B with a pre-core mutant is HBeAg− and anti-HBe+.
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TABLE 83-3 Approved Agents for Treatment of Chronic Hepatitis B*
PEG
IFN
-α
LAM
IVU
DIN
E
AD
EFO
VIR
ENTE
CA
VIR
TELB
IVU
DIN
E
TEN
OFO
VIR
Route Subcutaneous Oral Oral Oral Oral Oral
Dose 180 µg/wk 100 mg/day† 10 mg/day† 0.5 mg/day† (1 if lamivudine resistant)
600 mg/day† 300 mg/day†
Duration (wk) 48 ≥48 ≥48 ≥48 ≥48 ≥48
Tolerability Fair-poor: flulike symptoms
Good Good: follow renal function
Good Good Good: follow renal function
HBeAg seroconversion
27% 16%-21% 12% 21% 22% 21%
Undetectable HBV DNA‡
25%-63% 40%-73% 21%-51% 67%-90% 60%-88% 76%-93%
ALT normalization
38% 41%-75% 53% 72% 65% 74%
HBsAg loss 3% <1% 0% 2% <1% 3%
Viral resistance None 15%-30% Minimal None§ 6% 0%
ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e antigen; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; PEG IFN-α, pegylated interferon-α.
*All data are for 1 year unless otherwise noted.†Dose adjustment for creatinine clearance.‡Higher end of range for HBeAg-negative disease.§None; otherwise, 7% if preexisting lamivudine resistance.Modified from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2009;50:661-662.
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TABLE 83-4 Doses and Schedules of Licensed Hepatitis B Vaccines*
HEPATITIS B VACCINES AGE DOSE VOLUME SCHEDULEEngerix-B <20 yr 10 µg 10 µg/
0.5 mLInfants†: birth, 1-4, 6-18 mo
Older children: 0, 1-2, 4 mo
>20 yr 20 µg 20 µg/1 mL 0, 1, 6 mo
Diabetes 19-59 yr¶ 20 µg 20 µg/1 mL 0, 1, 6 mo
Dialysis and other immunocompromised
40 µg 2-20 µg/1 mL doses
0, 1, 2, 6 mo
Recombivax HB <20 yr 5 µg 5 µg/0.5 mL Infants†: birth, 1-4, 6-18 mo
Older children: 0, 1-2, 4 mo
11-15 yr 10 µg 10 µg/1 mL 0, 4-6 mo
>20 yr 10 µg 10 µg/1 mL 0, 1, 6 mo
Diabetes 19-59 yr¶ 10 µg 10 µg/1 mL 0, 1, 6 mo
Dialysis and other immunocompromised
40 µg‡ 40 µg/1 mL 0, 1, 6 mo
COMBINATION VACCINES AGE§ ANTIGEN VOLUME SCHEDULEComvax 6 wk-4 yr PedvaxHIB|| and
Recombivax0.5 mL 2, 4,
12-15 mo
Pediarix 6 wk-6 yr Engerix-B, Infanrix (DTaP), and IPV
0.5 mL 2, 4, 6 mo
Twinrix >18 yr Havrix (HAV) and Engerix-B (20 µg)
1 mL 0, 1, 6 mo
*All vaccines should be administered intramuscularly in the deltoid.†Infants born to hepatitis B surface antigen (HBsAg)-positive mothers should have hepatitis B immune globulin
(HBIG) within 12 hr of delivery, along with vaccine at a separate site. If mother’s HBsAg status is unknown, admin-ister vaccine within 12 hr and test mother. If mother is HBsAg positive, administer HBIG within 1 week.
‡Special formulation.§Birth dose should be monovalent vaccine only; subsequent doses can be combination.||PedvaxHIB, licensed Haemophilus influenzae type b vaccine; Infarix, licensed diphtheria, tetanus, and acellular
pertussis vaccine (DTaP); Havrix, licensed hepatitis A virus (HAV) vaccine.¶Hepatitis B vaccination may be administered at the discretion of the treating clinician to unvaccinated adults with
diabetes mellitus who are aged ≥60 years (see http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6050a4.htm).
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84 Human Parvoviruses, Including Parvovirus B19V and Human BocaparvovirusesKevin E. Brown
DEFINITION• Atleastfourdifferenttypesofparvovirusinfecthumans.• ParvovirusB19(B19V)cancauseerythemainfectiosum(slappedcheekdisease),transient
aplasticcrisis,andpureredcellaplasiaorfetalhydrops.• Humanbocaparvoviruses(HBoVs)cancauserespiratoryinfectionsandmaybeassociated
withsomecasesofgastroenteritis.• Humandependoparvovirusinfections(adeno-associatedviruses[AAVs])areasymptomatic,
andmodifieddependoparvovirusesareusedasvectorsforgenetherapy.• DiseaseassociationswithParv4infectionarenotclear.
EPIDEMIOLOGY• ParvovirusB19 infection isacommon infection inchildrenandyoungadults.Byage15,
50%ofchildreninAmericaandEuropewillhavebeeninfectedandhaveIgG.• B19Vismainlyspreadthroughtherespiratoryroute,although itmayalsobe transmitted
throughbloodandbloodproducts.• B19V infections in temperateclimatesaremorecommon in latewinter, spring,andearly
summer,withincreasedratesofinfectionevery3to5years.• HBoV infections are ubiquitous in young children, with most if not all children being
infectedwithHBoV1bytheageof6.
DIAGNOSIS• AlthoughtheslappedcheekrashofparvovirusB19infectionisclassic,itisdifficulttoaccu-
ratelydiagnoseoutsideofthecontextofanoutbreak.• DiagnosisofB19VrashisbydetectionofB19VIgMinserum.• Hematologic disease due to B19 can be diagnosed by detection of high-titer B19V DNA
(>106IU/mL)inbloodsamples.• Followinginfection,lowlevelsofB19VDNAmaybedetectedlifelong.Detectionoflow-level
B19VDNAinsamplesthereforedoesnotindicaterecentorcurrentinfection.• Similarly,long-termpersistenceofbocavirusDNAinrespiratoryandfecalsamplesindicates
that detection of viral DNA alone does not correlate with infection. Respiratory HBoV1infectionshouldbediagnosedbydetectionofviralDNAinserumorserology,orboth.
THERAPY• Treatmentforallparvovirusinfectionsismainlysymptomatic.• Intravenous immunoglobulin can be used for treatment of chronic anemia or pure red
aplasiaduetohigh-titerparvovirusB19infection.
PREVENTION• AvaccineforparvovirusB19isindevelopment.
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85 Orthoreoviruses and OrbivirusesRoberta L. DeBiasi and Kenneth L. Tyler
DEFINITION• Reovirusesarelineardouble-strandedRNAviruseswithbroadhostranges.• Thetermreovirusisanacronymforrespiratoryentericorphanvirus,whichemphasizesthe
anatomicsitefromwhichtheseviruseswereinitiallyisolated.
EPIDEMIOLOGY• Infectionofhumansiscommonbutisrarelyassociatedwithsignificantdisease.• Asymptomatic infection is common; symptomatic infection usually consists of mild, self-
limitedupperrespiratorytractandgastrointestinalillness.• Reoviruseshavebeen identifiedas thecausativeagent in rarehumancasesofmeningitis,
encephalitis,pneumonia,andmyocarditisandarepotentiallyassociatedwithbiliaryatresiaandcholedochalcysts.
MICROBIOLOGY• Five genera of the Reoviridae have been etiologically linked with diseases of humans:
Orthoreovirus, Orbivirus, Rotavirus, Coltivirus,andSeadornavirus.• Double-strandedRNAisorganizedinto10to12segments,whicharecapableofreassort-
mentandresultantgenerationofnovelviruses.
DIAGNOSIS• Laboratorydiagnosiscanbemadeserologicallybyafourfoldriseinacuteandconvalescent
serumantibodyresponseorbyvirusisolationfromserum,stool,respiratorysecretions,orcerebrospinalfluid.
THERAPY• Nospecifictherapyisavailable.
PREVENTION• Nospecificpreventativemeasuresarerecommended—reovirusesareubiquitous.
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86 Coltiviruses and SeadornavirusesRoberta L. DeBiasi and Kenneth L. Tyler
DEFINITION• ColtivirusandSeadornavirusaretwooffivegeneraoftheReoviridaevirusfamilythathave
beendocumentedtocausehumandisease.
EPIDEMIOLOGY• Coltiviruses associated with human disease include the type-specific Colorado tick fever
virus(CTFV;NorthAmerica),Eyachvirus(EYAV;France,Germany,CzechRepublic),andSalmonRivervirus(SRV;NorthAmerica).
• TheonlySeadornavirusimplicatedinhumandiseasetodateisBannavirus(BAV;IndonesiaandChina).
• Ticksaretheprincipalvectorsofcoltivirusesbuthavealsobeenisolatedfrommosquitoes,rodents,andhumans.
• ThedistributionofCTFVcoincideswiththerangeoftheprincipaltickvector.Thevirushasbeenisolatedin11states,primarilywithintheRockyMountainregion,aswellassouthwest-ernCanada.
• CTFVhasbeenisolatedfrompatientswithacutefebrilesyndromes,meningitis,andenceph-alitisinNorthAmerica.
MICROBIOLOGY• Coltiviruses and seadornaviruses are nonenveloped double-stranded RNA viruses with a
segmentedgenome.Coltiviruseshave12genesegmentsenclosedwithintwocapsids.
DIAGNOSIS• CTFVshouldbeconsideredinanyonepresentingwithafebrileillnessfollowingtickexpo-
sureinanendemicarea.• Patientsmayhavecerebrospinalfluidpleocytosis.Leukopeniaiscommon.• Serologic methods, including enzyme-linked immunosorbent assay, as well as serum and
cerebrospinal fluid reverse transcriptase–polymerase chain reaction have been used fordiagnosis.
• Viruscanalsobeisolatedincellculture.
THERAPY• Nospecifictherapyisavailable.
PREVENTION• Preventativemeasuresincludetickandmosquitorepellentssuchasdiethyltoluamide,physi-
calbarriers,andreductionofstandingwater.• CTFVpatientsshouldnotbeallowedtoserveasbloodproductorhematopoieticstemcell
donorsuntilinfectionhasfullyresolved.
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87 RotavirusesPhilip R. Dormitzer
DEFINITION• Rotavirusisanonenveloped,double-strandedRNAvirusthatisthemostimportantuniver-
salcauseofdehydratinginfantandchildhoodgastroenteritis.
VIRAL STRUCTURE AND REPLICATION• Theviralparticleisatriple-layeredicosahedron.• Genomeconsistsof11segmentsofdouble-strandedRNA.• TheouterlayerglycoproteinVP7andthespikeproteinVP4mediateentryintocellsandare
theneutralizationdeterminants.• Thevirusbindscellsurfacecarbohydrates.• Cellsareenteredbyviralpenetrationofthecellularmembrane.• Aftertheouterlayerisremoved,asubviralparticletranscribesandextrudesmRNA.• Newsubviralparticlesassembleinviroplasmsinthecytoplasm,andvirionsarecompleted
byadditionoftheouter-layerproteinsintheendoplasmicreticulum.
CLINICAL MANIFESTATIONS• Gastroenteritisduetorotavirusisnotreadilydistinguishedfromgastroenteritiscausedby
otheragentsonclinicalgroundsalone.• Mainsymptomsarediarrheaandvomiting.Severedehydrationanddeathcanresult.
PATHOGENESIS• Thevirusprimarilyinfectsepithelialcellsatthetipsoftheintestinalvilli.• Multifactorial pathogenesis of rotavirus diarrhea includes malabsorption due to loss of
intestinal epithelial cells, an enterotoxin, and enteric nervous system signaling to create asecretorystate.
SEROLOGIC CLASSIFICATION• GroupArotavirusescausemosthumandisease.• Thereisanextensivediversityofantigenictypes.• WithingroupA,rotavirushasadualserologicclassificationsystemwithGtypebasedon
VP7andPtypebasedonVP4.• Geneticclassificationisstartingtoreplaceserologicclassification.
EPIDEMIOLOGY• Infectionisuniversalinthefirstyearsoflife.• Infectionmaybesymptomaticorasymptomatic.• Severeillnessismostcommonbetween6monthsand2yearsofage.• Reinfectionoccursthroughoutlife.• Thereisalargeburdenofillnessinallsocioeconomicsettings,butmortalityisconcentrated
indevelopingcountries.
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• Annually,rotavirusescauseapproximately450,000deathsofchildrenyoungerthantheageof5years.
• Exchangeofstrainsandgenomesegmentsbetweenhumanrotavirusesandanimalrotavi-rusesmaintainsthediversityofcirculatingstrains.
IMMUNITY• Partialprotectionfromreinfectionisprovidedbypreviousinfection,withgenerallydecreas-
ingseverityofsubsequentinfections.• Serotypeinfluencesbutdoesnotdetermineprotectionfromreinfection.• VP4andVP7eachcontainserotype-specificandheterotypicneutralizingepitopes.• Neutralizingantibodiesblockthefunctionsoftheoutercapsidproteinsincellentry.• Non-neutralizingIgAagainstthemiddlelayerprotein,VP6,caninterferewithintracellular
virusreplication,astheantibodyistranscytosedacrossintestinalepithelialcells.• Humoral immunity appears to be the most important determinant of protection from
reinfection.• Cellularimmunitycontributestoclearanceofinfection.• Rotavirusinterfereswiththeinnateimmuneresponsebyseveralmechanisms.
DIAGNOSIS• Specificvirologicdiagnosisisnotnecessaryforroutineclinicalcarebutisusefulforepide-
miologicstudy,incomplicatedorprolongedcases,andtoreduceunnecessaryantibioticuse.• Antigencanbereadilydetectedinthestool,mostcommonlybyenzyme-linkedimmuno-
sorbentassay.• Thereisincreasinguseofnucleicacid–basedtestingforepidemiologicinvestigations.
THERAPY• Therapy is primarily supportive and aimed at maintaining hydration until the infection
resolves.• Nospecificantiviraltherapyisavailable.• Mildandmoderatedehydrationcanbetreatedeffectivelywithoralrehydrationsolutions.• Severedehydrationandtreatmentforpatientswithdepressedconsciousnessorileusrequire
theuseofintravenousfluids.• Inthecontextofmalnutrition,zincsupplementationmaybeausefuladjuncttooralrehydra-
tiontherapy.
IMMUNIZATION• Twolive-attenuated,oralrotavirusvaccineshavebeenlicensedandarecurrentlyinuse—a
monovalentvaccine(Rotarix)andapentavalentvaccine(RotaTeq).• Ararecomplicationofimmunization,intestinalintussusception,ledtothewithdrawalofa
previousrotavirusvaccine,butthereisconsensusthatthebenefitsofimmunizationwiththecurrentrotavirusvaccinesfaroutweightheriskforintussusception.
• Wherethevaccineshavebeenintroduced,theyhavedramaticallydecreasedsevererotavirusgastroenteritis and substantially decreased severe, dehydrating pediatric gastroenteritisoverall.
• Thenextmajorchallengeisdistributingrotavirusvaccinestothedevelopingcountrieswheremortalityisconcentrated.
• Despitelowerefficacyinimpoverishedsettingsthaninaffluentsettings,rotavirusvaccinescouldhavealargeimpactoninfantmortalityworldwide.
• Localproductionofnewrotavirusvaccinecandidatesindevelopingcountriescouldcontrib-utetoincreasedaccess.
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88 AlphavirusesLewis Markoff
DEFINITION• Alphaviruses,whichconstituteagenusofmorethan30viruses intheTogaviridae family,
arelipid-enveloped,positive-senseRNAviruses.• Allhumanpathogenicalphavirusesaremosquitoborne.
EPIDEMIOLOGY• The presence of infected mosquitoes is required for disease outbreak. Human-to-human
transmissiondoesnotoccur.• New World alphaviruses include Eastern, Western, and Venezuelan equine encephalitis
viruses (EEEV, WEEV, and VEEV, respectively), which are found in North and SouthAmerica.
• OldWorldalphaviruses,especiallychikungunya(CHIK),Sindbis,RossRiver,andO’nyong-nyong viruses, found in Europe, Africa, and Asia, cause a fever, arthralgia, and rashsyndrome.
• Inmostcases,exceptforCHIKvirus,thelifecycleofthevirusesrequiresmosquitoesandananimalhostinnature,otherthanhumans.
PATHOGENESIS• Alphaviruses enter cells by receptor-mediated endocytosis and exit by budding from the
plasmamembrane.• Alphavirusesenter thebodyviamosquitobitesandreplicate invarious tissues, including
Langerhanscells,whichthenmigrateto lymphnodes,causingviremia.Viremiaresults ininvasionofthecentralnervoussystem(CNS)byalphavirusesthatcauseencephalitisorofthejointsandinternalorgansbyvirusesthatcausefever,arthralgia,andrash.
• AllalphavirusessuppresstheinnateimmuneresponsebyinhibitingJAK/STATsignaling,amajorearlydeterminantofdiseaseseverity.
• Atlatertimes,recoveryismediatedbyvirus-neutralizingantibodiesandcytotoxicTcells.• In the CNS, virus replication in neurons is suppressed indefinitely by antibody-secreting
Bcells.
DIAGNOSIS• Knowledgeofthepatient’stravelhistoryisofmajorimportanceindiagnosis.• Thefever/arthralgia/rashsyndromecausedbyOldWorldalphavirusescanbeconfusedwith
manyotherviralexanthems.• Alphavirusencephalitisissimilarinpresentationtothatcausedbytheflaviviruses,WestNile
andSt.Louisencephalitisviruses.• Cultureofvirusfrombloodordetectionbyreverse-transcriptasepolymerasechainreaction
isnotrecommendedfordiagnosisofencephalitisbutmayoccasionallyyieldpositiveresultsintheacutephaseoffever/arthralgia/rashsyndrome.
• Detectionofvirus-neutralizingantibodies incombinationwithrecent travelhistory toanendemicareamaybemeaningful.
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• Virus-specificIgMorIgGclassantibodies,orboth,canbedetectedbyenzyme-linkedimmu-nosorbentassay;agreaterthanfourfoldriseintiterbetweenacuteandconvalescentseraorvirus-specificIgMincerebrospinalfluid,orboth,arediagnostic.
THERAPY• Atpresent,therearenoproductslicensedfortreatment.• Experimentaltherapiesthatseempromisingincludetheuseofhumanmonoclonalantibod-
ies,especiallyintreatmentofalphavirusencephalitis.• Forencephalitis,supportivemeasuresandintensivenursingcarearecurrentlyindicated.• Forfever/arthralgia/rashsyndrome,analgesicsandnonsteroidalanti-inflammatorydrugsare
themaintreatmentoptions.
PREVENTION• Veterinaryvaccinesareavailableforhorses,andtheirimmunizationagainstWEE,EEE,and
VEEisrequiredintheUnitedStates.• Thereareno licensedvaccines forpreventionofalphavirusdiseases inhumans,butunli-
censed vaccines against VEE, EEE, WEE, and CHIK are available for at-risk laboratoryworkers.
• Vaccinesareunderdevelopment,particularlyagainstCHIK.OnepromisingapproachistheuseofCHIKvirus–likeparticlesforimmunization.
• Theprimarymethodsfordiseasepreventioninhumansaremosquitoeradicationprograms,avoidance of mosquito-infested areas, and use of protection from mosquito bites, whereexposuretopossiblyinfectedmosquitoesisunavoidable.
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89 Rubella Virus (German Measles)Anne A. Gershon
DEFINITION• Rubellaisaninfectiousillnesscharacterizedbyfeverandmaculopapularrash,whichmay
beaccompaniedbyarthritis.• Manypostnatalinfectionsareasymptomatic.• Postnatalrubellaisaratherbenignillness,butcongenitalrubellacanresultinavarietyof
seriousmedicalproblems.• Manifestationsofcongenitalrubellaincludedeafness,cataractorglaucoma,congenitalheart
disease,andmentalretardation.• Rubellavaccinewasdevelopedprimarilytopreventcongenitalrubellafromoccurring.
EPIDEMIOLOGY• Intemperateclimates,diseaseoccursmainlyinthespring(ifvaccineisnotbeingused).• Rubellaissomewhatlesscontagiousthanmeasles.• WidespreadvaccinationintheAmericasledtotheeliminationofrubellaasof2009.• Globally, rubella and congenital rubella remain serious medical problems, especially in
Africa,someareasofEurope,SoutheastAsia,andtheWesternPacific.
MICROBIOLOGY• RubellaisanRNAvirus,amemberoftheTogaviridaefamilyandthegenusRubivirus.
DIAGNOSIS• Diagnosiscanbemadeserologically(enzyme-linkedimmunosorbentassay)withacuteand
convalescentserumsamples,orbydemonstrationofrubellaIgMantibodyonasingleserumsample.
• ApositivetestforviralRNAusingreverse-transcriptasepolymerasechainreactiononthroatswabs,cerebrospinalfluid,and/oramnioticfluidisespeciallyusefulfordiagnosisofcongeni-talrubella.
THERAPY• Noneisavailable.
PREVENTION• Live-attenuatedrubellavaccineiseffectiveandsafe,usuallyadministeredalongwithmeasles
andmumpsvaccines(MMR).
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Flaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)Stephen J. Thomas, Timothy P. Endy, Alan L. Rothman, and Alan D. Barrett*
DEFINITION• TheFlaviviridaeincorporatestheFlavivirus, Pestivirus,andHepacivirusgenera,whichcause
systemicfebrile,centralnervoussystem,and/orhemorrhagicfeversyndromes.
EPIDEMIOLOGY• Transmission and disease may occur with endemic, hyperendemic, and/or epidemic
patterns.• Yellow fever (YF) is found in tropical South America and sub-Saharan Africa. Disease is
severewithhighmorbidityandmortality.• Dengueiswidelydistributedthroughoutthetropicsandsubtropics.Severediseaseisinfre-
quent (~2% to 4% of apparent cases) but potentially fatal. Nonsevere disease (outpatient)accountsformuchofdengue’sglobalsocioeconomicimpact.
• Japaneseencephalitis(JE)virusisasignificantcauseofencephalitisinSoutheastandSouthAsia.Chronicmorbidityandmortalityarehighinsymptomaticcases.
• WestNilevirus(WNV),St.Louisencephalitis(SLE)virus,JEvirus,andtick-borneencepha-litis(TBE)virusarethemajorneurotropicmembersofthegenusFlavivirus.InfectionwithWNVisfoundworldwide,SLEisfoundintheAmericas,whereasTBEoccursfromWesternEuropetoRussia,Japan,andChina.Mostinfectionsaresubclinical.Clinicallyapparentcaseswithneurologicmanifestationshaveapredilectionforolderindividuals.
• Alkhurma hemorrhagic fever virus (AHFV), Kyasanur Forest disease virus (KFDV), andZika virus (ZIKV) infections are emerging or reemerging in the Middle East, India, andAfrica/Asia, respectively.All infections initiallyhavenonspecificclinicalfindings;personsinfectedwithAHFVandKFDVmaydevelophemorrhagicmanifestations.
MICROBIOLOGY• Flavivirusesareicosahedral,approximately50nmindiameter,approximately11-kbsingle-
stranded, positive-sense RNA viruses consisting of a lipid envelope covered densely withsurfaceprojectionsconsistingofM(membrane)andE(envelope)glycoproteins.Nonstructuralproteinsmakeuptheremainderofthegenome.
• Mutationsandreplicationerrorsarehigh.
DIAGNOSIS• Diagnosticapproachesaredictatedbythediseasecourse.• Duringtheviremicperiod,viralisolationandnucleicacidorantigendetectionfromblood
arepossible.• Duringthesubacuteperiod,early-phaseIgMantibodiesmaybedetectedinseraorcerebro-
spinalfluidusingvariousassayplatforms(e.g.,enzyme-linkedimmunosorbentassay,hemag-glutinationinhibition).
*Disclaimer:Theopinionsorassertionscontainedhereinaretheprivateviewsoftheauthor(SJT)andarenottobeconstruedasreflectingtheofficialviewsoftheU.S.ArmyortheU.S.DepartmentofDefense.
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• Duringtheconvalescentperiod,ariseinIgGbetweenacuteandconvalescentspecimensismeasuredtoidentifyaseroresponse(plaquereductionneutralizationtest).
THERAPY• Nolicensedorspecificantiviraltherapiesareavailable.• Treatmentissupportive,andoutcomesarevariable.
PREVENTION• U.S.-licensedvaccinesexistforYFandJE.VaccinesexistforTBEandKFDV.• Two recently completed phase III studies in Asia and Latin America of a live-attenuated
denguetetravalentvaccine(CYD-TDV)demonstratedmoderateefficacyagainstanydengueof any severity caused by any serotype and high efficacy against hospitalized and severedengue.
• Numerousvaccinedevelopmenteffortsareunderwayforadditionalflaviviruses.
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91 Hepatitis CStuart C. Ray and David L. Thomas
DEFINITION• HepatitisCvirus(HCV)isanenveloped,positive-strandRNAvirusthatisamemberofthe
Flaviviridaefamily,Hepacivirusgenus.• Itisamajorworldwidecauseofchronicliverdisease,includingcirrhosisandincreasedrisk
ofhepatocellularcarcinoma(HCC).
MICROBIOLOGY• HCVisroughlyspheroidandis55nmindiameter.• TheRNAgenomeis9.6kbinlengthandcontainsasinglelargeopenreadingframe,which
isprocessedintoat least10proteins, including3structuralproteinsand5proteinsof theviralRNAreplicasecomplex(NS3,NS4A,NS4B,NS5A,andNS5B)(seeFig.91-1).
• HCVhassixmajorgenotypesandprovisionallyaseventh.• Extensivequasispeciesvariationispresentineachinfectedindividual.
EPIDEMIOLOGY• Morethan185millionpersonsareHCVantibodypositiveworldwide.• Transmissionoccursmostcommonlybypercutaneousexposuretoblood.• Indevelopedcountries,mostHCVinfectionsareassociatedwithIVdrugabuse.• Inthedevelopingworld,transmissionoccursfromunsafemedicalpractices.• HCVmaybetransmittedsexually,butthisappearstobeinfrequentexceptinhigh-risksexual
activities.
CLINICAL MANIFESTATIONS• Acute illness caused by HCV infection is unusual, but it is typical of acute hepatitis and
consists of malaise, nausea, and right upper quadrant pain, followed by dark urine andjaundice.
• FulminanthepatitisduetoHCVinfectionisuncommoninWesterncountries.• ChronicinfectionwithHCVoccursinapproximately75%ofpatientsafteracuteinfection
withHCV.• Onceestablished,chronicinfectionpersistsfordecadesandcanbeassociatedwithcirrhosis,
metabolicdisorderssuchasinsulinresistanceandsteatosis,andHCC.
DIAGNOSIS• DiagnosisofHCVinfectionisusuallymadebyassaysofserumantibodytoHCVfollowed
bytestingforHCVRNA.• RNAtestsarealsousedtoassesstheeffectsoftreatment.• Liverbiopsiesandnoninvasivelivertestsareusedtoassessthestageofliverdiseases.
TREATMENT (SEE TABLE 91-1)• TheprimaryaimoftreatmentistoeradicateHCVinbloodandliverandthuspreventcom-
plicationsofHCVinfection.
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TABLE 91-1 AASLD and IDSA Recommendations for HCV Treatment-Naïve Patients: January 2015
GENOTYPE RECOMMENDATION*1a Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily–dosed dasabuvir (250 mg) and weight-based RBV for 12 wk (no cirrhosis) or 24 wk (cirrhosis)
Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV for 12 wk (no cirrhosis) or 24 wk (cirrhosis)
1b Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily–dosed dasabuvir (250 mg) for 12 wk. Weight-based RBV recommended for patients with cirrhosis
Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 wk (no cirrhosis) or 24 wk (cirrhosis)
2 Daily sofosbuvir (400 mg) and weight-based RBV for 12 wk (no cirrhosis) or 16 wk (cirrhosis)
3 Daily sofosbuvir (400 mg) and weight-based RBV for 24 wk
4 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV for 12 wk
Daily sofosbuvir (400 mg) and weight-based RBV for 24 wk
5 Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG IFN for 12 wk
6 Daily ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 wk
AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; PEG IFN, pegylated interferon; RBV, ribavirin.
*Listed alphabetically: see www.hcvguidelines.org for alternative treatments, treatments in experienced patients, and special populations.
FIGURE 91-1 Organization of the hepatitis C virus (HCV) genome and viral polyprotein. The 5′ and 3′ untranslated region (UTR) RNA structures (curves) flank the major open reading frame (ORF). Unlike eukaryotic mRNA, the viral RNA genome has 5′ triphosphate (“ppp”) and no 3′ poly-adenylation. The 5′ UTR contains an internal ribosomal entry site (IRES). Triangles indicate sites of cleavage by host cellular signal peptidase (black, open indicating additional processing by signal peptide peptidase) and viral (blue, open indicating cleavage by the NS2/NS3 cysteine protease) pro-teases are shown as triangles. Putative structural (gray) and nonstructural (blue) mature proteins (boxes) generated by these cleavage events are labeled, below which in blue are viral enzymatic functions NS2/NS3 cysteine protease (Cys Prot), NS3 serine protease (Ser Prot), NS3 helicase, and the NS5B RNA-dependent RNA polymerase (RdRP). Positions of the first and last nucleotides (nt) and amino acids (aa) of the polyprotein ORF are shown, based on reference genome H77 (GenBank accession number AF009606). Above the ORF are positions of the alternate reading frame protein (ARFP), variable regions HVR1 and V3, and (indicated by horizontal lines) the antigens included in the enzyme immunoassay serologic assay.
c200
ppp
IRES
ns5c100c33
SerProt
CysProt
RdRP
c22
nt 342aa1
93743011
3′UTR5′ UTR
Helicase
ARF V3
Core E1 E2 NS2 NS3 NS4B NS5A NS5Bp7
HVR1
4A
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• American Association for the Study of Liver Diseases (AASLD) and Infectious DiseasesSocietyofAmerica(IDSA)treatmentrecommendationsforhepatitisC,January2015:• SeeTable91-1• Genotype1a
• Ledipasvir/sofosbuvirfor12weeks• Paritaprevir/ritonavir/ombitasvir plus dasabuvir and weight-based ribavirin (RBV)
for12weeks(nocirrhosis)or24weeks(cirrhosis)• Sofosbuvir plus simeprevir with or without RBV for 12 weeks (no cirrhosis) or
24weeks(cirrhosis)• Genotype1b
• Ledipasvir/sofosbuvirfor12weeks• Paritaprevir/ritonavir/ombitasvirplusdasabuvirfor12weeks,plusRBVforpatients
withcirrhosis• Sofosbuvirplussimeprevirfor12weeks(nocirrhosis)or24weeks(cirrhosis)
• Genotype2• SofosbuvirandRBVfor12weeks(nocirrhosis)or16weeks(cirrhosis)
• Genotype3• SofosbuvirandRBVfor24weeks
• Genotype4• Ledipasvir/sofosbuvirfor12weeks• Paritaprevir/ritonavir/ombitasvirandRBVfor12weeks• SofosbuvirandRBVfor24weeks
• Genotype5• SofosbuvirandRBVandpolyethyleneglycol(PEG)for12weeks
• Genotype6• Ledipasvir/sofosbuvirfor12weeks
Cliniciansareurgedtoconsultonlineguidelines for the latestrecommendationsonHCVtreatment(www.hcvguidelines.org).
PREVENTION• Strategiesareprimarilydesignedtoreduceexposuretocontaminatedblood,throughscreen-
ingofbloodproducts,applicationofprecautionsinhealthcaresettings,andreductionofIVdrugabuserisks.
• DevelopmentofvaccinesagainstHCVischallengingbecauseofextensiveviraldiversity.
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92 Coronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)Kenneth McIntosh and Stanley Perlman
DEFINITION• Thecoronaviruses(CoVs)commonlycausemildbutoccasionallymoreseverecommunity-
acquiredacuterespiratoryinfectionsinhumans.CoVsalsoinfectawidevarietyofanimals,andseveralCoVs(e.g.,severeacuterespiratorysyndrome[SARS],MiddleEastrespiratorysyndrome[MERS])havecrossedthespeciesbarrier,producingoutbreaksofsevererespira-torydisease.AsofJanuary23,2015,956casesoflaboratory-confirmedMERSwerereportedtotheWorldHealthOrganization,with351deaths.
EPIDEMIOLOGY• Community-acquiredCoVinfectionscauseabout15%ofcommoncolds.Theyaretypically
epidemic in thewintermonths.MERShasoccurred inpatients in theArabianPeninsulaandthosewhorecentlytraveledfromthislocale.
MICROBIOLOGY• CoVs are members of the Nidovirales order, single-stranded, positive-sense RNA viruses
withalargegenome.Theymutateandalsorecombinefrequently.
DIAGNOSIS• LaboratorydiagnosisisbestaccomplishedbyfindingviralRNAthroughpolymerasechain
reaction.
THERAPY• TherearenoacceptedeffectiveantiviraldrugsforCoVs.
PREVENTION• Prevention is through epidemiologic methods. The SARS epidemic was halted through
carefulcasefinding,quarantine,anduseofbarrierprecautions.
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93 Parainfluenza VirusesMichael G. Ison
DEFINITION• Parainfluenzavirus(PIV)causesacuterespiratoryillness,includingcolds,croup,bronchi-
olitis,andpneumonia.
EPIDEMIOLOGY• PIV-1andPIV-2causeseasonaloutbreaksinthefall,withPIV-1causingepidemicsinodd-
numberedyears.Clinically,PIV-1isstronglyassociatedwithcroupinchildren.• PIV-3causesannualepidemicsinthespring; inyearswherePIV-1doesnotcirculate, the
seasonistypicallymoreactiveandprolonged.PIV-3isassociatedwithmoresevereinfec-tions,particularlyamongimmunocompromisedadultsandchildren.
• PIV-4isassociatedwithmilderdisease,typicallylimitedtotheupperairway.• Although antibodies are produced in response to clinical disease, reinfection is common
throughoutlife.• Disease, particularly associated with PIV-3, frequently progresses to the lower airway in
immunocompromisedadultsandchildrenandisassociatedwithsignificantmorbidityandmortality.
MICROBIOLOGY• Parainfluenzaisasingle-stranded,envelopedRNAvirusbelongingtotheParamyxoviridae
family.ItincludesPIV-1,PIV-2,PIV-3,andPIV-4.
DIAGNOSIS• National parainfluenza virus trends are available at www.cdc.gov/surveillance/nrevss/
human-paraflu/natl-trend.htm.• Laboratorydiagnosiscanbemadebycultureorpolymerasechainreaction(PCR)assay,with
improvedsensitivitywithmoleculardiagnosticmethods.
THERAPY• Croup is generally treated with glucocorticoids and nebulized epinephrine in young
children.• Although ribavirin and intravenous immunoglobulin have been used in the treatment of
immunocompromisedadultsandchildren,theirefficacyisuncertain.• Anumberofnovelantiviralsarecurrentlyunderdevelopment.
PREVENTION• StandardandcontactprecautionsarerecommendedtoavoidnosocomialspreadofPIVin
thehealthcaresetting.• Anumberoflive-attenuatedvaccinecandidatesareundergoingdevelopment.
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94 Mumps VirusNathan Litman and Stephen G. Baum
DEFINITION• Mumpsisanacuteviralinfectionmostcommonlymanifestasnonsuppurativeswellingand
tendernessoftheparotidorothersalivaryglandscausedbythemumpsvirus.• Lesscommonmanifestationsofmumpsincludemeningitis,encephalitis,epididymo-orchitis,
oophoritis,andpancreatitis.
EPIDEMIOLOGY• Mumps is endemic throughout the world, and humans are the only natural hosts for the
virus.• Incubationperiodisusually16to18dayswitharangeof2to4weeks.• Before the introduction of the mumps vaccine in the United States in 1967, epidemics
occurredevery2to5yearswithpeakincidencebetweenJanuaryandMay.• Since1967,therehasbeenmorethana99%declineintheannualU.S.incidenceofmumps.• Outbreaksofmumpshavebeenreportedthroughouttheworld,includingtheUnitedStates,
eveninpopulationswhohavereceivedtherecommendedtwo-dosemeasles-mumps-rubella(MMR)series.
MICROBIOLOGY• Mumpsisanenveloped,single-strandedRNAvirus.• Onlyoneserotypeofmumpsvirusexists,butthereare13genotypes.
DIAGNOSIS• Theclinicaldiagnosisismadeonthebasisofahistoryofexposureandofparotidswelling
andtenderness.• Thediagnosisisconfirmedbyisolationofmumpsvirusordetectionofmumpsnucleicacid
by polymerase chain reaction from clinical specimens or the presence of mumps-specificIgMantibodiesorafourfoldriseinmumpsIgGantibodiesinserum.
THERAPY• Therapyformumpsissymptomaticandsupportive.
PREVENTION• Immunization with live, attenuated mumps virus vaccine as part of the standard MMR
vaccineat12monthsand4to6yearsofageisrecommendedforallchildren;atwo-doseseriesofMMRisrecommendedfor individualsbeyondchildhoodwhohavenotreceivedthechildhoodseries.
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95 Respiratory Syncytial Virus (RSV)Edward E. Walsh and Caroline Breese Hall*
DEFINITION• Respiratorysyncytialvirus(RSV)causesacuteupperandlowertractrespiratoryillnesses.
EPIDEMIOLOGY• RSVcirculatesannuallyduringthewintermonthsintemperateclimates.• RSVistheleadingcauseofbronchiolitisininfants.• Reinfectioniscommonthroughoutlifeandcanbesevereinelderlyandimmunocompro-
misedpersons.• RSVisprimarilytransmittedbydirectcontactwithinfectedpersonsortheirsecretions.
MICROBIOLOGY• RSVisanenvelopednonsegmentedRNAvirusintheParamyxoviridaefamily.• RSVisolatescanbeclassifiedintoantigenicallydistinctgroups,AandB.
DIAGNOSIS• Clinicaldiagnosisininfantsisrelativelyaccurateduringthewintermonths;however,inolder
children and adults, laboratory confirmation by culture, antigen detection, or reverse-transcriptasepolymerasechainreactionisnecessary.
THERAPY• Treatmentformostinfantsandadultsissupportiveonly.• Aerosolizedribavirin,anucleosideanalogue,canbeconsideredforadministrationtohigh-
risk infants. It is also used to treat RSV in highly immunocompromised persons, with orwithoutanti-RSVimmunoglobulin,butitsefficacyisnotestablished.
PREVENTION• Attentiontoinfectioncontrolmeasures,suchashandhygieneandcontactprecautions,can
reducethespreadofRSV.• Palivizumab,ahumanizedneutralizingmonoclonalantibodytoRSV,isbeneficialforspecific
high-riskinfants,includingthosewithunderlyingcardiacandpulmonarydiseaseandlowgestationalage.
*CarenHallpassedawayin2012.Shewastheauthorforthisandotherchaptersforpreviouseditionsofthisbook.Thischapterisdedicatedtohermemory.
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96 Human MetapneumovirusAnn R. Falsey
DEFINITION• Human metapneumovirus (hMPV) is a paramyxovirus that causes acute respiratory tract
infections.
EPIDEMIOLOGY• Distributionisworldwide.• Infectionismostcommoninwinterandspringintemperateclimates.• hMPVcocirculateswithotherseasonalviruses,includinginfluenzaandrespiratorysyncytial
virus(RSV).• Infectionisuniversalbyage5years.• Reinfectionsoccurthroughoutlife.
MICROBIOLOGY• VirusisinfamilyParamyxoviridae,subfamilyPneumovirinae,genusMetapneumovirus;has
nonsegmentedsingle-strandedRNA(ssRNA).• Divergedfromavianmetapneumoviruses200to300yearsago.• Twomajorgenotypes(AandB)andfoursubgroups(A1,A2,B1,andB2).
DIAGNOSIS• Clinicalsyndromeisnotdistinctandrangesfromcommoncoldtoacuterespiratorydistress
syndrome.• Bronchiolitis,asthmaexacerbations,andpneumoniaoccurinchildren.• Diagnosis is best accomplished by reverse-transcriptase polymerase chain reaction (RT-
PCR)ofrespiratorysecretions.• ImmunofluorescenceassayofrespiratorysecretionsislesssensitivethanRT-PCRbutisan
acceptablemethodofdiagnosis.
THERAPY• Therapyissupportive.• Intravenousgammaglobulinandribavirinhavebeenusedinseverelyillimmunocompro-
misedpatients,butefficacy,ifany,isunclear.
PREVENTION• Novaccineisavailable.• Infection control measures include hand hygiene and use of masks, gowns, and gloves in
outbreaksituations.
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97 Measles Virus (Rubeola)Anne A. Gershon
DEFINITION• Measlesisahighlycontagiousviralinfection,usuallyofchildhood.• Thediseasepresentswithanonpruriticrashthatbeginsontheheadandfaceandspreads
downthebody,withfeverandmalaise.• Initially,beforetherashappears,measlescanresembleinfluenza.• Thereisusuallyaccompanyingconjunctivitis,cough,andcoryza.• Complications include infections of the respiratory tract and central nervous system
involvement.
EPIDEMIOLOGY• Measles is very contagious before the rash appears, which enhances the chance of spread
beforethediseaseisidentified.• Measlesisalsocontagiousforafewdaysafterrashonset.• Thevirusspreadsbydropletsandalsobytheairborneroute.• WidespreadvaccinationwithtwovaccinedosesintheAmericashasreducedtheincidence
ofmeaslessothatthevirusisnolongerendemicintheseregions.• However,measlesoutbreakscontinuetooccurintheUnitedStates(34outbreaksin2013to
2014,andalargeoutbreakin2015relatedtoexposureatDisneylandinCalifornia).• Whenvaccinationratesfallbelow95%,measlesoutbreakscanoccurifthevirusisreintro-
ducedintoapopulation.• Immunosuppressedpatientsareathighrisktodevelopseveremeasleswithoutnecessarily
manifestingarash.• Measlesvaccinationhasbeenshowntobeunrelatedtodevelopmentofautism.
MICROBIOLOGY• MeaslesiscausedbyanRNAvirusclassifiedasaMorbillivirusoftheParamyxoviridaefamily.
DIAGNOSIS• Clinically,measlesmaybeconfusedwithKawasakidisease.• Measlesvirusisdifficulttoculture.• Diagnosis is usually made clinically, particularly if Koplik spots on the oral mucosa are
observed.• Laboratorydiagnosiscanbemadebyreverse-transcriptasepolymerasechainreaction(RT-
PCR)onjustaboutanybodyfluidortissue.
THERAPY• Nospecifictherapyhasbeenproventobeuseful.• AdministrationofvitaminAoncedailybymouthfor2daysshouldbeconsideredforpatients
withmeasles.• ThemechanismofactionofvitaminAisthoughttobebyimmunomodulation.
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PREVENTION• Live-attenuatedmeaslesvaccineisadministeredtohealthychildrenat12to15monthsof
ageandagainatage4to6years.• Passive immunizationwith immunoglobulinGshouldbegiven tohigh-riskchildrenand
adultsexposedtomeaslesbuthavingnohistoryofmeasles.
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98 Zoonotic Paramyxoviruses: Nipah, Hendra, and MenangleAnna R. Thorner and Raphael Dolin
DEFINITION• HendraandNipahvirusesarehighlypathogenic zoonoticparamyxoviruses that emerged
duringthe1990sinAustraliaandSoutheastAsia,respectively.
EPIDEMIOLOGY• In 1994, in Queensland, Australia, Hendra virus caused two outbreaks of fatal illness in
horses and their human caretakers. Additional outbreaks involving humans occurred in2004,2008,and2009.
• Nipahviruswasfirst recognizedwhen it causedanoutbreakof severeencephalitis inpigfarmersinMalaysiaandabattoirworkersinSingaporein1998and1999.MultipleoutbreakshavebeendetectedsubsequentlyinBangladeshandIndia,includingcasesthathaveinvolvedhuman-to-humantransmission.
• Menanglevirus,anotherparamyxovirus,causeddecreasedfarrowingratesandstillbirthsinpigs,aswellasillnessintwohumansinAustraliain1997.
• ThePteropus speciesof fruitbat,alsoknownas theflyingfox, is thereservoirofall threeviruses.
CLASSIFICATION• NipahandHendravirusesaremembersoftheHenipavirusgenuswithintheParamyxovirinae
subfamilyoftheParamyxoviridaefamily.
CLINICAL MANIFESTATIONS• Nipah virus causes a severe and often fatal meningoencephalitis. Clinical manifestations
of Hendra virus infection range from a self-limited influenza-like syndrome to a fatalrespiratory illness or encephalitis. Menangle virus has caused an influenza-like illness intwopeople.
DIAGNOSIS• DiagnosticteststhatcanbeusedtodetectNipahandHendravirusesincludeculture,elec-
tronmicroscopy,immunohistochemistry,serology,andreal-timereverse-transcriptasepoly-merasechainreaction.
THERAPY• BecausenospecificantiviraltherapieshavebeenevaluatedforthetreatmentofNipahvirus
or Hendra virus infection, treatment involves only supportive care, such as intravenoushydrationandmechanicalventilation,whenindicated.
• A recombinant human monoclonal antibody, m102.4, directed against the henipavirusglycoprotein protects animals from disease after inoculation with Hendra virus orNipahvirus.
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ipah
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PREVENTION• Several vaccines have been developed against Nipah virus and Hendra virus, but none is
currentlyavailableforuseinhumans.• AHendravirussubunitvaccinewasshowntobehighlyeffectiveatpreventingHendravirus
infection in horses following a lethal challenge; it became available for use in horses inAustraliain2012.
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99 Vesicular Stomatitis Virus and Related VesiculovirusesSteven M. Fine
DEFINITION• Vesicularstomatitisvirus(VSV)isavesiculovirusthatcausesoutbreaksofstomatitis,mainly
inlivestockbutsometimesalsoinhumans.
EPIDEMIOLOGY• Alargepercentageofpeoplewholive inendemicareasare infectedandusuallyhavehad
mildorsubclinicaldisease.• Seasonaloutbreaksamonghorses,cattle,andotherlivestockhavethepotentialtocauselarge
economiclosses,particularlyinthesouthwesternUnitedStates.• EndemicdiseaseoccursinareasofCentralandSouthAmerica.• Themodeoftransmissionisnotknown,althoughthevirusisbelievedtobeintroducedto
aherdbyaninsectvector,anditcanthenspreadfromanimaltoanimalbydirectcontact.
MICROBIOLOGY• VSVisasingle-stranded,negative-strandRNAvirusthatisamemberoftheRhabdoviridae
family,genusVesiculovirus.
DIAGNOSIS• Samples from lesions can be tested by enzyme-linked immunosorbent assay, complement
fixation,orisolationofvirusintissueculture,aswellasbypolymerasechainreactionassays.• Themainpurposeofdiagnosisistoquicklydistinguishthediseasefromthemoredangerous
foot-and-mouthdiseaseinlivestock.
THERAPY• Therapyinhumansisgenerallynotrequired.• Thereisnoknownantiviraltreatment,sotherapyconsistsofsupportivemeasures.
PREVENTION• Quarantineofanimalsfrominfectedranchesiscommonlyinstituted.• Protectiveclothingandglovesshouldbewornwhenhandlinginfectedanimals.• Anexperimentalvaccineisintrials.Akilledvaccineforanimalsisapproved,butitsefficacy
isunknown.
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100 Rabies (Rhabdoviruses)Kamaljit Singh, Charles E. Rupprecht, and Thomas P. Bleck
DEFINITION• Rabies is a zoonotic encephalitis caused by different species of neurotropic viruses in the
Rhabdoviridaefamily.
EPIDEMIOLOGY• Rabiesisoneoftheoldesthumandiseases,withthehighestcasefatalityrate.• Approximately3.3billionpeopleliveinregionswhererabiesisenzootic.• Anestimated55,000peoplediefromrabieseachyear.• Althoughallagegroupsaresusceptible, rabies ismostcommoninchildrenyounger than
15years.• Bitesbyrabiddogscause99%ofhumandeathsglobally.• IntheUnitedStates,batsaccountformosthumanrabiescases.• Rabiesvirustransmissionmayalsooccurthroughtissueororgantransplantation.
MICROBIOLOGY• Rhabdovirusesarebullet-shaped,single-strandedRNAvirusesoftheorderMononegavirales,
familyRhabdoviridae,andgenusLyssavirus.• RabiesvirusisthetypespeciesoftheLyssavirusgenus.
DIAGNOSIS• Developmentofanacuteneurologicsyndromeafterthebiteofarabidanimalisclassically
recognizedindevelopingcountries.• Encephaliticrabiesoccursinthemajorityofpatientswithfever,hydrophobia,aerophobia,
agitation,autonomicoveractivitywithhypersalivation,coma,andparalysis.• Paralyticrabiesischaracterizedbyascendingflaccidquadriparesisandcoma.• Antemortem diagnosis can be made by direct immunofluorescent staining of skin biopsy
specimens,reverse-transcriptasepolymerasechainreactionofsalivaorskinbiopsy,ordetec-tionofantirabiesvirusantibodiesinserumorcerebrospinalfluid.
THERAPY• Thereisnoprovenantiviraltherapy.• Mostpatientswith rabiesvirus infectiondiewithina fewdays to2weeksafter theonset
ofcoma.
PREVENTION• Annually,morethan10millionpeoplereceiverabiespostexposureprophylaxis.• After exposure to a rabid animal, prevention consists primarily of prompt wound
cleansing.• Postexposureprophylaxisconsistsofpromptadministrationofrabiesimmuneglobulinand
rabiesvaccineaccordingtotheAdvisoryCommitteeonImmunizationPracticesandWorldHealthOrganizationguidelines.
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• BatrabiescausesthemajorityofhumancasesintheUnitedStates,andpostexposurepro-phylaxis depends on the type of exposure and availability of the animal for rabiesdiagnosis.
• Preexposure prophylaxis should be targeted to high-risk groups, including veterinarians,laboratoryworkers,andcertaintravelers.
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101 Marburg and Ebola Hemorrhagic Fevers (Marburg and Ebola Viral Diseases) (Filoviruses)Thomas W. Geisbert
DEFINITION• MarburgviraldiseaseandEbolaviraldiseasearesevereandoftenfataldiseasescharacterized
byfever,headache,malaise,myalgia,vomiting,diarrhea,coagulationdisorders,andmulti-organfailure.
EPIDEMIOLOGY• HumanoutbreaksoccursporadicallyinregionsofCentralAfrica.
• In2014,anextraordinarilylargeoutbreakofEbolaviraldiseasedevelopedinWestAfricaandstillcontinuesinearly2015.
• Recentevidencesuggeststhatbatsmayplayaroleasareservoirhost.• Themanner inwhichfilovirusoutbreaksare initiated isunknown;however, it is thought
thattheinitialcasesoccurasaresultofcontactwithaninfectedanimal.• Nosocomial transmissionhasoccurred frequentlyduringoutbreaksoffilovirusdisease in
endemicareas.
DIAGNOSIS• Clinicalsymptomsarenonspecific,butaconstellationofsymptoms,includingfever,head-
ache,malaise,myalgia,sorethroat,vomiting,diarrhea,andtheappearanceofamaculopapu-larrashmayindicateinfectionwithafilovirus.
• Reverse-transcriptasepolymerasechainreaction(RT-PCR)isthemostfrequentlyusedassaytodiagnosefilovirusinfection.
TREATMENT• Therearenoapprovedpostexposuretreatmentsforfilovirusinfections.• TreatingpatientsinfectedwithMarburgorEbolavirusesconsistsprimarilyofintensivesup-
portive care that is directed toward maintaining effective blood volume and electrolytebalance.
• Severalexperimentaltreatmentshaveshownpromiseinnonhumanprimatemodelsoffilo-virus infection, including vesicular stomatitis virus–based postexposure vaccines, smallinterferingRNAs,antisenseoligonucleotides,andpoolsofmonoclonalantibodies.
PREVENTION• TherearenoapprovedvaccinesagainstMarburgorEbolaviruses,butsignificantprogress
hasbeenmade in thedevelopmentofChAd3-andrecombinantvesicularstomatitisvirus(rVSV)-basedvaccines.
• Appropriatepersonalprotectionequipment(PPE)isessentialforhealthcareworkers.• Isolationofinfectedpatientsandclosecontactsisessential.• Avoidcontactwithbushmeatandsickanimals,particularlynonhumanprimates,inendemic
regions.
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102 Influenza (Including Avian Influenza and Swine Influenza)John J. Treanor
DEFINITION• Influenzavirusesareenveloped,negative-sense,single-strandedRNAviruseswhosegenome
issegmented.Theycauseepidemicacuterespiratorydiseasecharacterizedbyfever,cough,andsystemicsymptoms.Threetypes(A,B,andC)arerecognized,aswellasmanysubtypeswithinthetypeAviruses.
EPIDEMIOLOGY• Influenzavirusesaretransmittedbytherespiratoryrouteandcauselargeepidemics,which
generallyoccurduringthewinter in temperateclimates. Inadditionto infectinghumans,influenzaAvirusesinfectawidevarietyofanimals,particularlymigratorywaterfowl.NewinfluenzaAvirussubtypessporadicallyemergeinhumanstocausewidespreaddisease,orpandemics.
MICROBIOLOGY• Influenza viruses are readily isolated in eggs or mammalian cell culture at 33°C. They
undergoconstantantigenicevolution,referredtoasantigenicdriftorshiftthatallowsthemtoreinfectindividualswhohavehadpreviousinfections.
DIAGNOSIS• Inthecontextofrecognizedepidemics,influenzaisusuallydiagnosedclinicallyonthebasis
ofcharacteristicsymptomsoffeverandcough.Rapiddetectionofvirusinrespiratorysecre-tionsalsocanbeaccomplishedbyantigendetectionormoleculartechniquessuchaspoly-merasechainreactionassay.
THERAPY• Antiviraltherapywithoseltamivir,zanamivir,orperamivirisavailableandmayshortenthe
durationofillnessandreducetherateofcomplications.Therapyismosteffectivewhenusedearlyinthecourseofillness(seeTable102-1).
PREVENTION• Influenza vaccines are effective in the prevention of influenza illness, although improved
vaccinesareneeded.• Inactivatedandlive-attenuatedvaccinesareavailableintrivalentandquadrivalentformula-
tions(seeTable102-2).• Theobjectivesofvaccination includeprotectionof the individual,aswellasprotectionof
thepopulationthroughherdimmunity.Antiviraldrugscanalsobeusedprophylacticallyinselectedcircumstances.
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TABLE 102-1 Antiviral Chemotherapy and Chemoprophylaxis for Influenza
INFECTION DRUG ROUTE DOSAGEInfluenza A and B: treatment
Oseltamivir Oral Adults: 75 mg bid × 5 daysChildren aged 1-12 years: 30-75 mg bid, depending on weight†, × 5 days
Zanamivir Inhaled orally Adults and children aged ≥7 yr: 10 mg bid × 5 days
Influenza A: treatment
Amantadine* Oral Adults: 100 mg qd or bid × 5-7 daysChildren aged 1-9 yr: 5 mg/kg/day (maximum, 150 mg/day) × 5-7 days
Rimantadine* Oral 100 mg qd or bid × 5-7 days in adults
Influenza A and B: prophylaxis
Oseltamivir Oral Adults: 75 mg/dayChildren aged ≥1 yr: 30-75 mg/day, depending on weight†
Zanamivir Inhaled orally Adults and children aged ≥5 yr: 10 mg/day
Influenza A: prophylaxis
Amantadine* or rimantadine*
Oral Adults: 200 mg/dayChildren aged 1-9 yr: 5 mg/kg/day (maximum, 150 mg/day)
*Amantadine and rimantadine are not considered for use because of widespread resistance in influenza A/H3N2 and A/H1N1 viruses currently circulating (2012-2013). They may be considered if sensitivities become reestablished.
†For detailed dosage recommendations in children aged <1 yr, see www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm.
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TABLE 102-2 Influenza Vaccines Available in the United States, 2013-2014 Influenza Season*
VACCINE TRADE NAME MANUFACTURER AGE INDICATIONS ROUTEInactivated influenza vaccine, trivalent (IIV3), standard dose
Afluria CSL Limited ≥9 yr IM†
Fluarix GlaxoSmithKline ≥3 yr IM†
Flucelvax Novartis Vaccines ≥18 yr IM†
FluLaval ID Biomedical Corporation of Quebec (distributed by GlaxoSmithKline)
≥3 yr IM†
Fluvirin Novartis Vaccines ≥4 yr IM†
Fluzone Sanofi Pasteur ≥6 mo IM†
Fluzone Intradermal Sanofi Pasteur 18-64 yr ID
Inactivated influenza vaccine, trivalent (IIV3), high dose
Fluzone High-Dose Sanofi Pasteur ≥65 yr IM†
Inactivated influenza vaccine, quadrivalent (IIV4), standard dose
Fluarix Quadrivalent GlaxoSmithKline ≥3 yr IM†
FluLaval Quadrivalent
ID Biomedical Corporation of Quebec (distributed by GlaxoSmithKline)
≥3 yr IM†
Fluzone Quadrivalent
Sanofi Pasteur ≥6 mo IM†
Recombinant influenza vaccine, trivalent (RIV3)
FluBlok Protein Sciences 18-49 yr IM†
Live-attenuated influenza vaccine, quadrivalent (LAIV4)
FluMist Quadrivalent
MedImmune 2-49 yr IN
ID, intradermal; IIV, Inactivated influenza vaccine; IIV3, inactivated influenza vaccine, trivalent; IIV4, inactivated influenza vaccine, quadrivalent; IM, intramuscular; IN, intranasal; LAIV, live attenuated influenza vaccine; RIV, recombinant influenza vaccine.
*Immunization providers should check U.S. Food and Drug Administration-approved prescribing information for 2013-2014 influenza vaccines for the most complete and updated information, including (but not limited to) indica-tions, contraindications, and precautions. Package inserts for U.S.-licensed vaccines are available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm.
†For adults and older children, the recommended site of vaccination is the deltoid muscle. The preferred site for infants and young children is the anterolateral aspect of the thigh. Specific guidance regarding site and needle length for intramuscular administration may be found in the Advisory Committee on Immunization Practices General Recommendations on Immunization.
Modified from Centers for Disease Control and Prevention. Summary Recommendations: Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices—(ACIP)—United States, 2013-14. Available at http://www.cdc.gov/flu/professionals/acip/2013-summary-recommendations .htm#table1.
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103 California Encephalitis, Hantavirus Pulmonary Syndrome, and Bunyavirus Hemorrhagic FeversDennis A. Bente
DEFINITION• This largest family of RNA viruses has more than 350 named isolates that can be found
worldwide,anditsmembersareabletoinfectinvertebrates,vertebrates,andplants.
EPIDEMIOLOGY• Multiplemembersaresignificanthumanpathogenswiththeabilitytocauseseveredisease,
rangingfromfebrileillness,encephalitis,andhepatitistohemorrhagicfever.• Withexceptionofhantaviruses,bunyavirusesaretransmittedbyhematophagousarthropods,
includingticks,mosquitoes,andphlebotomineflies.• Hantavirusesaremaintainedinnaturethroughpersistentinfectionofrodents.
DIAGNOSIS• Earlydiagnosisisbasedonreverse-transcriptasepolymerasechainreactionassayofblood
samples.Inmostcases,thediagnosisisbasedonserologicinvestigationofacuteandearlyconvalescentsera.Diagnostictestsaretypicallyperformedinreferencelaboratories.
THERAPY• Nospecific therapy isavailable,andtreatment is typicallysupportive.Ribavirin treatment
has been studied only in some bunyavirus infections, and data from in vitro and in vivomodelsholdpromise.Ribavirinhasshownclinicalbenefitinhemorrhagicfeverwithrenalsyndrome(HFRS)and inCrimean-Congohemorrhagic fever(CCHF).However,compre-hensiveclinicaltrialshavenotbeenconducted.
PREVENTION• Nospecificpreventivemeasuresareavailable,yetexperimentalvaccinesforsomebunyavi-
ruseshavebeendeveloped.Individualprotectivemeasuressuchasarthropodrepellentsandinsecticide-impregnatedmosquitobednetsarerecommendedinendemicareas.
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104 Lymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)Alexey Seregin, Nadezhda Yun, and Slobodan Paessler
EPIDEMIOLOGY• Lymphocytic choriomeningitis virus (LCMV) is worldwide in distribution; Lassa fever is
foundinAfrica,andtheNewWorldcomplexvirusescirculateinSouthandNorthAmericaandcancausehemorrhagicfevers.
• Transmissionisbyrodents,withgenerallyhighspeciesspecificityofreservoirvectors.
MICROBIOLOGY• Thesepleomorphicvirusesare50to300nmindiameterwithtwosingleRNAsegmentswith
ambisensegeneorganization.
CLINICAL MANIFESTATIONS• LCMV:Febrileillnessisaccompaniedbyheadacheandsystemicsymptoms;coursemaybe
biphasic with meningitis presenting during second phase in 5 to 10 days; full recovery isusual,butimmunosuppressionmayresultindisseminatedandfataldisease.
• Lassa fever:Theillnessisusuallymild,butin5%to10%itmayresultinseveremultisystemdisease,resultingindeathin15%to25%ofhospitalizedpatients;fever,pharyngitis,retroster-nal pain, and proteinuria are the most common features; fatal cases usually occur in thesecondweekofillness,withhypotension,vasoconstriction,mucosalhemorrhages,andcapil-laryleaksyndrome.
• South American hemorrhagic fevers: Argentinean, Bolivian, and Venezuelan hemorrhagicfevershaveprogressivefever,malaise,andmyalgias,mostfrequentlyaffectingthelowerback;petechiaeandsmallvesiclesarefrequent;vasculardisease(capillaryleak),vasoconstriction,and shock may occur; various blood and neurologic abnormalities can be seen; overallmortalityis15%to30%;andconvalescencemaytakeweeks,butrecoveryisusuallywithoutsequelae.
DIAGNOSIS• Detectionofvirusisevidentinacutebloodspecimensbyreverse-transcriptasepolymerase
chainreactionassayorvirusculture,dependingontheparticularviralagent.• IgMantibodiesmaybedetectedbyserology,andincreases inantibodytiters(seroconver-
sion)canbenotedbycomparingacuteandconvalescentserumspecimens.
TREATMENT• Supportivetreatmentmaybelifesaving.• Convalescent human plasma has been shown to be effective in Argentinean hemorrhagic
feverbuthasnotbeenassuccessfulinLassafever.• Ribavirin treatment of patients hospitalized with Lassa fever as well as in patients with
ArgentineanandBolivianhemorrhagicfeversisbeneficial.
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PREVENTION• Reductionoftransmissionfromrodentstohumansisneeded.• Person-to-persontransmissioninhospitalsisaproblemwithLassafever,anduseofgloves
andgownsandcarefuldisposalofpatients’wastesandfomitesshouldbe implemented. Ifavailable,singleroomswithnegativepressureshouldbeutilized.
• Stepsshouldbetakentoavoid infectionin laboratoryworkerswhoexaminesamples thatmaycontainarenaviruses.
• Alive-attenuatedvaccineisavailableagainstArgentineanhemorrhagicfeverandislicensedinArgentina.
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105 Human T-Lymphotropic Virus (HTLV)Edward L. Murphy and Roberta L. Bruhn
DEFINITION• HumanT-lymphotropicvirus(HTLV)isahumanretrovirusofthesubfamilyRetroviridae
andgenusDeltaretrovirus.• ItcauseschronichumaninfectionbyintegrationofproviralDNAintothesomaticDNAof
hostTlymphocytes,withexpansionofinfectiousburdenbyproliferationofinfectedlym-phocytesmoreimportantlythanbyproductionoffreevirusparticles.
• Todate,fourtypesofthevirushavebeendiscovered:HTLV-1andHTLV-2infectionsareestimated in millions of humans, and HTLV-3 and HTLV-4 have occurred in only a fewisolatessincetheirdiscoveryinthepastdecade.
• HTLV-1causesadultT-cellleukemia,andbothHTLV-1andHTLV-2causeHTLV-associatedmyelopathy(HAM).
EPIDEMIOLOGY• HTLV-1 is endemic to central Africa, the Caribbean basin, parts of South America, and
southwesternJapanaswellasotherdiscretegeographicareas.Thereislimitedgeneticvaria-tionandclosehomologytoprimateT-lymphotropicviruses,suggestingseveralinstancesofcross-speciestransmission.
• HTLV-2isendemictoAmerindiantribesinNorth,Central,andSouthAmericaaswellasCentralAfricanpygmies.ItishyperendemicamonginjectiondrugusersinNorthAmericaandEurope.
• BothHTLV-1andHTLV-2aretransmittedbymother-to-childtransmissionpredominantlybybreast-feeding,bysexualtransmission,andbyparenteralinfection.
• Inendemicpopulations,bothretrovirusesshowanincreasedprevalenceinolderindividuals,andprevalenceisfrequentlyhigherinfemalesthaninmales.
DIAGNOSIS AND PATHOGENESIS• HTLVantibodiesmaybedetectedusingscreeningenzymeimmunoassaysandsupplemental
Westernblot/recombinantimmunoblot,withdifferentiationofHTLV-1fromHTLV-2usingtype-specificantigensinsupplementalassays.
• Polymerase chain reaction (PCR) assay to detect HTLV-1 or HTLV-2 proviral DNA inperipheralbloodmononuclearcellsmaybeperformedincaseswhereserologyisinconclu-sive. PCR assay is also useful in detecting infection in infants carrying passive maternalantibodies.
• Mostinfectedindividualsareasymptomatic.Twoto4percentofthoseinfectedwithHTLV-1willdevelopadultT-cellleukemia/lymphoma(ATL),characterizedbymonoclonalintegra-tionofHTLV-1provirusintoaT-lymphocyticmalignancy.
• One to 4 percent of those infected with either HTLV-I or HTLV-2 will develop HAM, aspastic paraparesis affecting predominantly the lower limbs and hyperactive bladder in apersoninfectedwithHTLV.
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THERAPY• NotreatmentiscurrentlyrecommendedforpersonswithasymptomaticHTLV-1orHTLV-2
infection.Periodicfollow-upshouldincludephysicalexaminationandcompletebloodcellcounttodetectATLorHAM.
• The lymphoma type of ATL is often treated initially with vincristine, cyclophosphamide,prednisolone,anddoxorubicin;survival ispoor.Chronic,smoldering,andleukemiatypesofATLoftenrespondbettertoacombinationofzidovudineandinterferon-α.
• Therapy for HAM is currently unsatisfactory. Corticosteroids may produce improvement,butsideeffectslimitthedurationoftherapy.Interferon-αandinterferon-1βhavebeenusedwithsomesuccess.Theanabolicsteroiddanazolmayrelievebladdersymptoms.
PREVENTION• Tointerruptmother-to-childtransmission,HTLV-infectedpregnantwomeninmiddle-and
high-incomecountriesshouldnotbreastfeedtheirinfantsifthiscanbeaccomplishedsafely.Limiting the duration of breast-feeding to less than 6 months may be attempted in low-incomecountries.
• Theuseofcondomsshouldberecommendedtopreventsexualtransmission.• InjectiondruguserswithHTLVinfectionshouldbeinstructednottoshareneedles.• TheU.S.FoodandDrugAdministrationrecommendsHTLVtestingofalldonatedblood
andtissue.Novaccineiscurrentlyavailable.
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106 Human Immunodeficiency VirusesMarvin S. Reitz, Jr., and Robert C. Gallo
DEFINITION• Human immunodeficiency virus (HIV) is a Lentivirus, family Retroviridae, that causes
acquired immunodeficiencysyndrome(AIDS).Thereare twotypes,HIV-1andHIV-2,ofwhichHIV-1isthemorewidelydistributedandmorepathogenic.
EPIDEMIOLOGY• HIVinfectionisworldwideindistributionandistransmittedbysexualactivityandintra-
venousdruguse.
MICROBIOLOGY• HIVisasingle-strandedpositive-senseRNAvirusthatcontainsthreestructuralgenes(gag,
pol,env)andsixregulatorygenes.HIVinfectsCD4+TcellsandusesitsreversetranscriptasetotranscribeitsRNAgenomeintodouble-strandedDNA,whichisintegratedintothehostcellgenome.
DIAGNOSIS• InfectionisestablishedbydetectionofviralRNA(virusload)orofimmunologicresponses
toviralproteins(Westernblot).
THERAPY AND PREVENTION• Antiretroviral therapy (ART) has been developed using nucleoside and non-nucleoside
reverse-transcriptase inhibitors,protease inhibitors, integrase inhibitors,andentry inhibi-tors.ARTcanalsodecreasetherateoftransmissionofinfection.VaccinedevelopmentseekstostimulateimmuneresponsestoHIVantigensthatwillinhibittransmissionand/orreplica-tionofvirus.
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107 PoliovirusJosé R. Romero and John F. Modlin
DEFINITION• Polioviruses are the cause of poliomyelitis, a systemic viral infection that predominantly
affectsthecentralnervoussystem,causingparalysis.Onlythreeserotypesexist(1to3).Thename of the disease (polios, “gray”; myelos, “marrow” or “spinal cord”), now commonlyshortenedtopolio,isdescriptiveofthepathologiclesionsthatinvolveneuronsinthegraymatter,especiallyintheanteriorhornsofthespinalcord.
EPIDEMIOLOGY• Wild-type poliovirus type 2 no longer circulates worldwide. Serotypes 1 and 3 have been
eradicatedfrommostoftheworld.Theyremainendemicinthreecountries(Afghanistan,Nigeria,andPakistan)andhaverecentlybeenreintroducedinseveralsub-SaharanAfricanandEasternMediterraneancountries.In2012,theannualnumberofcasesofpoliomyelitis(223)wasthelowestsincetheinitiationoftheglobalpolioviruseradicationeffortin1988.
MICROBIOLOGY• ThepoliovirusesaremembersofthegenusEnterovirus,familyPicornaviridae.Morphologi-
cally, they are small (30nm in diameter), nonenveloped, icosahedral-shaped viruses thatpossessasingle-stranded,positive-senseRNAgenome.
DIAGNOSIS• Poliovirusescanbeisolatedfromthroatsecretionsandfromfecesbutrarelyfromthecere-
brospinalfluid.CharacterizationisaccomplishedbysequencingofthemajorcapsidproteinVP1andisavailableonlyinpublichealthreferencelaboratories.
THERAPY• No specific therapy is available. Supportive measures to ensure airway patency, adequate
respiratoryeffort,andclearanceofsecretionsarethemainstayoftreatmentforseverecasesofparalysis.
PREVENTION• Vaccination using inactivated or live-attenuated oral vaccines has been essential in the
eliminationofthepolioviruses.Publichealthmeasures,suchasprovisionofpotablewaterand proper sewage disposal, play major roles in the community-wide control of thepolioviruses.
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108 Coxsackieviruses, Echoviruses, and Numbered Enteroviruses (EV-D68)José R. Romero and John F. Modlin
DEFINITION• Thecoxsackieviruses,echoviruses,andnumberedenterovirusesaremembersofthegenus
Enterovirus.• Thefourspecies(humanenterovirus[EV]AtoD)withinthegenuscontainmorethan100
serotypes.• Enteroviruses are responsible for a wide array of clinical syndromes involving multiple
organ systems, including acute meningitis, encephalitis, paralysis, exanthems, hand-foot-and-mouth disease, herpangina, myopericarditis, pleurodynia, and acute hemorrhagicconjunctivitis.
EPIDEMIOLOGY• Theenterovirusesarefoundworldwide.• Inregionswithtemperateclimates,themajorityofenteroviralinfectionsoccurduringthe
summerandearlyautumnmonths. In tropical regions, infectionsoccuryear-round,withincreasedfrequencyduringtherainyseason.
• AlargeoutbreakofEV-D68occurredintheUnitedStatesin2014.
MICROBIOLOGY• Morphologically, they are small (30nm in diameter), nonenveloped, icosahedral-shaped
virusesthatpossessasingle-stranded,positive-senseRNAgenome.
DIAGNOSIS• EnterovirusescanbeisolatedortheirgenomicRNAdetectedfromthroatsecretions,feces,
cerebrospinal fluid, and blood, as well as various tissues (heart, brain) and fluids (urine,pericardial,vesicle).
• Nucleicacidamplificationtestinghasbeenshowntobequickerandmoresensitivethancellcultureforenterovirusdetection.
• SerotypeidentificationisaccomplishedbysequencingofthemajorcapsidproteinVP1.
THERAPY• Therapyissupportive.• No specific antiviral therapy is currently available for the treatment of enterovirus
infections.• The investigational compound pleconaril, an inhibitor of viral binding and uncoating,
has undergone clinical studies in enteroviral-associated disease but is no longer underdevelopment.
PREVENTION• Contagioncanbepreventedbyhandwashingand,inthecaseofcertainserotypes,avoidance
ofenterovirus-contaminatedfomites.• Investigational vaccines are under development for the prevention of human EV-A71
infection.
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109 Human ParechovirusesJosé R. Romero and John F. Modlin
DEFINITION• Thehumanparechoviruses(HPeVs)aremembersofarelativelynewlycreatedgenusdesig-
natedParechovirusinthePicornaviridaefamily.Atleast16typeshavebeenidentified.• HPeVs are responsible for multiple clinical syndromes involving many organ systems,
includingundifferentiatedfebrileillness,meningitis,encephalitis,paralysis,andrespiratoryillnesses.
EPIDEMIOLOGY• HPeVsarefoundworldwide.• ThemajorityofHPeVinfectionsoccurduringthesummerandautumnmonths.
MICROBIOLOGY• Morphologically they are small (28nm in diameter), nonenveloped, icosahedral-shaped
virusesthatpossessasingle-stranded,positive-senseRNAgenome.
DIAGNOSIS• HPeVscanbeisolated,ortheirgenomicRNAcanbedetectedfromoralsecretions,feces,
cerebrospinalfluid,andblood.• Nucleic acidamplificationhasbeenquickerandmore sensitive thancell culture for their
detection.• Typeidentificationisaccomplishedbysequencingofthemajorcapsidprotein,VP1.
THERAPY• Therapyissupportive.Nospecificantiviraltherapyisavailable.
PREVENTION• Contagioncanbepreventedbyhandwashing.
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110 Hepatitis A VirusFrancisco Averhoff, Yury Khudyakov, and Beth P. Bell*
DEFINITION• HepatitisAisanacuteinflammatoryconditionofthelivercausedbyhepatitisAvirusand
characterizedbyconstitutionalsymptomsincludinganorexia, fatigueandweight loss,andjaundice.
MICROBIOLOGY• HepatitisAvirus(HAV)isanonenvelopedRNAvirusmemberofthepicornavirusfamily.
Threegenotypesinfecthumans(I,II,andIII).• HAVisrelativelyresistanttoheatbutcanbeinactivatedathighertemperatures.• HAVisresistanttoorganicsolventsanddetergentsandcansurviveinacidicenvironments
toapHof3.• HAVcanbeinactivatedbyhypochlorite(bleach)andquaternaryammoniumformulations
containingHCI(foundinmanytoiletcleaners).
EPIDEMIOLOGY• Transmissionisfecal-oralwithpeakviralsheddingbeforeonsetofsymptoms.• HumansaretheonlyimportantreservoirforHAV.• Spread is most commonly person to person (including sexual contact) but can occur as
foodborneandwaterbornetransmission,amonginjectiondrugusersandmenwhohavesexwithmen,andrarelybyinfectedbloodproducts.
• MostcommonriskfactorsintheUnitedStatesincludeinternationaltravelandclosecontact(sexualorhousehold)withahepatitisA–infectedperson.
• IntheUnitedStates,theincidenceofhepatitisAhasplummetedoverthepast15yearsasaresultofimplementationofroutinevaccinationofchildren.Largecommunity-wideepidem-icspreviouslycommonarenowrare.
• Globally, hepatitis A is one of the leading causes of vaccine-preventable deaths. Diseaseincidenceparadoxicallymayincreaseasimprovementinlivingconditionsdelaysinfectiontoolderages,whensymptomsarelikelytobemoresevere.
DIAGNOSIS• HepatitisAisnotclinicallydistinguishablefromotherformsofviralhepatitis.• LaboratorydiagnosisismadebydetectionofIgMantibodiestoHAVinasingle,acute-phase
serumsample.
THERAPY• Most illnesses are self-limited and can be managed with supportive and symptomatic
measures.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
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irus
• Fulminantcasesarerarebutneedtobemanagedappropriatelyandmayrequiretransplanta-tioninextremelyillpatients.
• ChronichepatitisAdoesnotoccur.
PREVENTION• IntheUnitedStates,vaccinationwithhepatitisAvaccineisrecommendedforallchildren
atage12to23months.Vaccinationofolderchildrenandadultsmaybewarranted,includingpatientswithchronichepatitisBandC(seeTable110-1).
• Vaccination of international travelers and persons in selected high-risk groups is recom-mended(seeTable110-1).
• AdministerpostexposureprophylaxiswithhepatitisAvaccine(preferred)orimmuneglobu-linifexposureoccurredwithintheprevious2weeks,ifpatientisimmunosuppressed,orifpatientisyoungerthan1yearofage(seeTable110-2).
TABLE 110-1 Recommendations for Routine Preexposure Use of Hepatitis A Virus Vaccine
GROUP COMMENTSChildren Vaccine should be given to all children at age 1 yr
(12-23 mo).* Vaccination of children 2-18 yr may also be warranted.†
International travelers‡ IG may be given in addition to or instead of vaccine; children <12 mo should receive IG (see Table 176-2)
Close contacts of newly arriving international adopteesMen who have sex with men
All persons who anticipate close personal contact (e.g., household contact or regular babysitter) during the first 60 days after arrivalIncludes adolescents
Illicit drug users Includes adolescents
Persons with chronic liver disease, such as those with hepatitis B or C
Increased risk of fulminant hepatitis A with HAV infection
Persons receiving clotting factor concentrates
Persons who work with HAV in research laboratory settings
HAV, hepatitis A vaccine; IG, immune globulin.*Hepatitis A vaccine is not licensed for children <12 months.†States and communities with existing vaccination programs for children age 2 to 18 years are encouraged to
maintain these programs. Catch-up vaccination for this age group may be warranted elsewhere in the context of ongoing outbreaks among children.
‡Persons traveling to Canada, Western Europe, Japan, Australia, or New Zealand are at no greater risk than in the United States.
From Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immuniza-tion. Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2006;55(RR-7):1-23; and Centers for Disease Control and Prevention. Updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of hepatitis A vaccine in close contacts of newly arriving international adoptees. MMWR Morb Mortal Wkly Rep. 2009;58:1006-1007.
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TABLE 110-2 Recommendations for Hepatitis A Postexposure Prophylaxis
GROUP* RECOMMENDED PROPHYLAXIS†
Persons 12 mo–40 yr Single antigen hepatitis A vaccine at age-appropriate dose
Persons >40 yr IG 0.02 mL/kg is preferred; vaccine can be used if IG cannot be obtained
Children <12 mo IG 0.02 mL/kg‡
Immunocompromised persons, persons who have chronic liver disease, and persons for whom vaccine is contraindicated
IG 0.02 mL/kg‡
IG, immune globulin.*Persons recently exposed to hepatitis A virus who have not previously received hepatitis A vaccine.†Postexposure prophylaxis should be given as soon as possible after exposure. The efficacy of immune globulin
or vaccine administered more than 2 weeks after exposure has not been established.‡In the event of ongoing exposure, persons for whom immune globulin is recommended should receive immune
globulin 0.06 mL/kg, repeated every 5 months during exposure.
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111 RhinovirusRonald B. Turner
VIROLOGY AND EPIDEMIOLOGY• RhinovirusesareunenvelopedRNAvirusesinthefamilyPicornaviridae.• One-hundredoneserotypeshavebeendetected,nowdividedintotwophylogeneticspecies
(humanrhinovirus[RV]-AandRV-B);athirdspecies,RV-C,alsoexists.• Rhinoviruses are among the most common pathogens of man, with an incidence of 0.5
infectionsperyearinadultsand2infectionsperyearinchildren.• Infections occur year-round, with seasonal peaks in the spring and fall in temperate
climates.
DIAGNOSIS• Thecommoncoldisthecharacteristicclinicalmanifestation.• Exacerbationsofasthmainchildrenarefrequentlyassociatedwithrhinovirusinfection.• Rhinovirusesmaycausebronchiolitisinyoungchildren.• Specificvirologicdiagnosisisbestaccomplishedwithpolymerasechainreactionbutisrarely
usefulforpatientmanagement.
THERAPY• Despitemultiplestudies,nospecificantiviraltherapyhasbeenestablished.
PREVENTION• Thereisnoproveninterventiontopreventrhinovirusinfection.
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112 Noroviruses and Sapoviruses (Caliciviruses)Raphael Dolin and John J. Treanor
DEFINITION• The genera Norovirus and Sapovirus, of the family Caliciviridae, cause acute
gastroenteritis.
EPIDEMIOLOGY• Noroviruses are the major worldwide cause of viral gastroenteritis, cause both foodborne
andperson-to-personoutbreaks,andcanbespreadviafomites.• Norovirusesaccountfor21millioncasesofgastroenteritisintheUnitedStatesannuallyand
forupto200,000deathsinthedevelopingworldamongchildrenyoungerthan5years.• Sapovirusescausegastroenteritislessfrequentlythannoroviruses.
MICROBIOLOGY• Norovirusesandsapovirusesaresingle-stranded,positive-senseRNAviruses.Eachisdivided
intofivegenogroupsandhasmultiplegenotypes.• Neithernorovirusesnorsapoviruseshavebeencultivatedinvitro.
CLINICAL MANIFESTATIONS• Illness caused by noroviruses and sapoviruses consists of combinations of vomiting and
diarrhea,oftenaccompaniedbyabdominalcramps,nausea,andlow-gradefever.• Illnessusuallylasts12to60hoursandremitsspontaneously.• More severe disease and even fatalities can occur in young children and in the elderly.
Immunocompromisedpatientsmayhaveprolongedsheddingofvirus,alongwithsevereandpersistentgastrointestinalillness.
DIAGNOSIS• Norovirusesmaybesuspectedasacauseofoutbreaksofgastrointestinalillnessiftheabove
clinical features are present, particularly if a large number of individuals are involved.However, the illness is not sufficiently distinctive in individual cases to permit a clinicaldiagnosistobemadeonclinicalgroundsalone.
• Specificdiagnosisismadebydetectionofvirusinstoolspecimensbyreverse-transcriptasepolymerase chain reaction assay. Enzyme immunoassays are also available, but they aregenerallyoflowsensitivity,althoughhighspecificity.
THERAPY• Onlysupportivetherapyisavailable,particularlymaintaininghydration,whichisallthatis
needed.
PREVENTION• Themaincontrolmeasuresaretopreventcontaminationoffoodsuppliesandwaterbygood
hygieneandbyrestrictionoffoodhandlingbyillindividualsuntilatleast2to3daysaftergastrointestinalillnesshasresolved.
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Sapo
viruses (C
aliciviruses)
• Vigoroushandwashingbyillindividualsshouldbemaintained.• DecontaminationofexposedsurfacesshouldbecarriedoutwithEnvironmentalProtection
Agency–recommendeddisinfectants;forexample,householdbleachshouldbecarriedoutat1:10to1:50dilutions.
• An initial clinical study of an investigational norovirus vaccine, consisting of virus-likeparticles,reducedexperimentallyinducedgastroenteritisby47%.
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113 Astroviruses and PicobirnavirusesRaphael Dolin and John J. Treanor
DEFINITION• Astrovirus causes acute gastroenteritis. Picobirnaviruses have been detected in stools but
havenotbeenestablishedascausesofillnessinhumans.
EPIDEMIOLOGY• Astrovirusesareworldwideindistribution,causediseasemostfrequentlyinyoungchildren,
butcanalsocausegastroenteritisinadultsandinimmunosuppressedpatients.Transmissionislikelybythefecal-oralroute.
MICROBIOLOGY• Astrovirusesaresingle-strandedRNAviruses,comprising8serotypes,withacharacteristic
star-shapedmorphologyseenonelectronmicrographs.Picobirnavirusesaredouble-strandedRNAviruseswithabisegmentedgenome.
CLINICAL MANIFESTATIONS• Illness induced by astroviruses consists of diarrhea, headache, malaise, nausea, low-grade
fever,and,lesscommonly,vomiting.Illnessmaybesomewhatlessseverethanthatseenwithrotaviruses.
DIAGNOSIS• Astroviruses instoolscanbedetectedbyelectronmicroscopy,enzymeimmunoassay,and
by reverse-transcriptase polymerase chain reaction assay, which is the most sensitivetechnique.
THERAPY• Treatmentissupportive.Intravenousimmuneglobulinhasbeenusedinimmunosuppressed
patients,butitsefficacyisnotestablished.
PREVENTION• Althoughvirus-likeparticlesfromastroviruseshavebeenproduced,vaccineshavenotbeen
developed.
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114 Hepatitis E VirusStephen R. Walsh
DEFINITION• Hepatitis E virus (HEV) is a member of the Hepeviridae family, genus Hepevirus, which
causes acute hepatitis in the normal host and chronic hepatitis in immunosuppressedpatients.
EPIDEMIOLOGY• HEVmaybethemostcommonformofacuteviralhepatitisandoccurs inbothsporadic
andepidemicforms.• HEVistransmittedbywaterbornespreadoffecallycontaminatedwaterorbyfecallytrans-
mittedzoonoticinfection.Person-to-persontransmissionisuncommon.• HEVisuniqueamongthehepatitisvirusesbecauseofitsdisproportionatelyhighmortality
rateinpregnantwomen(25%inthethirdtrimester).• HEVinfectionisuncommon,but likelyunderdiagnosedindevelopedcountries,andzoo-
noticinfectionsmayberesponsibleformanyofthecasesthatarelocallyacquiredindevel-opedcountries.
• ChronichepatitisEinfectionhasrecentlybeendescribedinimmunosuppressedpatients.
MICROBIOLOGY• HEVvirionsarenonenveloped,icosahedralparticlesofapproximately32-nmdiameter.• HEV has a single-stranded positive-sense RNA genome that contains three open reading
frames(ORFs).• Fourgenotypesand24subgenotypeshavebeendescribed.
DIAGNOSIS• Diagnosis of HEV had previously been made serologically, but molecular diagnosis via
polymerasechainreactionhasbettersensitivityandspecificityand is thediagnostic tech-niqueofchoice,ifavailable.
THERAPY• AcuteHEVinfectionisgenerallyself-limitedandrequiresonlysupportivecare.Severeacute
caseshavebeentreatedsuccessfullywithribavirin.• RibavirinmonotherapyappearstobehighlyeffectiveintreatmentofchronichepatitisEin
solid-organtransplantrecipients.
PREVENTION• Protecting water supplies from contamination with human feces is the most important
meanstopreventHEVinfection.• AvaccineusingtheORF2capsidproteinthatassemblesintovirus-likeparticles(Hecolin)
hasbeenshowntobesafeandeffectiveandislicensedinChina.
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B Prion Diseases
115 Prions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases)Patrick J. Bosque and Kenneth L. Tyler
DEFINITION• Priondiseasesaretransmissibleneurodegenerativeconditionsofmammalscharacterizedby
arapidlyprogressivedeclineofcognitive,motor,andotherbrainfunctions.• Prion diseases are biochemically defined by the accumulation of an abnormal form of a
normallyexpressedbrainprotein,theprionprotein(PrP).
EPIDEMIOLOGY• Humanpriondiseaseisrare;itsincidenceis1×10−6worldwide.• About90%ofcasesaresporadic.• About10%ofcasesaregenetic.• Infectioustransmissionaccountsforlessthan1%ofhumancases.
MICROBIOLOGY• ThecausativeagentiscomposedofanaggregateofmisfoldedformsofPrP.• The aggregate serves as a catalytic template for the further aggregation of PrP and thus
replicates.• Theprioncontainsnoinformation-bearingnucleicacid.
DIAGNOSIS• Treatablemimicsofpriondiseaseshouldbeexcludedbeforemakingthediagnosis.• CertaindiagnosiscanonlybemadebydetectingabnormalPrPaggregatesintissue,typically
brain.• Diagnosis is usually made by history and clinical signs and supported by ancillary tests,
including magnetic resonance imaging, electroencephalography, and cerebrospinal fluidanalysis.
THERAPY• Noeffectivetherapyexistsforprioninfection.
PREVENTION• Onlystandardprecautionsareneededformostprocedures,topreventiatrogenictransmis-
sionofpriondisease.• Additionalprecautionsareneededforneurosurgicalcases.• Transfusionofredbloodcellsandplasmaproteinproductscantransmitoneformofprion
disease,variantCreutzfeldt-Jakobdisease.• Tissuefrompersonswithpriondiseasemustnotbetransplanted.• Dietaryexposuretoruminantanimalprionsshouldbeavoided.
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C Chlamydial Diseases
116 Chlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)Byron E. Batteiger and Ming Tan
DEFINITION• Chlamydia trachomatisisanobligateintracellularbacteriumthatmainlyinfectsocularand
genitourinaryepithelium.• Theoculardiseasetrachomaistheleadinginfectiouscauseofblindnessworldwide.• Chlamydialgenitalinfectionsarethemostcommonbacterialsexuallytransmittedinfections
intheworld.• Lymphogranulomavenereum(LGV),causedbydistinctserovarsofC. trachomatis,isaless
commondiseasecharacterizedbyenlargedinguinallymphnodesorsevereproctocolitis.
EPIDEMIOLOGY• Trachoma is common in poor, rural areas of developing countries, with an estimated 40
millionactivecasesworldwide.• Activeinfectionintrachomalargelyaffectsyoungchildren,oftenthoseyoungerthan1year
ofage,whereasthescarringsequelaethatproduceblindnessoccurlaterinlife.• The sexually transmitted urogenital infections are common worldwide with an estimated
105.7millionnewcasesin2008.• Chlamydialgenitalinfectionsaremostprevalentamongadolescentwomenandmen,where
repeatedinfectionsarecommon.• Chlamydialgenital infectionsareoftenasymptomaticbutcancausereproductivesequelae
inwomen,includinginvoluntaryinfertilityandectopicpregnancy.• Transmissionduringvaginaldeliverycanleadtoneonatalconjunctivitisandpneumonia.• C. trachomatisinfectionsarereportabletotheCentersforDiseaseControlandPrevention
andallstatehealthdepartmentsintheUnitedStates.
PATHOPHYSIOLOGY• Diseasemanifestationsarelargelymediatedbythehostresponsetotheinfection,whichis
initiatedandsustainedbyactivelyinfectednonimmunehostepithelialcells.• Inasubstantialminorityofpersonswithtrachomaandgenitalinfections,thehostinflam-
matoryresponseleadstotissuescarring,resultinginend-organdysfunctionandsequelae.
MICROBIOLOGY• C. trachomatisisagram-negativebacterium,butGramstainisnotusedforidentification.• Theorganismiscultivatedincellculturebecauseitdoesnotgrowanddivideaxenically.• Thebacteriumreplicateswithinacytoplasmicinclusioninthehostcell.• The two morphologic forms are the infectious but nondividing elementary body and the
reticulatebody,whichisanintracellular,replicatingform.
DIAGNOSIS• Diagnosis of trachoma in endemic areas is typically by physical examination of the eye
accordingtocriteriaestablishedbytheWorldHealthOrganization.
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• Diagnosisofgenitalinfectionsrequiresmicrobiologictesting,ideallybynucleicacidampli-ficationtestsoffirst-catchurineinmenandvaginalswabsinwomen.
THERAPY (SEE TABLE 116-1)• Therapy of trachoma is generally provided by repeated mass treatment of hyperendemic
communitieswithsingle-doseazithromycin.• Recommendedtreatmentofuncomplicatedurogenital infectioniseitherazithromycin1g
orallyasasingledoseordoxycycline100mgorallytwicedailyfor7days.Treatmentofsexpartnersiscrucialtopreventrepeatedinfection.
• Treatmentofcomplicatedinfectionsrequireslongerdurationsoftherapy:forsalpingitis,14days;forepididymitis,10days;andforproctitis,7days.
• LGVistreatedwithdoxycyclinefor21days.
PREVENTION• Trachoma can be prevented by face washing, access to clean water, and improvements in
sanitation.• In the United States and other developed countries, prevention of sexually transmitted
genital infectionsandcomplicationsis largelyfocusedonscreeningandtreatingnonpreg-nantsexuallyactivewomenaged25yearsoryoungeronanannualbasis.UptakeofscreeningintheUnitedStatesisrelativelylow.
• Screeningofallpregnantwomenisrecommended.• Screeningandtreatmentofwomenolderthan25yearsofageisrecommendedifriskfactors
areidentified,suchasnewormultiplesexualpartners.• One-timescreeningandtreatmentinwomendecreasesriskofsymptomaticpelvicinflam-
matory disease in the following year. Data are currently lacking as to whether screeningprogramsreducepopulationprevalenceofchlamydialgenitalinfection.
• Screeningofyoungmeninhigh-risksettings(sexuallytransmitteddiseaseandadolescentclinics,correctionalfacilities)shouldbeconsideredifresourcesallow.
• No vaccine is currently available for either trachoma or chlamydial genital infections.Induction of sterilizing immunity appears unlikely, and future vaccine efficacy evaluationmaybebasedondemonstratingreducedriskofinflammatorysequelaeintheeyeandsymp-tomaticpelvicinflammatorydiseaseinwomen.
251C
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lamyd
ia tracho
matis (Trach
om
a, Gen
ital Infectio
ns, Perin
atal Infectio
ns, an
d Lym
ph
og
ranu
lom
a Ven
ereum
)
TABLE 116-1 Clinical Characteristics of Common Chlamydia trachomatis Infections
INFECTIONSYMPTOMS AND SIGNS
PRESUMPTIVE DIAGNOSIS
DEFINITIVE DIAGNOSIS TREATMENT
Men Nongonococcal urethritis
Urethral discharge, dysuria
Urethral leukocytosis; no gonococci seen
Urine or urethral NAAT
Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid, for 7 days
Epididymitis Unilateral epididymal tenderness, swelling; pain; fever, presence of NGU
Urine or urethral NAAT
Urethral leukocytosis; pyuria on urinalysis
STI likely: Ceftriaxone 250 mg IM plus doxycycline, 100 mg PO bid, for 10 days
History of insertive anal intercourse:Ceftriaxone, 250 mg IM, plus levofloxacin, 500 mg bid for 10 days
Proctitis (non-LGV)
Rectal pain, discharge and bleeding; history of receptive anal intercourse
≥1 PMN/OIF on rectal Gram stain; no gonococci seen
Urine or urethral NAAT; rectal culture or NAAT
Doxycycline, 100 mg PO bid, for 7 days
LGV Painful, tender inguinal lymphadenopathy, fever
“Groove sign” Urine, urethral, lymph node or rectal NAAT; rectal or lymph node culture; LGV-specific testing if available
Doxycycline, 100 mg PO bid, for 21 days
LGV proctitis Rectal pain, discharge, and bleeding in MSM; absence of inguinal lymphadenopathy
≥1 PMN/OIF on rectal Gram stain; no gonococci seen
Urine, urethral, or rectal NAAT; rectal culture; LGV-specific testing if available
Doxycycline, 100 mg PO bid, for 21 days
Conjunctivitis Ocular pain, redness, discharge; simultaneous genital infection
Gram stain of conjunctival swab negative for bacterial pathogens; PMNs on smear
Rectal culture or NAAT; NAAT of conjunctivae
Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid, for 7 days
Continued
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INFECTIONSYMPTOMS AND SIGNS
PRESUMPTIVE DIAGNOSIS
DEFINITIVE DIAGNOSIS TREATMENT
Women Cervicitis Mucopurulent cervical discharge; ectopy, easily induced bleeding
≥20 PMN/OIF on cervical Gram stain
Urine or cervical NAAT
Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid, for 7 days
Urethritis Dysuria, frequency; no hematuria
Pyuria on UA; negative urine Gram stain and culture
Urine, cervical, or urethral NAAT
Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid for 7 days
PID Lower abdominal pain, adnexal pain, cervical motion tenderness
Evidence of mucopurulent cervicitis
Urine or cervical NAAT
Outpatient: Ceftriaxone 250 mg IM as a single dose, plus doxycycline 100 mg PO bid for 14 days, with or without metronidazole, 500 mg PO bid for 14 days
Adults Conjunctivitis Ocular pain, redness, discharge; simultaneous genital infection
Gram stain of conjunctival swab negative for bacterial pathogens; PMNs on smear
DFA or NAAT on conjunctival swab
Azithromycin, 1 g PO (single dose)orDoxycycline, 100 mg PO bid for 7 days
Newborns Conjunctivitis Ocular pain, redness, discharge; simultaneous genital infection
Gram stain of conjunctival swab negative for bacterial pathogens; PMNs on smear
DFA or NAAT on conjunctival swab; vagina, rectum, pharynx also often positive
Erythromycin base 50 mg/kg/day, orally divided into four doses daily for 14 days; evaluate and treat parents as well
Pneumonia Staccato cough, tachypnea, hyperinflation
Diffuse interstitial infiltrate, eosinophilia
Nasopharyngeal NAATs or culture; MIF serology (IgM)
Erythromycin base 50 mg/kg/day, orally divided into four doses daily for 14 days; evaluate and treat parents as well
DFA, direct fluorescent antibody; IgM, immunoglobulin M; LGV, lymphogranuloma venereum; MIF, microimmuno-fluorescence; MSM, men who have sex with men; NAAT, nucleic acid amplification test; NGU, nongonococcal urethritis; OIF, oil immersion field; PMN, polymorphonuclear neutrophil; STI, sexually transmitted infection; UA, urinalysis.
TABLE 116-1 Clinical Characteristics of Common Chlamydia trachomatis Infections—cont’d
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117 Psittacosis (Due to Chlamydia psittaci)David Schlossberg
DEFINITION• Asystemicinfectionthatfrequentlycausespneumonia.
EPIDEMIOLOGY• Acquired by inhalation, after exposure to infected birds, although not all infected birds
appearill,andoccasionalpatientsprovidenohistoryofbirdexposure.
MICROBIOLOGY• TheetiologicagentisChlamydia psittaciofthefamilyChlamydiaceae.
DIAGNOSIS• Diagnosis is made serologically in most cases; when available, polymerase chain reaction
may be positive. Because diagnostic methods are imperfect, treatment should not awaitdefinitivediagnosis.
THERAPY• Doxycycline or tetracycline is treatment of choice. Macrolides and fluoroquinolones have
goodinvitroactivity,butthereislimitedclinicalexperience.
PREVENTION• Treatimportedbirdsandbirdsthathavesuspectedinfection.
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118 Chlamydia pneumoniaeMargaret R. Hammerschlag, Stephan A. Kohlhoff, and Charlotte A. Gaydos
MICROBIOLOGY AND EPIDEMIOLOGY• Obligateintracellularbacterium,mustbegrownintissueculture• Capableofcausingpersistentinfection,oftensubclinical• Worldwidedistribution,infectsmanyanimalsaswellashumans• Primarilyarespiratorypathogeninhumans,causingcommunity-acquiredpneumonia• Cancauseepidemicsinenclosedpopulations:militarybases,schools,nursinghomes
DIAGNOSIS• Chlamydia pneumoniaecausespneumonia;clinicallyitcannotbedifferentiatedfromother
causesofatypicalpneumonia,especiallyMycoplasma pneumoniae.• The most accurate method of diagnosis is identification of the organism in respiratory
samplesbycultureornucleicacidamplificationtest(NAAT).• Serology is of limited value, requires paired sera, and many patients who are positive by
cultureorNAATwillbeseronegative.
THERAPY• C. pneumoniaeissusceptibletomacrolides,quinolones,andtetracyclines.Dataonefficacy
arelimited,includingoptimaldoseanddurationoftherapy.• Ten-to14-daycoursesoferythromycin,clarithromycin,doxycycline,levofloxacin,ormoxi-
floxacinor5daysofazithromycinareclinicallyeffectiveandresult inapproximately80%microbiologiceradication.
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D Mycoplasma Diseases
119 Mycoplasma pneumoniae and Atypical PneumoniaRobert S. Holzman and Michael S. Simberkoff
DEFINITION• AtypicalpneumoniacausedbyMycoplasma pneumoniae isasyndromethat incontrast to
lobarpneumoniais:• Slowerinonset• Generallymilder• Notassociatedwithlobarconsolidation• Notassociatedwithresolutionbycrisis
• Manyotherviralandbacterialagentscanproduceanatypicalpneumoniasyndrome.
ETIOLOGIC AGENT• M. pneumoniae
• Bacteriumlackingcellwall• Adhesinsandadhesionorganelleimportantinpathogenesis• Fastidious• Maybecultivablefromsputumaftersymptomsofillnessresolve
EXTRAPULMONARY SITES AND MANIFESTATIONS OF INFECTION• Skin(maculopapularorvesicularrashes,Stevens-Johnsonsyndrome)• Cardiac(pericarditis,myocarditis)• Centralnervoussystem(encephalitisormeningitis,myelitis,radiculopathy)• Musculoskeletal(myalgia/arthralgia,rhabdomyolysis,arthritis)• Raynaud’sphenomenon• Renal(glomerulonephritis,nephroticsyndrome)• Hematologic
DIAGNOSIS• Clinicalsuspicionbysyndrome• Presenceofcoldagglutininsintheabsenceofanotherexplanation• DetectionofrisingtitersofantibodiestoM. pneumoniae• DetectionofM. pneumoniae–specificantigens• DetectionofM. pneumoniae–specificgeneticcomponents
TREATMENT• Macrolides(e.g.,azithromycin,500mgday1,250mgday2to5)
• Macrolideresistanceisincreasingandmaylimitusefulness• Tetracyclines(e.g.,doxycycline,100mgtwicedailyfor14days)• Fluoroquinolones(e.g.,moxifloxacin,400mgdailyfor14days)
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120 Genital Mycoplasmas: Mycoplasma genitalium, Mycoplasma hominis, and Ureaplasma SpeciesDavid H. Martin
MICROBIOLOGY AND TAXONOMY• ThegenitalmycoplasmasincludeMycoplasma hominis, Mycoplasma genitalium, Ureaplasma
urealyticum,andUreaplasma parvum.Thelattertwoonlyrecentlywereassignedtoseparatespecies.
• Thegenitalmycoplasmaslackcellwallsandhavethesmallestgenomesofknownfree-livingmicroorganisms.
EPIDEMIOLOGY• All of these organisms are primarily sexually transmitted but also may be transmitted to
infantsatbirth.Thereisevidencethattheymaypersistinchildrenintoadulthood.• TheepidemiologyofinfectionwithM. genitaliumcloselyparallelsthatofChlamydia tracho-
matisandNeisseria gonorrhoeae.
CLINICAL MANIFESTATIONS• U. urealyticumcausesurethritis,whereasU. parvumappearstobeacolonizer.Onlyrelatively
sexuallyinexperiencedmenaresusceptibletoU. urealyticumdisease,whichislikelyduetothedevelopmentofimmunityaftermultipleexposurestothiscommonurethralorganism.
• Althoughthepathogenesisisunclear,theureaplasmasarestronglyassociatedwithbroncho-pulmonarydysplasiainvery-low-birth-weightinfants.
• M. hominisplaysaminorroleingenitaltractdiseasebutisimplicatedinpostpartumfever,bacteremia,andpostoperativemediastinalandwoundinfections.
• M. genitaliumisacauseofurethritisinmenandendocervicitisinwomen.ItislikelyacauseofpelvicinflammatorydiseasebutappearstocausemilderdiseasethanN. gonorrhoeaeand C. trachomatis.
DIAGNOSIS• Mostclinicallaboratoriesarenotequippedtodiagnoseinfectionscausedbytheseorganisms.
OnlyM. hominisisdetectableusingmethodsroutinelyemployedinclinicallaboratories,butsensitivity is poor. The ureaplasmas require special media for growth, and M. genitaliumcannotbeculturedatalloutsideresearchlaboratories.Nucleicacidamplificationassaysforthisorganismhavebeendevelopedbutarenotingeneraluse.
THERAPY• TetracyclineclassdrugsareactiveagainstmostureaplasmasandM. hominisbutnotagainst
M. genitalium.MacrolidesareeffectivefortheureaplasmasbutnotforM. hominisandareonly partially effective for M. genitalium. Quinolones, especially moxifloxacin, are activeagainstallofthegenitalmycoplasmas.
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E Rickettsioses, Ehrlichioses, and Anaplasmosis
121 Rickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers)David H. Walker and Lucas S. Blanton
ETIOLOGY• Spottedfevergroup(SFG)rickettsiaearesmall,gram-negative,obligatelyintracellularbac-
teriathatcausetick-,mite-,andflea-bornehumaninfections.• In humans, rickettsiae infect endothelial cells and exert their pathophysiologic effects
throughendothelialinjury,witharesultantincreaseinvascularpermeability.
EPIDEMIOLOGY• Rickettsia rickettsii is the agent that causes Rocky Mountain spotted fever (RMSF).
Dermacentor variabilis,Dermacentor andersoni,andRhipicephalus sanguineustickstransmittheinfectionintheeasterntwothirds,western,andsouthwesternUnitedStates,respectively.RMSFalsooccursinCentralandSouthAmerica.
• IntheUnitedStates,RMSFismostprevalentintheSouthAtlanticandSouthCentralregions.Infections usually occur during the late spring and summer, when ticks are most active.Other tick-borne SFG rickettsiae with a broad range of distribution include R. conorii(Europe, Africa, and South Asia), R. sibirica (eastern Russia and Asia), R. africae (sub-Saharan Africa and West Indies), R. parkeri (North and South America), and R. slovaca(Europe).
• Rickettsia feliscausesflea-bornespottedfeverandhasaworldwidedistribution.
CLINICAL MANIFESTATIONS• RMSFtypicallymanifestswithfeverearlyinthecourse.Othermanifestationsincludehead-
ache,myalgias,nausea,vomiting,andabdominalpain.• Rashiscommonbutmaynotoccurinthefirstfewdaysofillness.Rashtypicallystartson
thewristsandanklesbeforespreadingproximally.Involvementofthepalmsandsolesoccursin36%to82%butisoftenalatesign.
• Skin necrosis, gangrenous digits, neurologic complications, azotemia, pulmonary edema,andacuterespiratorydistresssyndromearemanifestationsofsevereinfection.
• ThecasefatalityrateofRMSFis23%withoutappropriateantimicrobialtreatmentandupto4%despiteappropriateantimicrobials.
• OtherSFGrickettsiosesmanifestwithawidespectrumofdiseaseseveritybutaregenerallylessseverethanRMSFandoftenhaveanassociatedescharatthetickbitesite.
DIAGNOSIS• Theindirectimmunofluorescenceassayistheserologicmethodofchoice.Afourfoldrisein
immunoglobulin G titer from acute illness to convalescence retrospectively confirms thediagnosis.
• ImmunohistochemicaldetectionofSFGrickettsiaeinskinbiopsycanestablishthediagnosisduringacuteillness.
• Polymerasechainreactionamplificationofrickettsialnucleicacidsinblood,skinorescharbiopsy,orescharswabisausefultoolfordiagnosisandspeciesidentification.
• Treatmentshouldnotbewithheldwhileawaitinglaboratoryconfirmation.
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TREATMENT AND PREVENTION• Doxycycline,100mgtwicedailyfor7to10daysisthetreatmentofchoiceforRMSFand
otherSFGrickettsioses.• Chloramphenicolisanalternative,butitsuseisassociatedwithahighercasefatalityinthose
withRMSF.• AzithromycinandclarithromycinarealternativesforlesssevereSFGrickettsioses.• Prevention is aimed toward the avoidance of contact with vectors through repellents and
protectiveclothing.
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122 Rickettsia akari (Rickettsialpox)Didier Raoult
DEFINITION• Vesicularfeverwithescharcausedbymitebites;maybeconfusedwithanthrax.
EPIDEMIOLOGY• FoundworldwidebutisparticularlycommoninNewYorkCity.
MICROBIOLOGY• InfectioncausedbyintracellularRickettsia akari.
DIAGNOSIS• Basedonserologyandpolymerasechainreactionassayofswabfromavesicleoreschar.
THERAPY• Doxycycline,100mgtwicedailyfor7days.
PREVENTION• Mouseeradicationfrombuildingswillpreventtransmissiontohumans.
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123 Coxiella burnetii (Q Fever)Thomas J. Marrie and Didier Raoult
DEFINITION• Qfevercanbemanifestasaself-limitedfebrileillness,pneumonia,endocarditis,orhepatitis.
There are many other less common manifestations, such as meningitis, encephalitis, andosteomyelitis.Infectionsaredividedintoacuteandchronicforms.
EPIDEMIOLOGY• Q fever is a zoonosis that is usually acquired by inhalation or, much less commonly, by
ingestingunpasteurizedmilk.• Cattle,sheep,andgoatsarethemostcommonreservoirs.Infectedparturientcatsareimpor-
tantinthespreadofCoxiellainsomeareas.• Thereisanextensivewildlifereservoir.• Theenvironmentiscontaminatedatthetimeofparturitionbyaninfectedanimal.• Windbornespreadfromthecontaminatedenvironmentcanoccuroveradistanceofatleast
10km.• The distribution is worldwide, with the exception of New Zealand, Antarctica, and the
Arctic.
MICROBIOLOGY• Pleomorphicgram-negative(structurally—doesnotstainwithGramstain)coccobacillus• Coxiella burnetii—onlyspeciesinthegenus• Intracellularpathogen• Sporeformer• Undergoesphasevariation;acute infectionleadstoantibodypredominantlyagainstphase
IIantigens,whereaschronicinfections,suchasendocarditis,arecharacterizedbyimmuno-globulinG(IgG)antibodypredominantlyagainstphaseIantigens.
DIAGNOSIS• Inmostinstances,anindirectimmunofluorescentserologictestisthebestone.• A fourfold rise in titer between acute and convalescent samples is diagnostic of acute
disease.• Chronicinfectionisdiagnosedonthebasisofclinicalmanifestations(e.g.,endocarditis)in
conjunction with an IgG phase I titer that is equal to or exceeds phase II and is at least1:1600.
• Isolation of C. burnetii by using a shell vial technique can be done in Biosafety Level 3laboratories.
• PolymerasechainreactionassaycanbeusedtoamplifyC. burnetiiDNAfromavarietyofclinicalspecimens,suchasheartvalvesandjointfluid.Fluorescentinsituhybridizationcanidentifyorganismsintissue,althoughstandardhistopathologicstainsarenegative.
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xiella bu
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Fever)
THERAPY• AcuteQfever:10daysofdoxycycline,afluoroquinoloneoramacrolide• ChronicQfever:DoxycyclineplushydroxychloroquineuntilphaseIIgGantibodytitershave
declinedto1:800orless
PREVENTION• Goodanimalhusbandrypractices• Useofseronegativesheeporgoatsinresearchfacilities
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124 Rickettsia prowazekii (Epidemic or Louse-Borne Typhus)Lucas S. Blanton and David H. Walker
MICROBIOLOGY• Rickettsia prowazekiiisasmallobligatelyintracellulargram-negativecoccobacillus.• Its1.1-Mbgenomehasundergoneevolutionaryreduction,resultingintherelianceonthe
hostcellcytosolformanybiosyntheticfunctions.• Anextracellulardormantformremainsinfectiousinlousefecesformonthsorlonger.
EPIDEMIOLOGY• The agent is transmitted between patients by the human body louse (Pediculus humanus
corporis).• Licebecomeinfectedwhilefeedingonrickettsemicpatients.Theorganismisinoculatedinto
anewhostbyscratchingrickettsiae-ladenlousefeces into louse-bittenskinorbyrubbingintomucousmembranes.
• Recoveredpatientsremainlatentlyinfected,aresusceptibletoreactivationwithrickettsemia,andcanserveasasourceforanepidemic.
• Epidemics are associated with conditions that promote louse infestations through poorhygiene—poverty, cold climate, jails, and displacement of populations by wars and othercalamities.
• In North America, an extrahuman reservoir of R. prowazekii exists in flying squirrels(Glaucomys volans),withinfectionstransmittedtohumansbymucousmembraneorinha-lationalexposuretothesquirrel’sfleaorlousefeces.
CLINICAL MANIFESTATIONS• Frequentsymptomsincludefever,headache,chills,myalgia,andrash(seeTable124-1).• Untreatedillnessmayprogresstocausepulmonaryedema,encephalitis,anddeath.• Recrudescent typhus and flying squirrel–associated typhus manifest similarly but are less
severe.
DIAGNOSIS• The indirect immunofluorescence assay is the mainstay of serologic diagnosis. A fourfold
rise in immunoglobulin G (IgG) titer from acute illness to convalescence confirms thediagnosis.
• Polymerase chain reaction assay and immunohistochemical detection of R. prowazekii inbloodortissue,respectively,canestablishthediagnosisduringacuteillness.
• Treatmentshouldnotbewithheldwhileawaitinglaboratoryconfirmation.
TREATMENT AND PREVENTION• Doxycycline,100mgtwicedailyfor7to10days,isthetreatmentofchoice.Chloramphenicol
isanalternativetreatment.• Controlofbodylicebychangingandwashinggarmentsinhotwaterisessentialforpreven-
tionandoutbreakcontrol.
263C
hap
ter 124 Rickettsia p
row
azekii (Epid
emic o
r Lou
se-Bo
rne Typ
hu
s)
TABLE 124-1 Clinical Manifestations of Epidemic Typhus
Manifestation
PLACE
Burundi EthiopiaNumber of cases 102 60
Fever >39° C 100% 100%
Headaches 100% 100%
Any rash 25% 38%
Purpuric rash 11% 33%
Stupor 81% 35%
Coma 4% —
Cough 70% 38%
Nausea, vomiting 57% 43%
Conjunctivitis 15% 53%
Diarrhea 13% —
Splenomegaly 8% 13%
Photophobia — 33%
Myalgias 100% 70%
Data for Burundi from Fournier PE, Ndihokubwayo JB, Guidran J, et al. Human pathogens in body and head lice. Emerg Infect Dis. 2002;8:1515-1518; data for Ethiopia from Perine PL, Chandler BP, Krause DK, et al. A clinico-epidemiological study of epidemic typhus in Africa. Clin Infect Dis. 1992;14:1149-1158.
264
125 Rickettsia typhi (Murine Typhus)Lucas S. Blanton, J. Stephen Dumler, and David H. Walker
DEFINITION• MurinetyphusiscausedbyRickettsia typhi.• R. typhiisanobligatelyintracellulargram-negativebacterium.• Theorganisminfectsendothelialcellsinmammalianhostsandmidgutepithelialcellsinflea
hosts.
EPIDEMIOLOGY• Murinetyphusisdistributedworldwideandisprevalentintropicalandsubtropicalseaboard
regionswhererats(Rattusspp.)andtheirfleas(Xenopsylla cheopis)serveasreservoirsandvectors,respectively.
• IntheUnitedStates,mostcasesarereportedinsouthTexasandsouthernCaliforniawherethecatflea (Ctenocephalides felis) is thepredominantvectorandwhereopossumsare thesuspectedreservoir.
• Thediseaseistransmittedbytheinoculationofinfectedfleafecesintoafleabitewound.• Murinetyphusisincreasinglyrecognizedasanillnessintravelersreturningfromendemic
regionsthroughouttheworld.
CLINICAL MANIFESTATIONS• Commonsymptomsinearlyillnessincludefever,headache,nausea,andvomiting.• Rashiscommonasillnessprogresses.Itisusuallydescribedasmacularormaculopapular,
anditismostcommonlyobservedonthetrunk.• Theclinicalcourseisusuallyuncomplicated,but,occasionally,centralnervoussystemabnor-
malities,renalinsufficiency,respiratoryfailure,anddeathoccur.• Elevations in serum hepatic aminotransferase levels are frequent laboratory findings.
Vascular injuryoften leads tohypoproteinemia,hypoalbuminemia,andelectrolyteabnor-malities(e.g.,hyponatremiaandhypocalcemia).
DIAGNOSIS• Earlydiagnosisofmurinetyphusisbasedonclinicalsuspicionandepidemiology.• Immunofluorescenceassayisthemainstayofserologicdiagnosis,whichisgenerallyretro-
spective. A fourfold rise in IgG titer from acute illness to convalescence confirms thediagnosis.
• ImmunohistochemicaldetectionofR. typhiinaskinbiopsyspecimenorpolymerasechainreactionassayamplificationofrickettsialnucleicacidsinbloodorskinbiopsysamplescanestablishthediagnosisduringacuteinfection.
• Toavoidsevereorpotentiallyfatalinfection,treatmentshouldnotbewithheldwhileawait-inglaboratoryconfirmation.
TREATMENT AND PREVENTION• Doxycycline,100mgtwicedailyfor7to10days,isthetreatmentofchoice.Chloramphenicol
isanalternativetreatment.• Preventionisdirectedtowardthecontroloffleavectorsandpotentialfleahosts.
265
126 Orientia tsutsugamushi (Scrub Typhus)Didier Raoult
DEFINITION• Mite-bornerickettsiosis,presentingoneormorepapularlesionsthatformanescharatbite
sites,followedinseveraldaysbyrapidonsetoffever,headache,myalgia,andlocalandthengeneralizedadenopathy,oftenfollowedbyrash
EPIDEMIOLOGY• ExtremelycommoninruralAsiaandwesternAustralia
MICROBIOLOGY• CausedbyintracellularOrientia tsutsugamushi
DIAGNOSIS• Indirectfluorescentantibodyassayisstandardserology.Polymerasechainreactionassayof
swabortissueofescharpretreatmentisverysensitive.TheWeil-Felixtestisunreliablebutwidelyused.
THERAPY• Basedondoxycycline,100mgtwicedailyfor7days
PREVENTION• AvoidingmitebiteinruralAsiawithvectorcontrol
266
127
Ehrlichia chaffeensis (Human Monocytotropic Ehrlichiosis), Anaplasma phagocytophilum (Human Granulocytotropic Anaplasmosis), and Other AnaplasmataceaeJ. Stephen Dumler and David H. Walker
DEFINITION• InfectionbyintracellularbacteriaintheAnaplasmataceaefamily
MICROBIOLOGY• OrganismsofthefamilyAnaplasmataceaeoftheorderRickettsialesareobligatelyintracel-
lulargram-negativebacteria.• Ehrlichia chaffeensis, Ehrlichia canis, Ehrlichia muris,andNeorickettsia helminthoeca infect
mostlymonocytesandmacrophagesinbloodandtissuesofmammalianhosts.• Anaplasma phagocytophilumandEhrlichia ewingiiinfectmostlyneutrophilsandothergran-
ulocytesinthebloodofmammalianhosts.• ThemammaliantargetcellofNeoehrlichia mikurensisisnotknown.
EPIDEMIOLOGY• Humanmonocytotropicehrlichiosis(HME)andhumanE. ewingiiinfectionaredistributed
predominantly in south-central and eastern North America, where Amblyomma americanum ticks and white-tailed deer (Odocoileus virginianus) serve as vectors and reservoirs,respectively.
• Humangranulocyticanaplasmosis(HGA)isdistributedworldwide,especiallyinnorthernlatitudes of North America, Europe, and Asia, where Ixodes persulcatus clade ticks orHaemaphysalis longicornisticks(China)andmultiplesmallmammalsserveasvectorsandreservoirs.
• HumanE. muris–likeagentinfectionisdistributedintheupperMidwestoftheUnitedStates(WisconsinandMinnesota),whereIxodes scapularisticksandwhite-footedmiceandothersmallmammalsserveasvectorsandreservoirs.
• HumanN. mikurensisinfectionoccursinEuropeandnorthernChina,whereI. persulcatuscladeticksandsmallmammalsserveasvectorsandreservoirs.
• Sennetsuneorickettsiosisoccurs ineasternandsoutheasternAsia,wheredigeneantrema-todesserveasvectorsandaquaticanimals,mostlyfish,serveasreservoirs throughwhichinfection is acquiredbyoral transmission.Allmembersof theAnaplasmataceaeareobli-gatelyintracellularbacteriathatsurvivewithinvacuolesofhostcellsgenerallyderivedfromthebonemarrow,butalsooccasionallyendothelialcells.
CLINICAL MANIFESTATIONS• Frequentearlymanifestationsincludefever,headache,myalgia,nausea,andvomiting.• Rashisinfrequentorrare.• Theclinicalcourseisusuallyuncomplicated,butseverecomplicationscanincludeaseptic
shock–like syndrome, respiratory distress, meningoencephalitis, renal failure, and death,particularlyforHME.
• Leukopenia,thrombocytopenia,andelevationsinserumhepaticaminotransferaselevelsarefrequentfindings.
267C
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ter 127 Ehrlich
ia chaffeen
sis, An
aplasm
a ph
ago
cytop
hilu
m, an
d O
ther A
nap
lasmataceae
DIAGNOSIS• Early diagnosis of HME, HGA, and other human infections caused by bacteria in the
Anaplasmataceaefamilyisbasedonclinicalsuspicionandepidemiologicclues.• Rapidlaboratoryconfirmationcansometimesbeachievedbybloodsmearexaminationfor
morulae(inclusions)incirculatingleukocytesorbydetectionofbacterialDNAinbloodbypolymerasechainreactionassay.
• Seroconversionorfourfoldincreaseinantibodytiterfromacutetoconvalescentphasecon-firmsthediagnosisretrospectively.
• Earlytherapyimprovesoutcomesandpreventsseverecomplicationsorsequelae.
THERAPY• Doxycycline,100mgtwicedailyfor5to10daysuntilfeverisresolved,isthetreatmentof
choice.• Chloramphenicolshouldnotbeused.• Rifampinhasbeensuccessfullyusedinchildren.
PREVENTION• Prevention is directed toward avoidance of tick exposures and bites and early removal of
attachedticks.Neorickettsiosiscouldbepreventedbyavoidanceofuncookedorfermentedfishfoodproductsinregionswherethediseaseoccurs.
268
F Bacterial Diseases
128 Staphylococcus aureus (Including Staphylococcal Toxic Shock Syndrome)Yok-Ai Que and Philippe Moreillon
DEFINITION• Gram-positivepathogenresponsibleforsuperficialanddeep-seatedinfections• Frequentcolonizerofasymptomaticcarriers• Responsibleforbothpyogenicandtoxin-relateddiseases• Primarycauseofcommunity-andhospital-acquiredbloodstreaminfections• Firstcauseofinvasiveinfections,includinginfectiveendocarditisandosteomyelitis• Frequentlyresistanttomethicillin(methicillin-resistantS. aureus[MRSA])andallβ-lactam
drugs(inupto50%ofhospitalisolates)• Oftenco-resistanttomanyclinicallyavailableantibiotics
EPIDEMIOLOGY• Colonizeroftheanteriornostrilsin20%to40%ofthenormalpopulation• Numberonepublichealthproblemindrug-resistantnosocomialinfections• ClonalspreadofMRSAfromhealthcare(HCA-MRSA)andotherpermissiveenvironments
(seeFig.128-1)• Polyclonal dispersion of susceptible strains in the community; but successful clones of
community-acquired(CA)-MRSAmayspreadworldwide(e.g.,USA300)• Superantigenproducerresponsiblefortoxicshocksyndromeandfoodpoisoning
MICROBIOLOGY• Mostvirulentspeciesofthemorethan40Staphylococcusspp.taxa• Conservedcoregenomeofapproximately2.8millionbp• Multiple mobile genetic elements (MGEs); pathogenic and genomic islands, transposons,
andprophagesencodingvirulenceandantibiotic-resistancegenes(seeTables128-1,128-2,and128-3)
• EvolutionofsuccessfulclonesviamutationsandacquisitionofMGEs• MethicillinresistanceconferredbyapolymorphfamilyofSCCmeccassettes
DIAGNOSIS• Conventionalculturesmandatoryandcriticaltodetectnewresistancephenotypes• Prolongedincubationneededforsmall-colonyvariantsresponsibleforchronicinfection• Moleculartestsusefulforrapididentificationofknowndrug-resistancegenes• MoleculartypingcriticaltomanageMRSAepidemicsandinfectioncontrol
THERAPY• First choice for methicillin-susceptible S. aureus: penicillinase-resistantβ-lactam or first-
generationcephalosporin,forinstance,cephalexinordicloxacillinorally;nafcillinoroxacil-linintravenously;or,outsidetheUnitedStates,flucloxacillin.Alternativesincludeclindamycinortrimethoprim-sulfamethoxazoleorallyorintravenously).
• FirstchoiceforMRSAwouldbevancomycinordaptomycinintravenously,or,ifsusceptible,trimethoprim-sulfamethoxazoleorclindamycinorallyorintravenously.Alternativesinclude
269C
hap
ter 128 Staph
yloco
ccus au
reus (In
clud
ing
Staph
yloco
ccal Toxic Sh
ock Syn
dro
me)
ceftaroline,linezolid,ortelavancin;or,foracutebacterialskinandskinstructureinfections,dalbavancin,oritavancin,ortedizolid.
• Partnerdrugforcombinations:rifampin.• Benefitofaminoglycosidesnotwelldemonstrated.
PREVENTION• Decolonizationofstaphylococcalcarriers(seeTable128-4)• DetectionofHCA-MRSAandepidemicCA-MRSA• Hospitalhygienemeasures• Vaccinesindevelopment
FIGURE 128-1 Evolution of methicillin-susceptible Staphylococcus aureus (MSSA) into methicillin-resistant S. aureus (MRSA) as exemplified by sequence type 5 (ST5). ST5 belongs to clonal cluster 5 (CC5), which gathers S. aureus isolates sharing homologies in five of the seven genes (arcC, aroE, glpF, gmk, pta, tpi, and yqiL) compared with method of multilocus sequence typing (MLST). Parental ST5 is an MSSA that has been isolated in several countries, including Denmark, the Netherlands, and the United Kingdom. It acquired various types of SCCmec at several independent occasions, probably from CoNS donor strains. After SCCmec acquisition, new MRSA clones followed their own geographic and genetic evolution, spreading either as HCA-MRSA (SCCmec I, II, or III) or CA-MRSA clones (SCCmec IV) and sometimes evolving into new ST types (e.g., ST222, ST228, and ST308). Three clonal clusters (CC5, CC8, and CC30) generated six of the seven major pandemic MRSA clones described over the past 3 decades. (Modified from Robinson DA, Enright MC. Evolutionary models of the emergence of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2003;47:3926-3934.)
ST5HCA-MRSA
-Belgium
ST5HCA-MRSA
-USA
ST5CA-MRSAPediatric
-USA
ST5HCA-MRSA
-USA
ST5HCA-MRSA-New York
-Japan
ST5HCA-MRSA
-France-UK
ST5HCA-MRSA
-Slovenia
ST228HCA-MRSA-Germany
ST222HCA-MRSA
-Slovenia
ST5HCA-MRSA
-Ireland
ST308HCA-MRSA
-Ireland
SSCmectype III
SSCmectype II
SSCmectype I
SSCmectype IV
ST5-MSSA-Denmark-Netherlands-UKCC5
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TABLE 128-1 Staphylococcus aureus Extracellular Factors Involved in Pathogenesis and Response to Global Regulatory Elements during Bacterial Growth
Gen
e
Loca
tio
n
Pro
du
ct
Act
ivit
y/Fu
nct
ion
Tim
ing
*
AC
TIO
N O
F R
EG
ULA
TOR
Y
GEN
ES
†
agr
saeR
S
rot
sarA
Surface Proteinsspa Chromosome Protein A Anti-immune, anti-PMN Exp − ‡ +cna Chromosome Collagen BP Collagen binding Exp −fnbA Chromosome Fibronectin BPA Fibronectin binding Exp − +fnbB Chromosome Fibronectin BPB Fibronectin binding Exp − +clfA Chromosome Clumping factor A Fibrinogen binding Exp 0
clfB Chromosome Clumping factor B Fibrinogen binding Exp 0 + 0
lfb Chromosome Lactoferrin BP Lactoferrin binding Exp
Capsular Polysaccharidescap5 Chromosome Polysaccharide capsule
type 5Antiphagocytosis? Pxp + +
cap8 Chromosome Polysaccharide capsule type 8
Antiphagocytosis? Pxp +
Cytotoxinshla Chromosome α-Hemolysin Hemolysin, cytotoxin Pxp + + – ‡
hlb Chromosome β-Hemolysin Hemolysin, cytotoxin Pxp + + – ‡
hld Chromosome δ-Hemolysin Hemolysin, cytotoxin Pxp + 0 +hlg Chromosome γ-Hemolysin Hemolysin, cytotoxin Pxp + – ‡
lukS/F PVL phage PVL Leucolysin Pxp + –
Superantigenssea Bacteriophage Enterotoxin A Food poisoning, TSS Xp 0
seb SaPI3§ Enterotoxin B Food poisoning, TSS Pxp + ‡
sec SaPI4§ Enterotoxin C Food poisoning, TSS Pxp +sed Plasmid Enterotoxin D Food poisoning, TSS Pxp +eta ETA phage Exfoliatin A Scalded skin syndrome Pxp +etb Plasmid Exfoliatin B Scalded skin syndrome Pxp +tst SaPI1,2, bov1§ Toxic shock toxin-1 Toxic shock syndrome Pxp + ‡
EnzymesSplA-F Chromosome Serine protease-like Putative protease + –
ssp Chromosome V8 protease Spreading factor Pxp + 0 –
aur Chromosome Metalloprotease (aureolysin)
Processing enzyme? Pxp + –
sspB Chromosome Cysteine protease Processing enzyme? ? –
scp Chromosome Staphopain (protease II) Spreading, nutrition Pxp + –
geh Chromosome Glycerol ester hydrolase Spreading, nutrition Pxp + 0 – ‡
lip Chromosome Lipase (butyryl esterase) Spreading, nutrition Pxp + 0 ‡
fme Chromosome FAME Fatty acid esterification Pxp + ‡
plc Chromosome PI-phospholipase C Pxp +nuc Chromosome Nuclease Nutrition Pxp + +
271C
hap
ter 128 Staph
yloco
ccus au
reus (In
clud
ing
Staph
yloco
ccal Toxic Sh
ock Syn
dro
me)
Gen
e
Loca
tio
n
Pro
du
ct
Act
ivit
y/Fu
nct
ion
Tim
ing
*
AC
TIO
N O
F R
EG
ULA
TOR
Y
GEN
ES
†
agr
saeR
S
rot
sarA
has Chromosome Hyaluronidase Spreading factor Xp ‡
coa Chromosome Coagulase Clotting, clot digestion Exp + + +sak Bacteriophage Staphylokinase Plasminogen activator Pxp + 0
BP, binding protein; FAME, fatty acid modifying enzyme; PMN, polymorphonuclear neutrophil.*Timing: Xp, throughout exponential phase; Exp, early exponential phase only; Pxp, postexponential phase; 0,
no effect of gene on. Expression: +, upregulated; –, downregulated.†agr, accessory gene regulator; PVL, Panton-Valentine leukocidin; saeRS, S. aureus exoproteins; rot, repressor of
toxins; sarA, Staphylococcus accessory regulator.‡Controversial.§SaPI, S. aureus pathogenic island.Modified from Cheung AL, Projan SJ, Gresham H. The genomic aspect of virulence, sepsis, and resistance to killing
mechanisms in Staphylococcus aureus. Curr Infect Dis Rep. 2002;4:400-410; and Novick RP, Geisinger E. Quorum sensing in staphylococci. Ann Rev Genet. 2008;42:541-564.
TABLE 128-1 Staphylococcus aureus Extracellular Factors Involved in Pathogenesis and Response to Global Regulatory Elements during Bacterial Growth—cont’d
TABLE 128-2 Staphylococcus aureus MSCRAMMs Belonging to Sortase-Mediated Cell Wall–Associated Proteins
GEN
E
PRO
TEIN
AA
SOR
TASE
MO
TIF
LIG
AN
D
SPEC
IFIC
ITY
POTE
NTI
AL
IMPL
ICA
TIO
N
IN D
ISEA
SE
Spa Protein A 508 SrtA LPETG Antibody Fc fragment (IgG, IgM) von Willebrand’s factor, TNFR1, platelets
Experimental sepsis, experimental osteoarthritis
clfA Clumping factor A 933 SrtA LPDTG Fibrinogen, platelets Experimental endocarditis
clfB Clumping factor B 913 SrtA LPETG Fibrinogen, cytokeratin 10, platelets
Colonization of nasal mucosa
cna Collagen-binding protein
1183 SrtA LPKTG Collagen Experimental osteomyelitis, septic arthritis
fnA Fibronectin-binding protein A
1018 SrtA LPETG Fibronectin, fibrinogen, elastin
Experimental endocarditis
Platelets Cell invasion, experimental mastitis
fnB Fibronectin-binding protein B
914 SrtA LPETG Fibronectin, fibrinogen, elastin, platelets
Experimental mastitis
sdrC Serine-aspartate repeat protein
947 SrtA LPETG Undetermined —
sdrD Serine aspartate repeat protein
1315 SrtA LPETG Undetermined —
Continued
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GEN
E
PRO
TEIN
AA
SOR
TASE
MO
TIF
LIG
AN
D
SPEC
IFIC
ITY
POTE
NTI
AL
IMPL
ICA
TIO
N
IN D
ISEA
SE
sdrE Serine aspartate repeat protein
1166 SrtA LPETG Platelets —
pls Plasmin-sensitive protein
1637 SrtA LPDTG Cellular lipids, ganglioside M3; nasal epithelial cells
Colonization of nasal mucosa
sraP Serin-rich adhesin for platelets
2261 SrtA LPDTG Platelets Experimental endocarditis
(sasA)
IsdA Iron-regulated surface determinant A
354 SrtA LPKTG Fibrinogen, fibronectin Nasal colonization
(sasE) Hemoglobin/transferrin
IsdB Iron-regulated surface determinant B
645 SrtA LPQTG Hemoglobin/hemin —
(sasJ)
isdC Iron-regulated surface determinant C
227 SrtB NPQTN Hemin —
isdH Iron-regulated surface determinant H
895 SrtA LPKTG Haptoglobin Nasal colonization
(harA) Haptoglobin/hemoglobin complex
(sasI)
sasB S. aureus surface protein B
937 SrtA LPDTG Undetermined —
sasC S. aureus surface protein C
2186 SrtA LPNTG Undetermined —
sasD S. aureus surface protein D
241 SrtA LPAAG Undetermined —
sasF S. aureus surface protein F
637 SrtA LPKAG Undetermined —
sasG S. aureus surface protein G
1117 SrtA LPKTG Nasal epithelial cells Associated to invasive disease
sash (adsA)
S. aureus surface protein H
308 SrtA LPKTG Cell-wall associated adenosine, synthase
Escape phagocyte-induced killing
sasK S. aureus surface protein K
211 SrtA LPKTG Undetermined —
fmtB Formyl transferase B SrtA LPXTG Cell wall synthesis, β-lactam resistance
Antibiotic resistance
AA, protein length in amino acids; Srt, sortase; IgM, immunoglobulin M; MSCRAMMs, microbial surface compo-nents recognizing adhesive matrix molecules; TNFR1, TNF-receptor 1.
Modified from Roche FM, Massey R, Peacock SJ, et al. Characterization of novel LPXTG-containing proteins of Staphylococcus aureus identified from genome sequences. Microbiology. 2003;149:643-654; Clarke S, Foster S. Surface adhesins of Staphylococcus aureus. Adv Microb Physiol. 2006;51:187-224; and Dedent A, Marraffini L, Schneewind O. Staphylococcal sortases and surface proteins. In: Fischetti V, Novick RP, Ferretti J, et al, eds. Gram-Positive Pathogens. 2nd ed. Washington, DC: ASM Press; 2006:486-495.
TABLE 128-2 Staphylococcus aureus MSCRAMMs Belonging to Sortase-Mediated Cell Wall–Associated Proteins—cont’d
273C
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ccus au
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clud
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Staph
yloco
ccal Toxic Sh
ock Syn
dro
me)
TABLE 128-3 Summary of Major Mobile Genetic Elements in Sequenced Staphylococcus aureus Strains
S. AUREUS STRAIN
MR
SA25
2
N31
5
Mu
50
CO
L
8325
MW
2
MSS
A47
6
FPR
3757
JH1/
JH9
New
man
RF1
22
Clonal cluster
30 5 5 8 8 1 1 8 5 8 151
BacteriophageΦSa1 NI lukFM
ΦSa2 NI NI (Φ12)
PV-luk PV-luk NI
ΦSa3 chip scin
chip scin
chip sak
chip scin
scin sak
scin sak
chip scin
chip scin chip scin
sak sea
sak sep
sea Sak sea seg
sea seg
sak sak sak sea
sek sek
ΦSa4 NI NI
ΦSa5 NI (Φ11)
NI
ΦSa6 NI (L54a) NI NI NI
ΦSA7 NI
ΦSa8 NI
SAPIsSAPI1 seb ear ear
seq
seq sek sek
SAPI2 sel sec tst
sel sec tst
Mdr
SAPI3 fhuD ear sel sec
SAPI4 NI NI
SAPIbov tst sel
PlasmidsI ble
kn*ble kn*
ble kn*
tet tetK; NI
II cadAC cadDX blaZ cadD
blaZ cadD
blaZ arsR
arsBC* arsBC cadD aac/aph
III aac/aph
erm ileS
qacA
TransposonsTn552 blaZ
Tn554 erm spc
erm spc
erm spc
Tn5801 tetM
Tn976-like
NI NI
Continued
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TABLE 128-4 Example of Decontaminating Scheme for Patients Colonized or Infected with Methicillin-Resistant Staphylococcus aureus (MRSA)
Protective MeasuresPut patient in contact isolation (one or several contaminated patients in single room with restricted access)Use protective gown and glovesUse protective mask and glasses if risk for projection of contaminated liquidsClean hands with alcoholic solution at glove removal and between caregiving proceduresLeave any disposable item in room and discard for sterilization in special containers
Decontamination MeasuresApply nasal mupirocin (2%) every 8 hours for 5-7 daysApply chlorhexidine-based oral spray three to four times a day for 5-7 daysTake daily shower or clean body thoroughly with chlorhexidine-based soap for 5-7 daysIn the case of dental prostheses, clean and soak the prosthesis daily in chlorhexidine-based solution for 5-7 days
Control Cultures and DecisionTake control swabs of any contaminated sites 48 and 96 hours after the end of treatmentKeep isolation measures in force until laboratory results are availableIf no MRSA is present in control cultures, consider patient decontaminated. Relieve isolation and swab weekly
for follow-up cultures.If MRSA is present in control cultures, pursue isolation measures and repeat whole decontamination scheme
Modified from Current Recommendations at the University Hospital of Lausanne, Switzerland.
S. AUREUS STRAIN
MR
SA25
2
N31
5
Mu
50
CO
L
8325
MW
2
MSS
A47
6
FPR
3757
JH1/
JH9
New
man
RF1
22
SCCmec I mecA
mec II mecA mecA mecA mecA
mec III
mec IV mecA mecA arc
opp
non-mec
far1
aac/aph, aminoglycoside resistance; arc, arginine catabolism; arsBC, arsenic resistance genes; blaZ, penicillin resis-tance; bsa, bacteriocin biosynthesis genes; cadACDX, cadmium resistance genes; chip, chemotaxis inhibitory protein; ear, putative β-lactamase type protein; erm, erythromycin resistance; far1, fusidic acid resistance; fhuD, siderophore transporter; ileS, mupiricin resistance; lukFM, leukocidin; mdr, multidrug resistance; opp, oligo-peptide uptake; mecA, penicillin-binding protein 2a conferring resistance to methicillin; qacA, quaternary ammo-nium compound (antiseptic) resistance; PV-luk, Panton-Valentine leukocidin; sak, staphylokinase; SaPI, S. aureus pathogenicity island; SCC, staphylococcal cassette chromosome; scin, staphylococcal chemotaxis inhibitory protein; sea to sep, enterotoxin A to enterotoxin P; spc, spectinomycin resistance; tst, toxic shock syndrome toxin-1; tet and tetM, tetracycline resistance.
Note: Phage and SaPI families based on homology of integrase genes and insertion site. NI, Element present but no identified virulence or resistance gene. FPR3757 SCCmec is fused to ACME element; SaPIS belongs to SaPI1 family based on integrase and insertion site. RF122 has two phage fragments.
*Integrated plasmid.Modified from Lindsay J. S. aureus evolution: lineages and mobile genetic elements (MGEs). In: Lindsay J, ed.
Staphylococcus aureus Molecular Genetics. Norfolk, UK: Casiter Academic Press; 2008:45-69.
TABLE 128-3 Summary of Major Mobile Genetic Elements in Sequenced Staphylococcus aureus Strains—cont’d
275
129 Staphylococcus epidermidis and Other Coagulase-Negative StaphylococciMark E. Rupp and Paul D. Fey
MICROBIOLOGY• More than40speciesofcoagulase-negativestaphylococciaregram-positivecocci thatare
closely related to the intrinsically more virulent Staphylococcus aureus and differentiatedfromS. aureusbytheirinabilitytoproducecoagulase.
• Staphylococcus epidermidis, themostcommonclinicallyencounteredspeciesofcoagulase-negativestaphylococci,isaprominentpartofthenormalcommensalfloraofhumanskin.S. epidermidisowesitspathogenicsuccesstothreefactors:(1)itsnormalnicheonhumanskin,givingitaccesstoanydeviceinsertedorpassedthroughtheskin;(2)itsabilitytoadheretobiomaterialsandelaboratebiofilm;and(3)changesinthehumanhostpopulationresult-ing in greater numbers of immunosuppressed patients and greater use of bioprostheticdevices.
• Other noteworthy species of coagulase-negative staphylococci include S. saprophyticus, acommoncauseofuncomplicatedurinarytract infectioninsexuallyactivewomen;S. hae-molyticus, often resistant to glycopeptides; and S. lugdunensis, a more virulent coagulase-negativestaphylococcusthatmimicsinfectionsduetoS. aureus.
EPIDEMIOLOGY• S. epidermidisisaprominentcauseofintravascularcatheter-relatedinfectionandinfection
ofavarietyofmedicaldevices,suchasprostheticjoints,artificialheartvalves,andcerebro-spinalfluidshunts.
• StrainsofS. epidermidis canestablishpredominance inhospitalenvironmentsandspreadfromunittounit,hospitaltohospital,andcountrytocountry.
DIAGNOSIS• Differentiating“true”infection-causingcoagulase-negativestaphylococcifromcontaminants
can, at times, be a diagnostic challenge. Finding coagulase-negative staphylococci at highnumbersorrepetitivelyinsituationsclinicallyconsistentwithinfectionisindicativeofatrueinfection.Unfortunately,insomesituations,infectionsduetocoagulase-negativestaphylo-coccicanbeindolentanddiagnosisisdifficult.
THERAPY• MostnosocomialS. epidermidisstrainsaremultidrugresistant,andglycopeptideoralterna-
tiveantistaphylococcal antibioticsdirectedatmethicillin-resistant strainsareemployed intreatment. Isolates of S. epidermidis with an oxacillin minimal inhibitory concentration(MIC)of0.25µg/mLor lessmaybetreatedwithoxacillinornafcillin.Vancomycinis thedrugwithwhichthereisthemostclinicalexperienceincoagulase-negativestaphylococcalinfections,althoughcasereportssupportuseofdaptomycinandlinezolid.Mostspeciesaresusceptibleinvitrototheneweragents:telavancin,dalbavancin,oritavancin,ceftaroline,andtedizolid,aswellastotheolderagents,quinupristin-dalfopristin,andtigecycline,buttheirclinicalutilityforcoagulase-negativestaphylococcalinfectionsremainstobedefined.
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• In some situations, rifampin is added to the regimen for better activity against biofilm-associatedorganisms.
• Information isaccruingwithregard to treatmentofbiomaterial-based infectionswith thedeviceinsitu,butmostofthesedataareanecdotal.Ingeneral, infecteddevicesshouldberemovedwheneverpossible.Anumberofbiofilm-directedtherapeuticmodalitiesappeartoholdpromise.
PREVENTION• Biomedicaldevicesmustbeinsertedorimplantedwithscrupulousattentiontoasepticprac-
tices.Thereisgreatinterestindevelopingbiomedicaldevicesthatarelesspronetobacterialadherenceandinfection.
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130 Streptococcus pyogenesAmy E. Bryant and Dennis L. Stevens
DEFINITION• Streptococcus pyogenesisanimportantglobalhumanpathogenthatcausesawidevarietyof
acuteinfections,suchassofttissueinfectionsandpharyngitis;severelife-threateninginfec-tions,suchasstreptococcaltoxicshocksyndrome;anddevastatingpostinfectioussequelae,suchasrheumaticfeverandglomerulonephritis.
EPIDEMIOLOGY• Themostcommoninfectionisstreptococcalpharyngitis.• Superficialskinandsofttissueinfectionsincludeimpetigo,erysipelas,andcellulitis.• Severelife-threateninginfectionsincludescarletfever,bacteremia,pneumonia,necrotizing
fasciitis,myonecrosis,andstreptococcaltoxicshocksyndrome.• Postinfectioussequelae includeacuterheumatic feverandpoststreptococcalglomerulone-
phritis.
MICROBIOLOGY• S. pyogenesisagram-positive,β-hemolyticstreptococcusthatiscatalasenegative.Morethan
150differentstrainshavebeenidentifiedbasedondifferentM-proteintypes.ItisagroupAstreptococcus based on its carbohydrate structure, according to Lancefield typing ofβ-hemolyticstrains.Mucoidstrainsarerichinhyaluronicacidcapsule,andnumerousextra-cellular toxins are produced by most strains, which include streptolysin O, a cholesterol-specific cytolysin, streptolysin S, a cell-associated hemolysin, fibrinogen-binding proteins,streptokinase, numerous pyrogenic exotoxins that act as superantigens, and a cysteine-proteasecalledpyrogenicexotoxinB.
DIAGNOSIS• DiagnosisofS. pyogenespharyngitisissuspectedbasedonspecificclinicalcriteriaandcan
besubstantiatedbyrapidtestsorculture.• Similarly,impetigo,cellulitis,anderysipelasaresuspectedbasedonuniqueclinicalpresenta-
tions. Cultures of impetiginous lesions will distinguish Streptococcus from Staphylococcus aureus as the cause. Cultures of lesions associated with cellulitis and erysipelas are usefulonly20%ofthetime,andbloodculturesarerarelypositive.
• InvasiveS. pyogenesismoredifficulttodiagnoseearlyinthecourse,althoughbloodculturesare positive in more than 50% of cases. In the 50% of patients with necrotizing fasciitisassociatedwithaportalofentrysuchassurgicalincision,postpartumsepsis,orinsectbites,culturesofthesesitesarepositiveinthevastmajorityofcases.Inthe50%ofpatientswithnoportalofentry,infectionbeginsdeepinthefasciaandmuscle,andthesepatientspresentwithahistoryofpreviousnonpenetratingtrauma,severepain,andsystemictoxicity.Classicsigns of necrotizing infections are not apparent until late in the course at a time that thepatienthassystemicshockandorganfailure.
• Rheumatic fever is diagnosed based on clinical suspicion of patients with an antecedentpharyngitiswhopresentwithcarditis,Sydenham’schorea,migratoryarthritis,andevidence
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thatthepharyngitiswasduetoS. pyogenesbypositivecultureorrisinganti–streptolysinOtitersandusingtheJonescriteria,whicharereviewedelsewhere.
• Poststreptococcalglomerulonephritis isdiagnosedbasedonevidenceofrenal failurewithglomerular damage, as indicated by red blood cell casts and an antecedent streptococcalinfection,whichcanbeeitherpharyngitisorimpetigo.
THERAPY• Penicillinremainsthedrugofchoiceforthetreatmentofallstreptococcalinfections.• Mostcasesof impetigocanbe treatedwith topicalbacitracin,mupirocin,or retapamulin,
and only in severe cases or in epidemic situations is oral or parenteral administration ofpenicillinnecessary.
• SeverecasesofS. pyogenesinfections,suchasnecrotizingfasciitis,myonecrosis,andstrep-tococcaltoxicshocksyndrome,maybenefitfromclindamycin,whichsuppressestoxinpro-ductionandinanimalstudiesandlimitedhumanstudiesissuperiortopenicillin.Intensivecaresupport,aggressivefluidresuscitation,ventilatorsupport,andsurgicalinterventionarecommonlyrequired.
PREVENTION• Epidemics of streptococcal pharyngitis have been prevented in military recruits by the
administrationofmonthlybenzathinepenicillingivenintramuscularly.• Rheumaticfevercanbepreventedbyadministrationofpenicillinwithin9daysoftheonset
ofstreptococcalpharyngitis.Secondaryprophylaxisshouldbeconsideredinpatientswithrheumaticheartdiseasebasedonage,smallchildreninthehousehold,andexposuretocasesofstreptococcalinfection.
• Improvedlivingconditions,improvedpersonalhygiene,andtopicaltreatmentofimpetigi-nouslesionscanpreventspreadtosusceptibleindividuals.
• Prevention of secondary cases should be considered in health care workers and familymembers with prolonged, intimate contact with patients with necrotizing fasciitis/streptococcaltoxicshocksyndrome,particularlythosewhoareimmunocompromised,havevaricella,havehadrecentsurgery,orhaverecentlygivenbirth.Theriskforsecondarysevereinfectionislow,butcolonizationandstreptococcalpharyngitiscanoccurcommonly.Oralpenicillinfor7to10daysisreasonable,althoughnodefinitivestudieshavebeendone.
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131 Nonsuppurative Poststreptococcal Sequelae: Rheumatic Fever and GlomerulonephritisStanford T. Shulman and Alan L. Bisno
DEFINITIONS• Acuterheumaticfever(ARF)andacutepoststreptococcalglomerulonephritis(APSGN)are
immune-mediatedillnessesthatdevelopaftersomegroupAstreptococcalinfections.• ARF predominantly affects the heart and joints and can lead to chronic rheumatic heart
disease,whereasAPSGNisanimmune-complexnephritis.
EPIDEMIOLOGY• ARFcanfollowanuntreatedgroupAstreptococcalinfectionofthepharynxinindividuals
whoappeartobegeneticallysusceptible.• ARFismostfrequentinchildren5to15yearsofageandoccursmostcommonlyinwinter
orspring.• ARF now is much less common in developed areas of the world, compared with several
decadesago.MostcasesnowoccurindevelopingcountriesorinminoritypopulationswithinAustraliaandNewZealand.
• APSGNcanfollowgroupAstreptococcalinfectionsoftheskinorthroat.• PostpharyngealAPSGNoccursmainlyinschool-agedchildreninwinterorspring,whereas
postpyodermaAPSGNismostcommoninpre–school-agedchildreninlatesummerorfall.
MICROBIOLOGY• CertainMtypesofgroupAstreptococci(GAS;M-1,M-3,M-5,M-6,M-14,M-18,M-19)
areconsideredrheumatogenic,thatis,theyhavemuchgreaterabilitytotriggertheimmuneeventsthatresultinARFwhencomparedtononrheumatogenictypes.Themolecularbasisofrheumatogenicityisunknown.
• NephritogenicMtypesofGASarethosewithgreatpropensitytoleadtoAPSGN,specificallyM-1,M-4,M-12,andM-25afterpharyngitisandM-2,M-9,M-55,M-57,M-59,M-60,andM-61afterpyoderma.Thespecificantigen(s)involvedinthisimmune-complexnephritisisstillsomewhatunclear.
DIAGNOSIS• Diagnosis of ARF is based upon the Jones criteria, comprising five major criteria, four
minor criteria, and a requirement for evidence of antecedent group A streptococcalinfection.
• ThefivemajorJonescriteriaarecarditis,arthritis,chorea,erythemamarginatum,andsub-cutaneousnodules.Thefourminorcriteriaarefever,arthralgia,elevatedacute-phasereac-tants (erythrocyte sedimentation rate, C-reactive protein), and prolonged P-R interval.DiagnosisofARFrequiresonemajorplusatleasttwominorcriteriaortwomajorcriteriaplusevidenceofantecedentgroupAstreptococcalinfection.
• ThediagnosisofAPSGNisgenerallybaseduponacuteonsetofhematuriawithhypertension,azotemia,hypocomplementemia,andwithevidenceofrecentstreptococcalpharyngitisorpyoderma.
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THERAPY• Treatment of ARF includes an anti-inflammatory agent (aspirin for those with arthritis
and/or mild carditis; corticosteroids for those with moderate or severe carditis [see Table131-1]);anagentsuchasphenobarbital,diazepam,haloperidol,valproate,orrisperidoneforthosewithchorea;andaprophylacticantibiotic.Asingledoseofintramuscular(IM)ben-zathinepenicillin(oranalternativeagentforpenicillin-allergicindividuals)isindicated.
• TreatmentofAPSGNincludescorrectionofcirculatoryoverloadandhypertensionbysaltandfluidrestriction,diureticsasneeded,antihypertensivesonly if severehypertensionorhypertensiveencephalopathyispresent.Immunosuppressivesarenotbeneficial.
PREVENTION• BecauseARFfrequentlyrecurswithsubsequentgroupAstreptococcalpharyngitisepisodes,
long-term prophylaxis is indicated with IM benzathine penicillin every 4 weeks or oralpenicillinVtwicedaily,orforpenicillin-allergicindividualswithdailysulfadiazine,macro-lide,orazalide(seeTable131-2),usuallyatleastuntilage21.
• BecauseAPSGNonlyveryrarelyrecurs,nopreventativeantibiotictherapyisindicated.
TABLE 131-1 Suggested Schedule of Anti-inflammatory Therapy in Rheumatic Fever
CLINICAL SEVERITY TREATMENTArthralgia or mild arthritis; no carditis Analgesics only, such as codeine or propoxyphene
Moderate or severe arthritis; no carditis, or carditis with or without cardiomegaly, but without failure
Aspirin, 50-70 mg/kg/day for 3 wk, increased if necessary; 25-35 mg/kg/day for the subsequent 6 wk
Carditis with congestive failure, with or without joint manifestations
Prednisone, 2 mg/kg, max 60 mg/day; methylprednisone sodium succinate intravenous in fulminating cases; after 2-3 wk, slow withdrawal to be completed in 3 more wk; aspirin to be continued for 1 mo after discontinuation of prednisone
From Stollerman GH. Rheumatic Fever and Streptococcal Infection. New York: Grune & Stratton; 1975.
TABLE 131-2 Secondary Prevention of Rheumatic Fever (Prevention of Recurrent Attacks)
AGENT DOSE MODEBenzathine penicillin G 600,000 U for children ≤27 kg (60 lb), 1.2 million U
for those >27 kg (60 lb) every 4 wk*Intramuscular
Penicillin V 250 mg twice daily Oral
Sulfadiazine 0.5 g once daily for patients ≤27 kg (60 lb) Oral
1.0 g once daily for patients >27 kg (60 lb)
For Individuals Allergic to Penicillin and SulfadiazineMacrolide or azalide Variable Oral
*In high-risk situations, administration every 3 weeks is justified and recommended.From Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of
acute streptococcal pharyngitis. Circulation. 2009;191:1541-1551.
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132 Streptococcus pneumoniaeEdward N. Janoff and Daniel M. Musher
EPIDEMIOLOGY• Streptococcus pneumoniae is the leading cause of pneumonia and bacterial meningitis in
childrenyoungerthan5yearsandolderadultsworldwide.• The incidence ishighest inchildrenyounger than2yearsandadultsolder than65years;
mortalityishighestinolderadults.• Asymptomatic colonization is common and precedes almost all symptomatic clinical
infections.• Large outbreaks are uncommon, but smaller outbreaks occur under crowded conditions
(prisons,nursinghomes,militarytraining).• Groupsatincreasedriskforseriouspneumococcaldiseaseincludeindividualsattheextremes
ofage(particularly<2yearsand>65yearsofage),thosewithunderlyingorgandysfunction(aspleniaandsplenicdysfunction,chronicheart,lung,liver,andkidneydisease),andimmu-nocompromisingconditions (particularlyantibodydefects, complementdeficiencies,neu-tropenia,andmalignancies).
MICROBIOLOGY• Streptococcus pneumoniaeisagram-positive,α-hemolytic,lancet-shapeddiplococcusandis
bilesolubleandoptochinsensitive.• Streptococcus pneumoniaeiscatalase-negativebutproduceshydrogenperoxide.• Therearemorethan92capsularpolysaccharideserotypesthatconferresistancetophago-
cytosis;serotypeisdeterminedbytheQuellungreaction.• Effectivephagocytosisandkillingtypicallyrequireantibodies,mostoftentocapsularpoly-
saccharides,complement,andphagocytes(neutrophilsandmacrophages).• Pneumolysin is thecholesterol-binding,pore-formingprimarytoxinthatcausesbothepi-
thelialandendothelialdamageandperturbscomplementactivity.
DIAGNOSIS• PerformGramstainandcultureofgood-qualitysputum(<10epithelialcells,>25neutrophils/
high-powerfieldor>10neutrophils/epithelialcell)frompatientswithpneumonia,ofcere-brospinalfluidfrompatientswithmeningitis,andofmiddleearfluidbytympanocentesisfrom patients with otitis media. Among adults with pneumonia, approximately 10% havepositivebloodcultures,halfofwhichgrowS. pneumoniae.
• Perform urine antigen detection in adults (≈70% sensitive in adults with bacteremia; notspecificinchildren).
CLINICAL MANIFESTATIONS• Otitismediaisthemostcommonclinicalsyndrome,butpneumococcalpneumoniainchil-
drenandadultsunderliesmostseriousinfectionsanddeath.• Thespectrumof infectionranges fromasymptomaticpharyngealcolonizationtomucosal
disease(otitismedia,sinusitis,pneumonia)toinvasivedisease(bacteriainanormallysterilesite;bacteremia,meningitis,empyema,endocarditis,arthritis).
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• Most invasivedisease results frombacteremic seeding,butmeningitis andempyemamayalsoresultfromextensionoflocalinfection.
THERAPY• A β-lactam antibiotic is the mainstay of therapy for pneumococcal infection. Decreased
sensitivitytopenicillinderivesfromstructuralmodificationsofpenicillin-bindingproteins,effectsthatcompromisetheefficacyofpenicillinintreatmentofmeningitisandotitismedia,buttypicallynotpneumonia.
• Intravenoustherapy,particularlyceftriaxoneandcefotaxime,arerecommendedfortherapyofbacteremiaandmostoften,withtheinitialadditionofvancomycin,meningitis.
• Respiratory quinolones, linezolid, vancomycin, and macrolides all show clinical activityagainst S. pneumoniae. Combined therapy with a β-lactam and macrolide may improveoutcomes.
PREVENTION• Two vaccines provide protection against invasive pneumococcal disease: a pneumococcal
polysaccharide-protein conjugate vaccine (PCV13) with the 13 most common pediatriccapsular serotypes for children (>90%protection)anda23-valentpolysaccharidevaccineforadults(PPSV23)(54%to81%protection).ThechildhoodPCV13alsopreventsuptoonethirdofchildhoodbacterialpneumoniaandsomeproportionofmeningitisandotitismedia.Theefficacyof the23-valentpolysaccharidevaccineagainstadultpneumonia is lessclear.Both PPSV23 and PCV13 are now approved independently for use in older adults. Forimmunocompromised adults, vaccination with the 13-valent conjugate, followed greaterthanorequalto8weekslaterwiththe23-valentpolysaccharidevaccine,isrecommended.Widespread pneumococcal vaccination of children has reduced the overall incidence ofinvasivediseaseandhospitalizationforpneumoniainallagegroupsintheUnitedStates.
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133 Enterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc SpeciesCesar A. Arias and Barbara E. Murray
MICROBIOLOGY AND TAXONOMY• Enterococci are gram-positive facultatively anaerobic bacteria that usually appear oval in
shapeandcanbeseenassinglecells,pairs,shortchains,orevenverylongchains.• Enterococci are capable of growing in medium containing 6.5% sodium chloride and at
temperaturesbetween10°and45°Candareabletohydrolyzeesculininthepresenceof40%bilesalts.
• Enterococcus faecalisandEnterococcus faeciumarethemostclinicallyrelevantspecies.• Most clinically relevant species of enterococci produce a leucine aminopeptidase and a
pyrrolidonylarylamidase.• TheformerStreptococcus bovisgroupisnowdividedintothreemainspecies:S. gallolyticus,
S. pasteurianus,andS. infantarius.• TheLeuconostocgenuscomprisescatalase-negative,gram-positivecocci,usuallyarrangedin
pairsorchainsandareintrinsicallyresistanttovancomycin.
COLONIZATION, VIRULENCE, AND GENOMICS• Enterococciarenormalcommensalsofthegastrointestinaltract.• Enterococci are capable of dominating the gut microbiota of hospitalized patients who
receivebroad-spectrumantibiotics.• Specific hospital-associated genetic lineages of E. faecium and E. faecalis have evolved to
becomesuccessfulinthenosocomialenvironment.• TheStreptococcus gallolyticusgroupoforganismsalsocarriesgenesencodingpotentialcell
surfacedeterminantsthatinteractwithhostproteins.
EPIDEMIOLOGY• Enterococciareorganismsknowntocausehospital-associatedinfectionsinpatientswhoare
criticallyillorimmunosuppressed.• Enterococci are among the most common organisms causing infective endocarditis, both
hospital-andcommunity-associated.• Enterococciareabletospreadinthehospitalusuallyviathehandsofhealthcareworkers
andtheenvironment.• Infectioncontrolmeasuresarecriticaltopreventacquisitionofthesemicroorganisms.• Infective endocarditis and bacteremia caused by S. gallolyticus is highly associated with
gastrointestinalmalignancies.
CLINICAL PRESENTATIONS• Enterococciarecapableofcausingbloodstreaminfections,bothincommunity-andhospital-
associatedclinicalsettings.• Infectiveendocarditis isoneof themost seriousand life-threatening infectionscausedby
enterococci.• Enterococciareoneoftheleadingcausesofnosocomialurinarytractinfections.
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• Enterococci have been described in soft tissue infections, intra-abdominal infections andmeningitis.
• S. gallolyticusgroupoforganismshavebeenassociatedwithinfectiveendocarditis.• Leuconostoc causes opportunistic infections mainly in immunocompromised patients,
althoughcasesinimmunocompetentpatientshavebeenreported.
THERAPY AND ANTIMICROBIAL RESISTANCE• WhereasmostE. faecalis isolatesaresusceptibletoampicillinandvancomycin,E. faecium
oftenexhibithighminimalinhibitoryconcentrationsofampicillin,andmostclinicalisolatesintheUnitedStatesarevancomycin-resistant.
• Bactericidaltherapyforenterococcioftenrequirestheuseofacellwallagentplusanami-noglycosideorceftriaxone.
• Therapyofchoiceforsevereinfectionscausedbyenterococciisthecombinationofampicillinplusaminoglycoside(gentamicinandstreptomycin).
• AmpicillinplusceftriaxoneisanalternativetherapyforE. faecalisendocarditis.• TherapyofsevereinfectionscausedbyE. faeciumischallenging,andnoreliabletherapyis
currentlyavailable.• Linezolid and quinupristin-dalfopristin are two U.S. Food and Drug Administration–
approved drugs for multidrug resistant E. faecium, but these compounds have importantlimitationsbecauseofthelackofbactericidaleffect,toxicity,sideeffects,andemergenceofresistance.
• Daptomycinisalipopeptideantibioticwithinvitrobactericidalactivityagainstenterococci,but development of resistance during therapy seems to be a limitation for the use of thisantibiotic.
• Daptomycincombinations(withβ-lactams,aminoglycosides,and/ortigecycline)mayoffersome promise in the future for the treatment of multidrug-resistant enterococcalinfections.
• The therapy of choice for endocarditis caused by S. gallolyticus group of organisms is aβ-lactamincombinationwithanaminoglycosideforatleastpartofthetherapy.
• AmpicillinorpenicillinisthedrugofchoiceforthetreatmentofLeuconostocinfections.
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134 Streptococcus agalactiae (Group B Streptococcus)Morven S. Edwards and Carol J. Baker
DEFINITION• Group B streptococci (GBS) are gram-positive bacteria that cause invasive hematogenous
infectioninat-riskindividuals.
EPIDEMIOLOGY• GBSasymptomaticallycolonizethelowergastrointestinalorgenitaltractinapproximately
onefourthtoonethirdofadultmenandwomen.• Distributionisworldwide,butratesvarygeographically.• Invasiveinfectionriskisenhancedinneonatesandinfantsyoungerthan3months;pregnant
womenandadultswithdiabetesmellitus;andpersonswithliverorkidneydisease,cancer,heartorvasculardisease,orneurologicimpairment.
MICROBIOLOGY• β-Hemolyticstreptococciexhibitanarrowzoneofhemolysisonbloodagar.• GBShaveapolysaccharidecapsulewithpilus-like structures that enhanceadherenceand
invasion.• GBSgrowreadilyinbloodculturemediaandspecimensfromcerebrospinalfluidandother
sitesofinfection.
DIAGNOSIS• Inadults,onsetisacute,withchillsandfever,oracute-on-chronic,withindolentsymptoms,
especiallyinassociationwithskinandsofttissuemanifestations.• In infants younger than 3 months, bacteremia without a focus; meningitis; or, less often,
otherfocalinfections,suchaspneumoniaorsofttissueinfection,occur.• GrowthofGBSfrombloodoranothernormallysterilesiteisdiagnostic.
TREATMENT• Penicillinisthedrugofchoice;isolatesareuniformlysusceptibletoβ-lactamsandmerope-
nem.Isolatesaregenerallysusceptibletovancomycin;therehavebeenonlyafewcasereportsofresistance.
• Thedurationoftreatmentrangesfrom10daysforuncomplicatedbacteremiatoa4-weekminimumtreatmentcourseforendocarditis.
PREVENTION• Intrapartum antibiotic prophylaxis given to colonized parturients during labor prevents
early-onsetinfectionsinneonates,thusreducingtheoverallrateofneonatalsepsis(seeTable134-1).
• Aglycoconjugatevaccineisinclinicaltrialsandoffersthepotentialforpreventionofinfec-tionsinpregnantwomenandyounginfants,aswellas invasiveinfectionsinnonpregnantadults.
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TABLE 134-1 Indications and Nonindications for Intrapartum Antibiotic Prophylaxis to Prevent Early-Onset GBS Disease
INTRAPARTUM GBS PROPHYLAXIS INDICATED
INTRAPARTUM GBS PROPHYLAXIS NOT INDICATED
Previous infant with invasive GBS disease Colonization with GBS during a previous pregnancy (unless an indication for GBS prophylaxis is present for current pregnancy)
GBS bacteriuria during any trimester of the current pregnancy*
GBS bacteriuria during previous pregnancy (unless an indication for GBS prophylaxis is present for current pregnancy)
Positive GBS vaginal-rectal screening culture in late gestation† during current pregnancy*
Negative vaginal and rectal GBS screening culture in late gestation† during the current pregnancy, regardless of intrapartum risk factors
Unknown GBS status at the onset of labor (culture not done, incomplete, or results unknown) and any of the following:• Delivery at <37 wk gestation• Amniotic membrane rupture ≥18 hr• Intrapartum temperature ≥100.4° F (≥38.0° C)‡
• Intrapartum NAAT§ positive for GBS
Cesarean delivery performed before onset of labor on a woman with intact amniotic membranes, regardless of GBS colonization status or gestational age
GBS, group B streptococci/streptococcal; NAAT, nucleic acid amplification test.*Intrapartum antibiotic prophylaxis is not indicated in this circumstance if a cesarean delivery is performed before
onset of labor on a woman with intact amniotic membranes.†Optimal timing for prenatal GBS screening is at 35-37 weeks’ gestation.‡If amnionitis is suspected, broad-spectrum antibiotic therapy that includes an agent known to be active against
GBS should replace GBS prophylaxis.§NAAT for GBS is optional and might not be available in all settings. If intrapartum NAAT is negative for GBS but
any other intrapartum risk factor (delivery at <37 weeks’ gestation, amniotic rupture at ≥18 hours, or temperature ≥100.4° F [≥38.0° C]) is present, then intrapartum antibiotic prophylaxis is indicated.
From Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010;59(RR-10):1-32.
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135 Viridans Streptococci, Nutritionally Variant Streptococci, Groups C and G Streptococci, and Other Related OrganismsScott W. Sinner and Allan R. Tunkel
DEFINITION• Discussedinthischapterarethemajorhumanviridansstreptococci,groupsCandGstrep-
tococci, Streptococcus iniae and Streptococcus suis, and the genera Gemella, Abiotrophia, Granulicatella, Rothia,andPediococcus.
EPIDEMIOLOGY• Many of these streptococci exist as normal microbiota on various mucosal surfaces of
humans,particularlytheoralcavity.• Although generally considered to be bacteria of low virulence, they can cause significant
infections,oftenasaresultofweakhostdefenses,highinoculaatthesitesofcolonization,andvulnerablehumantissuesthatmaybepronetoinfectionaftertransientbacteremia.
• SomespeciesofgroupsCandGstreptococci,alongwithS. iniae,aremoreoftencommensalsorpathogensofanimalsbutcancausehumaninfectionaftersignificantcontactofhumanswiththeanimalsinquestion.
MICROBIOLOGY• The viridans streptococci are typically facultatively anaerobic, nonmotile, non–spore-
forminggram-positivecoccithatarebothcatalaseandcoagulasenegativeandeitherα-orγ-hemolyticonbloodagar.
• The nutritionally variant genera Abiotrophia and Granulicatella need either supplementalpyridoxalorcysteineforgrowthonagar.
• GroupsCandGstreptococcidonotalwaysreliablyfitintopredictablespeciationschemesandformrelativelylargecoloniesthatareoftenβ-hemolytic.
DIAGNOSIS• Clinicaldiagnosisofinfectionscausedbytheseorganismsdependsonthesiteofinfection
andthestatusofthehost.• Someofthemostcommonorsignificantsyndromesincludepharyngitis,softtissueinfec-
tions,primarybacteremiainneutropenichosts,endocarditis,andmeningitis.• Microbiologicdiagnosisbeginswithtypicalbacterialculturemethodsinvirtuallyallcases,
but these may be supplemented by latex agglutination studies, automated speciation andsusceptibilitytechniques,culturesonnutrient-enrichedagar,ormoleculartechniquessuchaspolymerasechainreactionassay.
THERAPY• First-linetherapyformostinfectionscausedbytheseorganismsispenicillin,iftheisolateis
susceptible.• Cephalosporinsandvancomycinarethemoststudiedsecond-linetherapies,foruseincases
ofdrugresistanceorallergyorintolerance.• Useandoveruseofβ-lactams,macrolides,andfluoroquinolonesinrecentdecadeshasled
toaslowbutclearincreaseindrugresistance.
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• Therouteanddurationoftherapydependlargelyonthesiteofinfectionandthestatusofthehost.
PREVENTION• Becausemostoftheseorganismsareconsideredpartofthenormalmicrobiotaofhumans,
preventionofinfectionislargelyaccomplishedbymaintainingarobustimmunesystem,aswellasmaintaininghealthymucosalsurfaces(e.g.,practicinggooddentalhygiene).
• Fortheoccasionalorganismthatcanbeacquiredfromanimals,avoidanceofspecificanimalcontactisthebestprevention.
• Certaingroupsofpatientsmayenjoythebenefitsofthefollowingadditionalspecificpreven-tive strategies: antimicrobial prophylaxis for certain dental procedures in patients at thehighest risk for endocarditis, antimicrobial prophylaxis for high-risk neutropenic patientsreceiving cytotoxic chemotherapy for malignancy, and appropriate surgical prophylaxis atthetimeofimplantationofvariousforeignbodies.
289
136 Streptococcus anginosus GroupCathy A. Petti and Charles W. Stratton IV
DEFINITION• The Streptococcus anginosus (milleri) group comprises three distinct species: S. anginosus,
S. constellatus,andS. intermedius.
EPIDEMIOLOGY• TheStreptococcus anginosusgroupcomprisesnormalmicrobiotaofthegastrointestinaltract
and oropharynx, and when pathogenic, is often associated with abscess formation andendocarditis.
MICROBIOLOGY• These microorganisms are microaerophilic, catalase-negative, gram-positive cocci and
are easily identified by conventional methods. They are generally susceptible toβ-lactamantibiotics.
DIAGNOSIS• Dependingontheclinicalpresentation,infectionsareusuallydiagnosedbyculturingaspeci-
menfromthesourceofinfection.
THERAPY• β-Lactam antibiotics are generally used; abscesses may require incision and drainage as
well as antimicrobial therapy with broader coverage, such as that provided by ampicillin/sulbactamorpiperacillin/tazobactam.
PREVENTION• Notapplicable.
290
137 Corynebacterium diphtheriae (Diphtheria)Rob Roy MacGregor
DEFINITION• Corynebacterium diphtheriae,agram-positivebacillus,classicallyproducesepidemicupper
respiratorytractinfectionswithhighmortalityratesinunimmunizedsubjects.
EPIDEMIOLOGY• Humansare theonlyknownreservoir, and thedisease spreadsviaairanddirect contact.
Asymptomaticcarriageisimportantintransmission.DiphtheriaisnowrareintheWestandendemicintheThirdWorld,especiallySoutheastAsia.Fewerthan5000annualcaseshavebeenreportedworldwidesince2000.
MICROBIOLOGY• Thebacillusisnonsporulating,unencapsulated,andnonmotile.Itproducesbrowncolonies
andhalosontelluritemediumandrequireslysogenicβ-phagetoproducetoxinresponsibleforthedisease.Fourbiovarsand86ribotypeshavebeenidentifiedfortracking.Nontoxigenicstrainsoccasionallycausedisease,asdotoxin-producingCorynebacterium ulceransstrains.
CLINICAL MANIFESTATIONS• Subacutefaucialinfectioncauseslow-gradefever,hoarseness,pain,andanecroticpseudo-
membrane that can extend to larynx and cause stridor and fatal obstruction. Circulatingtoxin causes potentially fatal carditis and motor neuropathy. Cutaneous infection causesindolentulcers.
DIAGNOSIS• Diagnosisispresumptive,basedontonsillitis/pharyngitiswithnecroticmembrane,hoarse-
ness,palatalparalysis,low-gradefever,andrecenttraveltoanendemicarea.Confirmationis made by observing brown colonies on tellurite medium, a distinctive Gram stain, andbiochemicaltests.Polymerasechainreactionshowsatoxingene,whichisthekeytoalertthelaboratoryforculture.
THERAPY• Diphtheriaantitoxin(DAT),producedinhorsesandobtainedfromtheCentersforDisease
ControlandPrevention,mustbegivenintravenouslywithoutwaitingfordiagnosisconfir-mation.Thedosedependsonthedurationandextentofdisease.Testpatientsfirstforhorseproteinhypersensitivity.Considertracheostomytoprotectairway.Cardiographicmonitor-ingiswisebecauseoftoxincardiotoxicity.Antibioticsaregivenorallyorparenterallyfor14days tostop toxinproductionanderadicate throatcarriage.Adultscanbegivenprocainepenicillin600,000units IMevery12hoursuntiloralmedication is tolerated, followedbypenicillinV250mgorerythromycin500mgevery6hours.
291C
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ryneb
acterium
dip
hth
eriae (Dip
hth
eria)
PREVENTION• ToxoidimmunizationconsistsofTDaP5timesupto7yearsofage.Tdboostersshouldbe
givenat10-yearintervals.Penicillinorerythromycinshouldbegivenfor14daystocarriersto prevent clinical infection or spread. Close contacts of cases should be cultured, givenantimicrobialprophylaxis,and,ifnotfullyimmunized,vaccinated.
292
138 Other Coryneform Bacteria and RhodococciRose Kim and Annette C. Reboli
DEFINITION• Coryneformbacteriaencompassseveralgenera,ofwhichCorynebacteriumisthemostfre-
quentlyencounteredinclinicalinfections.• Coryneformbacteriaarecharacterizedas irregularlyshaped,non–spore-forming,aerobic,
gram-positiverods.
EPIDEMIOLOGY• Coryneformbacteriaareubiquitousintheenvironment(soilandwater),commensalcolo-
nizersofskinandmucousmembranesinhumans,andcommensalsinanimals.• Infectionscausedbycoryneformbacteriaarebroadlycategorizedascommunityacquiredor
nosocomial;sporadiccasesofzoonoseshavebeenreported.• Rhodococcus equiusuallyoccursinindividualswithdefectivecell-mediatedimmunity,par-
ticularlywithhumanimmunodeficiencyvirusinfection,withorwithoutahistoryofanimalexposure.
MICROBIOLOGY• Coryneformbacteriareadilygrowonstandardculturemedia.Forlipophilicstrains,growth
isenhancedwithadditionofTween80.• Species identification and antimicrobial testing of coryneform bacteria is recommended
whenspecimensarecollectedfromnormallysterilesites, there ispresenceofhighcolonycounts with a strong leukocyte reaction, or there is recovery of high colony counts ofCorynebacterium urealyticumfromurineculture.
• Moleculartests,suchas16sribosomalRNAsequencing,andmatrix-assistedlaserdesorption/ionizationtime-of-flightmassspectrometryareusedforspeciesidentificationofcoryneformbacteria,includingRhodococcus, Gordonia,andTsukamurella.
DIAGNOSIS• Coryneformbacteriaareconsideredclinicallysignificantwhenpatientspresentwithsymp-
toms consistent with infection, along with recovery of bacteria as outlined above(“Microbiology”).
THERAPY• Coryneformbacteriaareuniformly susceptible toglycopeptides, suchasvancomycinand
teicoplanin,andmoststrainsaresusceptibletodaptomycinandlinezolid.• Rhodococcus equi is usually susceptible to vancomycin, teicoplanin, erythromycin, fluoro-
quinolones,rifampin,carbapenems,aminoglycosides,andlinezolid.
PREVENTION• Prevention of infections caused by coryneform bacteria includes proper skin antisepsis
beforeinvasiveproceduresandcautionwhenhandlinganimals.
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139 Listeria monocytogenesBennett Lorber
DIAGNOSIS• Clinical settings inwhich listeriosis shouldget strongconsideration include immunosup-
pressionandpregnancy(seeTable139-1).• Cultureofblood,cerebrospinalfluid,orothernormallysterilebodyfluidor,inthecaseof
gastroenteritis,fromstool.• Serologynotusefulforinvasivedisease.
MICROBIOLOGY• Short,gram-positiverod;growsreadilyonbloodagar;tumblingmotility.• Maybemistakenfordiphtheroidcontaminant.• Willgrowinrefrigeratedfood.
EPIDEMIOLOGY• Zoonosis,particularlyherdanimals.• Human transmission from contaminated food or from pregnant woman to fetus or
newborn.• Highestfoodrisksfromdelicatessen-stylemeatsandunpasteurizedcheeses.• Mostcasesoccurinneonates,pregnantwomen,persons60yearsorolder,andthosewith
impairedcell-mediatedimmunityresultingfromunderlyingcondition(hematologicmalig-nancy, organ or bone marrow transplantation, acquired immunodeficiency syndrome) ortherapy(corticosteroids,antitumornecrosisfactoragents).Notifylaboratoryforspecialstoolculturesifoutbreakoffebrilegastroenteritis.
CLINICAL SETTINGS• Neonatalsepsisormeningitis.• Meningitisorfocalcentralnervoussystem(CNS)lesionsinimmunosuppressedpatientsor
thoseolderthan50years.• Rhombencephalitisoccurs inpreviouslyhealthypatientswhodevelop fever,cranialnerve
palsies,cerebellarsignsandhemiparesis,hemisensorydeficits,orboth.• Feverinpregnancy,especiallythirdtrimester.• Outbreakoffoodbornefebrilegastroenteritis.
TREATMENT• Ampicillin(2gIVevery4hours).Addgentamicin(5mg/kgperday)forCNSinfectionor
endocarditis.• Trimethoprim-sulfamethoxazole(5/25mg/kgIVevery8hours)forpenicillinallergic.
• Add one of the above to vancomycin and ceftriaxone regimen for suspected bacterialmeningitisinpersonsolderthan50yearsbecausevancomycinandceftriaxoneareinad-equateforlisterialmeningitis.
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PREVENTION• Isolationnotnecessary.• Foodsafetyrecommendationsforthoseatrisk(seeTable139-2).• Pneumocystisprophylaxiswithtrimethoprim-sulfamethoxazolepreventslisteriosis.
TABLE 139-1 Clinical Settings in Which Listeriosis Should Be Considered Strongly in the Differential Diagnosis• Neonatalsepsisormeningitis• Meningitisorparenchymalbraininfectionin:
• Patientswithhematologicmalignancies,AIDS,organtransplantation,corticosteroidimmunosuppression,andthosereceivinganti-TNFagents
• Patientswithasubacutepresentationofmeningitis• Adultsolderthan50years
• Simultaneousinfectionofthemeningesandbrainparenchyma• Subcorticalbrainabscess• Spinalsymptomsinthesettingofacutebacterialmeningitisofuncertainetiology• Feverduringpregnancy,particularlyinthethirdtrimester• Blood,CSF,orothernormallysterilespecimenreportedtohave“diphtheroids”onGramstainorculture• Foodborneoutbreakoffebrilegastroenteritiswhenroutineculturesfailtoidentifyapathogen
AIDS,acquiredimmunodeficiencysyndrome;CSF,cerebrospinalfluid;TNF,tumornecrosisfactor.
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TABLE 139-2 Dietary Recommendations for Preventing Foodborne Listeriosis
General RecommendationsWashing and Handling Food
Rinserawproducethoroughlyunderrunningtapwaterbeforeeating,cutting,orcooking.Eveniftheproducewillbepeeled,itshouldstillbewashedfirst.
Scrubfirmproduce,suchasmelonsandcucumbers,withacleanproducebrush.Drytheproducewithacleanclothorpapertowel.
Keep Your Kitchen Cleaner and Safer
Washhands,knives,countertops,andcuttingboardsafterhandlingandpreparinguncookedfoods.BeawarethatListeria monocytogenescangrowinfoodsintherefrigerator.Therefrigeratorshouldbe40°F
orlowerandthefreezer0°Forlower.Cleanupallspillsinyourrefrigeratorrightaway,especiallyjuicesfromhotdogandlunchmeatpackages,
rawmeat,andrawpoultry.
Cook Meat and Poultry Thoroughly
Thoroughlycookrawfoodfromanimalsources,suchasbeef,pork,orpoultrytoasafeinternaltemperature.Useprecookedorready-to-eatfoodassoonasyoucan.Donotstoretheproductintherefrigeratorbeyond
theuse-bydate.Useleftoverswithin3to4days.
Choose Safer Foods
Donotdrinkraw (unpasteurized) milk,anddonoteatfoodsthathaveunpasteurizedmilkinthem.
Recommendations for Persons at Higher Risk*Meats
Donoteathotdogs,luncheonmeats,coldcuts,otherdelicatessenmeats(e.g.,bologna),orfermentedordrysausages,unlesstheyareheatedtoaninternaltemperatureof165°Foruntilsteaminghotjustbeforeserving.
Avoidgettingfluidfromhotdogandlunchmeatpackagesonotherfoods,utensils,andfoodpreparationsurfaces,andwashhandsafterhandlinghotdogs,luncheonmeats,anddelicatessenmeats.
Donoteatrefrigeratedpâtéormeatspreadsfromadelicatessenormeatcounterorfromtherefrigeratedsectionofastore.Foodsthatdonotneedrefrigeration,suchascannedorshelf-stablepâtéandmeatspreads,aresafetoeat.Refrigerateafteropening.
Cheeses
Donoteatsoftcheesesuchasfeta,quesoblanco,quesofresco,brie,Camembert,blue-veined,orpanela(quesopanela)unlessitislabeledas“MADEWITHPASTEURIZEDMILK.”
Seafood
Donoteatrefrigeratedsmokedseafood,unlessitiscontainedinacookeddish,suchasacasserole,orunlessitisacannedorshelf-stableproduct.
Cannedandshelfstabletuna,salmon,andotherfishproductsaresafetoeat.
Melons
Washhandswithwarmwaterandsoapforatleast20secondsbeforeandafterhandlinganywholemelon.Scrubthesurfaceofmelonswithacleanproducebrushunderrunningwateranddrythemwithaclean
clothorpapertowelbeforecutting.Besurethatyourscrubbrushissanitizedaftereachuse.Promptlyconsumecutmelonorrefrigeratepromptly.Keepyourcutmelonrefrigeratedfornomorethan
7days.Discardcutmelonsleftatroomtemperatureformorethan4hours.
*Recommendationsforpersonsathigherrisk,suchaspregnantwomen,personswithweakenedimmunesystems,andolderadults,inadditiontotherecommendationslistedunderGeneralRecommendations.
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140 Bacillus anthracis (Anthrax)Gregory J. Martin and Arthur M. Friedlander*
EPIDEMIOLOGY AND MICROBIOLOGY• Sporadicworldwide,anthraxismostcommoninAfrica,theMiddleEast,andLatinAmerica.• Naturallyacquiredhumancasesareusuallyassociatedwithanimalproducts.• Spore-forminggram-positivebacillusgrowsreadilyinthelaboratory.• Spores,whenprotectedfromultravioletlight,remainviablefordecadesorlonger.• Pathogenicityisassociatedwithedemaandlethaltoxinsandacapsule.
CLINICAL MANIFESTATIONS AND DIAGNOSIS• Cutaneous anthrax:95%ofnaturallyacquiredcasesarethisform.Afterskininoculation,a
pruriticpapuleformsin2to5days.Vesiclesrupture,leadingtoformationofablackescharat the base of a shallow ulcer. An injectional form has been newly described in injectionheroin users and associated with a more aggressive course. Surgical débridement may berequired.Gramstainofvesiclefluid,scrapingofbaseofulcer,orpunchbiopsymayshowgram-positivebacilliandapaucityofpolymorphonuclearneutrophils.Cultureofmaterialisfrequentlypositive.Directfluorescentantibody(DFA)testandpolymerasechainreaction(PCR)assayalsomaybeused.
• Inhalational anthrax:resultsfromhandlingofanimalproducts,suchaswool,hides,orbonesorafterintentionalsporereleaseinbioterrorism.Thisformhasthemostdangerouspresenta-tion,withnear100%mortalitywithoutearlyantibiotics.It isprimarilyamediastinal(notanairspace)process.Bloodandpleuralfluidculturesarepositive.PleuralfluidGramstainmaybepositive.DFAtestorPCRassaymaygivemostrapidresults.
• Gastrointestinal anthrax:responsibleforapproximately1%ofhumancasesandoccurstypi-cally1to5daysafteringestionofcontaminatedmeat.Blood,stool,andascitesshouldallbeobtainedforculture,DFAtesting,andPCRassay.Gramstainingofasciticfluidmayrevealgram-positivebacilli.
• Anthrax meningitis:secondaryseedingofthemeningesoccursduringbacteremiainfulmi-nant disease. Death occurs within 24 hours in 75% of cases. Cerebrospinal fluid revealsgram-positive bacilli, and cultures are positive. DFA test and PCR assay may provide themostrapiddiagnosis.
THERAPY• Rapidinitiationofantibioticsforallstagesiscrucial(seeTable140-1).• Forcutaneousanthrax,ciprofloxacinordoxycyclinealoneisused.• Inhalational, gastrointestinal, and injectional anthrax and anthrax meningitis should be
treated with two bactericidal agents, preferably a quinolone such as ciprofloxacin and aβ-lactamsuchasmeropenem,combinedwithaproteinsynthesisinhibitorsuchaslinezolid,
*The opinions and assertions herein are those of the authors and should not be construed as official orrepresenting the views of the Office of Medical Services of the Department of State, the Department ofDefense,ortheU.S.government.
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racis (An
thrax)
TABLE 140-1 Intravenous Triple Therapya for Severe Anthraxb with Possible or Confirmed Meningitis
1. A Bactericidal Agent (Fluoroquinolone)Ciprofloxacin 400 mg q8h
or
Levofloxacin 750 mg q24h
or
Moxifloxacin 400 mg q24h
plus
2. A Bactericidal Agent (β-Lactam)
a. For All Strains, Regardless of Penicillin Susceptibility or if Susceptibility Is Unknown
Meropenem 2 g q8h
or
Imipenemc 1 g q6h
or
Doripenem 500 mg q8h
or
b. Alternatives for Penicillin-Susceptible Strains
Penicillin G 4 million units q4h
or
Ampicillin 3 g q6h
plus
3. A Protein Synthesis InhibitorLinezolidd 600 mg q12h
or
Clindamycin 900 mg q8h
or
Rifampine 600 mg q12h
or
Chloramphenicolf 1 g q6-8h
Duration of TherapyFor 2-3 weeks or longer, until clinically stable. Will require prophylaxis to complete an antibiotic course of up to 60 days from onset of illness.
aDrug names in boldface are preferred agents. Alternative selections are listed in order of preference for therapy for patients who cannot tolerate first-line therapy or if first-line therapy is unavailable.
bSevere anthrax includes meningitis; inhalational, injectional, and gastrointestinal; and cutaneous with systemic involvement, extensive edema, or lesions of the head or neck.
cIncreased risk for seizures associated with imipenem/cilastatin therapy.dLinezolid may exacerbate thrombocytopenia; use for >14 days carries additional hematopoietic toxicity.eRifampin is not a protein synthesis inhibitor but may be used based on in vitro synergy.fShould only be used if other options are not available, owing to toxicity concerns.Data from Hendricks KA, Wright ME, Shadomy SV, et al; Workgroup on Anthrax Clinical Guidelines. Centers for
Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis. 2014;20. doi: 10.3201/eid2002.130687.
clindamycin,rifampin,orchloramphenicol.Considercentralnervoussystempenetrationofantibioticsfortreatmentofpotentialmeningitis.
• Immunotherapeuticssuchasanthraximmuneglobulinandraxibacumabshouldbeconsid-eredinconjunctionwithantibioticsinseverecasesandinsomesporeexposures.
PREVENTION• Current vaccines are cell-free supernatants of protective antigen adsorbed to aluminum
hydroxide.• PostexposurevaccinationmustbedoneunderCentersforDiseaseControlandPrevention
InvestigationalNewDrugprotocol(intheUnitedStates)at0,2,and4weeksandadminis-teredsubcutaneously.
ANTHRAX AS AN AGENT OF BIOTERRORISM• Anthraxisgenerallyconsideredthemostlikelyagentforbioterrorismviaanaerosolroute.• Gramquantitiesofstablesporesareeasytotransportandcouldcausethousandsofcases.• Earlyidentificationofthefirstcasesisdifficultowingtothepresentationwithnonspecific
flulikesymptoms.• Nasalswabsareusedtoidentifyexposureareas,nottodetermineindividualexposures.• Exposed patients should be given antibiotic prophylaxis with 60 days of ciprofloxacin or
doxycyclineandanthraximmunizationat0,2,and4weeks.• Exposedpatientsshouldbedecontaminatedwithsoapandwater.Surfacesmayberemedi-
atedwithanumberofdifferentchloride-containingcompounds,includinghouseholdbleach.• Anthraxisnottransmissiblefrompatientsaftertheyhavebeendecontaminated,andisola-
tionisnotrequired.
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141 Bacillus Species and Related Genera Other Than Bacillus anthracisThomas Fekete
DEFINITION• Gram-positivespore-formingbacilli
EPIDEMIOLOGY• Worldwidedistribution• Commonlyfoundinsoilandwater• Majorpathogensofinsects• Infrequentcauseofinfectioninmammals(includinghumans)• Normalflorainchildrenandadults
MICROBIOLOGY• Aerobicorfacultativelyanaerobic• Easilycultivatedwithstandardculturetechnique• Numerousgenera(>56)andspecies(>545)• Frequentlytoxinproducing,andtoxincontributestomanyclinicalmanifestationsofdisease• Susceptibilitytestsnotstandardizedbutcanbehelpful
DIAGNOSIS• Cultureonroutinemediaatstandardtemperatures(25°to37°C)• Canbechallengingtodistinguishtruepathogenfromcontaminant• CharacteristicGramstainpropertiesbutcanbeconfusedwithClostridium• Forfoodpoisoning,canbeisolatedfromfoodproducts• Shouldbesuspectedwhensterilizationofequipmentisinadequate• Infectionmayfollowtraumaticinjury
THERAPY• Foodpoisoningisnormallyself-limitedandrequiresonlysupportivetreatment• Deepinfectionrequiresantibiotics• Vancomycinandfluoroquinolonesusuallyactive• Mayrequireremovalofforeignbodysuchasvascularcatheter
PREVENTION• Optimalmanagementandstorageoffood• Carefulattentiontosterilizationtechniques• Earlyremovalofunneededdevices
299
142 Erysipelothrix rhusiopathiaeAnnette C. Reboli
DEFINITION• Erysipelothrix rhusiopathiaeisapleomorphic,nonsporulatinggram-positivebacillus.• It causes three major forms of disease in humans: erysipeloid (localized cutaneous infec-
tion), diffuse cutaneous infection, and systemic infection (bacteremia with or withoutendocarditis).
EPIDEMIOLOGY• A zoonosis, it is widespread in nature and infects wild and domestic animals, including
swine,poultry,sheep,andfish.• Infectioninhumansisusuallyduetooccupationalexposure.• Portalofentryisusuallythroughabrasionsorpuncturewoundsoftheskin,butinfection
mayalsofollowingestionofundercookedporkorseafood.
MICROBIOLOGY• Itisanaerobeorfacultativeanaerobe.• Moststrainsproducehydrogensulfide,adiagnosticallyimportantreaction.• Itissometimesconfusedwithothergram-positivebacilli.• Vitek2andtheAPICorynesystemarereliableforidentification.
DIAGNOSIS• Aprovisionaldiagnosiscanoftenbemadebasedonahistoryofappropriateepidemiologic
exposureand,inthecaseoferysipeloid,characteristicphysicalfindings.• Definitivediagnosisrequiresisolationoftheorganismfromblood,othersterilebodyfluid,
orabiopsyspecimen.• Standardmethodsforculturingbloodorbiopsytissuesuffice.• Thepolymerasechainreactionassayhasbeenusedforrapiddiagnosisinswineandhasbeen
appliedsuccessfullytohumanandenvironmentalsamples.
THERAPY• E. rhusiopathiaeishighlysusceptibletopenicillins,cephalosporins,clindamycin,imipenem,
linezolid,daptomycin,andciprofloxacin.• Moststrainsareresistanttovancomycin,sulfadrugs,andaminoglycosides.• Erysipeloidmayresolveintheabsenceoftherapy;however,appropriatetherapyshortensthe
illnessandreducestheriskforrelapse.• Penicillinisthedrugofchoiceforallformsofinfection.Whenβ-lactamsarecontraindicated,
useoffluoroquinolones,daptomycin,linezolid,orclindamycinmaybeconsidered.
PREVENTION• Handhygiene,useofprotectiveattiresuchasgloves,anddisinfectionofcontaminatedsur-
facesareessential.• Commercialvaccinesareavailableforveterinaryuse.
300
143 Whipple’s DiseaseThomas Marth and Thomas Schneider
DEFINITION• Whipple’sdisease (WD) isa raresystemic infectiousdisordercausedby theactinomycete
Tropheryma whipplei.
EPIDEMIOLOGY• ClassicWDisrareandisfoundinmiddle-agedindividuals,approximatelythreetimesmore
ofteninmenthaninwomen.• T. whippleiisfoundfrequentlyinthestoolsofchildrenwithacutediarrhea.• T. whippleicancauseculture-negativeendocarditis.
MICROBIOLOGY AND PATHOGENESIS• T. whippleiisagram-positivebacteriumwithhighguanineandcytosinecontent.• T. whippleiisresistanttoglutaraldehyde.• ThehallmarkofWDistheinvasionoftheintestinalmucosawithmacrophagesincompetent
todegradeT. whipplei.• An immunologicdefect in thepathogenesisofWDisevidentand includesmacrophages,
Tcells,andanimpairedhumoralimmuneresponse.
CLINICAL FEATURES AND DIAGNOSIS• WD occurs as an acute transient disease (presenting, e.g., with fever and diarrhea in
children).• WDoccursinalocalizedform(e.g.,endocarditisorcentralnervoussystemdisease).• WDoccursinvariousclinicalmanifestationsinassociationwithimmunosuppression.• WDoccursasaclassicsystemicdiseasewithweightloss,arthralgia,diarrhea,andapossible
broadspectrumofclinicalsignsandsymptoms.• Diagnosis is established usually by duodenal biopsy showing typical periodic acid–Schiff
positivecellsinthelaminapropria.• Diagnosisshouldbeconfirmedbypolymerasechainreactionassayorimmunohistochem-
istry,whichcanbeperformedalternativelyfromvariousorgansamplesorbodyfluids.
THERAPY• IVinductiontherapywithceftriaxonefor2to4weeks.• Followedbylong-termtherapywithoraltrimethoprim-sulfamethoxazolefor1year.• Closefollow-upoftreatmentsuccessoverseveralyears.• Complications:relapses,neurologicdefects,heartvalvedestruction,immunereconstitution
inflammatorysyndrome.
PREVENTION• Ubiquitousbacterialagent,preventionnotyetpossible.
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144 Neisseria meningitidisDavid S. Stephens and Michael A. Apicella
DEFINITION• Neisseria meningitidis,thecauseofepidemiccerebrospinalfever(firstdescribedin1805),is
anobligatehumanbacterialpathogenmostoftenpresentingasacutebacterialmeningitis,mildbacteremiatodevastatingsepticemia,andpneumonia.
MICROBIOLOGY• N. meningitidisisagram-negativediplococcus(0.6×0.8µm)andmemberofthebacterial
familyNeisseriaceaethatincludesthehumanpathogenNeisseria gonorrhoeae.
BIOLOGY AND PATHOGENESIS• Meningococcalbiologyandpathogenesisaredefinedby(1)N. meningitidiscolonizationand
virulencefactors,(2)transmissionandacquisitionamonghumans,and(3)humansuscep-tibility to invasive meningococcal disease. These factors influence disease incidence andseverityandpreventionstrategies.
EPIDEMIOLOGY• Diseaseoccursworldwide,butincidenceisvariable.ClonalcomplexesST-5andST-7(cap-
sularserogroupA);ST-41/44,ST-32,ST-18,ST-269,ST-8,andST-35(serogroupB);ST-11(serogroups C or W-135); ST-23 and ST-167 (serogroup Y); and ST-181 (serogroup X)meningococcicurrentlycausealmostallinvasivemeningococcaldisease(seeFig.144-1).
CLINICAL MANIFESTATIONS AND PATHOPHYSIOLOGY• Commonpresentationsofinvasivemeningococcaldiseasearemeningococcemiaandacute
meningitis.Lesscommonpresentationsareprimarypneumonia(upto10%,especiallywithserogroupY), septic arthritis (2%),purulentpericarditis, chronicmeningococcemia, con-junctivitis,epiglottitis,sinusitis,otitis,urethritis,andproctitis.
• Meningococcemia: In20%to30%ofcases, septicemiawithshock is thedominantclinicalfindingwithsuddenonsetoffever,generalizedmalaise,weakness,coldextremitiesandskinpallor,leukocytosisorleukopenia,rash,headacheand/ordrowsiness,andhypotension.
• Meningitis:Meningitisisthemostcommonpresentationofinvasivemeningococcaldiseaseand occurs in 40% to 65% of cases, reflecting the meningeal tropism of N. meningitidis.Findingsincludesudden-onsetheadache,fever,vomiting,myalgias,photophobia,irritability,decreasedabilitytoconcentrate,agitation,drowsinessandmeningealsigns(neckstiffness,Kernig’s or Brudzinski’s sign), and cloudy cerebrospinal fluid. Rash may or may not bepresent.
• Rash:Skinlesionsarepresentin28%to77%ofpatientswithinvasivemeningococcaldiseaseonadmissionbutmaynotalwaysbepetechialorpurpuric.
• Complement system deficiencies increase risk for meningococcal disease, in particularC5-C9terminalpathwaydeficiencies,properdindeficiency,andC3deficiency.
• Chronic meningococcemia manifests as intermittent fever (often low grade), migratoryarthralgiasorarthritis,andanonspecific,oftenmaculopapularrash.
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COMPLICATIONS• Immunecomplex–mediatedcomplicationsmayfollowmeningococcaldisease.• Long-termsequelaeoccurin11%to19%ofcases.• Familyandcommunityimpactissignificant.
DIAGNOSIS• Thedefinitivediagnosisofinvasivemeningococcaldiseaseisbasedonbacteriologicisolation
orantigenorDNAidentification(bypolymerasechainreactionassay)ofN. meningitidisinausuallysterilebodyfluid,suchasblood,cerebrospinalfluid,synovialfluid,pleuralfluid,urine,orpericardialfluid.
TREATMENT• Invasive meningococcal disease is a medical emergency, and early antibiotic treatment
shouldbetheprimarygoal(seeTable144-1).• Adjuvanttherapyandsupportivecareshouldbeprovided.
FIGURE 144-1 Epidemiology of meningococcal disease by serogroup. Group B outbreaks are noted by country and year of onset. Clonal complexes ST-5 and ST-7 (serogroup A); ST-41/44, ST-32, ST-18, ST-269, ST-8, and ST-35 (serogroup B); ST-11 (serogroups C or W-135); ST-23 and ST-167 (serogroup Y); and ST-181 (serogroup X) meningococci currently cause almost all invasive meningococcal disease. (Modified from Stephens DS, Greenwood B, Brandtzaeg P. Epidemic men-ingitis, meningococcaemia, and Neisseria meningitidis. Lancet. 2007;369:2196-2210.)
Chile 1985
Brazil 1985
South Africa 1980
New Zealand 1992
Australia 1982
Japan 1979
Cuba 1980
Spain 1974
Norway 1969
Oregon 1994 B, Y, C
A, W-135, C, X
B, A, W-135, Y, C
W-135, B, Y, A
A, B, C
A, C
B, C
B, C, Y
B, C, Y
TABLE 144-1 Antibiotic Treatment of Meningococcal Meningitis and MeningococcemiaCeftriaxone*: in children age >3 mo: 50 mg/kg IV q12h; adults: 1-2 g IV q12h
orCefotaxime 50-75 mg/kg q6-8h, maximum dose 12 g/day
orPenicillin G, 50,000 U/kg IV q4h, up to 4 million U q4h
orMeropenem, 2 g IV q8h, 6 g/dayIf patient is allergic to penicillin and cephalosporins, use chloramphenicol, 25 mg/kg IV q6h up to 1 g q6h.
*Because of concerns in neonates from calcium/ceftriaxone precipitates and displacement of bilirubin from albumin by ceftriaxone, neonates younger than 3 months of age should be started on cefotaxime, 50 mg/kg every 6 to 8 hours.
Modified from Shin SH, Kwang Kim SK. Treatment of bacterial meningitis: an update. Exp Opin Pharmacother. 2012;13:2189-2206.
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TABLE 144-2 Antibiotic Chemoprophylaxis for Household or Intimate Contacts*
ANTIBIOTIC DOSAGE COMMENTRifampin Adults: 600 mg q12h for 2 days
Children <1 mo: 5 mg/kg q12h for 2 daysChildren >1 mo: 10 mg/kg q12h (maximum, 600 mg) orally for 2 days
Rifampin can interfere with efficacy of oral contraceptives and some seizure prevention and anticoagulant medications; may stain soft contact lenses. Not recommended for pregnant women.
Ceftriaxone Children <15 yr: 125 mg, single IM doseChildren >15 yr and adults: 250 mg, single IM dose
Ceftriaxone is recommended for prophylaxis in pregnant women.
Ciprofloxacin Adults: 500 mg, single dose Not recommended routinely for persons <18 yr, but use in infants and children (20 mg/kg) may be justified after careful assessment of the risks and benefits. Not recommended for pregnant or lactating women. Cases of ciprofloxacin resistance have been reported, and use for prophylaxis should be based on local sensitivity of the meningococcus to the drug.
Azithromycin 10 mg/kg (maximum, 500 mg) single dose
Equivalent to rifampin for eradication of meningococci from nasopharynx, but data are limited.
*Recommended groups for chemoprophylaxis, based on exposure to the index patient in the week before onset of illness:
• Household contacts and persons sharing the same living quarters, particularly young children• Daycare center, nursery school or child care contacts, frequent playmates of young children• Close social contacts that were exposed to oral secretions in week before onset, such as by kissing or sharing
eating or drinking utensils or toothbrushes• For airline travel lasting more than 8 hours, passengers who are seated directly next to an infected person
should receive prophylaxis.• Routine prophylaxis is not recommended for health care professionals unless they have had intimate exposure
to respiratory secretions of an infected person.• Because the risk for secondary cases is highest during the first few days after exposure, chemoprophylaxis
should be initiated as soon as possible, ideally <24 hours after identification of the index patient.• If more than 14 days have passed since the last contact with the index patient, chemoprophylaxis is not likely
to be of benefit.• Pharyngeal cultures are not helpful in determining the need for chemoprophylaxis and may unnecessarily
delay the use of effective chemoprophylaxis.• Chemoprophylaxis has also been recommended for patients given penicillin or chloramphenicol for treatment
since pharyngeal carriage may not be eliminated with these antibiotics and the patient could remain colonized with a virulent strain.
• Ceftriaxone is recommended for pregnant women.• May want to avoid ciprofloxacin or azithromycin in individuals at risk of QT-prolongation.
PREVENTION• Chemoprophylaxiseliminatesmeningococcifromclosecontactsofconfirmedorpresump-
tivecases,protectssusceptibleindividuals,anddisruptsthefurtherspreadofmeningococci.Recommended antibiotics are rifampin, ceftriaxone, ciprofloxacin, and azithromycin (seeTable144-2).
• Meningococcalpolysaccharide-conjugatevaccinesarelicensedforpreventionofmeningo-coccaldisease(seeTable144-3)andarerecommendedforadolescentsandothersatriskformeningococcaldisease.
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TABLE 144-3 Conjugate Vaccines for Neisseria meningitidis: United States, 2015Menveo (Novartis) Meningococcal (groups A, C, Y, and W-135)
Oligosaccharide Diphtheria CRM197 Conjugate
Menactra (Sanofi Pasteur) Meningococcal (groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine
MenHibrix (GlaxoSmithKline) Meningococcal groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine
Bexsero (Novartis) Meningococcal group B Recombinant Protein Vaccine
Trumenba (Pfizer) Meningococcal group B Recombinant Protein Vaccine
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145 Neisseria gonorrhoeae (Gonorrhea)Jeanne M. Marrazzo and Michael A. Apicella
DEFINITION• Gonorrhea is a sexually transmitted infection caused by the organism Neisseria
gonorrhoeae.
EPIDEMIOLOGY• Gonorrheaoccursmostcommonlyinadolescentsandyoungadultsworldwide.• Overall, incidencehasbeendeclining;however,anexceptionisamongmenwhohavesex
withmen.• N. gonorrhoeaeisthecausativeagenttoconsiderinevaluationofgenitalinflammatorysyn-
dromes,includingcervicitis,urethritis,andpelvicinflammatorydisease.• Most infections, however, involve neither signs nor symptoms; thus, routine screening of
youngwomen(≤25years)orolderwomenwithkeyriskfactorsisrecommended.• Untreatedmaternalinfectionmayresultinophthalmianeonatorum,whichmaybeavoided
byneonatalprophylaxis.
MICROBIOLOGY• Thisgram-negative,intracellulardiplococcusisafastidiousmicroorganismthatgrowsonly
invitroinanarrowtemperaturerange(35°Cand38°C)oncomplexmedia.• Ithasamarkedabilitytodevelopresistancetoantibiotics;recentlytherehasbeentheglobal
appearanceofstrainswithincreasingresistancetothird-generationcephalosporins.• Thegonococcusisnaturallycompetent.Thisisafactorthathasledtotherapidacquisition
ofantimicrobialresistance.• N. gonorrhoeaeisanexclusivehumanpathogen.Itutilizesdifferentpathogenicmechanisms
toinfecttheepitheliumofmenandwomen.Inmen,theasialoglycoproteinreceptorpresenton the urethral epithelia interacts with the terminal galactose of the lipo-oligosaccharide(LOS)toenterhumancells.Inwomen,acooperativeinteractionoccursbetweenC3bcova-lentlylinkedtotheLOS,gonococcalporinandpilus,andcomplementreceptor3(CR3)onthesurfaceofthecervicalepithelialcell.
DIAGNOSIS• Cultureornucleicacidamplificationtestingaresensitiveandspecificandcanbeperformed
atallpotentiallyinfectedanatomicsites.
THERAPY• Optionsarelimited,givenwidespreadresistancetonumerousantibioticclasses.• Parenteral therapy with a third-generation cephalosporin is currently recommended and
shouldbeaccompaniedbytreatmentwithazithromycinordoxycyclineforadditionalcover-age(seeTable145-1).
• Sexpartnersofinfectedpeopleshouldbetreatedpresumptively,regardlessofdiagnostictestresults.
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• Patientswhofailtreatmentwithstandardregimensshouldundergoassessmentforreinfec-tion;ifreinfectionisunlikely,antibioticresistanceshouldbeconsidered.
PREVENTION• Becauseoftheasymptomaticnatureofmostinfections,routinescreeningofyoungwomen
(≤25years)andpregnantwomenisrecommended.• Condomsareveryeffectiveinpreventingtransmission.
TABLE 145-1 Options for the Treatment of Gonorrhea*
Uncomplicated Infection of the Cervix, Urethra, and RectumCeftriaxone, 250 mg IM single dose
Infection of the PharynxCeftriaxone, 250 mg IM single dose
Conjunctivitis (Not Ophthalmia Neonatorum)Ceftriaxone, 1 g IM single dose
Disseminated Gonococcal InfectionCeftriaxone, 1 g IM or IV every 24 hr for 24-48 hr† after improvement, with switch to oral therapy for completion of 1 wk total antibiotic therapy, including cefixime, 400 mg PO twice daily
Meningitis and EndocarditisCeftriaxone, 1-2 g IV every 12 hr for 10-14 days (meningitis) or ≥4 wk (endocarditis)
Ophthalmia NeonatorumCeftriaxone, 25-50 mg/kg IV or IM in a single dose, not to exceed 125 mg‡
IM, intramuscular; IV, intravenous; PO, orally.*Treatment of gonorrhea in the adult should always be accompanied by treatment of chlamydial infection, and
patients should abstain from sex during treatment. Azithromycin, given as a single oral dose of 1 g, is preferred. Test of cure at 7 days is recommended if the ceftriaxone regimen is not used.
†Ceftriaxone administered IM may be reconstituted in 1% lidocaine solution to minimize injection pain. Alternative parenteral regimens include cefotaxime, ceftizoxime, and spectinomycin. See www.cdc.gov/std/treatment for specific regimens.
‡Topical antibiotic therapy alone is inadequate for treatment of ophthalmia neonatorum.Modified from Centers for Disease Control and Prevention. Update to CDC’s sexually transmitted diseases treat-
ment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb Mortal Wkly Rep. 2012;61:590-594; and www.cdc.gov/std/treatment.
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146 Moraxella catarrhalis, Kingella, and Other Gram-Negative CocciTimothy F. Murphy
DEFINITION• Moraxella catarrhalis is a gram-negative diplococcus that colonizes the upper respiratory
tractofchildren.• It isacommoncauseofotitismedia inchildrenandexacerbationsofchronicobstructive
pulmonarydisease(COPD)inadults.• Kingella kingaeisanincreasinglyrecognizedpathogenthatcausesosteoarticularinfections
andbacteremiainyoungchildren.
EPIDEMIOLOGY• M. catarrhalisisrecoveredexclusivelyfromhumans.• Nasopharyngealcolonizationiscommonininfancyandchildhoodanddecreaseswithage.• K. kingaecolonizestheoropharynxofchildrenandismoreoftenisolatedfromthosewho
attenddaycarecenters.Infectionsoccursporadically,butoccasionalclustersareseen.
MICROBIOLOGY• M. catarrhalisiseasilyoverlookedinculturebecauseitisphenotypicallyidenticaltoNeisseria
inGramstainandoncultureplates.• M. catarrhalisproducesoxidase,catalase,andDNAse,whichareusedforspeciation.
DIAGNOSIS• AnetiologicdiagnosisofthemostcommonclinicalmanifestationsofM. catarrhalis(otitis
media inchildrenandexacerbationsofCOPDinadults) isnotmaderoutinely inclinicalpractice. Rather, these infections are usually treated empirically, based on a presumptivediagnosisusingclinicalmanifestations.
• A diagnosis of K. kingae infections is made by recovering the organism in culture fromnormally sterile body fluid, including blood and joint fluid aspirate. Polymerase chainreaction–basedassaysaremoresensitivethancultureindetectingtheorganisminjointfluid.
THERAPY• Most isolates of M. catarrhalis produceβ-lactamase and are thus resistant to ampicillin.
Isolates are susceptible to amoxicillin/clavulanic acid, macrolides, fluoroquinolones, andextended-spectrumcephalosporins.
• OtitismediaandexacerbationsofCOPDaretreatedwithoralantimicrobialagents,withthechoicegenerallyguidedbyexpertguidelines.
• K. kingaeisolatesaresusceptibletopenicillinsandcephalosporins.
PREVENTION• Novaccinesareavailablecurrently,butresearchisinprogresstodevelopvaccinestoprevent
M. catarrhalisinfections,includingotitismediaandexacerbationsofCOPD.
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147 Vibrio choleraeMatthew K. Waldor and Edward T. Ryan
MICROBIOLOGY AND EPIDEMIOLOGY• Vibrio choleraeisacurvedmotilegram-negativebacillus.• V. choleraeisanoninvasiveintestinalpathogen.• V. choleraeO1andO139serogrouporganismsarethecausesofepidemiccholera.• Non-O1andnon-O139V. choleraecancauseisolatedcasesofusuallymildgastroenteritis.• Cholera results from secretory diarrhea caused by the actions of cholera toxin (CT) on
intestinalepithelialcells.• CT is an adenosine diphosphate–ribosylating enzyme that leads to chloride, sodium, and
waterlossfromintestinalepithelialcells.• V. choleraehasanaquaticreservoir,particularlyinbrackishestuarinewater.• Thefecal-oraltransmissionisassociatedwithunsafewaterandinadequatesanitation.• Thereareanestimatedthreetofivemillioncholeracases,resultinginapproximately100,000
deathseachyear.• Thecurrentcholeraglobalpandemicbeganin1961andrepresentstheseventhinthehistori-
calrecord.• Choleraisnowendemicinmorethan50countries.• Choleracanleadtoexplosiveepidemicsandoutbreaks.• ThecurrentpandemiciscausedbyV. choleraeO1ElTororganisms,withthelargestburdens
inSouthAsia,sub-SaharanAfrica,andHaiti.
CLINICAL MANIFESTATIONS• Acuteseverewaterydiarrheacanresultindeathfromdehydrationwithin6to12hoursof
onsetofclinicalsymptoms.• Bowelmovementsduringcholeracanbecomeprogressivelymorewatery,eventuallyresem-
blingricewaterwithafishyodor.• Vomiting,ileus,andmusclecrampsarecommon.• Thepresenceoffevershouldpromptconsiderationofadditionaldiagnoses.• Complicationsofcholeralargelyreflectthoseresultingfromhypotensionandhypoperfusion
and may include acute renal tubular necrosis and stroke, usually in older individuals.Aspiration pneumonia from vomiting may also occur. Death from cholera almost alwaysresultsfromdehydration.
DIAGNOSIS• Cholerashouldbeconsideredwhenanadultorchildaged5yearsorolderdevelopssevere
dehydrationordiesofacutewaterydiarrheainanyarea,orwhenanindividualaged2yearsorolderdevelopsacutewaterydiarrheainanareaknowntobeendemicforcholera.
• Rapidantigentestsareavailable,includingdipstickstoolassays.• Confirmatory microbiologic culturing permits definitive identification and assessment of
antimicrobialresistanceprofiles.
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TABLE 147-1 Composition of Cholera Stools and Therapeutic Fluids for Cholera
CONCENTRATION (MMOLES/L)
Na+ K+ Cl− HCO3− Carbohydrate Comments
Intravenous fluid
LRS 130 4 109 28 — (278 if D5LR available)
LRS contains potassium and bicarbonate and is preferred over normal saline. Both LRS and NS can be supplemented with dextrose. Dhaka solution more closely approximates losses during cholera, but is not readily available.
Normal saline 154 0 154 0 —
Cholera saline (“Dhaka solution”)
133 13 154 48 140
Oral rehydration therapy
ORS (WHO, 2002)*
75 20 65 10 (citrate)
75 (glucose) WHO ORS uses glucose as a carbohydrate source. Rice-based ORS formulations have been found in randomized trials to reduce the duration of diarrhea and stool losses in severe cholera.A homemade preparation of ORS could be used in an emergency situation.
Rice-based ORS(e.g., CeraORS 75)
75 20 65 10 (citrate)
27 g rice syrup solids
Homemade ORS: 12 tsp table salt
and 6 tsp table sugar in1 L of safe water
≈75 0 ≈75 0 ≈75
Electrolyte losses in stools (composite estimates)
Cholera stool, adult
130 20 100 45 — Mean maximal rate of purging in severe cholera may exceed 10 mL/kg/hr. Sodium losses in cholera stools exceed those seen in other causes of diarrheal illness.
Cholera stool, child
100 30 90 30 —
Noncholera stool, child (ETEC)
50 35 25 20 —
Cl−, chloride ion; D5LR, 5% dextrose in lactated Ringer’s solution; ETEC, enterotoxigenic Escherichia coli; HCO3−,
bicarbonate ion; K+, potassium ion; LRS, lactated Ringer’s solution; Na+, sodium ion; NS, normal saline; ORS, oral rehydration solution; WHO, World Health Organization.
*In 2002, the WHO replaced its previous formulation of ORS with the current lower osmolarity formulation to reflect the broad use of ORS for treating dehydration from all-cause gastroenteritis.
Modified from Harris JB, Larocque RC, Qadri F, et al. Cholera. Lancet. 2012;379:2466-2476.
MANAGEMENT• Thecornerstoneofmanagementisrapidassessmentofthedegreeofdehydration,followed
bypromptfluidrestoration(seeTable147-1)aswellasvigorousmonitoringandmatchingofongoingfluidlosses.
• Severedehydration(>10%fluidloss),mayrequiregreaterthan100mL/kgoffluidreplace-ment to restore euvolemia, ideally administered within the first 3 to 4 hours of clinicalpresentation.
• Additional stool losses shouldbematchedatapproximately10 to20mL/kgperdiarrhealstoolorvomitingepisode.
• Moderatedehydration(5%to10%fluidloss)mayrequire75to100mL/kgoffluidresuscita-tionwithinthefirst3to4hoursofclinicalpresentation.Individualswithnoormilddehy-drationmaybetreatedwithoralrehydrationsolution(ORS)aloneorliquidadlibitum.
• IntravenousfluidsareindicatedforseveredehydrationandinthoseunabletoingestadequateORS. Lactated Ringer’s solution supplemented with 5% dextrose (D5LR) (ideally supple-mentedwithadditionalpotassium)isanoptimalchoiceforpatientswithcholera,althoughintravenous normal saline or normal saline supplemented with dextrose (and potassium)canalsobeused.
• Oral rehydration treatment should be encouraged among all individuals able to ingest,regardlessofdegreeofdehydration,andregardlessofpotentialongoingadministrationofintravenousfluid.
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TABLE 147-2 Antimicrobial Options for Treating Patients with Cholera
CLASS ANTIBIOTIC PEDIATRIC DOSE* ADULT DOSE COMMENTSMacrolides Erythromycin 12.5 mg/kg/dose qid
× 3 days250 mg qid × 3 days
Single-dose azithromycin is often the preferred therapy, especially in children, and has been shown to be more effective than ciprofloxacin in randomized trials in regions where reduced susceptibility to fluoroquinolones are common. Rare reports of macrolide resistance.
Azithromycin 20 mg/kg × single dose
1 g × single dose
Fluoroquinolones Ciprofloxacin 15 mg/kg/dose bid × 3 days
500 mg bid × 3 days
In highly susceptible strains, single-dose ciprofloxacin compares favorably against erythromycin and doxycycline in randomized trials. Reduced susceptibility to fluoroquinolones has become common in endemic areas and is associated with treatment failure.
Tetracyclines Tetracycline 12.5 mg/kg/dose qid × 3 days
500 mg qid × 3 days
Antibiotic resistance to all tetracyclines is common. Empirical use often reserved for outbreaks caused by documented susceptible isolates. Tetracyclines are not recommended for pregnant women or children less than 8 yr.
Doxycycline 4-6 mg/kg × single dose
300 mg × single dose
bid, twice a day; qid: four times a day.*Pediatric doses, based on weight; should not exceed maximum adult dose.Modified from Harris JB, Larocque RC, Qadri F, et al. Cholera. Lancet. 2012;379:2466-2476.
• ORScanbemadeinresource-limitedsettingsbyadding 12 tspoftablesaltto6tspoftablesugar in 1L of safe water, ideally supplemented with locally available potassium sources,suchascoconutmilk,bananas,ororangejuice.
• Antibioticsplayasecondaryrole in the treatmentof individualswithcholeraandusuallyinvolve administration of a macrolide or fluoroquinolone antibiotic. Tetracyclines can beused innonpregnant individualsolder than7years inareaswithconfirmedsusceptibility(seeTable147-2).
• Antibioticsdecreasethedurationofdiarrheaandmaylimitsecondarytransmission.
PREVENTION• Controlprimarily focusesonsurveillance,casedetection,fluidresuscitationandmanage-
ment,vaccination,andprovisionofsafewaterandadequatesanitation.• Twooralkilledcholeravaccinesarecurrentlycommerciallyavailableandapprovedbythe
WorldHealthOrganization(seeTable147-3).• Additionalcholeravaccinesareunderdevelopment.
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TABLE 147-3 Internationally Available and WHO Prequalified Oral Killed Cholera Vaccines
VA
CC
INE
DO
SES*
DO
SIN
G
INTE
RV
AL*
DO
SIN
G
VO
LUM
E*
BO
OST
ERS*
PRO
TEC
TIV
E EF
FIC
AC
Y
CO
MM
ENTS
REF
EREN
CES
Shanchol (Shantha Biotechnics–Sanofi Pasteur) Possible longer term protection than that afforded by Dukoral.Does not require buffer to administer vaccine.Currently more affordable than Dukoral.Currently undergoing field studies in Kolkata/Orissa, India, and Dhaka, Bangladesh, and pilot roll out in a number of countries, including Haiti.
82-88
≥1 yr of age
2 14 days (7-42 probably permissible)
1.5 mL Every 2 yr
60%-70% protective efficacy decreasing to baseline over 36-60 mo in older children and adults; 40% protective efficacy and shorter duration in younger children
Dukoral† (Crucell) Licensed in many countries.Has been safely administered to individuals infected with HIV.Provides short-term protection against diarrhea caused by heat-labile toxin expressing strains of ETEC.
89-96
Children 2 to <6 yr of age
3 14 days (7-42 permissible)
3 mL vaccine and 75 mL buffer
Every 6 mo
60%-85% protective efficacy within 6 mo of vaccination, decreasing to baseline over 24-36 mo
≥6 yr of age
2 14 days (7-42 permissible)
3 mL vaccine and 150 mL buffer
Every 2 yr
ETEC, enterotoxigenic Escherichia coli; HIV, human immunodeficiency virus; WHO, World Health Organization.*Per manufacturer.†Field studies have involved both the current preparation of WC-rBS vaccine, supplemented with recombinant
cholera toxin B subunit (rBS), and an initial preparation of WC-BS containing nonrecombinant B subunit (BS).Modified from Harris JB, Larocque RC, Qadri F, et al. Cholera. Lancet. 2012;379:2466-2476.
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148 Other Pathogenic VibriosMarguerite A. Neill and Charles C. J. Carpenter
DEFINITION• Vibriosaregram-negativerodswhoseenvironmentalnicheisprimarilymarineandestuarine
waters.• Theymayalsobefoundinfreshwatersources.• Thehalophilicvibriosrequirehigherconcentrationsofsaltforgrowth.
EPIDEMIOLOGY• The most common Vibrio species causing human illness are Vibrio parahemolyticus and
Vibrio vulnificus.• The incidence of vibriosis in the United States has been increasing in the past 15 years,
indicatingthatcurrentpreventioneffortsarenoteffective.• IllnessismorecommoninthewarmersummermonthswhenVibriopopulationsarehigher
andthereisincreasedhumanexposurefromshellfishconsumptionandrecreationalwaterexposure.
• Vibrio species primarily cause diarrhea of varying severity, soft tissue infection, and/orbacteremia.
• V. vulnificus causes a distinct soft tissue infection with rapidly developing hemorrhagicbullae.
• Vibrioinfectionsaremoresevereandmoreoftenfatalinpeoplewithcirrhosisorunderlyingliverdisease.
MICROBIOLOGY• Themajorpathogenicvibriosgrowwellinbloodculturemediaandcommonnonselective
mediausedforwoundcultures.• Selectivemediasuchasthiosulfatecitratebilesaltssucrosefacilitatesidentificationfromfecal
specimens.
DIAGNOSIS• Vibrioinfectionshouldbesuspectedinpeoplewithdiarrhea,sepsis,orwoundinfectionafter
seafoodconsumptionormarinewaterexposure.
THERAPY• RapidrecognitionofpossibleV. vulnificusinfectioniskeytoimprovingsurvivalandrequires
antimicrobialtreatmentaswellassurgicaldébridement• Survival is improved in V. vulnificus infection when a third-generation cephalosporin
is added to doxycycline or a quinolone, provided débridement of necrotic tissueisdone.
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• Treatmentwithdoxycyclineoraquinolonecandecreasesymptomsandfecal shedding inpeoplewithdiarrheacontinuingfor5days.
PREVENTION• Novaccineisavailableforthenoncholeravibrios.• Thorough cooking of seafood with prompt consumption or refrigeration is needed to
decreasetheriskforVibrioinfection.
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149 Campylobacter jejuni and Related SpeciesBan Mishu Allos, Nicole M. Iovine, and Martin J. Blaser
DEFINITION• Campylobacterspp.aresmall,curved,gram-negativerodsthatcauseacutegastrointestinal
illnessthattypicallylastsfrom1to7days.Thediarrheaisfrequentlybloodyandisassociatedwithabdominalpain.C. jejuniisthemostcommonhumanclinicalisolate,butmanyotherCampylobacterspp.havebeenidentified.
EPIDEMIOLOGY• Campylobacter spp. are found inavarietyof animals andarea commoncauseofhuman
diarrhealdiseaseworldwide.Indevelopednations,theincidencepeaksinlatesummerandfall,butinfectionsoccuryear-roundindevelopingcountries.Transmissiontohumansoccursmostcommonlyfromconsumptionorhandlingofpoultry.
MICROBIOLOGY• Many,butnotall,Campylobacterspp.thriveat42°C.Theorganismsarequitesmall(0.3to
0.6µmindiameter)andmotile.Theyaremicroaerophilicandgrowbestatanoxygencon-centrationof5%to10%.
DIAGNOSIS• Thegoldstandardfordiagnosisisviaisolationoftheorganismfromastooloroccasionally
abloodculture.
THERAPY• Themostimportanttenetoftreatmentistoreplacefluidandelectrolytestopreventdehydra-
tion.Antibioticsmayshortenthedurationofsymptoms.Erythromycin,250mgfourtimesperdayfor5to7days,willtreatmostinfections.Extended-spectrummacrolidesareequallyefficacious.
PREVENTION• Thebestwaytopreventinfectionisbythoroughlycookingpoultryandotherfoodsofanimal
originbeforeconsuming them.Meticulousattention toavoidcross-contaminationduringfood preparation may also prevent some infections. No effective vaccine is currentlyavailable.
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150 Helicobacter pylori and Other Gastric Helicobacter SpeciesTimothy L. Cover and Martin J. Blaser
DEFINITION• Helicobacter pylori is a gram-negative bacterium that persistently colonizes the human
stomach.• Most H. pylori–colonized persons remain asymptomatic, but the presence of H. pylori is
associatedwithanincreasedriskofpepticulcerationandgastriccancer.
EPIDEMIOLOGY• H. pylori is present in humans throughout the world, but the prevalence is variable and
dependsonageandgeography.• TheprevalenceofH. pyloriindevelopedcountrieshasbeendecliningoverthepastseveral
decades.
MICROBIOLOGY• H. pyloriisaurease-positive,gram-negative,spiral-shapedbacterium.
DIAGNOSIS• Noninvasiveapproachesareserology,ureabreathtest,andstoolantigentest.• Invasiveapproachesareendoscopyandanalysisofgastrictissue.
THERAPY• Treatmentisnotindicatedexceptinpatientswithpepticulcerationorpatientsconsidered
tohaveahighrelativeriskofgastriccancer.
PREVENTION• PreventionofH. pyloriacquisitionbyimmunizationisnotroutinelypracticed.
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151 EnterobacteriaceaeMichael S. Donnenberg
DEFINITION• Family of gram-negative, non–spore-forming facultative anaerobes that ferment glucose,
reducenitratetonitrite,andproducecatalase
EPIDEMIOLOGY• Cause a wide variety of diseases in humans of all ages, the spectrum of which varies by
organismandsubtype
MICROBIOLOGY• IncludesEscherichia coli, Proteusspp.,Klebsiellaspp.,andCitrobacterspp.amongothers• Salmonellaspp.,Shigellaspp.,Yersiniaspp.(seediscussionsinotherchapters)
DIAGNOSIS• Standardculturetechniques• Specific subtypes identified by immunoassays for toxin production or polymerase chain
reactionassayforvirulencegenes• Pulsed-fieldgelelectrophoresishelpfulinidentifyingoutbreaks
THERAPY• Variesbyorganism,site,andsusceptibilitypatternandcanincludearangefromantimicro-
bialagentsbeingcontraindicatedtobeinguntreatablewithcurrentlyavailableantimicrobialagents
PREVENTION• Strict adherence to infection control measures for nosocomial spread of highly resistant
strains• Reduceriskforfoodborneinfectionsbyobservinggoodfoodhygiene• Nocurrentlylicensedvaccine
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152 Pseudomonas aeruginosa and Other Pseudomonas SpeciesErika D’Agata
EPIDEMIOLOGY• Pseudomonasspeciesaregram-negativebacteriathatinhabitdiverseenvironments,includ-
ingsoil,water,plants,insects,andanimals.• P. aeruginosaisthemostimportantPseudomonasspeciesaffectinghumans,causingserious
infectionsassociatedwithsubstantialmorbidityandmortality.• OtherPseudomonasspecies,includingP. fluorescens, P. luteola, P. putida,andP. stutzeri,are
lessvirulentbutarestillimplicatedinawidevarietyofinfections,primarilyoccurringamongimmunocompromisedpatients.
• P. aeruginosahasmanyvirulencefactors,includingpili,flagella,enzymesecretionsystems,andquorum-sensingmolecules.
• P. aeruginosa isoneofthemostfrequentpathogensimplicatedinhospital-acquiredinfec-tions, including ventilator-associated pneumonia and catheter-associated urinary tractinfections. Long-term acute care hospitals have very high rates of infections causedbyP. aeruginosa
• CharacteristicinfectionscausedbyP. aeruginosaincludeecthymagangrenosum,malignantotitisexterna,hothand-footsyndrome,andhottubfolliculitis.
• Resistancetosingleandmultipleantimicrobialagentsisrisingrapidly.
MICROBIOLOGY OF P. AERUGINOSA• P. aeruginosaisanaerobicrod-shapedbacteria.• Growthoccursinavarietyofculturemediaformingsmoothroundcolonies,withacharac-
teristicgrapelikeor“corn-taco”odor,andagreen-bluecoloration.• Identificationisbasedoncolonymorphology,coloration,oxidasepositivity,andgrowthat
42°C.
THERAPY• The efficacy of treatment with two antipseudomonal antimicrobial agents versus mono-
therapyhasnotbeendefinitivelyanswered.• The majority of evidence suggests that empirical treatment with combination therapy is
indicatedifantimicrobialresistanceratesarehigh.• Streamlining to a single antimicrobial agent, once antimicrobial susceptibility profiles are
available,shouldthenbeconsidered.
318
153 Stenotrophomonas maltophilia and Burkholderia cepaciaAmar Safdar
MICROBIOLOGY AND EPIDEMIOLOGY• Stenotrophomonas maltophilia and Burkholderia cepacia are gram-negative bacteria that
acquire motility via multitrichous polar flagella. They do not ferment glucose, and manyclinicalisolatestendtogiveaweakoxidasereaction.
• Slow-growingmorphotypes,knownassmall-colonyvariantsofB. cepaciaandS. maltophilia,mayappearandexhibitahighdegreeofresistancetoantibioticsandmaygoundetectedinroutinecultures.
• Thesefree-livingorganismsarepresentinmostaquaticandhumidenvironments,includinghospitaldrinkingwater.
• Burkholderia cenocepaciaandBurkholderia multivoransaretheprominentbacterialstrainsisolated from patients with cystic fibrosis. Patient-to-patient transmission is believed tocontributetocolonization.
• Community-acquiredS. maltophiliapneumoniahasemergedasaseriousconcerninpatientswithnoknownriskfactors,suchascriticalunitstay;mechanicalventilationorprolongedtreatment-induced neutropenia; recent carbapenem, higher-generation cephalosporin, orfluoroquinolonetherapy;orextendedhospitalstays.
CLINICAL MANIFESTATIONS• S. maltophiliamayinvolveanyorgan.Lungsarefrequentsitesofinfection.Pulmonaryinfec-
tion is often preceded by respiratory tract colonization. Lobular or lobar consolidation iscommon,whereaspleuraleffusionsareseldomnoted.
• Most S. maltophilia bloodstream infections arise from infected indwelling intravascu-lar devices. Non–catheter-related bacteremia is often seen in patients with prolongedneutropenia.
• S. maltophilia wound infections in burn patients are being reported as the second mostcommon gram-negative bacterial infections after those caused by Aeromonas hydrophila.Skinlesionsinmostlyneutropenicpatientsaredifficulttodistinguishfrompyodermagan-grenosum, leukemiacutis, vasculitis, anddisseminatedPseudomonas, Fusarium, Candida,andrapidlygrowingmycobacterialinfections.
• Inpatientswithcysticfibrosis,afterinitialB. cepaciainfection,50%ofpatientswithB. mul-tivoransmaydevelopchronicasymptomaticbacterialcolonization,whereasnearlyall(94%)patientswithB. cenocepaciaretainbacterialpresenceaftertheinitialinfectionepisode.
COMPLICATIONS• LackofacuteinflammationmayunderwhelminitialclinicalpresentationofS. maltophilia
pneumoniaintheimmunosuppressedpatient.Patientsmaypresentwithseriouspulmonaryhemorrhage at the time of diagnosis owing to high propensity for tissue necrosis andhemorrhage.
• Non–catheter-related S. maltophilia bacteremia is a serious complication associated withhighrateof treatmentfailureanddeath.Patientsoftenhaveprofoundneutropenia lastinglongerthan10days;andinnearly70%ofpatients,hematogenousdisseminationarisesfrom
319C
hap
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trop
ho
mo
nas m
altop
hilia an
d B
urkh
old
eria cepacia
lungorsofttissueinfection.Indicatorsforpooroutcomeincancerpatientsincludeneutro-peniamorethan10days,bacteremicpneumonia,shocksyndrome,severethrombocytope-nia,anddelayinappropriatetherapy.
• B. cenocepacia isassociatedwithprolongedrespiratorytractcolonization,andtheriskfordeathwithinvasivediseaseismorethanfivefoldhighercomparedwithinfectionsduetotheothereightB. cepaciacomplexgenomovars.
• B. cepaciacomplexinfectioninpatientswithcysticfibrosiswithdiminishedforcedexpira-toryvolumein1secondhassteadilybeenassociatedwithpoorprognosis.Infectionincriti-callyillpatients,presenceofsepticshock,andadvancedunderlyingconditionsalsoheraldhighermortality.
DIAGNOSIS• EarlydiagnosisrequiresahighlevelofsuspicionforS. maltophilialunginfection.• Up to 36% of Burkholderia species may be misidentified by automated systems as other
nonfermentativebacteria,suchasAchromobacterorRalstonia.• Swiftandaccuratemolecularmethodsusing16Sor23SribosomalRNAgenesequencing
mayreplaceconventionalmethods.• Whole-cell matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
holdspromiseasarapid,accurateidentificationmethodforB. cepaciaandS. maltophilia.
THERAPY• Monotherapyisnotrecommended,owingtohighfrequencyoftreatmentfailureandinfec-
tionrelapse.• Trimethoprim-sulfamethoxazole(TMP/SMX)hasthemostpotentandreliableinvitroactiv-
ityagainstclinicalisolatesofS. maltophilia;however,drugresistancehasincreasedamong30%to40%ofdisease-associatedisolatesworldwide.
• Thenewerfluoroquinolones,suchasmoxifloxacin,showimprovedactivityagainstS. malto-philia.However,resistancehasdevelopedaftersingle-drugtherapy,whichcanbepreventedbydrugcombinationsincludingticarcillin-clavulanicacidand/orTMP/SMX.
• Carbapenems, TMP/SMX, chloramphenicol, and tetracycline are active against mostB. cepaciacomplexisolates.Treatmentpendingsusceptibilitytestingwilldependonexperi-enceoftheinstitution.
• Most active drugs against B. cepacia include minocycline (38%), meropenem (26%), andceftazidime(23%).Ceftazidime,tobramycin,andciprofloxacinretainantimicrobialactivityagainstplanktonicandbiofilm-embeddedorganisms.
PREVENTION• Nosocomialoutbreaksunderscore thecurrentpracticeofstrict infectionpreventionmea-
sures with main emphasis on decreasing transmission on health care workers’ hands andcohort segregation of infected or colonized hospitalized patients with multidrug-resistantbacteria.
• Continuedsurveillanceofhospitalwatersupplyremainscriticalinpreventingiatrogenicandhospital-relatedacquisitionofthesefreeliving,nearlyubiquitousbacteria.
• Immunization:preclinicalexperimentsusingoutermembraneprotein immunogenicepit-opesagainstB. multivoransandB. cenocepaciaappearpromising.
• Immunotherapy: various strategies to boost innate local immune response against gram-negativebacteriaarebeinginvestigated.
320
154 Burkholderia pseudomallei and Burkholderia mallei:Melioidosis and GlandersBart J. Currie
DEFINITION• Melioidosis isadiseaseofhumansandanimalsresulting frominfectionwiththesoiland
waterbacteriumBurkholderia pseudomallei.• GlandersisadiseaseprimarilyofhorsesresultingfrominfectionwithBurkholderia mallei.
EPIDEMIOLOGY: MELIOIDOSIS• ThemajorendemicregionsformelioidosisareSoutheastAsiaandnorthernAustralia.• Caseshaveoccurredinothertropicalandsubtropicallocations,suchastheIndiansubcon-
tinent,China,Africa,theCaribbean,andCentralandSouthAmerica.• Mostcasesoccurduringtherainyseason,andclusterscanfollowsevereweatherevents.• Exposure occurs through percutaneous inoculation, inhalation, and ingestion (more
commonwithglanders).• Zoonoticandnosocomialinfectionsareexceedinglyrarewithmelioidosis(morecommon
withglanders).• Disease and outcomes are tightly linked to risk factors, especially diabetes (see
Table154-1).
MICROBIOLOGY• B. pseudomalleiisasmall,gram-negative,oxidase-positive,motile,aerobicbacillus.• B. malleiisasmall,gram-negative,oxidase-positive,nonmotileaerobicbacillus.• B. mallei does not persist in the environment outside its equine host, and genetic studies
suggest that B. mallei evolved in animals from the environmental pathogen B. pseudomallei.
DIAGNOSIS: MELIOIDOSIS• MostinfectionswithB. pseudomalleiareasymptomatic.• Eighty-fivepercentofcasesareacuteillnessafterrecentinfection;11%arechronicinfections
(sick more than 2 months), and activation from latency is rare (longest is 62 years afterinfection).
• Over half are bacteremic, and up to one quarter present with septic shock with highmortality.
• Presentationispneumoniainabouthalfofcases,buttherearediverseotherpresentations(seeTable154-2).
• Cultureisrequiredfordiagnosisbyusingblood,sputum,urine,pus,anditisfacilitatedbyinoculatingswabsfrompus,throat,andrectumdirectlyontoselectivemedium.
• IdentificationofB. pseudomalleiandB. malleibyvariousmethodscanbeproblematic.• LocallydevelopedantigenandDNAdetection techniquesareavailable insome locations.
Serologyhaspoorspecificitybecauseofbackgroundpositivityinendemicregions.
321C
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rkho
lderia p
seud
om
allei and
Bu
rkho
lderia m
allei: Melio
ido
sis and
Glan
ders
TABLE 154-1 Risk Factors for Melioidosis
RISK FACTOR* THAILAND (% OF CASES) AUSTRALIA (% OF CASES)Diabetes 23-60 37
Alcohol excess 12 39
Renal disease 20-27 10
Chronic lung disease NR 27
Thalassemia 7 0
No risk factors 24-36 20
NR, not reported.Australia data from Currie BJ, Fisher DA, Howard DM, et al. Endemic melioidosis in tropical northern Australia: a
10-year prospective study and review of the literature. Clin Infect Dis. 2000;31:981-986.*Not listed: malignancy, steroid therapy, iron overload, cardiac failure.Thailand data from Punyagupta S. Melioidosis: review of 686 cases and presentation of a new clinical classifica-
tion. In: Punyagupta S, Sirisanthana T, Stapatayavong B, eds. Melioidosis. Bangkok: Bangkok Medical; 1989:217-229; Chaowagul W, White NJ, Dance DA, et al. Melioidosis: a major cause of community-acquired septicemia in northeastern Thailand. J Infect Dis. 1989;159:890-899; Suputtamongkol Y, Chaowagul W, Chetchotisakd P, et al. Risk factors for melioidosis and bacteremic melioidosis. Clin Infect Dis. 1999;29:408-413; and Limmathurotsakul D, Chaowagul W, Chierakul W, et al. Risk factors for recurrent melioidosis in northeast Thailand. Clin Infect Dis. 2006;43:979-986.
TABLE 154-2 Clinical Presentations and Outcomes of Melioidosis in Northern Australia
TOTAL BACTEREMIC NONBACTEREMIC
NumberDeaths (Mortality) Number
Deaths (Mortality) Number
Deaths (Mortality)
Septic Shock Present
116 (21%) 58 (50%) 103 48 (47%) 13 10 (77%)
Pneumonia 88 43 (49%) 78 35 (45%) 10* 8 (80%)
No evident focus 13 8 (62%) 12 7 (58%) 1† 1 (100%)
Genitourinary 10 5 (50%) 9 4 (44%) 1‡ 1 (100%)
Osteomyelitis/septic arthritis
4 2 (50%) 4 2 (50%) 0 0 (0%)
Soft tissue abscess 1 0 (0%) 0 0 1 0 (0%)
Not Septic Shock 424 (79%) 19 (4%) 195 13 (7%) 229 6 (3%)
Pneumonia 190 12 (6%) 89 9 (10%) 101 3 (3%)
Skin infection 68 0 (0%) 1 0 (0%) 67 0 (0%)
Genitourinary 66 2 (3%) 41 2 (5%) 25 0 (0%)
No evident focus 52 2 (4%) 47 2 (4%) 5 0 (0%)
Soft tissue abscess(es)
18 0 (0%) 4 0 (0%) 14 0 (0%)
Osteomyelitis/septic arthritis
16 0 (0%) 10 0 (0%) 6 0 (0%)
Neurologic 14 3 (21%) 3 0 (0%) 11 3 (27%)
Total 540 77 (14%) 298 (55%) 61 (20%) 242 (45%) 16 (7%)
*Seven blood cultures not done; three blood cultures negative.†Culture was positive for Burkholderia pseudomallei only from rectal swab, although fatal septic shock.‡Blood culture not done.From Currie BJ, Ward L, Cheng AC. The epidemiology and clinical spectrum of melioidosis: 540 cases from the
20-year Darwin prospective study. PLoS Negl Trop Dis. 2010;4:e900.
322Part
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ctio
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ease
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hei
r Et
iolo
gic
Ag
ents
THERAPY• Ceftazidimeoracarbapenem± trimethoprim-sulfamethoxazole(TMP-SMX) isgiven ini-
tially,followedbyTMP-SMX(seeTables154-3and154-4).• Therapyofglandersisasformelioidosis,althoughgentamicin,azithromycin,orclarithro-
mycinmayhavearole.
PREVENTION• Melioidosis:Educationisneededinendemicareasaboutminimizingexposuretowetseason
soils, surface water, and potential aerosols during windy monsoonal rains, especially fordiabetics.
• Cysticfibrosispatientsshouldconsideravoidingtraveltohigh-riskareas.• Glanders: Control of glanders in the equine species and strict precautions to prevent
laboratory-acquiredinfectionarecrucial.• Vaccinesareunderdevelopmentforbothmelioidosisandglanders.
TABLE 154-3 Antibiotic Therapy for Melioidosis
Initial Intensive Therapy (Minimum of 10-14 Days)Ceftazidime (50 mg/kg, up to 2 g) q6horMeropenem (25 mg/kg, up to 1 g) q8horImipenem (25 mg/kg, up to 1 g) q6hAny one of the three may be combined with TMP-SMX (6/30 mg/kg, up to 320/1600 mg) q12h
(recommended for neurologic, cutaneous, bone, joint, and prostatic melioidosis)
Eradication Therapy (Minimum of 3 Months)TMP-SMX (6/30 mg/kg, up to 320/1600 mg) q12h
TMP-SMX, trimethoprim-sulfamethoxazole.
TABLE 154-4 Duration of Antibiotic Therapy for Melioidosis
ANTIBIOTIC DURATION-DETERMINING FOCUS
MINIMUM INTENSIVE PHASE DURATION (WK)*
ERADICATION PHASE DURATION (MO)
Skin abscess 2 3
Bacteremia with no focus 2 3
Pneumonia Without lymphadenopathy† or ICU admission
2 3
With either lymphadenopathy† or ICU admission
4 3
Deep-seated collection‡ 4§ 3
Osteomyelitis 6 6
Central nervous system (CNS) infection 8 6
Arterial infection‖ 8§ 6
CNS, central nervous system; ICU, intensive care unit.*Clinical judgement to guide prolongation of intensive phase if improvement is slow or if blood cultures remain
positive at 7 days.†Defined as enlargement of any hilar or mediastinal lymph node to greater than 10-mm diameter.‡Defined as abscess anywhere other than skin, lungs, bone, CNS, or vasculature; septic arthritis is considered a
deep-seated collection.§Intensive phase duration is timed from date of most recent drainage or resection where culture of the drainage
specimen or resected material grew Burkholderia pseudomallei or where no specimen was sent for culture; clock is not reset if specimen is culture-negative.‖Most commonly presenting as mycotic aneurysm.
323
155 Acinetobacter SpeciesMichael Phillips
DEFINITION AND EPIDEMIOLOGY• Acinetobacterspeciesareassociatedwithspecificecologicniches.• A. baumannii and the closely related and phenotypically indistinguishable A. pittii and
A. nosocomialiscausethebulkofhumaninfectionsandaretypicallyacquiredinthehealthcaresetting.
• Acinetobacterspeciesreadilyincorporatemultipleresistancemechanisms,andpan-resistantstrainshaveemerged.
THERAPY• Antimicrobial treatment isbasedonantimicrobialsusceptibility testing.Potentialoptions,
withadultdosagefornormalrenalfunction,includethefollowing:• Cefepime,2gIVevery8hours• Imipenem,1gIVevery6hours• Meropenem,1gIVevery8hours• Ampicillin/sulbactam,3g/1.5gevery6hours(sulbactamistheactivecomponent)• Tigecycline,100mgIVloadingdose,then50mgIVevery12hours• Colistin(colistimethatesodium),5mg/kgloadingdose,then2.5mg/kgevery12hours• Polymyxin B, 2.5mg/kg on day 1, then either 2.5mg/kg daily or 1.25mg/kg every 12
hours(polymyxinB1mg=10,000units)
PREVENTION• Prevention of Acinetobacter transmission in health care settings requires a multifactorial
approach,withenvironmentaldisinfectionandhandhygieneasthecornerstone.• TheemergenceofA. baumanniistrainsresistanttoessentiallyallpotentantimicrobialagents,
coupledwithadearthofantibioticsindevelopment,constitutesasignificantpublichealththreat.
324
156 Salmonella SpeciesDavid A. Pegues and Samuel I. Miller
DEFINITION• SalmonellosisincludesgastroenteritisandotherinfectionscausedbynontyphoidalSalmonella
(NTS).
EPIDEMIOLOGY• Thereareapproximately1millioncasesofNTSinfectionannuallyintheUnitedStates.• Nontyphoidal salmonellosis isassociatedwithdiverse reservoirs, including freshandpre-
paredfooditemsandotheranimalsources.
MICROBIOLOGY• Therearemorethan2500Salmonellaserotypes.• Strains with multidrug resistance and decreased susceptibility to fluoroquinolones are
increasinglyprevalent.
DIAGNOSIS• FreshlypassedstoolshouldbeplateddirectlyonMacConkeyagarormoreselectivemedia.• Obtainbloodculturesforpatientssuspectedofbacteremiaorvascularinfection.• Serogroupingisperformedwithcommerciallyavailableantisera.
THERAPY• Antimicrobial therapy is not indicated for uncomplicated Salmonella gastroenteritis and
prolongsthedurationoffecalcarriage.• Ceftriaxoneorfluoroquinolonesshouldbeadministeredempiricallyfortreatmentofsevere
gastroenteritisorwhenoccurringinhigh-riskpatientsandfordirectedtherapyofbacteremiaorfocalinfectionswithNTS.
PREVENTION• ControloffoodborneoutbreaksofNTSdependonacoordinatedpublichealthresponseand
identificationofcontrollablehazardsfromthefarmtothetable.
325
157 Bacillary Dysentery: Shigella and Enteroinvasive Escherichia coliHerbert L. DuPont
DEFINITION• Diarrhea illnesscausedbystrainsof invasive formsofShigellaor invasiveEscherichia coli
comprisesbacillarydysentery.
EPIDEMIOLOGY• Shigellosis is the most infectious (communicable from person to person) of the bacterial
enteropathogens.
MICROBIOLOGY• Shigellaspp.aresmallgram-negativerodsinthefamilyEnterobacteriaceae.• SimilartostrainsofShigella,enteroinvasiveE. colipossessessomaticantigensandaplasmid
thatcontrolsinvasiveness.
DIAGNOSIS• Patientspassingbloodystoolsorthoseassociatedwithothercasesofshigellosisshouldhave
stoolsprocessedforShigella.• Thesoonerastoolspecimeniscultured,thehighertheyieldforShigella.• Once specimens are plated on gram-negative media at 37°C and incubated overnight,
lactose-negativecoloniesaretestedbiochemicallyandserologicallyforShigella.
THERAPY• Antibioticsareusefulinthemanagementofshigellosisandcanbelivesavingforinfection
causedbytheShigabacillus(S. dysenteriae1).• Thetreatmentofchoiceforadultsisafluoroquinoloneantibioticgivenfor3days.• Forchildren,cephalosporin,ciprofloxacin,orazithromycinmaybeused.
PREVENTION• Because person-to-person spread is so important in Shigella infection, hand washing and
otherhygienicmethodsshouldbeusedtopreventspread.• VaccinesareindevelopmenttopreventShigellainfection.
326
158 Haemophilus Species, Including H. influenzae and H. ducreyi (Chancroid)Timothy F. Murphy
DEFINITION• Gram-negativecoccobacilluswithfastidiousgrowthrequirements.• Nontypeable(nonencapsulated)Haemophilus influenzaeisacommoncauseofotitismedia
inchildrenandexacerbationsofchronicobstructivepulmonarydisease(COPD)inadults.• EncapsulatedH. influenzaetypebcausesinvasiveinfections,includingmeningitisandepi-
glottitis,inchildrenyoungerthan6years.• Haemophilus ducreyicauseschancroid,agenitalulcerdiseasethatfacilitateshumanimmu-
nodeficiencyvirustransmission.• OtherHaemophilusspeciesareunusualcausesofhumandisease.
EPIDEMIOLOGY• Theecologicnicheisthehumanrespiratorytract.• ColonizationofthenasopharynxbynontypeableH. influenzaebeginsininfancy,iscommon
duringchildhood,andpersistsatalowerrateinadults.• InvasiveH. influenzaetypebinfectionsarerareinregionsoftheworldwhereH. influenzae
typebconjugatevaccinesareusedwidelybutareprevalentinregionswherethevaccineisnotused.
• The prevalence of chancroid appears to be decreasing, based on the number of reportedcases,butthedifficultyindiagnosismayresultinunderestimatesofprevalence.
MICROBIOLOGY• ManymembersofthegenusHaemophilusarepartofthenormalbacterialfloraofthehuman
upperrespiratorytract.• Fastidiousgrowthrequirementsareusedtodistinguishthespeciesinthelaboratory.
DIAGNOSIS• Anetiologicdiagnosisofmostcommonclinicalmanifestationsofnontypeablestrains(otitis
media inchildrenandexacerbationsofCOPDinadults) isnotmaderoutinely inclinicalpractice. Rather, these infections are usually treated empirically, based on a presumptivediagnosisbyusingclinicalmanifestations.
• InvasiveinfectionscausedbyH. influenzaetypebareestablishedbyisolatingtheorganismordetectingcapsularantigenfromnormallysterilebodyfluids,includingcerebrospinalfluidorblood.
THERAPY• OtitismediaandexacerbationsofCOPDaretreatedwithoralantimicrobialagents,withthe
choicegenerallyguidedbyexpertguidelines.• H. influenzaetypebmeningitis:ceftriaxone,75to100mg/kgdividedinto12hourlydoses
orcefotaxime,200mg/kg/day,divided into sixhourlydoses.Alsoadministerdexametha-sone,0.6mg/kg/dayIVinfourdivideddosesfor4daystochildrenolderthan2months.
• Chancroid:azithromycin,1gorally(singledose)orceftriaxone,250mgIM(singledose).
327C
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op
hilu
s Species, In
clud
ing
H. in
flu
enzae an
d H
. du
creyi (Ch
ancro
id)
PREVENTION• Allchildrenshouldreceive theH. influenzae typebconjugatevaccineseriesbeginningat
2monthsaspartofroutinechildhoodvaccination.• Incompletelyimmunizedhouseholdcontactsofcasesofmeningitisshouldreceiverifampin
prophylaxis(20mg/kgoncedaily[600mgmaximum]for4days).• Sexualcontactsofpatientswithchancroidshouldbetreated,evenifasymptomatic.
328
159 Brucellosis (Brucella Species)H. Cem Gul and Hakan Erdem
DIAGNOSIS• Brucellosis isdiagnosedbyisolationofBrucella fromblood,bonemarrow,ortissueorby
serology,althoughthepolymerasechainreactionassayisavailableinafewlaboratories.Thepreferredserologyisthetubeagglutinationtestwithatiterofatleast1:160.TheRose-Bengalcardagglutinationtestisusefulforscreening.Brucella canisrequiresaseparateserology.
MICROBIOLOGY• Brucella melitensis, Brucella suis, Brucella abortus,and,rarely,B. caniscausebrucellosisand
arenonmotilegram-negativecoccobacilli.
EPIDEMIOLOGY• AlthoughuncommonintheUnitedStates,brucellosisisaworldwidezoonosisofwildand
domesticanimals,principallycattle,swine,goats,andsheep.Infectionisacquiredbycontactwith infected animals, their tissues, or ingestion of unpasteurized milk or dairy productsfrominfectedcows,goats,andsheep.
CLINICAL SETTINGS• Fever, sweating,myalgia,weight loss,headache,andmalaisewithout localizingsymptoms
are evident. Lymphadenopathy or hepatosplenomegaly may occur. Onset can be acute orinsidiousandpersistforweeksormonthsifuntreated.
• Focal infections include osteomyelitis (particularly spondylitis or sacroiliitis), epididymo-orchitis,endocarditis,meningitis,meningoencephalitis,andmyeloradiculitis.
TREATMENT• Doxycyclinewithstreptomycin is thestandardregimen.Foralternativesand treatmentof
neurobrucellosis,seeTable159-1.
329C
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cellosis (B
rucella Sp
ecies)
TABLE 159-1 Treatment of Brucellosis
CLINICAL FORM PREFERRED REGIMEN ALTERNATIVE REGIMENUncomplicated Doxycycline 100 mg PO twice daily
for at least 6 wkDoxycycline 100 mg PO twice daily for at least 6 wk
plus plus
Streptomycin 1 g IM daily for 2-3 wk Gentamicin 5 mg/kg IM daily for 1 wk
or
Doxycycline 100 mg PO twice daily for at least 6 wk
plus
Rifampin 600-900 mg (15 mg/kg) once daily for at least 6 wk
Neurobrucellosis Ceftriaxone 2 mg IV twice daily for at least 1 mo
Trimethoprim-sulfamethoxazole 160/800 mg PO twice daily for 5-6 mo
plus plus
Doxycycline 100 mg PO twice daily; for 4-5 mo
Doxycycline 100 mg PO twice daily; for 5-6 mo
plus plus
Rifampin 600-900 mg (15 mg/kg) PO once daily for 4-5 mo
Rifampin 600-900 mg (15 mg/kg) PO once daily for 5-6 mo
330
160 Francisella tularensis (Tularemia)Robert L. Penn
DEFINITION• TularemiaisthezoonoticdiseasecausedbyFrancisella tularensis.
EPIDEMIOLOGY• TularemiaiswidelydistributedbutisprimarilyadiseaseoftheNorthernHemisphere.• IntheUnitedStatesthemajorityofcasesreportedin2010occurredinArkansas,Missouri,
Kansas,SouthDakota,California,andOklahoma.• TularemiapeaksinthelatespringandsummerintheUnitedStates.• Lagomorphsandrodentsareimportantanimalreservoirs.• MajorvectorsoftransmissionincludeticksandbitingfliesintheUnitedStatesandmosqui-
toesinEurope.• Other routes of transmission include aerosol droplets, contaminated mud or water, and
animalbites.• Occupations that have an increased risk for tularemia include laboratory worker, farmer,
landscaper,veterinarian,sheepworker,hunterortrapper,andcookormeathandler.• Tularemiaspreadbyaerosolisapotentialbioterroristweapon.
MICROBIOLOGY• Francisellaorganismsaresmall,aerobic,pleomorphicgram-negativecoccobacilli.• F. tularensisrequirescysteineorcystine(oranothersulfhydrylsource)forgrowthandthere-
forewillnotgrowwellonmostroutinesolidmedia.• Although thereare three species in thegenusFrancisella and fourF. tularensis subspecies
(seeTable160-1),onlyF. tularensis subsp. tularensisandF. tularensis subsp.holarcticaarerelativelycommon.
• Infections caused by F. tularensis subsp. tularensis are generally more severe than thosecausedbyF. tularensissubsp.holarctica.
• Theinfectiousdoseinhumansis10to50organismswheninjectedintradermallyorwheninhaled.
• F. tularensisisafacultativeintracellularpathogenthatsurviveswithinhostmacrophagesbyimpairingphagosome-lysosome fusion,and it is capableof suppressingoravoidingmanyotherhumoralandcellularhostdefenses.
• Recoveryfrominfectiondependsondevelopmentofhostcell-mediatedimmunity.
CLINICAL MANIFESTATIONS• Tularemiastartsabruptlywithfever,chills,headache,anorexia,andfatigueafteranaverage
incubationperiodof3to5days.• Therearesixmajorpatternsofillness:ulceroglandular(seeFig.160-1),glandular,oculoglan-
dular, pharyngeal, typhoidal, and pneumonic (see Fig. 160-2); pneumonic and typhoidaltularemiaareexpectedtobetheprimaryformsresultingfromabioterrorismevent.
• Secondaryrashesarerelativelycommon.
331C
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larensis (Tu
laremia)
• Themostcommoncomplicationsoftularemiaarelymphnodesuppurationandpersistentdebility.
DIAGNOSIS• Diagnosisrestsonclinicalsuspicion,andbecauseofitspotentialdanger,laboratoryperson-
nelshouldbenotifiedwhenevertularemiaissuspected.• F. tularensisisaTier1selectagent,anditspossessionandshipmentaretightlyrestricted.• Routineculturesandsmearsareoftennegative,andthediagnosisisusuallyconfirmedsero-
logically;directfluorescentantibodyandpolymerasechainreactiontestsforrapiddiagnosisareavailableinspecializedlaboratories.
THERAPY• Streptomycinandgentamicinarethedrugsofchoiceforallformsoftularemiaexceptmen-
ingitis(seeTable160-2).• Selectedadultsandchildrenwithmildtomoderatediseasemaybetreatedwithoralagents
(seeTable160-2).• Surgicaltherapyislimitedtodrainageofsuppuratednodesorofempyemas.
TABLE 160-1 Characterization of Francisella Species
FEA
TUR
E
F. TULARENSIS SUBSPECIES
F. P
HIL
OM
IRA
GIA
F. H
ISPA
NIE
NSI
S
tula
ren
sis
ho
larc
tica
no
vici
da
Cysteine growth requirement + + – – –
Growth in broth plus 6% NaCl – – +* +† NA
Motility – – – – NA
Oxidase – – – +† +Nitrate reduction – – – – NA
Acid from:
Glucose +* +* +* +* + Glycerol + – + + +Gelatin hydrolysis – – – * NA
Relative virulence
Humans High Intermediate Low Low Low
Rabbits High Low Low NA NA
NA, not available; NaCl, sodium chloride.*Variable or delayed.†Using Kovacs test; negative using cytochrome-oxidase test.Data from Huber B, Escudero R, Busse HJ, et al. Description of Francisella hispaniensis sp. nov., isolated from
human blood, reclassification of Francisella novicida (Larson et al. 1955) Olsufiev et al. 1959 as Francisella tularensis subsp. novicida comb. nov. and emended description of the genus Francisella. Int J Syst Evol Microbiol. 2010;60(pt 8):1887-1896; Petersen JM, Schriefer ME, Araj GF. Francisella and Brucella. In: Versalovic J, Carroll KC, Funke G, et al, eds. Manual of Clinical Microbiology. Vol 1. 10th ed. Washington, DC: ASM Press; 2011:751-769; Sjöstedt AB. Francisella. In: Brenner DJ, Krieg NR, Staley JT, et al, eds. Bergey’s Manual of Systematic Bacteriology. Vol 2. 2nd ed. New York: Springer-Verlag; 2005:200-210; and Escudero R, Elia M, Saez-Nieto JA, et al. A possible novel Francisella genomic species isolated from blood and urine of a patient with severe illness. Clin Microbiol Infect. 2010;16:1026-1030.
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PREVENTION• The best prevention is avoiding exposure to the organism; a vaccine for tularemia is not
available.• Patientswithtularemiadonotneedspecialisolationbecauseperson-to-personspreaddoes
notoccur.Standardprecautionsforhandlingcontaminatedsecretionsareadequate.• Antibiotic prophylaxis after potential exposures of unknown risk such as tick bites is not
recommended.• Eitherciprofloxacin,500mg,ordoxycycline,100mg,givenorallytwicedailyfor14daysis
recommendedforadultswithsuspectedorprovenhigh-riskexposuretoF. tularensis.• Observation without prophylactic antibiotics is appropriate for exposed children (except
duringabioterroristevent)andforadultswithlowerriskexposures.
FIGURE 160-1 Examples of primary lesions seen in ulceroglandular tularemia. A, Large cervical and submandibular lymph nodes in a young child; an ulcer was found under the hairline on her forehead at the site of a tick bite. B, Papule undergoing central necrosis with desquamation on the thigh of a middle-aged man. C, Inguinal adenopathy and suppurative mass in a young hunter who had carried a dead hare at his side. D, Penile ulcer that was suspected of being syphilis or another sexually transmitted disease until the history of a recent tick bite was obtained by the infec-tious diseases consultant. E, Cervical ulcer and nodular adenopathy with a sporotrichoid appearance in a 6-year-old girl who had a tick removed from the area of the ulcer 2 weeks before presentation. The nodes coalesced, suppurated, and required drainage after 3 days of gentamicin therapy. Cultures of the ulcer and node drainage both grew F. tularensis. (A and C courtesy Dr. Joseph A. Bocchini, Louisiana State University Health Sciences Center, Shreveport, LA; D courtesy Dr. John W. King, Louisiana State University Health Sciences Center, Shreveport, LA; and E courtesy Dr. Robin Trotman, CoxHealth Infectious Diseases Specialty Clinic, Springfield, MO.)
FIGURE 160-2 Chest radiograph of untreated tularemia pneumonia. This patient remained symptomatic for more than 3 months. The diagnosis was established serologically when poorly developed granulomas were found in a transbronchial biopsy specimen, other causes were excluded, and the exposure history was finally obtained. (From Penn RL, Kinasewitz GT. Factors associated with a poor outcome in tularemia. Arch Intern Med. 1987;147:265-268.)
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INDICATION AND PATIENT GROUP RECOMMENDED ANTIBIOTICS AND DOSAGES
Moderate to Serious DiseaseAdults Streptomycin,* 10 mg/kg IM q12h for 7-10 days (not to
exceed 2 g/day), orGentamicin,* 5 mg/kg/day IM or IV divided q8h for 7-10 days
Children Streptomycin,* 15 mg/kg IM q12h for 7-10 days (not to exceed 2 g/day), orGentamicin,* 2.5 mg/kg IM or IV q8-12h for 7-10 days
Mild DiseaseAdults Ciprofloxacin,† 500 mg orally twice daily for 14 days, or
Doxycycline, 100 mg orally twice daily for 14 days
Children Doxycycline,‡ 2-4 mg/kg/day orally divided q12h or once daily for 14 days (not to exceed 200 mg/day)
MeningitisAdults Streptomycin or gentamicin in the doses given for moderate
to serious disease plus either chloramphenicol, 15-25 mg/kg IV q6h (not to exceed 4 g/day), or doxycycline, 100 mg IV twice daily for 14-21 days
Children Streptomycin or gentamicin in the doses for moderate to serious disease plus either chloramphenicol, 15 mg/kg IV q6h (not to exceed 4 g/day), or doxycycline, 2-4 mg/kg/day IV divided q12h or once daily (not to exceed 200 mg/day) for 14-21 days
*The streptomycin and gentamicin doses listed are for patients with normal renal function, and they need to be adjusted for renal impairment. In adults with normal renal function, once-daily administration of gentamicin also is acceptable.
†A ciprofloxacin dose of 750 mg twice daily also has been used in some reports.‡Doxycycline should be used in patients younger than 8 years of age only if the risks are outweighed by the
benefits.
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161 Pasteurella SpeciesJohn J. Zurlo
DEFINITION• Frequentcauseofskinandsofttissueinfectionsfollowingananimalbiteorscratch• Oftenpartofamixedbacterialinfection• Complicationsincludesepticarthritisandosteomyelitis• Lessfrequentlycausespneumoniainpatientswithunderlyinglungdisease• Otherdeep-seatedcomplicationsareuncommonbutcarryhighmorbidityandmortality
EPIDEMIOLOGY• Worldwidedistribution• Principalreservoirisanimals• Infectionmostoftenoccursfollowingbitesorscratchesfromdogsandespeciallycats• Infections have been reported following bites or scratches from a large number of other
animals• Infectionsalsooccurinindividualswithanimalexposurewithoutbitesorscratches
MICROBIOLOGY• Nonmotile,facultativelyanaerobic,gram-negativecoccobacilli• Growsbestonsheepbloodandchocolateagar,notusuallyonMacConkeyagar• Somewhatfastidious• Canbedifficulttoisolatefromnonsterilespecimens,especiallysputum• P. multocida with three subspecies: multocida, septica, gallicida (least common)
(seeTable161-1)• SeveralotherrelatedspeciesofgenusPasteurellacausehumandisease
DIAGNOSIS• Progressiveskinandsofttissueinflammationfollowingananimalbiteinjury,especiallyfol-
lowingpuncturewounds• Isolation of the organism from wound/tissue culture, often as part of a mixed bacterial
infection• Sputumorpleuralfluid isolates frompatientswithunderlying lungconditionspresenting
withlowerrespiratorytractinfections
THERAPY• Treatinfectedbitewoundsempiricallywithbroad-spectrumantibioticsuntilmicrobiology
isestablished:ampicillin/sulbactam3gIVq6horpiperacillin/tazobactam3.375gIVq6h• For patients withβ-lactam allergy, use a fluoroquinolone, doxycycline, or trimethoprim/
sulfamethoxazolealongwithanaerobiccoverage(metronidazoleorclindamycin)• OncedefinedasPasteurellaspecies,penicillinistheagentofchoice• β-lactamresistanceisrare,mostlydescribedinrespiratoryisolates• Aggressivesurgicaldébridementofsofttissueinfections
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PREVENTION• Antimicrobialprophylaxisforselectedbitewounds,usuallywithamoxicillin/clavulanicacid
875mgorallytwicedailyfor5days
TABLE 161-1 Pasteurella Species
Pasteurella sensu strictoP. multocida
Subspecies multocida
Subspecies septicum
Subspecies gallicida
P. canis
P. dagmatis
P. stomatis
Pasteurella-related SpeciesP. aerogenes
P. bettyae
P. caballi
P. pneumotropica
Data from Versalovic J, Carroll KC, Jorgensen JH, et al, eds. Manual of Clinical Microbiology, 10th ed. Washington, DC: ASM Press; 2011:574-587.
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162 Yersinia Species (Including Plague)Paul S. Mead
DEFINITION• Threehumanpathogens:Yersiniaenterocolitica,Y.pseudotuberculosis,Y.pestis• Zoonoseswithmultipleanimalhosts,widespreadinenvironment• Allhavetropismforlymphnodes,butclinicalillnessandecologydiffer
EPIDEMIOLOGY• GloballydistributedbutY. pestisusuallyfoundwithindistinctecologicfoci• Y. enterocolitica, Y. pseudotuberculosis: fecal-oral transmission, enteric pathogens, more
commoninchildren,illnessoftenself-limited• Y. pestis:vectorborne,highlyinvasive,allages,frequentlyfatal,potentialbioterrorismagent
MICROBIOLOGY• Aerobic,gram-negativemembersofEnterobacteriaceae• Growthat37°ConMacConkeyagar,sheepblood(Y. pestis, Y. pseudotuberculosis), Salmonella-
Shigellamedia(Y. enterocolitica),andbrain-heartinfusion• Automatedidentificationsystemsmaymisidentify
CLINICAL MANIFESTATIONS AND DIAGNOSIS• Regionalsuppurativelymphadenitis,sepsis,orfulminantpneumoniawithplague• Bioterrorismmassexposure:fulminantpneumonia• EnteritisandpseudoappendicitiswithY. enterocolitica, Y. pseudotuberculosis• Reactivearthritisorerythemanodosummayfollowdiarrhea;HLA-B27predisposes• Cultureofblood,stool,bubo,orsputum• Acuteandconvalescentserology
THERAPY• Immediateuseofantimicrobialagents:lifesavingforplagueorYersiniabacteremia• Plague:streptomycin,1gtwicedaily;gentamicin,5mg/kgoncedaily;orlevofloxacin,500
to750mgoncedaily,preferred(seeTable162-1foroptions)• Y. enterocolitica, Y. pseudotuberculosis(aminoglycosides,tetracycline,fluoroquinolones)• Antimicrobialagentsgenerallyunnecessaryforenteritisormesentericlymphadenitis
PREVENTION• Safehandlingandpreparationofporkproducts• Avoidunpasteurizedmilkanddairyproducts• Reducerodentharborage;controlfleasonpets• Avoidcontactwithrodentsandsickanimals• Bioterrorismexposure:doxycycline100mgtwicedailyorlevofloxacin500mg,oncedaily
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TABLE 162-1 Working Group on Civilian Biodefense Recommendations for Treatment of Adult Patients with Pneumonic Plague
Contained Casualty SettingPreferred Choices
Streptomycin, 1 g IM twice daily
Gentamicin, 5 mg/kg IM or IV once daily or 2 mg/kg loading dose followed by 1.7 mg/kg IM or IV three times daily
Alternative Choices
Doxycycline, 100 mg IV twice daily or 200 mg IV once daily*
Ciprofloxacin, 400 mg IV twice daily†
Chloramphenicol, 25 mg/kg IV four times daily
Mass Casualty Setting or Postexposure ProphylaxisPreferred Choices
Doxycycline, 100 mg orally twice daily*
Ciprofloxacin, 500 mg orally twice daily†
Alternative Choice
Chloramphenicol, 25 mg/kg orally four times daily
*Doxycycline and ciprofloxacin are pregnancy categories D and C, respectively.†Ciprofloxacin has not been approved by the U.S. Food and Drug Administration (FDA) for this indication. Since
the publication of the Working Group Recommendations, levofloxacin has been approved by FDA treatment of plague. Therefore, levofloxacin, at adult dosages of 500 to 750 mg once daily, should be considered the fluoro-quinolone of choice for treatment and prophylaxis of plague.
Modified from Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 2000;283:2281-2290.
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163 Bordetella pertussisValerie Waters and Scott A. Halperin
DEFINITION• Pertussis,infectionwithBordetella pertussis,isdividedinthreestages:
• Catarrhal stage: rhinorrhea, nonpurulent conjunctivitis, occasional cough, low-gradefever
• Paroxysmalstage:paroxysmsorfitsofcoughing,inspiratorywhoop• Convalescentstage:graduallydiminishingcoughlastingupto8weeks
• Clinicalcasedefinition:coughgreaterthanorequalto14daysandoneormoreofthefol-lowing:paroxysmalcough,inspiratorywhoop,orpost-tussivevomiting
EPIDEMIOLOGY• With introduction of whole-cell pertussis vaccine in 1940s, pertussis rates dropped
dramatically.• Peaksofdiseasecontinuetooccurevery3to5years.• Most cases, hospitalizations, and deaths occur in unimmunized infants younger than 6
monthsofage.• Outbreaksinchildrenwithhighvaccineratesmaybepartlyduetowaningimmunityfrom
acellularpertussisvaccine.
MICROBIOLOGY• Bordetellaspeciesaresmallgram-negativecoccobacilli;growthisfastidious.• Filamentoushemagglutininandfimbriaearetwomajoradhesins.• Pertussistoxin(PT)helpsorganismevadehostdefensesandcausessystemicmanifestations;
italsoactsasanadhesin.
DIAGNOSIS• Diagnosisistraditionallymadebyculturefromnasopharyngealswabsoraspirates;specific
swabs,transportmedia,andgrowthmediashouldbeusedtoenhancerecovery.• NewerpolymerasechainreactionassaysaremoresensitivefordetectionofB. pertussisand
aretheprocedureofchoice.• AntibodiestoB. pertussisPTcanbeusedfordiagnosis.• Directfluorescentantibodyisavailablebutnotrecommended.
THERAPY• Erythromycin, 40 to 50mg/kg/day in four divided doses, is recommended for children
(maximum 2g/day) or clarithromycin, 15mg/kg/day in two divided doses (maximum1g/day)for7to14days.Azithromycinisrecommendedforinfantsyoungerthan1monthofage.Fivedaysofazithromycinisprobablyeffectivefortreatmentorprophylaxisinadults(500mg first day, then 250mg daily) and is better tolerated and has fewer serious druginteractionsthanerythromycin,500mgfourtimesdailyfor14days.
• Supportivecareisparamountinmanagementofpertussis,especiallyininfants.
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PREVENTION• Immunizationisthesinglemosteffectivemeansofpreventingpertussis.• PertussisimmunizationscheduleintheUnitedStatesandCanadaforchildrenandadoles-
cents:DTaP(diphtheriatoxoid,tetanustoxoid,acellularpertussisvaccine,pediatricformula-tion)2,4,6,and18months,withboosterat4to6years;andTdap(tetanustoxoid,diphtheriatoxoid,acellularpertussisvaccine,adultformulation[reduceddosesof“d”and“ap”compo-nents])forpreadolescents/adolescents.
• In the United States and Canada, all adults age 19 years and older are recommended toreceiveasingledoseofTdap.Theexceptionispregnantwomenwho,intheUnitedStates,arerecommendedtoreceiveTdapforeachpregnancy, ideally in the27thto36thweekofpregnancy,toprotecttheirnewbornsfrompertussis.
• AllhealthcareworkerswithpatientcontactshouldbegivenasingledoseofTdapif theyhave not been vaccinated as an adult, irrespective of when they received the last dose oftetanustoxoid.
• Prophylaxiscanbeconsideredforclosecontactsexposedwithin21daysofonsetofcoughinthe indexcase.Adultsandadolescentsaregivenerythromycin500mgfourtimesdailyfor7to14days,azithromycin500mgthefirstdayand250mgdailyfor4additionaldays,orclarithromycin500mgtwicedailyfor7days.
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164 Rat-Bite Fever: Streptobacillus moniliformis and Spirillum minusRonald G. Washburn
DEFINITION• Rat-bitefeverisanacutefebrileillnesscharacterizedbyrashandrelapsingfever.
EPIDEMIOLOGY• The infection is transmittedbybitesor scratches fromrodentsorcarnivores thatpreyon
rodentsorbyingestionofcontaminatedmilkorwater.Rat-bitefeverisnotgenerallyreport-able,andtheincidenceisprobablyhigherthantheliteraturereflects.
MICROBIOLOGY• In the United States and Europe, rat-bite fever is caused by Streptobacillus moniliformis,
a fastidious gram-negative bacillus. In Asia, the causative organism is Spirillum minus, aspirochetethathasneverbeengrowninculture.
DIAGNOSIS• S. moniliformisisdiagnosedbyclinicalpresentationpluscultureinenrichedmediaorpoly-
merasechainreaction.S. minusisdiagnosedbyclinicalpresentationplusdirectvisualizationorxenodiagnosis.
THERAPY• Penicillinisthetreatmentofchoiceforbothtypesofrat-bitefever.
PREVENTION• Preventivemeasuresincludeeradicationofrats,avoidanceofnonpasteurizedmilkandwater,
anduseofglovesbylaboratoryworkerswhenhandlingrats.
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165 Legionnaires’ Disease and Pontiac FeverPaul H. Edelstein and Craig R. Roy
DEFINITION• Legionnaires’diseaseisanoncontagioustypeofbacterialpneumoniacausedbyLegionella
spp.bacteria,mostcommonlyL. pneumophila.• Pontiacfeverisaseveralday–long,nonpneumonic,febrile,influenza-likeillnessassociated
withexposuretoLegionellaspp.thatresolvesspontaneously.• Legionellosis includesLegionnaires’disease,Pontiac fever, andextrapulmonaryLegionella
spp.infectionnotassociatedwithpneumonia.
EPIDEMIOLOGY• Legionnaires’diseaseisacquiredbyinhalingawateraerosolcontainingLegionellaspp.bac-
teria,andpossiblybymicroaspiratingLegionellaspp.–containingwater.• About 20 to 80 cases annually per million population occur in most developed coun-
tries, with the elderly, males, cigarette smokers, and immunosuppressed patients mostatrisk.
• About 1% to 5% of patients hospitalized for community-acquired pneumonia haveLegionnaires’disease.
• PontiacfeverisassociatedwithinhalationofLegionellaspp.–containingwaterbutnotneces-sarilycausedbythebacterium.Itoccursinsporadicandepidemicformatapparentlylowincidencebutmaybemorecommonthanisreported.
MICROBIOLOGY• Constituted of more than 58 known species, the Legionella bacteria are ubiquitous in the
aqueousenvironmentandprobablymoistsoils.• Optimalbacterialgrowthrequiresspecializedmediathatcontaincysteineandiron.• Thebacteriaarefacultativeintracellularparasitesoffree-livingamebasandhumanmono-
cytesandmacrophagesthatusehostlikeproteinstomasqueradeashostandtoavailthem-selvesofintracellularresources.
DIAGNOSIS• ClinicalandroentgenographicdifferentiationofLegionnaires’diseasefromcommoncauses
ofpneumoniaisnotgenerallypossible.• Specific and specialized laboratory testing can be helpful for disease diagnosis but is
not highly sensitive in all settings. Urine antigen testing, the most commonly used test,is about 70% and 30% sensitive in community-acquired and nosocomial disease,respectively.
THERAPY• Macrolides,tetracyclines,andquinoloneantimicrobialscanallbeusedtosuccessfullytreat
thedisease,withazithromycinandlevofloxacinbeingthemostactive.
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• Forcure,3to14days’therapyisrequired,dependingondiseaseseverity,hostfactors,andtypeoftherapyused.
PREVENTION• Novaccineisavailable.• Properenvironmentaldesignandmaintenancereducediseaserisk.
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166 CapnocytophagaJ. Michael Janda
DEFINITION• Endogenousorzoonotic-associatedinfectionshavebeenreported,dependingonthespecies
ofCapnocytophagainvolved.• Symptomsrangefromsepsis(mostoften)withandwithoutcentralnervoussysteminvolve-
menttooculardisease,illnessesassociatedwithpregnancy,andthoseinvolvingbone,joints,andsofttissues.
EPIDEMIOLOGY• Endogenous infections arise in children or adults with blood dyscrasias and significant
neutropenia.• Sepsis arises fromhumanspecies seeding into thecirculatory system throughabradedor
damagedgumsorgingivalpocketsintheoralcavity.• Mortalityrateislow(<5%)withappropriatetreatment.• Zoonotic infections arise primarily in males from a dog bite or intimate contact with
dogs.• Persons most at risk include dog owners, breeders, veterinarians, kennel workers, or
hunters.• Individualsathighest risk fordeveloping serious life-threatening infectionswithdissemi-
nated intravascular coagulation include splenectomized persons or functionally asplenicpatientsandthosewithethanolabuseorimmunosuppression.
• Reportedmortalityratesrangefrom20%to33%.
MICROBIOLOGY• Bacilliaregramnegativewithtaperedends.• Theyare slowgrowingand fastidious, requiring3 to10daysof incubationonsupportive
media.• Nostandardizedmethodofdeterminingdrugsusceptibilitiesexists,but testingshouldbe
attempted,ifpossible.
DIAGNOSIS• IshistorycompatiblewithCapnocytophagainfection(dogbite)?• DoesGramorWright-Giemsastainofbloodorother sterile specimensshowbacilliwith
taperedendssometimeswithinpolymorphonuclearleukocytes?• Conventional tests that include catalase, oxidase, and arginine dihydrolase are slow but
reliable.• Rapidmoleculartestsinclude16SrRNAgenesequencingforrapiddiagnosisonspecimens
oridentificationofisolatedorganismsandmatrix-assistedlaserdesorption/ionizationtime-of-flight(MALDI-TOF)massspectrometryforfutureorganismcharacterization.
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THERAPY• Infectionisbroadlysusceptibletomanyantimicrobialagents.• Penicillin/β-lactamaseinhibitorcombinationorextended-spectrumcephalosporinisdrug
offirstchoice.• Acquireddrugresistancehasbeenreportedinsomeisolates.
PREVENTION• Cliniciansmustbemadeawareoftheseorganisms,thediseasestheycause,andthepatients
atrisk.• Laboratoriesmayrequireextra incubationtime,aspecializedincubationatmosphere,and
richermediatoisolatetheseorganisms.• Userapidtestingmethodstodecreasetimetodiagnosis.
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167 Bartonella, Including Cat-Scratch DiseaseTejal N. Gandhi, Leonard N. Slater, David F. Welch, and Jane E. Koehler
EPIDEMIOLOGY AND MICROBIOLOGY• Fastidious,facultativelyintracellular,pleomorphicgram-negativebacilli• Transmissionviafecesofarthropodvectorsorbydirectinoculationintononintactskin• Bartonella bacilliformis: endemic only in the Andes mountains; reservoir—humans, and
possibly,ananimalreservoir• Bartonella henselae: globally endemic; reservoir—cats; vector—cat flea; transmitted to
humansusuallyviacatscratch• Bartonella quintana:sporadicoutbreaksworldwide;associatedwithhomelessnessandother
conditionsofpoorsanitation;reservoir—humans;vector—humanbodylouse
CLINICAL FEATURES• Chronicbloodstreaminfections(formonths)isahallmarkofBartonellainfections• B. bacilliformis:biphasicillness;Oroyafever(acutephase)characterizedbyfever,hemolytic
anemia,andhigh fatalityratewhenuntreated;verrugaperuana(latephase)characterizedbycropsofangioproliferativeskinlesionswithanevolutionofstages
• B. henselae:cat-scratchdisease(CSD):self-limitedregionallymphadenopathy• B. henselae:bacillaryangiomatosis(BA):vascularproliferativedisorderobservedinpatients
withadvancedhumanimmunodeficiencyvirus(HIV)infectionandotherimmunocompro-misingconditions;cutaneousBA,hepatic,andsplenicbacillarypeliosis(BP)
• B. henselae:bloodculture–negativeendocarditis,usuallyinpatientswithpreexistingvalvularlesions
• B. henselae:causeoffeverofunknownorigin(FUO)inimmunocompetentchildren,andinimmunocompromisedpatients(HIV-infectedandtransplantrecipients)
• B. quintana:trenchfever:usuallyaself-limitedfebrileillness• B. quintana:bloodculture–negativeendocarditis;canoccur inpatientswithnormalheart
valves• B. quintana:bacillaryangiomatosis(cutaneous,subcutaneous,osseous)• B. quintana:causeofFUOinHIV-infectedpatients
DIAGNOSIS• Difficulttoculture• Serology:mainstayfordiagnosis,butcross-reactivityamongBartonellaspeciescommon• Histopathology:CSD—granulomatousinflammation;BA—vascularproliferation;Warthin-
StarryorSteinerstaindemonstratesBartonellabacilliintissue• Polymerasechainreactiontestingontissueorblood
THERAPY• CSD:notreatment(self-limited);possiblyazithromycinforsevereCSD• Endocarditis:doxycyclinefor6weeksandgentamicinforfirst2weeks;renalinsufficiency
commoninBartonellaendocarditis,thusrifampincanbesubstitutedforgentamicininthesettingofrenalinsufficiency
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• Bacteremia:doxycyclinefor4weeksandgentamicinforfirst2weeks• BA/BP:doxycycline isfirst choiceanderythromycinorazithromycin is secondchoice; in
HIV-infectedandtransplantrecipients,doxycyclineispreferredduetotolerabilityissuesanddrug-drug interaction potential with erythromycin; duration of 3 months or longer forcutaneousdiseaseand6monthsor longerforsevereBartonella infection(e.g.,BP,centralnervoussystem)
• Neuroretinitis:doxycyclineandrifampinfor4to6weeks
PREVENTION• Avoidarthropodvectors;eradicatebodylicetoreduceriskofB. quintana• Avoidcatscratches,bites,licks,andcatfleastoreduceriskofB. henselae;controlofcatflea
infestationisimportant
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168 Klebsiella granulomatis (Donovanosis, Granuloma Inguinale)Ronald C. Ballard
DEFINITION• Donovanosisisanulcerativesexuallytransmittedinfectioncausedbyanintracellularbac-
terium,Klebsiella granulomatis.
EPIDEMIOLOGY• Donovanosisislargelyconfinedtodiscretegeographicareasofthetropics.• Donovanosisissexuallytransmittedbutoflowinfectivity.
MICROBIOLOGY• Klebsiella granulomatisisagram-negative,encapsulated,intracellularbacteriumexhibiting
bipolardensities.
DIAGNOSIS• For microscopic examination, biopsies or smears are obtained from the margin of active
lesionsfor“Donovanbodies.”
THERAPY• Thetreatmentofchoiceisazithromycin,1gweeklyforupto4to6weeks.• Treatmentshouldbecontinueduntilcompleteepithelializationhasoccurred.
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169 Other Gram-Negative and Gram-Variable BacilliJames P. Steinberg and Eileen M. Burd
SHORT VIEW SUMMARYDefinition• Gram-negative and gram-variable aerobic bacilli that are less commonly encountered as
causesofinfectionandarenotdiscussedinotherchaptersareconsideredhere.• Thetaxonomyofmanyoftheseorganismshasbeenandcontinuestobeinastateofflux.• The organisms considered are broadly divided into those that ferment glucose and
those that weakly ferment or do not ferment glucose. Specific genera considered includeAggregatibacter, Aeromonas, Cardiobacterium, Chromobacterium, Dysgonomonas, Plesiomonas, Achromobacter, Alcaligenes, Chryseobacterium, Elizabethkingia, Comamonas, Delftia, Eikenella, Flavobacterium, Myroides, Ochrobactrum, Oligella, lesscommonspeciesofPseudomonas, Ralstonia, Cupriavidus, Rhizobium, Roseomonas, Shewanella, Sphingobacterium, Sphingomonas, Bergeyella, Weeksella, Gardnerella, Mobiluncus,uncommonNeisseriaspecies,and Centers for Disease Control and Prevention Groups NO-1, WO-1, WO-2, O-1, O-2,andO-3.
Epidemiology• Someofthesegram-negativebacilliareubiquitousintheenvironment.• Manyaregenerallyconsideredtobeoflowvirulencebutmaybeopportunisticpathogens
undercertaincircumstances.• Some infections have been linked to hospital sources, particularly unclean water sources,
nonsterileenvironmentalsurfaces,orcontaminatedsolutions.
Microbiology• Manyoftheseorganismsarefastidiousanddifficulttogrow.• Identificationofglucosenonfermentinggram-negativebacilliposesachallengetoclinical
laboratories because conventional biochemical systems frequently fail to provide accurateidentification.Accurateidentification,especiallytospecieslevel,oftenrequirescellwallfattyacid analysis, 16S rRNA gene sequencing–based technologies, or matrix-assisted laserdesorption/ionization-timeofflightmassspectrometry.
Diagnosis• The types of infections caused by these organisms are quite varied and are diagnosed by
analysisofculturesofsamplestakenfromtheinfectionsite.• Becausetheseorganismsareinfrequentlyencounteredandareoftenoflowvirulence,inter-
pretationofcultureresultsmustbecorrelatedwithclinicalfindings.
Therapy• Thesmallnumberofpatientsreportedandthevarietyofantibioticregimensuseddonot
permitidentificationoftheoptimaltherapeuticregimenformostoftheseorganisms.
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• MethodsforantibioticsusceptibilitytestingformanyoftheseorganismsarenotstandardizedandClinicalandLaboratoryStandardsInstitutebreakpointsforinterpretationmaynotbeavailable.
• Someoftheenvironmentalbacteriaareofconcernbecausetheycarryresistancegenesontransferablegeneticelementsandcouldserveasreservoirsofresistancegeneswhenintro-ducedintotheclinicalsetting.
• Someof these infectionsmaybedifficult toeradicatewhenthecausativebacteriaexist inwell-developedbiofilms.
Prevention• Attentionshouldbegiven topractices topreventdevice-related infections,particularly in
immunocompromisedindividuals.• Hospital-basedprogramsofsurveillanceandmethodsforpreventionandcontroltoelimi-
natehealthcare–associatedinfectionsshouldbeimplemented.
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170 Syphilis (Treponema pallidum)Justin D. Radolf, Edmund C. Tramont, and Juan C. Salazar
DEFINITION• Syphilis is a chronic, multistage sexually transmitted disease caused by the spirochete
Treponema pallidum.
EPIDEMIOLOGY• AccordingtotheWorldHealthOrganization,11millionnewcasesofvenerealsyphilisoccur
globallyeachyear.• Globally,1.5millionpregnantwomenareestimatedtobeinfectedeachyear;approximately
one third of these infections will result in stillbirths or other adverse outcomes ofpregnancy.
• Indevelopingcountries,transmissionislargelyheterosexual,whiletransmissionamongmenwhohavesexwithmenpredominatesinindustrializednations.
• Genitalulcerscausedbysyphilisareamajorcofactorforbidirectionaltransmissionofhumanimmunodeficiencyvirus(HIV).
MICROBIOLOGY• T. pallidumsubspeciespallidum, pertenue,andendemicumcausevenerealsyphilis,yaws,and
endemicsyphilis,respectively.Treponema carateumcausespinta.• Allpathogenictreponemesarenoncultivableandindistinguishablebyroutineclinicallabo-
ratorytests.• HumansaretheonlynaturalhostsforT. pallidumsubsp.pallidum.• T. pallidumpossessesbothinnerandoutermembranes;itsoutermembranelackslipopoly-
saccharideandcontainsapaucityofintegralmembraneproteinsandsurface-exposedlipo-proteins,henceitsdesignationas“thestealthpathogen.”
• T. pallidummustacquireessentiallyallnutrientsfromitsobligatehumanhostandgeneratesadenosinetriphosphateprimarilybyglycolysis.
• T. pallidumdisseminatesearlyduringthecourseofinfectionandinvadesthecentralnervoussysteminasubstantialpercentageofpersonswithearlysyphilis.
DIAGNOSIS• BecauseT. pallidum cannotbecultivated invitro,diagnosisof syphilisdependsondirect
demonstrationoftreponemesinclinicalsamplesorreactivityinserologictests,orboth.• Darkfieldmicroscopyandpolymerasechainreactionareusefulfordetectingtreponemesin
exudativelesions,principallychancres.• Serodiagnosisofsyphilisinvolvestwotypesofserologictests:nontreponemalandtrepone-
mal.Theformerdetectsantibodiesagainstlipoidalantigens(primarilycardiolipin),whereasthelatterdetectsantibodiesagainstT. pallidumproteins.
• Nontreponemalantibodytestsareusedasindicatorsofdiseaseactivity;nontreponemaltiterstendtodeclinewiththerapy.Treponemaltestsremainreactiveforlife.
• Treponemaltestsareusedtoconfirmthatreactivityinnontreponemaltestsisduetosyphilisasopposedtobeingabiologicfalsepositive.
352Part
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THERAPY• PenicillinGisthepreferredformoftherapyforallstagesandtypesofinfection.• 2.4 million units of IM benzathine penicillin is the Centers for Disease Control and
Prevention–recommendedregimenforearlysyphilisregardlessofHIVstatus.• Doxycyclineisthepreferredalternativefornonpregnant,penicillin-allergicpatients.• Penicillin-allergicpregnantfemalesshouldbedesensitized.
PREVENTION• Prophylactic treatment is indicatedforpartnersexposedtoknownactivecaseswithinthe
past90daysregardlessofwhetherlesionsarepresentorserologiesarereactive.• Earlyidentificationandtreatmentofgestationalsyphilispreventscongenitalinfection.
353
171 Endemic TreponematosesEdward W. Hook III
DEFINITION• Theendemictreponematosesincludeyaws,endemicsyphilis,andpinta.Allarecutaneous
diseasesmostcommoninchildrenandcausedbytreponemescloselyrelatedtoTreponema pallidum,thecausativeagentofsyphilis.
EPIDEMIOLOGY• Theendemictreponematosesarespreadonlyfromhumantohumanbydirectcontact.The
infectionsaremostcommoninchildrenbutifuntreatedmayprogresstocausechronicskinandbonedisease.Overthepast2decades,yawsrateshaveincreasedworldwide.Endemicsyphilisandpintaremainveryuncommon.
MICROBIOLOGY• Thetreponemalspeciesthatcausetheendemictreponematosescannotbeeasilyculturedfor
diagnosis.Microbiologicdiagnosisismostoftenbasedonnontreponemalandtreponemalserologicreactivityintestsdesignedforsyphilisdiagnosis.
DIAGNOSIS• Thediagnosisofendemictreponematosesisbasedonclinicalrecognitionofcompatibleskin
lesions,confirmedbyserologictesting.
THERAPY• Untilrecently,benzathinepenicillinwasthemainstayoftherapyoftheendemictreponema-
toses.Recently,azithromycinhasbeenprovenasaneasy-to-administeralternativetopenicil-lininjectionsfortherapyofyaws.
PREVENTION• Yawsappearstobeamenabletomasstherapyasacontrolandpreventionmeasure.In2012,
the World Health Organization announced plans to embark on mass therapy initiativesdesignedtoeliminateyawsby2020.
354
172 Leptospira Species (Leptospirosis)David A. Haake and Paul N. Levett
DEFINITION• LeptospirosisiscausedbyinfectionwithpathogenicspirochetesofthegenusLeptospira.
EPIDEMIOLOGY• Leptospirosisisazoonosisofglobaldistribution.• Leptospirosisismaintainedinnaturebychronicrenalinfectionofcarrieranimals,especially
rodents.• Infections typicallyoccur followingoccupationalorrecreationalexposure towaterorsoil
contaminatedwithrodenturine.• Indevelopingcountrieswithpoorhousingstandards,leptospirosisoutbreaksoccurregularly
inurbansettingsafterheavyrainfallandflooding.
MICROBIOLOGY• Twenty-onenamed leptospiral specieshavebeendescribed,ofwhich11areknown tobe
pathogenic(seeTable172-1).
DIAGNOSIS• Clinicaldiagnosisrequiresahighindexofsuspicionbasedonepidemiologicexposure.• Serologictestsarehelpfulwhenpositivebutmayhavepoorsensitivityduringthefirstweek
ofillness.• Thesignsandsymptomsofearlyleptospirosisarenonspecific.
THERAPY• Antibiotictherapy(seeTable172-2)shouldbeinitiatedasearlyinthecourseofthedisease
assuspicionallows.Formilddisease,doxycycline,amoxicillin,ororalampicillinisrecom-mended.Formoreseveredisease,intravenousceftriaxone,ampicillin,orpenicillinisused.
• Patientswithearlyrenaldiseasewithhigh-outputrenaldysfunctionandhypokalemiashouldreceiveaggressivevolumerepletionandpotassiumsupplementation.
• Patientswhoprogresstooliguricrenalfailureshouldundergorapidinitiationofhemodialy-sisorperitonealdialysis,whichistypicallyrequiredononlyashort-termbasis.
PREVENTION• Themosteffectivepreventivestrategy is toreducedirectcontactwithpotentially infected
animalsandindirectcontactwithurine-contaminatedsoilandwater.• Chemoprophylaxiswithdoxycycline200mgonceaweekisrecommendedfor individuals
whowillbeunavoidablyexposedtoendemicenvironments.
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sis)
TABLE 172-1 Species of Leptospira and Some Pathogenic Serovars
SPECIES SELECTED PATHOGENIC SEROVARSL. interrogans Icterohaemorrhagiae, Copenhageni, Canicola, Pomona,
Australis, Autumnalis, Pyrogenes, Bratislava, Lai
L. noguchii Panama, Pomona
L. borgpetersenii Ballum, Hardjo, Javanica
L. santarosai Bataviae
L. kirschneri Bim, Bulgarica, Grippotyphosa, Cynopteri
L. weilii Celledoni, Sarmin
L. alexanderi Manhao 3
L. alstonii Sichuan
L. meyeri Sofia
L. wolffii Khorat
L. kmetyi Manilae
L. wolbachii Nonpathogen
L. biflexa Nonpathogen
L. vanthielii Nonpathogen
L. terpstrae Nonpathogen
L. yanagawae Nonpathogen
L. idonii Nonpathogen
L. inadai Indeterminate
L. fainei Indeterminate
L. broomii Indeterminate
L. licerasiae Indeterminate
TABLE 172-2 Antimicrobial Agents Recommended for Treatment and Chemoprophylaxis of Leptospirosis
INDICATION COMPOUND DOSAGEChemoprophylaxis Doxycycline 200 mg PO orally once per week
Treatment of mild leptospirosis Doxycycline 100 mg bid PO
Ampicillin 500-750 mg q6h PO
Amoxicillin 500 mg q6h PO
Treatment of moderate to severe leptospirosis
Penicillin 1.5 MU IV q6h
Ceftriaxone 1 g IV q24h
Ampicillin 0.5-1 g IV q6h
356
173 Relapsing Fever Caused by Borrelia SpeciesJames M. Horton
DEFINITION• RelapsingfeveriscausedbyspirochetesoftheBorreliagenus.• Theillnessischaracterizedbyrelapsingfeverswithspirochetesevidentonabloodsmear.
ORGANISM• Borrelia species are divided between B. burgdorferi, which causes Lyme disease, and the
Borreliaspeciesthatcauserelapsingfever.• Therelapsingfeverspeciesaredividedbetweenthelouse-borneandtick-bornespecies.
EPIDEMIOLOGY• Tick-bornerelapsingfeveroccursonalmosteverycontinent,butintheUnitedStatesit is
endemicintheRockyMountains.
PATHOPHYSIOLOGY• The spirochete changes surface antigens about every 7 days, causing the cyclic, relapsing
fever.
CLINICAL MANIFESTATIONS• The patient presents with fever for 3 days alternating with afebrile periods lasting about
7days.
DIAGNOSIS• Spirochetescanbeseenontheperipheralbloodsmearduringfebrileperiods.
THERAPY• Doxycyclineorpenicilliniseffectivetreatment.• Jarisch-Herxheimerreactionsarecommon,andthepatientshouldbeobservedinaclinic
orhospitalforabout3hoursafterstartingantibiotictherapy.
PREVENTION• Postexposuretherapywithdoxycyclineispreventive.
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174 Lyme Disease (Lyme Borreliosis) Due to Borrelia burgdorferiAllen C. Steere
DEFINITION• Atick-borneinfectioncausedbythespirocheteBorrelia burgdorferisensulatoleadingtoa
multisystemillnessprimarilyintheskin,joints,nervoussystem,heart,oracombinationofthese.
EPIDEMIOLOGY• The vectors of Lyme disease are 14 closely related ixodid tick species that are part of the
Ixodes ricinuscomplex.• ThediseaseoccursinpartsofNorthAmerica,Europe,andAsia.• Thedisorder in theUnitedStatesoccursprimarily in threedistinct foci: in theNortheast
fromMainetoNorthCarolina;intheMidwestinWisconsin,Minnesota,andMichigan;andintheWest,primarilyinnorthernCalifornia.
• Thepeakonsetofearlyinfectionisinthesummermonths.• About30,000casesarereportedyearlyintheUnitedStates,mostlyfromthenortheastern
UnitedStates.
MICROBIOLOGY• ThegenusBorreliacurrentlyincludes13closelyrelatedspeciesknowncollectivelyasBorrelia
burgdorferisensulato(B. burgdorferiinthegeneralsense).• Thehumaninfectioniscausedprimarilybythreepathogenicspecies:B. burgdorferisensu
stricto (B. burgdorferi in the strict sense) is the sole cause in the United States, whereasBorrelia afzeliiandBorrelia gariniiaretheprimarycausesoftheinfectioninEurope.
DIAGNOSIS• CultureofB. burgdorferiinBarbour-Stoenner-Kelly(BSK)mediumpermitsdefinitivediag-
nosisbuthasbeenpossiblereliablyonlyfrombiopsiesoferythemamigransskinlesions,anearlydiseasemanifestation.
• DiagnosisisusuallybasedoncharacteristicclinicalfindingsandapositiveIgGserologictestresult,usingatwo-testapproachofenzyme-linkedimmunosorbentassayandWesternblot.
THERAPY• Forearly infection,appropriateoralantibiotic therapy (usuallydoxycycline,100mg twice
dailyoramoxicillin,500mgthreetimesdaily)for14to21daysisusuallysuccessful.• Forneurologicinvolvementorsomecasesofarthritis,intravenousantibiotictherapy(often
ceftriaxone,2gdaily)for28daysmaybenecessary.
PREVENTION• Personalprotectionmethodstoavoidtickbitesandtickchecksafterexposureinendemic
areasarethemajorpreventionstrategies.• AvaccineforLymediseaseconsistingofrecombinantOspAwithadjuvantwasshowntobe
safeandeffective,butthevaccineisnotnowavailable.
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175 Clostridium difficile InfectionDale N. Gerding and Vincent B. Young
DEFINITION• Clostridium difficileinfection(CDI)isacutediarrheaandcolitisthatismostoftenpreceded
by antimicrobial use and is caused by an anaerobic spore-forming, toxin-producingbacterium.
EPIDEMIOLOGY• C. difficileisfoundinwater,soil,meats,andvegetablesandisparticularlycommoninhealth
careenvironments,wherethesporesaredifficult toeradicate.Patientsareexposedtoandingest C. difficile spores in the health care setting from contact with the environment orhealthcareworkerswhodonotpracticegoodhandhygiene.
• Ifthepatienthastakenantibioticsrecently,thenormalmicrobiotaislikelytobedisrupted;andinthisdisruptedmicrobiota,theingestedspores,whichareresistanttostomachacid,cangerminateandproliferateinthecolon,producingtwomajortoxins:TcdAandTcdB.
• Thetwotoxinsproduceamarkedneutrophilicinflammatoryresponseinthecolon,resultingin diarrhea, erosion of the mucosa, and formation of pseudomembranes composed ofnecroticcellsandproteinaceousmaterialthatextendoverthemucosalsurface.
• Recurrenceofdiarrheaaftertreatmentoccursin25%ofpatientsandrequiresre-treatment.
MICROBIOLOGY• C. difficileisanobligategram-positiveanaerobicbacteriumthatcansurviveinenvironments
underaerobicconditionsbyformingspores.• ThemajorityofstrainsproducebothtoxinsAandB.Athirdtoxin,binarytoxin,isproduced
by recent epidemic strains that have caused outbreaks with increased severity andmortality.
• SomestrainsofC. difficilelackthegenesfortoxinproductionandarenontoxigenicandnotbelievedtocauseCDI.
DIAGNOSIS• DiagnosisofCDI isbasedon thepresenceofclinical symptoms(usuallydefinedasmore
thanthreewatery,looseorunformedstoolswithin≤24hours)coupledwithadiagnostictest(usuallyofastoolspecimen)thateitherdetectsthepresenceoftheC. difficileorganismoritstoxingenesordetectsC. difficiletoxinusinganenzymeimmunoassayorcellcytotoxinassay.
THERAPY• Thefirststepsineffectivetreatmentaretostopanytherapywiththeoffendingantibioticand
providefluidandelectrolytesupport,ifneeded.• Specific treatment consists of metronidazole or vancomycin orally for mild-to-moderate
disease,vancomycinorallyforseveredisease(whitebloodcellcount>15,000/mLorcreati-nineconcentration>1.5timesbaseline),andvancomycinorallyorbynasogastrictubeplus
359C
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ifficile In
fection
intravenousmetronidazoleforseverecomplicated(alsocalledfulminant)CDIthatpresentsashypotension,shock,ileus,ormegacolon.
• Patients with recurrent CDI may benefit from fidaxomicin treatment, and multiple CDIrecurrencesareeffectivelytreatedbyfecalmicrobiotatransplant(FMT).
PREVENTION• Prevention in the health care environment is focused on preventing patient exposure to
sporesofC. difficilebyutilizingisolation,cohorting,glovesandgowns,andhandwashing(alcoholrubsareineffectiveagainstspores).Bleachisusedintheenvironmenttoeradicatespores.
• Itisexceedinglydifficulttopreventsporeexposure,soantimicrobialstewardshipprogramstoreduceunnecessaryantimicrobialuseareextremelyeffective in limitingthenumberofsusceptiblepatients.
• A number of new preventive approaches are undergoing clinical investigation, includingvaccinestoinduceantibodiestotoxinsAandB,monoclonalantibodiestoprovidepassiveimmunity,andbiotherapeutics thatare livebacterialorganismssuchasFMTorsporesofnontoxigenicC. difficile.
360
176 Tetanus (Clostridium tetani)Aimee Hodowanec and Thomas P. Bleck
DEFINITION• Tetanus is a nervous system disease caused by a toxin (tetanospasmin) produced by
Clostridium tetani.• Tetanusisdividedintofourclinicaltypes:generalized, localized, cephalic,andneonatal.
EPIDEMIOLOGY• Acuteinjuryandinjectiondruguseareriskfactorsfortetanus.• Tetanusisrareindevelopedcountriesduetotheavailabilityofeffectivevaccines.• Indevelopingcountries,neonataltetanuscanoccurwhenthereisfailureofaseptictechnique
andmothersareinadequatelyimmunized.• IntheUnitedStates, tetanusismorecommoninpeopleolderthan60years, likelydueto
waningimmunity.
MICROBIOLOGY• C. tetaniisanobligatelyanaerobicbacillus.• Tetanusproducestwotoxins:tetanospasminandtetanolysin.• Itdevelopsaterminalsporethatisextremelystableintheenvironment,retainingtheability
togerminateandcausediseaseindefinitely.
DIAGNOSIS• Diagnosisoftetanusreliesonhistoryandexaminationfindings.• CulturingC. tetaniisdifficultandnothelpful.
THERAPY• Theairwaymustbesecuredatthetimeofpresentation.• Benzodiazepinesprovidethemainstayofsymptomatictherapy.• Passive immunizationwithhumantetanus immuneglobulin(HTIG)shortens thedisease
courseandmaylessendiseaseseverity.• Antibiotictherapywithmetronidazole(Flagyl)mayimproveoutcomes.
PREVENTION• AllchildrenshouldbevaccinatedagainsttetanusthroughDTaPvaccineseries.• Adultsshouldreceiveatetanusbooster(Td)every10years.OneoftheTddosesshouldbe
replacedwithTdap.• Woundmanagementofminor,cleanwoundsshouldincludecompletionoftetanusimmu-
nizationifincomplete,oraboosterdoseofvaccine(Td),ifthelastdosewasgivenmorethan10yearsbefore.PatientswithseriouscontaminatedwoundsshouldalsoreceiveHTIG.
361
177 Botulism (Clostridium botulinum)Aimee Hodowanec and Thomas P. Bleck
DEFINITION• Botulismisatoxin-mediatedparalyticillnesscausedbyClostridium botulinum.Itisclassified
asfoodbornebotulism,infantbotulism,woundbotulism,iatrogenicbotulism,botulismofundeterminedetiology,orinhalationalbotulism.
EPIDEMIOLOGY• Foodbornebotulismoccursinoutbreaks,whereasotherformsaresporadic.• Foodbornebotulismisassociatedwithhome-cannedorfermentedfoods.• Infantbotulismhistoricallyisassociatedwithhoneyingestion.• Woundbotulismisassociatedwithinjectiondruguseof“black-tar”heroin.• BotulinumtoxinsAandBareusedfortherapeuticandcosmeticpurposesandmaycause
iatrogenicbotulism.• Botulismisapotentialbioterrorismagentdeployedbyaerosoloringestion.
MICROBIOLOGY• C. botulinumisagram-positive,strictlyanaerobicbacillusthatformsasubterminalspore.• C. botulinumproducessevendistincttoxins,designatedtypesAthroughG.
DIAGNOSIS• Presumptivediagnosisbasedonclinicalpresentation:acute,bilateralcranialneuropathies
withsymmetricaldescendingweakness.• Mousebioassayisthegoldstandardforbotulinumtoxin.• Cultureofserum,stool,andenvironmentalsamplesrequiresstrictanaerobicconditionsand
islowyield.• Characteristicelectrophysiologicstudyfindingsaresuggestiveofbotulism.
THERAPY• Supportivecareremainsthemainstayofbotulismtreatment.• HeptavalentbotulinumantitoxinisavailablefornoninfantbotulismintheUnitedStates.• Human botulinum immune globulin (BabyBIG) is available for the treatment of
infant (younger than 1 year) botulism. To obtain, contact the California Department ofHealth Services, Infant Botulism Treatment and Prevention Program (510-540-2646;www.infantbotulism.org).
PREVENTION• Properfoodpreparationpreventsfoodbornebotulism.• Thereisnocurrentlyavailablevaccine.
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178 Gas Gangrene and Other Clostridium-Associated DiseasesAndrew B. Onderdonk and Wendy S. Garrett
CHARACTERISTICS OF CLOSTRIDIUM SPP.• MemberofthephylumFirmicutes• Anaerobicgram-positiverodscapableofformingendospores• Ubiquitousinnature• Phenotypic classification methods include carbohydrate fermentation, detection of short-
chainfattyacidendproductsoffermentation,Gram-stainmorphology,colonymorphology,anddetectionofspecifictoxins
• Variousspeciesassociatedwithhumandisease(seeTable178-1)
CLOSTRIDIUM PERFRINGENS AND CLOSTRIDIAL MYONECROSIS (GAS GANGRENE)• C. perfringensproducesavarietyoftoxins(seeTable178-2)• Most common following traumatic crushing injuries that result in lowered tissue oxygen
levels,penetratingtraumainvolvingforeignbodiescontaminatedwithsoil,gastrointestinalorbiliarytractsurgery,andsepticabortion
• Diagnosis: Initial symptoms include severe pain, redness at the wound site followed byrapidlyspreadingbrowntopurplediscoloration,edemaandgas,andserosanguineousdis-chargewithacharacteristic“mousy”odor.Full-blownsepsiswithhypotension,renalfailure,andmetabolicacidosisoccursrapidly.
• Treatmentinvolvespromptsurgicaldébridementofinfectedtissues, includingamputationforextremities,orhysterectomyinuterinegasgangrene.Antibiotictreatmentisalsoimpor-tant, and most strains are sensitive to penicillin, metronidazole, clindamycin, and thecarbapenems.
FOOD POISONING CAUSED BY CLOSTRIDIUM PERFRINGENS• C. perfringenstypeAinvolvedinmostcases• Involvestheingestionofatleast108viableenterotoxin-producingcells• Periodofincubationis7to15hours;casesresolvespontaneouslywithin24to48hours
OTHER CLOSTRIDIAL INFECTIONS• Bacteremia—clostridia account for 1% of all positive blood cultures. Risk factors include
hemodialysis,intestinalmalignancy,andinflammatoryboweldisease.• Biliarytractinfections—clostridiacanbeisolatedfrommorethan20%ofdiseasedgallblad-
ders,andC. perfringensaccountsfor50%.• Femalegenitaltractinfections—clostridiaarepresentinupto20%ofnon–sexuallytransmit-
teddiseasegenitalinfectionsandmaybepresentaspartofbacterialvaginosis.C. perfringensandC. sordelliicanbeisolatedfrompostpartumandpostabortioninfections.
• Pleuropulmonaryinfections—clostridiaarerecoveredfromupto10%ofpulmonaryinfec-tionswithC. perfringensaccountingforthemajority.
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lostrid
ium
-Asso
ciated D
iseases
TABLE 178-1 Clostridial Species Commonly Associated with Human Disease
SPEC
IES
SPO
RE
LOC
ATI
ON
LEC
ITH
INA
SE
PRO
DU
CED
LIPA
SE
ENTE
RO
TOX
INS
PRO
DU
CED
HIS
TOTO
XIN
S,
HEM
OLY
SIN
S,
PRO
TEA
SES
NEU
RO
TOX
INS
PRO
DU
CED
Tissue InfectionsC. perfringens ST, C + − Yes Yes No
C. ramosum T − − No Yes No
C. septicum ST − − No Yes No
C. sordellii ST + − No Yes No
C. bifermentans ST + − No Yes No
C. tertium T − − No Yes No
C. sphenoides ST − − No Yes No
C. baratii ST − − No Yes No
C. novyi ST + + No Yes No
C. histolyticum ST − − No Yes No
IntoxicationsC. difficile ST − − Yes Yes No
C. botulinum ST, T − + No Yes Yes
C. tetani T − − No Yes Yes
C, centrally; ST, subterminally; T, terminally.
TABLE 178-2 Toxins Produced by Clostridium perfringens
TOXIN STRAIN TYPES BIOLOGIC ACTIVITYα All strains Lecithinase
β B and C Necrotoxin, necrosis of the bowel
ε B and D Lethal, hemorrhagic
ι E Adenosine diphosphate ribosylating; lethal
cpe enterotoxin A, C, and D Cytopathic
Neuraminidase All strains Hydrolyzes N-acetylneuraminic acid
δ B and C Hemolysins
κ All strains Collagenase
λ B, D, and E Protease
µ All strains Hyaluronidase
ν All strains DNAase
364
179 Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)Wendy S. Garrett and Andrew B. Onderdonk
DEFINITION• Bacteroides, Porphyromonas, Prevotella,andFusobacteriumspp.accountforthemajorityof
infectionscausedbyanaerobicgram-negativerods.BilophilaandSutterellaspp.alsocausehumaninfections,althoughtheyarelessfrequentlyencountered.
EPIDEMIOLOGY• Theseorganismsarepartof thenormalhumanmicrobiomeandcanbe isolated fromthe
oralcavity,gastrointestinaltract,andvaginalvaultofhumans.
MICROBIOLOGY• Theorganismsareobligatelyanaerobic,gram-negative,non–spore-formingrods.Members
ofthisgroupcanbeproteolytic,saccharolytic,orboth.Somespeciesproducecatalaseandsuperoxide dismutase in low concentrations. Some species have capsular polysaccharidesthat have been shown to be potent immunomodulators, whereas other species produceabundantproteasesthatcandegradetissue.
DIAGNOSIS• Identification in theclinical laboratory includescolonymorphology,Gramstain,pigment
productionvisualizedinnaturallightandasfluorescenceemissionafterexposuretoultra-violetlight,andnumerousbiochemicaltests(e.g.,Vitek).
THERAPY• Treatmentisdirectedbycultureandsensitivitytestresults(seeTable179-1).
TABLE 179-1 Antibiotic Sensitivities of Medically Important Gram-Negative Anaerobic Rods
PEN
ICIL
LIN
β-LA
CTA
M
PIPE
RA
CIL
LIN
/TA
ZOB
AC
TAM
AM
OX
ICIL
LIN
/C
LAV
ULA
NIC
AC
ID
CLI
ND
AM
YC
IN
CA
RB
APE
NEM
MET
RO
NID
AZO
LE
MO
XIF
LOX
AC
IN
Bacteroides fragilis group R V S S V S S S
Prevotella R V S S S S S S
Porphyromonas R V S S S S S S
Fusobacterium S V S S S S S S
R, resistant >30%; S, sensitive <5%; V, variable >5%.
365
180 Mycobacterium tuberculosisDaniel W. Fitzgerald, Timothy R. Sterling, and David W. Haas
MICROBIOLOGY• HumansaretheonlyreservoirforMycobacterium tuberculosis.• Theorganismisanacid-fast,aerobicbacilluswithahighcellwallcontentofhigh-molecular-
weightlipids.• Visiblegrowthtakes3to8weeksonsolidmedia.• Anestimated10,000organisms/mLarerequiredforsputumsmearpositivity.• Incompletenecrosisproducescheesy,acellularmaterial(i.e.,caseousnecrosis).• Pulmonarycavitiescontainhugenumbersoforganisms.
EPIDEMIOLOGY• M. tuberculosis infects one third of the world’s population, with 8.7 million new cases
reportedeachyear.• Almostallinfectionsareduetoinhalationofdropletnuclei.• Keydeterminantsof infectionof tuberculin-negativepersonsareclosenessofcontactand
infectiousnessofthesource.• Thestrongestriskfactorforprogressiontoactivetuberculosisisacquiredimmunodeficiency
syndrome(AIDS).• GreatestcaseratesareincountriesheavilyaffectedbyAIDS.• Drugresistancecanbeprimaryorsecondary.• Multidrug-resistant tuberculosis (MDR-TB) indicates resistance to both isoniazid and
rifampin.• Extensivelydrug-resistanttuberculosis(XDR-TB)indicatesresistancetoisoniazid,rifampin,
afluoroquinolone,andasecond-lineinjectabledrug.• TransmissionofXDR-TBisofimmenseconcern.
IMMUNOLOGY AND PATHOGENESIS• Infectionrequiresacellularimmuneresponse.• Airbornedropletnuclei reach the terminal air-spaceswhere theyare ingestedbyalveolar
macrophagesandthencarriedbylymphaticstoregionallymphnodes.• Occult preallergic lymphohematogenous dissemination occurs to the lung apices and
elsewhere.• Granulomasformwhenantigenloadissmallandtissuehypersensitivityishigh.• Ageinfluenceslikelihoodandpatternofdisease.• Tuberculosis in advanced AIDS is characterized by middle or lower lung field location,
absenceofcavitation,increasedextrapulmonarydisease,andanegativetuberculintest.
TUBERCULIN SKIN TESTING AND INTERFERON-γ RELEASE ASSAYS• TodetectlatentM. tuberculosisinfection,apositiveskintestisdefinedbyinduration.• Skintestingisrecommendedforpersonsathighriskfordevelopingtuberculosisandthose
withpossiblelatentinfectionwhocanbetreatedifthetestispositive.
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• Theskintestisnegativeinatleast20%ofactivetuberculosiscases.• Interferon-γreleaseassaysmaybeusedinsteadofskintesting.
DIAGNOSIS• Cultureisthegoldstandard.• Liquidbrothculturesrequire1to3weekstodetectorganisms.• Nucleicacidamplificationtestshavesensitivitiesandspecificitiesthatapproachculture.• Threesputumspecimensincreasesensitivity.• Aradiographshowingapatchyornodularinfiltrateinthelungapicesishighlysuggestive,
especiallyiftheinfiltrateiscavitary.• Pulmonarytuberculosiscanoccurinpersonswithnormalchestradiographs.
THERAPY (SEE TABLES 180-1 AND 180-2)• Multidrugregimens,typicallystartingwithatleastfouractivedrugs,arerecommended.• Atleast6monthsoftherapyisusuallyrequired.• Isoniazid(INH)isthecornerstoneoftherapy;rifampin,thesecondmajorantituberculous
agent, causes many drug-drug interactions; pyrazinamide is essential for 6-monthregimens.
• Adjustmentofdosesofantiretroviralagentsduringtreatmentoftuberculosiswithrifampinand rifabutin is discussed in Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases,8thEdition,Chapter38.
• Directlyobservedtherapyiscrucial.• Susceptibilitytestingisimportanttoguidetherapy.• Withappropriatechemotherapy,patientsbecomenoninfectiouswithin2weeks.• TreatmentofXDR-TBisusuallyassociatedwithpooroutcomes.• BedaquilineisarecentlyapproveddrugforMDR-TB.
THERAPY FOR LATENT INFECTION• IntheUnitedStates,9monthsofINHiswidelyprescribedforlatentinfection.• Twelve weeks of directly observed, once-weekly INH plus rifapentine is as effective as
9monthsofINH.Foradultsweighingmorethan50kg,thedoseofbothdrugsis900mgonceaweek.
PREVENTION• Casefindingandtreatmentisthemosteffectivemethodoftuberculosiscontrol.• Hospitalizedhumanimmunodeficiencyvirus–positivepatientswithrespiratorysymptoms
shouldbeadmittedtonegative-pressureisolationrooms.N95masksareusedforhealthcareworkers.
• ChildhoodbacillusCalmette-Guérinvaccination inhigh-burdencountriesdecreases inci-denttuberculosis.
367C
hap
ter 180 Myco
bacteriu
m tu
bercu
losis
TABLE 180-1 Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms
INITIAL PHASE CONTINUATION PHASE
Reg
imen
Dru
gs
Inte
rval
an
d
Do
ses*
(M
inim
al
Du
rati
on
)
Reg
imen
Dru
gs
Inte
rval
an
d
Do
ses*
† (M
inim
al
Du
rati
on
)
Ran
ge
of
Tota
l D
ose
s (M
inim
al
Du
rati
on
)
1 INHRIFPZAEMB
7 days/wk for 56 doses (8 wk) or 5 days/wk for 40 doses (8 wk)‡
1a INH/RIF 7 days/wk for 126 doses (18 wk) or 5 days/wk for 90 doses (18 wk)‡
182-130 (26 wk)
1b INH/RIF Twice weekly for 36 doses (18 wk)§
92-76 (26 wk)
1c‖ INH/RPT Once weekly for 18 doses (18 wk)
74-58 (26 wk)
2 INHRIFPZAEMB
7 days/wk for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 days/wk for 10 doses (2 wk),‡ then twice weekly for 12 doses (6 wk)
2a INH/RIF Twice weekly for 36 doses (18 wk)§
62-58 (26 wk)
2b‖ INH/RPT Once weekly for 18 doses (18 wk)
44-40 (26 wk)
3 INHRIFPZAEMB
Three times weekly for 24 doses (8 wk)
3a INH/RIF Three times weekly for 54 doses (18 wk)
78 (26 wk)
4 INHRIFEMB
7 days/wk for 56 doses (8 wk) or 5 days/wk for 40 doses (8 wk)§
4a INH/RIF 7 days/wk for 217 doses (31 wk) or 5 days/wk for 155 doses (31 wk)§
273-195 (39 wk)
4b INH/RIF Twice weekly for 62 doses (31 wk)§
118-102 (39 wk)
EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine.*When directly observed therapy is used, drugs may be given 5 days/wk and the necessary number of doses
adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice.
†Patients with cavitation on an initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 weeks; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase.
‡Five-day-a-week administration is always given by directly observed therapy.§Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/mm3.‖Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time
of completion of 2 months of therapy and who do not have cavitation on an initial chest radiograph. For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months.
Modified from Centers for Disease Control and Prevention. Treatment of tuberculosis. American Thoracic Society, CDC and Infectious Diseases Society of America. MMWR Recomm Rep. 2003;52(RR-11):1-88.
368Part
II
Infe
ctio
us
Dis
ease
s an
d t
hei
r Et
iolo
gic
Ag
ents
TAB
LE 1
80
-2
Firs
t-Li
ne T
ub
erc
ulo
sis
Med
icati
on
s*
DR
UG
DO
SE
(MA
XIM
UM
)M
AJO
R A
DV
ERSE
REA
CTI
ON
SR
ECO
MM
END
ED
MO
NIT
OR
ING
DO
SAG
E FO
RM
SC
OM
MEN
TS
Iso
nia
zid
* (I
NH
)D
aily
C:
10-1
5 m
g/kg
(30
0 m
g)A
: 5
mg/
kg (
300
mg)
Onc
e w
eekl
yC
: N
ot r
ecom
men
ded
A:
15 m
g/kg
(90
0 m
g)Tw
ice
wee
kly
C:
20-3
0 m
g/kg
(90
0 m
g)A
: 15
mg/
kg (
900
mg)
Thre
e tim
es w
eekl
yC
: N
ot r
ecom
men
ded
A:
15 m
g/kg
(90
0 m
g)
Hep
atic
enz
yme
elev
atio
n, p
erip
hera
l ne
urop
athy
, he
patit
is,
rash
, C
NS
effe
cts,
in
crea
sed
phen
ytoi
n, (
Dila
ntin
), an
d di
sulfi
ram
(A
ntab
use)
leve
ls
Base
line
hepa
tic e
nzym
es.
Repe
at m
onth
ly if
bas
elin
e ab
norm
al,
risk
fact
ors
for
hepa
titis
, or
sym
ptom
s of
ad
vers
e re
actio
ns.
Scor
ed t
able
ts:
50 m
g,
100
mg,
and
300
mg
Syru
p: 5
0 m
g/5
mL
Aqu
eous
sol
utio
n (IV
/IM):
scar
ce a
nd m
ay n
ot b
e av
aila
ble
Hep
atiti
s ris
k in
crea
ses
with
age
and
al
coho
l con
sum
ptio
n. O
verd
ose
may
be
fata
l. A
lum
inum
-con
tain
ing
anta
cids
re
duce
abs
orpt
ion.
Pyr
idox
ine
(vita
min
B6)
m
ay d
ecre
ase
perip
hera
l neu
ritis
and
CN
S ef
fect
s.
Rif
amp
in*
(RIF
)D
aily
C:
10-2
0 m
g/kg
(60
0 m
g)A
: 10
mg/
kg (
600
mg)
Onc
e w
eekl
yC
: N
ot r
ecom
men
ded
A:
Not
rec
omm
ende
dTw
ice
wee
kly
C:
10-2
0 m
g/kg
(60
0 m
g)A
: 10
mg/
kg (
600
mg)
Thre
e tim
es w
eekl
yC
: N
ot r
ecom
men
ded
A:
10 m
g/kg
(60
0 m
g)
Hep
atiti
s, f
ever
, th
rom
bocy
tope
nia,
flul
ike
synd
rom
e, r
ash,
gas
troi
ntes
tinal
ups
et,
rena
l fai
lure
. Re
duce
s le
vels
of
man
y dr
ugs,
in
clud
ing
met
hado
ne,
war
farin
(C
oum
adin
), bi
rth
cont
rol p
ills,
the
ophy
lline
, da
pson
e,
keto
cona
zole
, PI
s, a
nd s
ome
NN
RTIs
. O
rang
e di
scol
orat
ion
of s
ecre
tions
(sp
utum
, ur
ine,
sw
eat,
tea
rs)
and
may
per
man
ently
st
ain
soft
con
tact
lens
es.
CD
C n
o lo
nger
rec
omm
ends
ro
utin
e m
onito
ring
test
s.
How
ever
, m
any
clin
icia
ns
cont
inue
to
orde
r ba
selin
e C
BC,
plat
elet
s, h
epat
ic
enzy
mes
. Re
peat
if b
asel
ine
abno
rmal
, ris
k fa
ctor
s fo
r he
patit
is o
r sy
mpt
oms
of
adve
rse
reac
tions
.
Cap
sule
s: 1
50 m
g an
d 30
0 m
gSy
rup:
can
be
form
ulat
ed
from
cap
sule
s by
pha
rmac
yA
queo
us s
olut
ion
(IV/IM
): sc
arce
and
may
not
be
avai
labl
e
Patie
nts
on m
etha
done
will
nee
d an
in
crea
sed
dose
of
met
hado
ne (
aver
age
50%
) to
avo
id o
piat
e w
ithdr
awal
. In
tera
ctio
n w
ith m
any
drug
s le
ads
to
decr
ease
d le
vels
of
one
or b
oth.
May
m
ake
gluc
ose
cont
rol m
ore
diffi
cult
in
diab
etic
s. C
ontr
aind
icat
ed f
or p
atie
nts
taki
ng P
Is a
nd s
ome
NN
RTIs
. W
omen
on
birt
h co
ntro
l pill
s ne
ed a
bar
rier
met
hod
whi
le o
n rif
ampi
n.
Pyra
zin
amid
e (P
ZA)
Dai
lyC
: 15
-30
mg/
kg (
2 g)
A:
15-3
0 m
g/kg
(2
g)O
nce
wee
kly
C:
Not
rec
omm
ende
dA
: N
ot r
ecom
men
ded
Twic
e w
eekl
yC
: 50
mg/
kg (
2 g)
A:
50-7
0 m
g/kg
(4
g)Th
ree
times
wee
kly
C:
Not
rec
omm
ende
dA
: 50
-70
mg/
kg (
3 g)
Gas
troi
ntes
tinal
ups
et,
hepa
toto
xici
ty,
hype
ruric
emia
, ar
thra
lgia
s, r
ash,
gou
t (r
are)
Scor
ed t
able
ts:
500
mg
May
com
plic
ate
man
agem
ent
of d
iabe
tes
mel
litus
. Tr
eat
incr
ease
d ur
ic a
cid
only
if
sym
ptom
atic
. M
ost
com
mon
rea
son
for
TB p
atie
nts
expe
rienc
ing
GI u
pset
.
Eth
amb
uto
l† (EM
B)
Dai
lyC
: 15
-20
mg/
kg (
1000
mg)
A:
15-2
5 m
g/kg
(16
00 m
g)O
nce
wee
kly
C:
Not
rec
omm
ende
dA
: N
ot r
ecom
men
ded
Twic
e w
eekl
yC
: 50
mg/
kg (
2.5
g)A
: 50
mg/
kg (
4 g)
Thre
e tim
es w
eekl
yC
: N
ot r
ecom
men
ded
A:
25-3
0 m
g/kg
(24
00 m
g)
Dec
reas
ed r
ed-g
reen
col
or d
iscr
imin
atio
n,
decr
ease
d vi
sual
acu
ity (
optic
neu
ritis
), ra
shBa
selin
e te
sts
of v
isua
l acu
ity
and
colo
r vi
sion
. M
onth
ly
test
ing
for
patie
nts
taki
ng
>15-
25 m
g/kg
, fo
r th
ose
taki
ng E
MB
for >2
mo,
and
fo
r pa
tient
s w
ith r
enal
in
suffi
cien
cy.
Tabl
ets:
100
mg
and
400
mg
Opt
ic n
eurit
is m
ay b
e un
ilate
ral;
chec
k ea
ch e
ye s
epar
atel
y. N
ot r
ecom
men
ded
for
child
ren
too
youn
g to
mon
itor
visi
on
unle
ss d
rug
resi
stan
t. U
se lo
wes
t po
ssib
le
dose
in r
ange
(ex
cept
for
dru
g-re
sist
ant
patie
nts)
. EM
B sh
ould
be
disc
ontin
ued
imm
edia
tely
and
per
man
ently
for
any
si
gns
of v
isua
l tox
icity
.
Rif
abu
tin
(R
BT)
Dai
lyC
: N
ot r
ecom
men
ded
A:
5 m
g/kg
(30
0 m
g)O
nce
wee
kly
C:
Not
rec
omm
ende
dA
: N
ot r
ecom
men
ded
Twic
e w
eekl
yC
: N
ot r
ecom
men
ded
A:
5 m
g/kg
(30
0 m
g)Th
ree
times
wee
kly
C:
Not
rec
omm
ende
dA
: 5
mg/
kg (
300
mg)
Hep
atiti
s fe
ver,
thro
mbo
cyto
peni
a,
neut
rope
nia,
leuk
open
ia,
flulik
e sy
mpt
oms,
hy
peru
ricem
ia.
Ora
nge
disc
olor
atio
n of
se
cret
ions
(sp
utum
, ur
ine,
sw
eat,
tea
rs)
and
may
per
man
ently
sta
in s
oft
cont
act
lens
es.
Redu
ces
leve
ls o
f m
any
drug
s, in
clud
ing
met
hado
ne,
war
farin
(C
oum
adin
), bi
rth
cont
rol p
ills,
the
ophy
lline
, da
pson
e,
keto
cona
zole
, PI
s, a
nd N
NRT
Is.
With
in
crea
sed
rifab
utin
leve
ls,
seve
re a
rthr
algi
as,
uvei
tis,
leuk
open
ia o
ccur
.
Base
line
hepa
tic e
nzym
es.
Repe
at if
bas
elin
e va
lues
ab
norm
al,
risk
fact
ors
for
hepa
titis
, or
sym
ptom
s of
ad
vers
e re
actio
ns.
Cap
sule
s: 1
50 m
gPa
tient
s on
met
hado
ne m
ay n
eed
an
incr
ease
d do
se t
o av
oid
opia
te
with
draw
al.
Inte
ract
ion
with
man
y dr
ugs
lead
s to
dec
reas
ed le
vels
of
one
or b
oth.
M
ay m
ake
gluc
ose
cont
rol m
ore
diffi
cult
in d
iabe
tics.
Wom
en o
n bi
rth
cont
rol p
ills
need
to
use
a ba
rrie
r m
etho
d w
hile
on
rifab
utin
.In
com
bina
tion
with
NN
RTIs
or
PIs,
do
sage
s ch
ange
sig
nific
antly
.
369C
hap
ter 180 Myco
bacteriu
m tu
bercu
losis
TAB
LE 1
80
-2
Firs
t-Li
ne T
ub
erc
ulo
sis
Med
icati
on
s*
DR
UG
DO
SE
(MA
XIM
UM
)M
AJO
R A
DV
ERSE
REA
CTI
ON
SR
ECO
MM
END
ED
MO
NIT
OR
ING
DO
SAG
E FO
RM
SC
OM
MEN
TS
Iso
nia
zid
* (I
NH
)D
aily
C:
10-1
5 m
g/kg
(30
0 m
g)A
: 5
mg/
kg (
300
mg)
Onc
e w
eekl
yC
: N
ot r
ecom
men
ded
A:
15 m
g/kg
(90
0 m
g)Tw
ice
wee
kly
C:
20-3
0 m
g/kg
(90
0 m
g)A
: 15
mg/
kg (
900
mg)
Thre
e tim
es w
eekl
yC
: N
ot r
ecom
men
ded
A:
15 m
g/kg
(90
0 m
g)
Hep
atic
enz
yme
elev
atio
n, p
erip
hera
l ne
urop
athy
, he
patit
is,
rash
, C
NS
effe
cts,
in
crea
sed
phen
ytoi
n, (
Dila
ntin
), an
d di
sulfi
ram
(A
ntab
use)
leve
ls
Base
line
hepa
tic e
nzym
es.
Repe
at m
onth
ly if
bas
elin
e ab
norm
al,
risk
fact
ors
for
hepa
titis
, or
sym
ptom
s of
ad
vers
e re
actio
ns.
Scor
ed t
able
ts:
50 m
g,
100
mg,
and
300
mg
Syru
p: 5
0 m
g/5
mL
Aqu
eous
sol
utio
n (IV
/IM):
scar
ce a
nd m
ay n
ot b
e av
aila
ble
Hep
atiti
s ris
k in
crea
ses
with
age
and
al
coho
l con
sum
ptio
n. O
verd
ose
may
be
fata
l. A
lum
inum
-con
tain
ing
anta
cids
re
duce
abs
orpt
ion.
Pyr
idox
ine
(vita
min
B6)
m
ay d
ecre
ase
perip
hera
l neu
ritis
and
CN
S ef
fect
s.
Rif
amp
in*
(RIF
)D
aily
C:
10-2
0 m
g/kg
(60
0 m
g)A
: 10
mg/
kg (
600
mg)
Onc
e w
eekl
yC
: N
ot r
ecom
men
ded
A:
Not
rec
omm
ende
dTw
ice
wee
kly
C:
10-2
0 m
g/kg
(60
0 m
g)A
: 10
mg/
kg (
600
mg)
Thre
e tim
es w
eekl
yC
: N
ot r
ecom
men
ded
A:
10 m
g/kg
(60
0 m
g)
Hep
atiti
s, f
ever
, th
rom
bocy
tope
nia,
flul
ike
synd
rom
e, r
ash,
gas
troi
ntes
tinal
ups
et,
rena
l fai
lure
. Re
duce
s le
vels
of
man
y dr
ugs,
in
clud
ing
met
hado
ne,
war
farin
(C
oum
adin
), bi
rth
cont
rol p
ills,
the
ophy
lline
, da
pson
e,
keto
cona
zole
, PI
s, a
nd s
ome
NN
RTIs
. O
rang
e di
scol
orat
ion
of s
ecre
tions
(sp
utum
, ur
ine,
sw
eat,
tea
rs)
and
may
per
man
ently
st
ain
soft
con
tact
lens
es.
CD
C n
o lo
nger
rec
omm
ends
ro
utin
e m
onito
ring
test
s.
How
ever
, m
any
clin
icia
ns
cont
inue
to
orde
r ba
selin
e C
BC,
plat
elet
s, h
epat
ic
enzy
mes
. Re
peat
if b
asel
ine
abno
rmal
, ris
k fa
ctor
s fo
r he
patit
is o
r sy
mpt
oms
of
adve
rse
reac
tions
.
Cap
sule
s: 1
50 m
g an
d 30
0 m
gSy
rup:
can
be
form
ulat
ed
from
cap
sule
s by
pha
rmac
yA
queo
us s
olut
ion
(IV/IM
): sc
arce
and
may
not
be
avai
labl
e
Patie
nts
on m
etha
done
will
nee
d an
in
crea
sed
dose
of
met
hado
ne (
aver
age
50%
) to
avo
id o
piat
e w
ithdr
awal
. In
tera
ctio
n w
ith m
any
drug
s le
ads
to
decr
ease
d le
vels
of
one
or b
oth.
May
m
ake
gluc
ose
cont
rol m
ore
diffi
cult
in
diab
etic
s. C
ontr
aind
icat
ed f
or p
atie
nts
taki
ng P
Is a
nd s
ome
NN
RTIs
. W
omen
on
birt
h co
ntro
l pill
s ne
ed a
bar
rier
met
hod
whi
le o
n rif
ampi
n.
Pyra
zin
amid
e (P
ZA)
Dai
lyC
: 15
-30
mg/
kg (
2 g)
A:
15-3
0 m
g/kg
(2
g)O
nce
wee
kly
C:
Not
rec
omm
ende
dA
: N
ot r
ecom
men
ded
Twic
e w
eekl
yC
: 50
mg/
kg (
2 g)
A:
50-7
0 m
g/kg
(4
g)Th
ree
times
wee
kly
C:
Not
rec
omm
ende
dA
: 50
-70
mg/
kg (
3 g)
Gas
troi
ntes
tinal
ups
et,
hepa
toto
xici
ty,
hype
ruric
emia
, ar
thra
lgia
s, r
ash,
gou
t (r
are)
Scor
ed t
able
ts:
500
mg
May
com
plic
ate
man
agem
ent
of d
iabe
tes
mel
litus
. Tr
eat
incr
ease
d ur
ic a
cid
only
if
sym
ptom
atic
. M
ost
com
mon
rea
son
for
TB p
atie
nts
expe
rienc
ing
GI u
pset
.
Eth
amb
uto
l† (EM
B)
Dai
lyC
: 15
-20
mg/
kg (
1000
mg)
A:
15-2
5 m
g/kg
(16
00 m
g)O
nce
wee
kly
C:
Not
rec
omm
ende
dA
: N
ot r
ecom
men
ded
Twic
e w
eekl
yC
: 50
mg/
kg (
2.5
g)A
: 50
mg/
kg (
4 g)
Thre
e tim
es w
eekl
yC
: N
ot r
ecom
men
ded
A:
25-3
0 m
g/kg
(24
00 m
g)
Dec
reas
ed r
ed-g
reen
col
or d
iscr
imin
atio
n,
decr
ease
d vi
sual
acu
ity (
optic
neu
ritis
), ra
shBa
selin
e te
sts
of v
isua
l acu
ity
and
colo
r vi
sion
. M
onth
ly
test
ing
for
patie
nts
taki
ng
>15-
25 m
g/kg
, fo
r th
ose
taki
ng E
MB
for >2
mo,
and
fo
r pa
tient
s w
ith r
enal
in
suffi
cien
cy.
Tabl
ets:
100
mg
and
400
mg
Opt
ic n
eurit
is m
ay b
e un
ilate
ral;
chec
k ea
ch e
ye s
epar
atel
y. N
ot r
ecom
men
ded
for
child
ren
too
youn
g to
mon
itor
visi
on
unle
ss d
rug
resi
stan
t. U
se lo
wes
t po
ssib
le
dose
in r
ange
(ex
cept
for
dru
g-re
sist
ant
patie
nts)
. EM
B sh
ould
be
disc
ontin
ued
imm
edia
tely
and
per
man
ently
for
any
si
gns
of v
isua
l tox
icity
.
Rif
abu
tin
(R
BT)
Dai
lyC
: N
ot r
ecom
men
ded
A:
5 m
g/kg
(30
0 m
g)O
nce
wee
kly
C:
Not
rec
omm
ende
dA
: N
ot r
ecom
men
ded
Twic
e w
eekl
yC
: N
ot r
ecom
men
ded
A:
5 m
g/kg
(30
0 m
g)Th
ree
times
wee
kly
C:
Not
rec
omm
ende
dA
: 5
mg/
kg (
300
mg)
Hep
atiti
s fe
ver,
thro
mbo
cyto
peni
a,
neut
rope
nia,
leuk
open
ia,
flulik
e sy
mpt
oms,
hy
peru
ricem
ia.
Ora
nge
disc
olor
atio
n of
se
cret
ions
(sp
utum
, ur
ine,
sw
eat,
tea
rs)
and
may
per
man
ently
sta
in s
oft
cont
act
lens
es.
Redu
ces
leve
ls o
f m
any
drug
s, in
clud
ing
met
hado
ne,
war
farin
(C
oum
adin
), bi
rth
cont
rol p
ills,
the
ophy
lline
, da
pson
e,
keto
cona
zole
, PI
s, a
nd N
NRT
Is.
With
in
crea
sed
rifab
utin
leve
ls,
seve
re a
rthr
algi
as,
uvei
tis,
leuk
open
ia o
ccur
.
Base
line
hepa
tic e
nzym
es.
Repe
at if
bas
elin
e va
lues
ab
norm
al,
risk
fact
ors
for
hepa
titis
, or
sym
ptom
s of
ad
vers
e re
actio
ns.
Cap
sule
s: 1
50 m
gPa
tient
s on
met
hado
ne m
ay n
eed
an
incr
ease
d do
se t
o av
oid
opia
te
with
draw
al.
Inte
ract
ion
with
man
y dr
ugs
lead
s to
dec
reas
ed le
vels
of
one
or b
oth.
M
ay m
ake
gluc
ose
cont
rol m
ore
diffi
cult
in d
iabe
tics.
Wom
en o
n bi
rth
cont
rol p
ills
need
to
use
a ba
rrie
r m
etho
d w
hile
on
rifab
utin
.In
com
bina
tion
with
NN
RTIs
or
PIs,
do
sage
s ch
ange
sig
nific
antly
.
Cont
inue
d
370Part
II
Infe
ctio
us
Dis
ease
s an
d t
hei
r Et
iolo
gic
Ag
ents
DR
UG
DO
SE
(MA
XIM
UM
)M
AJO
R A
DV
ERSE
REA
CTI
ON
SR
ECO
MM
END
ED
MO
NIT
OR
ING
DO
SAG
E FO
RM
SC
OM
MEN
TS
Rif
apen
tin
e (R
PT)
Onc
e w
eekl
y on
lyC
: N
ot a
ppro
ved
for
use
in
child
ren
A:
10 m
g/kg
(60
0 m
g)(D
ata
indi
cate
tha
t 90
0 m
g of
RPT
is w
ell-t
oler
ated
an
d C
DC
is r
ecom
men
ding
th
is h
ighe
r do
se f
or la
tent
tu
berc
ulos
is.)
Hep
atiti
s, t
hrom
bocy
tope
nia,
neu
trop
enia
, le
ukop
enia
, hy
peru
ricem
ia,
flulik
e sy
ndro
me.
Red
uces
leve
ls o
f m
any
drug
s,
incl
udin
g m
etha
done
, w
arfa
rin (
Cou
mad
in),
birt
h co
ntro
l pill
s, t
heop
hylli
ne,
daps
one,
ke
toco
nazo
le,
PIs,
and
NN
RTIs
. O
rang
e di
scol
orat
ion
of s
ecre
tions
(sp
utum
, ur
ine,
sw
eat,
tea
rs)
and
may
per
man
ently
sta
in
soft
con
tact
lens
es.
Base
line
hepa
tic e
nzym
es,
CBC
, an
d pl
atel
ets.
Rep
eat
if ba
selin
e va
lues
are
abn
orm
al,
risk
fact
ors
for
hepa
titis
are
pr
esen
t, o
r th
ere
are
sym
ptom
s of
adv
erse
re
actio
ns.
Tabl
ets
(film
-coa
ted)
: 15
0 m
gIn
dica
tions
: Pu
lmon
ary
TB
patie
nts
who
are
HIV
ne
gativ
e, n
onca
vita
ry,
not
preg
nant
, w
ith o
rgan
ism
s pa
n-se
nsiti
ve a
nd c
ultu
re
nega
tive
at 2
mon
ths
(tw
o co
nsec
utiv
e ne
gativ
e cu
lture
s).
Adm
inis
tere
d on
ce w
eekl
y w
ith IN
H
durin
g th
e co
ntin
uatio
n ph
ase
of t
reat
men
t.
See
drug
inte
ract
ions
with
rifa
mpi
n.
A, a
dult;
C, c
hild
; CBC
, com
plet
e bl
ood
cell
coun
t; C
DC
, Cen
ters
for
Dis
ease
Con
trol
and
Pre
vent
ion;
CN
S, c
entr
al n
ervo
us s
yste
m; H
IV, h
uman
imm
unod
efici
ency
viru
s; IM
, int
ram
uscu
lar;
IV
, in
trav
enou
s; N
NRT
Is,
non-
nucl
eosi
de r
ever
se-t
rans
crip
tase
inhi
bito
rs;
PIs,
pro
teas
e in
hibi
tors
; PO
, or
ally
.*C
ombi
natio
n dr
ugs
are
reco
mm
ende
d in
the
rar
e in
stan
ce i
n w
hich
a p
atie
nt i
s pl
aced
on
self-
adm
inis
tere
d th
erap
y: I
sona
Rif
cont
ains
IN
H,
150
mg,
RIF,
300
mg;
Rifa
mat
e co
ntai
ns
INH
, 15
0 m
g, R
IF, 3
00 m
g; R
ifate
r co
ntai
ns IN
H,
50 m
g, R
IF, 1
20 m
g, a
nd P
ZA,
300
mg.
† In 2
003,
the
CD
C r
ecom
men
ded
dosi
ng b
ased
on
wei
ght
rang
es f
or P
ZA a
nd E
MB.
Aft
er r
evie
win
g av
aila
ble
data
, th
e M
aryl
and
TB E
xper
t pa
nel
reco
mm
ende
d th
at t
he p
revi
ousl
y re
com
men
ded
dosa
ge r
ange
s be
util
ized
, ad
visi
ng u
se o
f th
e lo
wes
t po
ssib
le d
ose
in t
he d
ose
rang
e.M
odifi
ed fr
om th
e 20
07 M
aryl
and
Gui
delin
es fo
r Pre
vent
ion
and
Trea
tmen
t of T
uber
culo
sis.
Ava
ilabl
e at
htt
p://p
hpa.
dhm
h.m
aryl
and.
gov/
OID
PCS/
CTB
CP/
CTB
CPD
ocum
ents
/tbg
uide
lines
.
TAB
LE 1
80
-2
Firs
t-Li
ne T
ub
erc
ulo
sis
Med
icati
on
s—co
nt’
d
371
181 Mycobacterium leprae (Leprosy)Cybèle A. Renault and Joel D. Ernst
MICROBIOLOGY AND EPIDEMIOLOGY• Acid-fast–andGramstain–positiveMycobacterium lepraecannotbeculturedinvitro.• Predominantmodeoftransmissionislikelythroughrespiratorydropletsornasalsecretions,
althoughtransmissionmayalsooccurthroughskincontact,transplacentally,viabreastmilk,andafterzoonotic(particularlyarmadillo)exposure.
• Risk factors for clinical disease include age (bimodal distribution: adolescents and adultsolderthan30yearsareathighestrisk),gender(nodifferencesnotedinchildren,althoughadultmenhavedoubletheriskcomparedwithadultwomen),anddegreeofcontact(indi-vidualsincontactwithpatientswithmultibacillarydiseaseareathighestrisk).
• Estimates of leprosy incidence and prevalence are underestimated owing to difficulty indiagnosingsubclinicaldisease(themajorityofthoseinfected)andinlightoftheassociatedstigmatizationofinfectedindividuals.
CLINICAL MANIFESTATIONS AND IMMUNOLOGIC SPECTRUM OF DISEASE• Clinicalandpathologicmanifestationsarise inadistinctandwell-characterizedspectrum
basedonhostimmuneresponsetotheorganism.Spectrumrangesfromtuberculoidleprosy(smallnumberofskinlesions,fewbacilli inlesions,andarobustT-lymphocyteresponse)to lepromatous leprosy (larger number of skin lesions, clinically apparent infiltration ofperipheralnerves,largenumberofbacilli,andalowT-lymphocyteresponse).
• Clinicalmanifestationsvarysignificantly,dependingonthesubtypeofdisease.Therearetwoclinicalclassificationsystems:WorldHealthOrganization(WHO)(usedinresource-limitedsettings)andRidley-Jopling(usedwhenhistopathologyisavailable).
• Skin lesions are hypopigmented, erythematous, or infiltrative with or without neurologicsignsorsymptoms,includinghypoesthesia,weakness,autonomicdysfunction,orperipheralnervethickening.
• Peripheralsensorynervedamage(mediateddirectlybyM. lepraeorbytheimmuneresponseto the organism) is the leading cause of functional morbidity and is seen throughout thediseasespectrum.
• Reactions include reversal reactions, which present most often as increased erythema ofpreexisting skin lesions and progressive peripheral neuropathy, and erythema nodosumleprosum(ENL),whichpresentsassystemicsignsandpainfulerythematousskinnodules.
DIAGNOSIS• Leprosy isdiagnosedusinga combinationof clinical examinationand skin slit smearsor
skinbiopsy.• Skinslitsmear:HeatfixationandZiehl-NeelsenorFitestainingareusedtoevaluatebacillary
loadandtypicallydoneinsixsites.• Skinbiopsy:Histopathologyisthegoldstandardforestablishingadefinitivediagnosisand
for accurately classifying the subtype of disease but is often not available in endemiccountries.
372Part
II
Infe
ctio
us
Dis
ease
s an
d t
hei
r Et
iolo
gic
Ag
ents
• M. lepraepolymerasechainreactionassayisnotcurrentlyavailableforcommercialusebutcanbeperformedinspecializedcenters(e.g.,NationalHansen’sDiseaseProgram[NHDP])to identify the organism in skin specimens that stain positive for acid-fast organisms butwherecultureresultsarenegative.
THERAPY (SEE TABLE 181-1)• Dapsone,rifampin,andclofaziminearethethreeestablishedantimicrobialagents.Alternative
agents includeofloxacin,minocycline,andclarithromycin.Standardtherapyusesmultipledrugstoincreasecurerateandpreventemergenceofdrugresistanceandtreatmentfailure.
• Recommendedtreatmentcoursesvarybasedonsubtypeofdiseaseandresourcesavailable.Althoughboth theWHOandNHDPrecommendmultipledrug therapy, theU.S. recom-mendationsincludedailyrifampin(incontrasttomonthlydosing)andrecommendlongerdurationsoftherapycomparedwithWHOrecommendations.
• Choiceof therapy for reversal reactions shouldbemadebasedon the severityofdisease.TreatmentofchoiceforbothreversalandENLreactions,particularlyinthesettingofacuteneuritis,iscorticosteroids.Thalidomide(forENLonly)andclofaziminearecorticosteroid-sparingagents thatcanbeused inchroniccases.Multipledrug therapy shouldalwaysbecontinuedinpatientspresentingwithreactions.
TABLE 181-1 Recommended Regimens to Treat Leprosy in Adults
Disease Stage Agent
WHO RECOMMENDATIONS
U.S. (NHDP) RECOMMENDATIONS
Dose Duration Dose DurationPaucibacillary or “tuberculoid” disease (TT, BT)
Dapsone 100 mg/day 6 mo 100 mg/day 12 mo
Rifampin 600 mg/mo 600 mg/day
Multibacillary or “lepromatous” disease (BB, BL, LL)
Dapsone 100 mg/day 12 mo 100 mg/day 24 mo
Rifampin 600 mg/ mo 600 mg/day
Clofazimine 50 mg/day, 300 mg/mo
50 mg/day
BB, mid-borderline; BL, borderline lepromatous; BT, borderline tuberculoid; LL, lepromatous leprosy; NHDP, National Hansen’s Disease Program; TT, tuberculoid; WHO, World Health Organization.
373
182 Mycobacterium avium ComplexFred M. Gordin and C. Robert Horsburgh, Jr.
MICROBIOLOGY AND EPIDEMIOLOGY• Mycobacterium avium and Mycobacterium intracellulare are closely related in a complex
(MAC).• MACisfoundinwater,soil,andanimalsbutnotspreadfrompersontoperson.• Thesourcefromwhichpatientsacquirethediseaseisusuallyunknown.• MACcausespulmonarydisease,lymphadenitis,anddisseminateddisease.• Pulmonary disease occurs in older patients with chronic obstructive pulmonary disease,
priorpneumonia,cysticfibrosis,andsteroiduse,aswellasolderwomenwithnopredispos-ingfactors.
• Lymphadenitisismostlyinchildrenyoungerthan5yearsofage.• Disseminateddiseaseoccursmostlyinpatientswithacquiredimmunodeficiencysyndrome
andaCD4+cellcountlessthan50/mm3.
CLINICAL MANIFESTATIONS AND DIAGNOSIS• Pulmonarydiseasecanbe infiltrativewithorwithoutcavities,nodular (solitaryormulti-
nodular), pleural, or as a hypersensitivity pneumonitis. It can closely mimic tuberculosis.Diagnosisrequiresatriadofclinicalsymptoms,radiographicabnormalities,andculture.
• Lymphadenitisisusuallycervicofacial,unilateral,andpainless.Diagnosisisvialymphnodeaspirationorexcision.
• Disseminated disease is usually accompanied by fever, weight loss, and night sweats.Diagnosis ismade inmore than90%ofpatientsbybloodcultures forM. aviumcomplex(MAC).
TREATMENT (SEE TABLES 182-1 AND 182-2)• Forpulmonarydisease:
• Starttreatmentforpulmonarydiseasewithclarithromycinorazithromycin,plusetham-butolandeitherrifampinorrifabutin.Moreadvanceddiseasemayrequiretheadditionofaminoglycosides,usuallyamikacin.
• Treat pulmonary disease until cultures have been negative for at least 12 months; theusualtotaldurationis18to24months.
• Hypersensitivitypneumonitismaybetreatedwithavoidanceofexposureorshort-terminhaledsteroids,orboth.
• Lymphadenitiscanbetreatedwithsurgicalexcisionorclarithromycinplusethambutoluntilthenoderesolves.
• Humanimmunodeficiencyvirus(HIV)-infectedpatientswithdisseminateddiseaseshouldbe treated with clarithromycin plus ethambutol and possibly rifabutin or rifampin. Theseindividualsshouldhaveantiretroviraltherapyinitiatedafter2to4weeks.AntibiotictherapyfordisseminatedMACshouldbecontinuedfor1yearandmaythenbediscontinuediftheCD4+cellcountisgreaterthan100/mm3.Immunereconstitutioninflammatorysyndromemaycomplicaterecovery.
374Part
II
Infe
ctio
us
Dis
ease
s an
d t
hei
r Et
iolo
gic
Ag
ents
PREVENTION• HIV-infected persons with fewer than 50 CD4+ cells/mm3 should be given azithromycin
1200mg once weekly to prevent disseminated MAC. This can be stopped once sustainedCD4+cellcountsabove100/mm3haveoccurred.
TABLE 182-1 Drugs Employed in the Treatment of Mycobacterium avium Complex Disease
DRUG USUAL DAILY DOSE*USUAL INTERMITTENT DOSE
COMMON ADVERSE EFFECTS
Clarithromycin 500 mg bid 1 g tiw GI distress, bitter taste, rash, hearing loss, drug interactions
Azithromycin 250 mg qd 500-600 mg tiw GI distress, hearing loss
Ethambutol 15 mg/kg qd 25 mg/kg tiw At high doses: optic neuritis, GI distress
Rifabutin 300 mg qd 300 mg tiw GI distress, hepatitis, neutropenia, drug interactions; at high doses: uveitis, arthralgias
Rifampin 600 mg qd 600 mg tiw GI distress, hepatitis, neutropenia, drug interactions
Amikacin Not recommended 15 mg/kg IV tiw Vestibular and auditory abnormalities, renal toxicity
Streptomycin Not recommended 15 mg/kg IM (maximum tiw 1 g)
Vestibular and auditory abnormalities, renal toxicity
GI, gastrointestinal; tiw, three times weekly; IM, intramuscularly; IV, intravenously.*Oral dosing unless otherwise indicated.
TABLE 182-2 Regimens for Pulmonary Mycobacterium avium Complex
INITIAL THERAPY FOR NODULAR/BRONCHIECTATIC DISEASE
INITIAL THERAPY FOR CAVITARY DISEASE
ADVANCED (SEVERE) OR PREVIOUSLY TREATED DISEASE
Clarithromycin 1000 mg tiw orAzithromycin 500-600 mg tiw plus
Clarithromycin 500-1000 mg/day orAzithromycin 250-300 mg/day plus
Clarithromycin 500-1000 mg/day orAzithromycin 250-300 mg/day plus
Ethambutol 25 mg/kg tiw plus Ethambutol 15 mg/kg/day plus Ethambutol 15 mg/kg/day plus
Rifampin 600 mg tiw Rifampin 600 mg/day with or without
Rifabutin 300 mg/day orRifampin 600 mg/day plus
Streptomycin orAmikacin
Streptomycin orAmikacin
tiw, three times weekly.Modified from An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous myco-
bacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416.
375
183 Infections Caused by Nontuberculous Mycobacteria Other Than Mycobacterium Avium ComplexBarbara A. Brown-Elliott and Richard J. Wallace, Jr.
DEFINITION• ComposedofspeciesotherthanMycobacterium tuberculosiscomplex(MTBC)• Previouslyknownas“atypicalmycobacteria”or“mycobacteriaotherthanM. tuberculosis”• Morethan150speciesofnontuberculousmycobacteria(NTM)• Dividedintorapidly,intermediate,andslowlygrowingspecies
EPIDEMIOLOGY• Mostspeciesareworldwideandubiquitousintheenvironment,includinghouseholdwater,
pottingsoil,vegetablematter,animals,andbirds.• NTMincludepathogensandnonpathogens.• Casesinchronic(e.g.,pulmonary)infectionsinvolvepatientswithunderlyingdiseasesuch
asbronchiectasisandcysticfibrosis.• Othercasesinvolveextrapulmonarysites,includingskinandsofttissue,bones,joints,bursae,
tendonsheaths,lymphnodes,eyes,ears,blood,brain,andcerebrospinalfluid.
MICROBIOLOGY• Acid-fastbacilli(AFB)stainpoorlywithGramstaining.• Identification of definitive species level is only accomplished by molecular or proteomic
methodsatpresent.
Rapidly Growing Mycobacteria• Rapidly growing mycobacteria (RGM) produce mature colonies on solid media within
7days.• Routineculturemediasuchasbloodagar,chocolateagar,trypticasesoyagar,mostMTBC
media(Middlebrook7H10or7H11agarandLowenstein-Jensenagar),andvariousbroths,includingrapidbrothdetectionsystems,supportthegrowthofmostspecies.
• Preferenceisfor28°to30°Cincubationforsomespecies,althoughmanyspeciesalsogrowat35°C.
• SomeRGM,especiallyMycobacterium abscessus,areadverselyaffectedbyharshdecontami-nationmethodsthatareusedforisolationofMTBC.
• Currently six groups of pathogenic species are defined based on presence or absence ofpigmentandgeneticrelatedness.
Intermediately Growing Mycobacteria• MostMTBCmediaincludingMiddlebrook7H10or7H11agarandLowenstein-Jensenagar
supportgrowthofspecies.• Theyrequire7to10daystoreachmaturegrowth.• Primarilytwopigmentedspeciesareinvolved:
• Mycobacterium marinum (pathogen) grows optimally at 28° to 30°C and is associatedwithmarinewaterandmarineanimals.
376Part
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us
Dis
ease
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r Et
iolo
gic
Ag
ents
• Mycobacterium gordonae(nonpathogen)growsoptimallyat35°to37°Candisacommontapwatercontaminant.
Slowly Growing Mycobacteria• Producematurecoloniesinmorethan7daysonsolidmedia• Most MTBC media, including Middlebrook 7H10 or 7H11 agar, Lowenstein-Jensen agar,
Middlebrookbroth,andrapiddetectionbrothsystems,supportgrowthofspecies,exceptforfastidious species such as Mycobacterium haemophilum (requires hemin or iron) andMycobacterium genavense(requiresMycobactinJ).
• MostspeciesexceptM. haemophilum (28°to30°C),Mycobacterium xenopi (42°to45°C),andsomeenvironmentalspeciesgrowoptimallyat35°to37°C.
DIAGNOSISPulmonary• SignsandsymptomsofNTMlungdiseasearevariableandnonspecific.• Patientsoftenpresentwithchroniccoughorthroatclearing,withorwithoutsputumproduc-
tionandseverefatigue.Lessfrequentlymalaise,dyspnea,fever,hemoptysis,andweightlossmayoccur.
• ClinicaldiagnosisdependsonmultiplepositivemicrobiologicculturesofrespiratorysamplesforAFB.
• FollowtheAmericanThoracicSocietyguidelinesfordiagnosis.• High-resolutionchestcomputedtomographyisuseful.• Routinechestradiographsarerecommended.• SinglepositivesputumculturesarenotdefinitiveforNTMdisease.• ExpertconsultationisrequiredforpatientswithinfrequentlyencounteredspeciesofNTM.
Extrapulmonary• Infectionmayinvolvefever,drainage,bacteremia,granulomatoussystemicinfections,necro-
sis,etc.dependingonthesiteofinfection.• Clinicaldiagnosisdependsonpositivemicrobiologicsmearsandculturesformycobacteria
ofdrainage,biopsytissue,orbodyfluid,leadingtoisolationofspecificNTM.
THERAPYRapidly Growing Mycobacteria• Pulmonary disease
• MostpulmonarydiseaseiscausedbyM. abscessusorM. abscessussubsp.massiliense.• Antimicrobial therapy alone is generally unsuccessful for microbiologic eradication of
M. abscessus.• Rifampin, rifabutin, ethambutol, isoniazid, streptomycin, and pyrazinamide are not
effective.• Multidrugregimensofmacrolides(azithromycinorclarithromycin),high-doseIVcefox-
itin(8to12g/dayindivideddoses)orimipenem(1gtwicedaily),andlow-doseparen-teral amikacin (peaks in the 20 to 25µg/mL range on once-daily dosing) probablyoptimalforM. abscessus.DailyIVtigecyclineoftenincluded;dosageadjustmentisusuallynecessary for clinical improvement, not cure. The role of inhaled amikacin is not yetestablished.
• PatientswithM. abscessusare treated forseveralmonthsuntilclinically improvedandmayrequireseveralcoursesoftreatment.
• Macrolides may not be useful for isolates of M. abscessus (but not M. massiliense), Mycobacterium fortuitum,andMycobacterium smegmatisthatcontainfunctionalinduc-ibleermgenes.
• OtherantimicrobialsareoftenusefulforspeciesotherthanM. abscessus(minocycline,doxycycline, trimethoprim/sulfamethoxazole [TMP-SMX], quinolones, linezolid, and,forMycobacterium chelonae,tobramycin).
• Extrapulmonary disease
377C
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ns C
aused
by N
on
tub
erculo
us M
ycob
acteria Oth
er Than
Myco
bacteriu
m A
vium
Co
mp
lex
• Generallycliniciansprescribeamultidrugregimenbasedoninvitrosusceptibilitytesting,includingamacrolide(exceptincaseoferm-positivespecies).
• Rifampin,rifabutin,ethambutol,andisoniazidarenoteffective.• Patientswithsignificantdiseasearetreatedfor6months,dependingontheseverityof
infection.• OtherantimicrobialsoftenusefulforspeciesoftheM. fortuitumgroupareminocycline,
doxycycline,TMP-SMX,quinolones,linezolid,and,forM. chelonae,tobramycin.
Intermediately Growing Mycobacteria• M. marinumisfoundonskinandinsofttissueinfections(usuallyhands).• Treatmentoptionsincludemacrolides,rifampin,TMP-SMX,oracombinationofrifampin
andethambutol.
Slowly Growing Mycobacteria• Pulmonary disease
• Antibiotic treatmentgenerally follows theregimen forMycobacterium avium complex:rifampin, ethambutol, and a macrolide (clarithromycin or azithromycin) with adjust-mentsdependingoninvitroantimicrobialsusceptibilitytesting.
• Patientsaregenerallytreatedfor12monthsofculturenegativity.• Extrapulmonary disease
• Treatment is the same as for pulmonary disease except that it is usually for 6 monthsdependingontheseverityofinfection.
PREVENTION• Noevidenceofperson-to-personspreadofNTMexists.• Tap(household)waterisconsideredthemajorreservoirformostcommonNTMspecies.• BiofilmsmayrenderNTMlesssusceptibletodisinfectantsandantimicrobials.• Publichealthconcernsareincreasing.
378
184 Nocardia SpeciesTania C. Sorrell, David H. Mitchell, Jonathan R. Iredell, and Sharon C-A. Chen
DEFINITION• NocardiosisresultsfrominfectionbymembersofthegenusNocardia,whichareubiquitous
environmental saprophytes that cause localized or disseminated disease in humans andanimals.
MICROBIOLOGY AND EPIDEMIOLOGY• Microscopically,Nocardiaappearasgram-positive,beaded,weaklyacid-fast,branchingrods.• Molecular speciation has revolutionized taxonomy by identifying several new species
and reassigning species, especially from the commonest pathogenic group, the formerN. asteroidescomplex.
• Infectionarisesbydirectinoculationthroughtheskinorbyinhalation.• MycetomasfromNocardiaspecies,mostoftencausedbyN. brasiliensis,affectimmunocom-
petenthostsintropicalcountries.• Immunocompromise,alcoholism,andcertain lungdiseasespredisposepatientstopulmo-
nary and disseminated nocardiosis, most often due to N. cyriacigeorgica, N. nova, orN. farcinica.
CLINICAL MANIFESTATIONS• Primaryskininfectioncancausesporotrichoidlesionsandleadtopyogenicabscessesorto
chronicallyprogressive,destructivediseasewithsinustractformation(mycetoma)usuallyonadistallimb.
• Presentationoflungdiseasemaybesubacuteorchronicwithproductiveornonproductivecough, dyspnea, hemoptysis, and fever and other systemic symptoms. Cavity formationwithinthepneumoniaorspreadtothecentralnervoussystem(CNS),orboth,aresuggestiveofnocardiosis.IsolatedCNSlesionsalsooccurandtheirpresentationcanbeinsidious.
DIAGNOSIS• Cerebralimaging,preferablymagneticresonanceimaging,shouldbeperformedinallcases
ofpulmonaryanddisseminatednocardiosistoruleoutinsidiousCNSdisease.• Themicrobiology laboratoryshouldbe informedof suspectednocardiosisbecause itmay
not be detected by routine laboratory methods. Respiratory secretions, skin biopsies, oraspiratesfromdeepcollectionsarethemostusefulandaretypicallypositiveonGramstain.Modifiedacid-faststainofsputumorpusishelpfulinsuggestingthediagnosis.GrowthofNocardiaspeciesmaytake48hourstoseveralweeksbutusually3to5days.
• Speciesidentificationispredictiveofantimicrobialsusceptibility;itrequiresmoleculariden-tificationtestsbasedonnucleicacidtechnology(NAT).
• Recentlymassspectrometryanalysisusingmatrix-assistedlaserdesorption/ionizationtime-of-flightmass spectrometryhasbeen reported tobea reliable andmore rapidalternativetoNAT.
379C
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ecies
THERAPY AND FOLLOW-UP• Trimethoprim-sulfamethoxazole(TMP-SMX)isthemainstayoftreatment,andmonother-
apyisusuallysuccessfulinpatientswithisolatedskininfectionormycetomasthatarenotextensive(seeTable184-1).
• In systemicdisease, speciationand/or susceptibility testing results shouldguidedefinitivecombinationtherapy.
• EmpiricaltherapywithamikacinandimipenemormeropenemoramikacinandTMP-SMXarerecommendedinimmunocompromisedpatientsorthosewithdisseminateddiseasebutnobraininvolvement.
• For isolated cerebral disease, empirical TMP-SMX plus imipenem or meropenem aresuitable.
• When additional sites are involved or the patient has life-threatening disease, empiricalthree-drugregimenssuchasTMP-SMX,imipenemormeropenem,andamikacin(orceftri-axone,inpatientswithrenalfailure)arepreferred.Initialadjunctivetherapywithlinezolidisanoption,especiallyifoneoftheseclassesofdrugiscontraindicated.
• Clinical improvement isgenerallyevidentwithin3 to5daysor,at themost,7 to10daysafterinitiationofappropriatetherapy.
• Prolongedtherapyisnecessarytopreventrelapse.• Surgical excision may be required depending on the extent and site of the lesions or the
responsetomedicaltherapy,orboth.• Patientswithdeep-seatedinfectionshouldbemonitoredclinicallyandradiologicallyduring
andforupto12monthsaftercessationoftherapy.
TABLE 184-1 Antimicrobial Susceptibility of Selected Nocardia Species
N.
cyri
acig
eorg
ica
N.
farc
inic
a
N.
no
va c
om
ple
x
N.
tran
sval
ensi
s co
mp
lex
N.
bra
silie
nsi
s
Trimethoprim-sulfamethoxazole S R S S S
Amoxicillin clavulanate R V R V S
Ceftriaxone S R S S R
Imipenem S S S S R
Amikacin S S S R S
Linezolid S S S S S
Moxifloxacin V S R ND R
Clarithromycin R R R S R
Minocycline V R V R R
Tigecycline V R V ND S
ND, no data; R, generally inactive; S, generally active (some isolates may be resistant); V, may be active but resistance common.
Data taken from multiple published sources.
380
185 Agents of ActinomycosisThomas A. Russo
DEFINITION• Indolentinfection• Chronicity,crossestissueboundaries,masslikefeatures• Mimicsmalignancy• Sinustract(s)maydevelop,resolve,andrecur• Refractoryorrelapsinginfectionmayoccurafterashortcourseoftherapy
MICROBIOLOGY• PrimarilycausedbyActinomycesspp.• Gram-positive,primarilyfilamentousbacteria• Mostareanaerobes,fewaremicroaerophilic• “Companionorganisms”areusuallypresent
EPIDEMIOLOGY/PATHOGENESIS• Humancommensaloforal,gastrointestinal,pelvicmucosa• Disruptionofmucosalsurfaceinitiatingfactor• Allagesandnormalhostsinfected• Associationwithintrauterinedevicesandbisphosphonates
CLINICAL MANIFESTATIONS• Allorgansandsitescouldbeinvolved• Orocervicofacialmostcommon• Classicpresentationaspainlessmassatangleofthejaw• Alternativepresentationsaremyriad
DIAGNOSIS• Challenging,oftenmissed,mistakenforcancer• Sulfurgranules• Informlaboratory• Priorantibioticscaninhibitgrowthonculture• Increasingroleforpolymerasechainreaction• Oftenmadeviapathologyafterpotentiallyunnecessarysurgery
THERAPY• Basedonclinicalexperience,individualized• Highdoseandprolongedcourseofantibiotics• Standard2to6weeksintravenously,followedby6to12monthsorally• Imaginghelpfulindefiningduration• Penicillin,tetracyclines,erythromycin,andclindamycinhavegreatestexperience• Ashortcourseoftreatmentdirectedagainst“companionorganisms”maybewarranted• Medicaltherapyusuallycurative,evenwithextensivedisease• Interventionalradiologyfordrainageofaccessibleabscess• Surgeryreservedforcriticalsites(e.g.,centralnervoussystem)andrefractorydisease
381
G Mycoses
186 Aspergillus SpeciesThomas F. Patterson
DEFINITION• AspergillosisiscausedbyspeciesofthemoldAspergillus.• Syndromesrangefromcolonization;fungusballduetoAspergillus(aspergilloma);allergic
responsestoAspergillus,includingallergicbronchopulmonaryaspergillosis;tosemi-invasiveorinvasiveinfections,fromchronicnecrotizingpneumoniatoinvasivepulmonaryaspergil-losisandotherinvasivesyndromes.
EPIDEMIOLOGY• The highest incidence of infection occurs in patients undergoing hematopoietic stem cell
transplantationorsolid-organtransplantation(seeTable186-1).• Infection is more likely in patients with extensive immunosuppression or in those with
relapseorrecurrenceofunderlyingmalignancy.• Improvedsurvivalhasbeennotedwithearlydiagnosisandnewertherapies,butmortality
ratesinseverelyorpersistentlyimmunosuppressedpatientsaresubstantial.
MICROBIOLOGY• Culture-baseddiagnosisisusefultoestablishthespecificdiagnosis.• Aspergillusspeciescomplexesexhibitdistinctantifungalsusceptibilitiessothatculture-based
diagnosisisclinicallyrelevant(seeTable186-2).• Molecularanalysisisrequiredtoestablishspecies-levelidentity.• Increasingratesofantifungalresistancearereportedinsomesettingswithaglobalcloneof
antifungal-resistantspecies.
DIAGNOSIS• Proveninfectionisestablishedbycultureoftheorganism.• Biomarkers such as galactomannan,β-D-glucan, and polymerase chain reaction assay are
usefulforestablishingprobablediagnosis.• Serialassessmentofbiomarkersmaybeusefulformeasuringresponsetotherapy.
THERAPY• Voriconazoleisrecommendedforprimarytherapyinmostpatients(seeTable186-3).• LiposomalamphotericinBcanbeusedasprimarytherapyinpatientsinwhomvoriconazole
isnottoleratedorcontraindicatedbecauseofdruginteractionsorotherreasons.• AlternativeagentsforsalvagetherapyincludeamphotericinBlipidcomplex,theechinocan-
dins(caspofungin,micafungin,oranidulafungin),posaconazole,oritraconazole.• Combinationtherapyisnotrecommendedforroutineuse,butsomesubgroupsofpatients
(e.g.,thosewithearlydiagnosisofinfectionbasedondetectionofgalactomannanorthosewithfailureofprimarytherapywithasingleagent)maybenefitfromsuchanapproach.
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ents
PREVENTION• Antifungalprophylaxiswithposaconazoleorpossiblyvoriconazoleisrecommendedinhigh-
riskpatients.• Therisk-benefitratioofprophylaxisinindividualpatientsatriskshouldbeconsidered.• Infectioncontrol is importanttoreducerisk inhospitalizedpatients,but longdurationof
risk (>180days) inhigh-riskhematopoietic stemcell transplantor solid-organ transplantpatientsmakescommunity-acquiredinfectionlikely.
TABLE 186-1 Incidence and Mortality of Invasive Aspergillosis in Transplantation
Type of Transplant
INCIDENCE (%)
12-Week Mortality (%)Range MeanAllogeneic stem cell 2.3-11 7 40-75
Autologous stem cell 0.5-2 1 50
Lung 2.4-9 6 5-21
Liver 1-8 4 45-59
Heart 0.3-6 2 15-21
Kidney 0.1-2 0.5 25-48
Data from the following sources:Kontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic
stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50:1091-1100.
Neofytos D, Treadway S, Ostrander D, et al. Epidemiology, outcomes, and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience. Transpl Infect Dis. 2013;15: 233-242.
Steinbach WJ, Marr KA, Anaissie EJ, et al. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect. 2012;65:453-464.
Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50: 1101-1111.
Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev. 2005;18:44-69.Neofytos D, Fishman JA, Horn D, et al. Epidemiology and outcome of invasive fungal infections in solid organ
transplant recipients. Transpl Infect Dis. 2010;12:220-229.Baddley JW, Andes DR, Marr KA, et al. Factors associated with mortality in transplant patients with invasive asper-
gillosis. Clin Infect Dis. 2010;50:1559-1567.
383C
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ergillu
s Species
TABLE 186-2 Characteristics of Aspergillus Species Associated with Invasive Infection
ASP
ERG
ILLU
S SP
ECIE
S
FREQ
UEN
CY
OF
SPEC
IES
CO
MPL
EX I
SOLA
TED
IN
C
LIN
ICA
L IN
FEC
TIO
N (
%)
CO
LON
Y C
HA
RA
CTE
RIS
TIC
S
MIC
RO
SCO
PIC
FEA
TUR
ES
CLI
NIC
AL
SIG
NIF
ICA
NC
E
A. fumigatus 50-67 Smoky gray-green; may have pale yellow or lavender reverse; grows at 50° C
Columnar; uniseriate; smooth to finely roughened conidia 2-3.5 µm
Most common invasive species; most pathogenic
A. flavus 8-14 Olive to lime green Radiate to loosely columnar; uniseriate or biseriate; rough conidiophore; conidia 3-6 µm
Sinusitis; skin infection; produces aflatoxin
A. terreus 3-5 Beige to cinnamon buff
Columnar; biseriate; globose; small 2-2.5 µm conidia; globose accessory conidia along hyphae
Increasingly detected; resistant to amphotericin B; more susceptible to newer azoles
A. niger 5-9 Initially white, rapidly turning black with yellow reverse
Radiate; biseriate; globose, black, very rough conidia 4-5 µm
Uncommon in invasive infections; superficial agent of otic disease; colonization
Data from the following references:Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis: disease spectrum, treatment practices, and
outcomes. I3 Aspergillus Study Group. Medicine (Baltimore). 2000;79:250-260.Alastruey-Izquierdo A, Mellado E, Cuenca-Estrella M. Current section and species complex concepts in Aspergillus:
recommendations for routine daily practice. Ann N Y Acad Sci. 2012;1273:18-24.Balajee SA, Kano R, Baddley JW, et al. Molecular identification of Aspergillus species collected for the Transplant-
Associated Infection Surveillance Network. J Clin Microbiol. 2009;47:3138-3141.Sutton DA, Fothergill AW, Rinaldi MG, eds. Guide to Clinically Significant Fungi. Baltimore: Williams & Wilkins;
1998.
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TABLE 186-3 Antifungal Agents for Invasive Aspergillosis
AG
ENT
CLA
SS
RO
UTE
OF
AD
MIN
ISTR
ATI
ON
DO
SE
CO
MM
ENTS
Primary TherapyVoriconazole Azole IV/
oral6 mg/kg (IV) q12h × 2 doses, followed by 4 mg/kg (IV) q12h or 200 mg (PO) q12h. Some experts advise oral dosing as 4 mg/kg (PO) q12h.
Recommended for primary therapy in most patients due to randomized trial demonstrating improved survival as compared with amphotericin B deoxycholate; caution for use in patients with potential liver toxicity and for drug interactions; measurement of serum levels advocated for efficacy and avoidance of toxicity (controversial)
Alternative Primary TherapyLiposomal amphotericin B
Polyene IV 3 mg/kg/day Well tolerated; minimal infusion reactions or nephrotoxicity; initial doses of 10 mg/kg/day more toxic and not more effective
Other AgentsAmphotericin B Polyene IV 1-1.5 mg/kg/day Previous gold standard; significant
toxicity in higher doses; limited efficacy in high-risk patients
Amphotericin B lipid complex
Polyene IV 5 mg/kg/day Indicated for patients intolerant or refractory to standard therapy; case-controlled data suggest better efficacy than amphotericin B deoxycholate
Amphotericin B colloidal dispersion
Polyene IV 3-6 mg/kg/day More infusion-related toxicity than other lipid formulations; efficacy similar to amphotericin B in primary treatment
Posaconazole Azole Oral Investigational in United States for Aspergillus treatment: 400 mg (PO) bid; prophylaxis 200 mg (PO) tid
Oral formulation; efficacy in salvage therapy and prophylaxis
Itraconazole Azole Oral 200 mg bid (PO) Erratic bioavailability improved with oral solution; serious cardiac adverse events with higher doses, drug interactions common; intravenous formulation not currently available
Caspofungin Echinocandin IV 50-70 mg/day Approved for refractory infection and intolerance to standard therapy; well tolerated; limited efficacy as monotherapy for primary infection; preclinical and anecdotal data showing improved efficacy in combination with azoles
Micafungin Echinocandin IV Investigational in United States for Aspergillus treatment (50-100 mg/day)
Efficacy for prevention and salvage treatment of aspergillosis
Anidulafungin Echinocandin IV Investigational for Aspergillus (100 mg/day)
Combination trial data showing improved outcomes in patients with galactomannan diagnosis of invasive pulmonary aspergillosis
385
187 Agents of Mucormycosis and EntomophthoramycosisDimitrios P. Kontoyiannis and Russell E. Lewis
DEFINITION• Mucormycosisisanaggressive,angioinvasivefungalinfectioncausedbyfilamentousfungi
inthesubphylumMucormycotina,whichafflictimmunocompromisedorseverelyhypergly-cemicpatients.Skinandsofttissueinfectionsinimmunocompetentpatientsmaybeencoun-teredinpatientswithseveresofttissuetrauma(e.g.,tornadoes,combatinjuries).
• Entomophthoramycosisisarareinfectionoftheparanasalsinuses,subcutaneoustissues,orgastrointestinaltractcausedbyfilamentousfungiinthesubphylumEntomophthoramycotina,whichareprincipallyencounteredinthetropics.
EPIDEMIOLOGY• Mucormycosis is acquired primarily via inhalation of environmental sporangiospores in
immunocompromisedhosts.Theinfectionmaybreakthroughantifungalprophylaxisregi-mensusedtoreducetheriskofaspergillosis.
• Entomophthoramycosis typically causes indolent subcutaneous infections localized to thesinuses,headandface(conidiobolomycosis),ortrunkandarms(basidiobolomycosis)frominhalationorminortrauma.Gastrointestinalbasidiobolomycosishasoccurred inArizonaandtheNearEastandisperhapsacquiredbyingestion.
MICROBIOLOGY• Mostcommonculture-confirmedcasesintheliteratureareRhizopusspecies(47%),Mucor
species(18%),Cunninghamella bertholletiae (7%),Apophysomyces elegans (5%),Lictheimia (Absidia) species (5%), Saksenaea species (5%), and Rhizomucor pusillus (4%), with otherspecies(8%)accountingfortheremainingcases.
• Conidiobolus coronatusandConidiobolus incongruuscauseconidiobolomycosis.Basidiobolus ranarumcausesbasidiobolomycosis.
DIAGNOSIS• Ahighindexofsuspicioninimmunocompromisedpatientsisessentialbecausemostsigns,
symptoms,andradiographicsignsarenonspecific.Cultureshaveapoorsensitivity.Diagnosisis typically established by histopathologic documentation of “ribbon-like” angioinvasivehyphaeintissue,thoughthisispronetoerror.
TREATMENT• Lipid formulations of amphotericin B are the drug of choice. Some patients can then be
transitionedtooralposaconazoleifabsorptionisadequate.
PREVENTION• Giventherarityofmucormycosisandentomophthoramycosis,primaryprophylaxis isnot
recommended. Secondary or potentially indefinite prophylaxis should be considered forimmunocompromisedpatientswithpreviousepisodesofmucormycosis,dependingonthestatusofunderlyingimmunosuppression.
386
188 Sporothrix schenckiiJohn H. Rex and Pablo C. Okhuysen
MICROBIOLOGY AND EPIDEMIOLOGY• Adimorphicfungus,withbuddingyeastintissueandamoldinculture• Worldwidedistribution,especiallyintropicalandsubtropicalregions• Acquisitionisassociatedwithexposuretosoil,plants,plantproducts(hay,straw,sphagnum
moss),andavarietyofanimals(especiallycats)• Growsslowlyonfungalculturefrominvolvedtissues
DIAGNOSIS• Lymphocutaneousdiseases:presentationwithanindolentpapulonodularlesion,sometimes
ulcerating,shouldsuggestthediagnosis.Secondarylesionsalonglymphangiticchannelsarecharacteristic. Biopsy will show pyogranulomas without visible organisms; culture will bepositive.
• Themostcommonextracutaneousformisosteoarticular.Pulmonarydisease(usuallycavi-tary)andmeningealdiseasearealsowelldescribed.Allarediagnosedbyculturewithorgan-ismsnotcommonlyseenonexaminationoftissuesandfluidsexceptincavitarypulmonarydisease.
• Multifocaldisseminationmayalsooccur,inimmunocompromisedsubjects:culturesofskinlesions and joints are usually positive, whereas blood and bone marrow cultures are onlyoccasionallypositive.
• Serodiagnosticmethodsremainexperimental.
THERAPY• Itraconazoleat200mg/dayorally is thetreatmentofchoicefor lymphocutaneousdisease,
with3to6monthsoftherapytypicallyneededforcompleteresolution.• Therapywithasaturatedsolutionofpotassiumiodideisalsoeffectiveforlymphocutaneous
disease,althoughassociatedwithmanysideeffects.• Itraconazoleisalsoactiveinextracutaneousdisease,butextendedtherapymayberequired.
Indifficultsettings,amphotericinBisalsoemployed.Improvementofimmunestatus(e.g.,introductionofantiretroviraltherapyinsubjectswithhumanimmunodeficiencyviruscoin-fection,reductionofimmunosuppressiveagents)isuseful.
387
189 Agents of ChromoblastomycosisDuane R. Hospenthal
DEFINITION• Chronicfungalinfectionlimitedtotheskinandsubcutaneoustissue• Scalynodular,tumorous,verrucous,plaque,orcicatriciallesions,typicallyaffectingthelower
extremities• Definedbythemicroscopicpresenceofmuriformcells
EPIDEMIOLOGY• Worldwidedistribution,withmostcasesoccurringintropicalandsubtropicalregions• LargestnumbersofcasesreportedfromMadagascar,Brazil,Mexico,Venezuela,andCosta
Rica• Male predominance, ages 40 to 69; commonly associated with outdoor activities such as
farmingorwoodcuttingandwithabsenceoffootwear
MICROBIOLOGY• MostcommonlycausedbyFonsecaea pedrosoi• Less commonly caused by Cladophialophora carrionii, Fonsecaea monophora, Fonsecaea
nubica, Phialophora verrucosa,orRhinocladiella aquaspersa• Otherdark-walledfungirarelyreportedascausativeagents
DIAGNOSIS• Presence of muriform cells (also called sclerotic, copper penny, or Medlar bodies)
pathognomonic• Muriformcellsobservedmicroscopicallyinskinscrapingspreparedwithpotassiumhydrox-
ideorinroutinelystainedskinbiopsyspecimens• Cultureonstandardmycologicmediapossiblebutnotalwaysnecessary
THERAPY• Noproventreatmentidentified• Small lesions treated successfully with surgical excision, liquid nitrogen or topical heat
application,orphotocoagulation;useofcurettageandelectrocauterydiscouragedbecauseofreportsofdiseasespreadaftertheiruse
• Oral itraconazole or terbinafine in combination with local liquid nitrogen therapy mosteffectivetherapy
• Posaconazole used successfully in small number of patients refractory to itraconazole orterbinafine
PREVENTION• Novaccineavailable• Needforfootwearandproperprotectiveclothing
388
190 Agents of MycetomaDuane R. Hospenthal
DEFINITION• Mycetoma is an infection of the skin and subcutaneous tissue characterized by a triad of
localizedswelling,drainingsinuses,andgrains(aggregatesofinfectingorganisms).• Itmostcommonlyaffectsasinglesite,typicallyinvolvingthelowerextremity,andespecially
thefoot.• Eumycetoma (eumycotic mycetoma) is mycetoma caused by fungi, most commonly
Madurella mycetomatis.• Actinomycetoma (actinomycotic mycetoma) is mycetoma caused by bacteria, most com-
monlyNocardia brasiliensis.
EPIDEMIOLOGY• Distributionisworldwidewithmostcasesoccurringintropicalandsubtropicalregions.• Largest numbers of cases are reported from Africa, Latin America, and the Indian
subcontinent.• Mycetoma occurs predominantly in men, ages 20 to 40, typically with occupations that
exposethemtotheenvironment.
MICROBIOLOGY• M. mycetomatis, Madurella grisea,andPseudallescheria boydiiarethemostcommoncauses
ofeumycetoma,althoughmanyothergeneraandspeciesoffungihavebeenreportedasetio-logicagents.
• N. brasiliensis, Actinomadura madurae, Streptomyces somaliensis,andActinomadura pelletieriare the most common causes of actinomycetoma, although disease secondary to otherspeciesofActinomadura, Nocardia,andStreptomyceshasbeendescribed.
DIAGNOSIS• Clinicalpresentationoftheclassictriadofchronic,painless,softtissueswellingwithdraining
sinusesthatdischargegrainsispathognomonic.• Microscopic examination of the grains can differentiate between eumycetoma and
actinomycetoma.• Cultureofcausativeagentfromgrainscanbetterdirectselectionofantimicrobialtherapy.• Radiographictechniques(plainradiographs,ultrasound,computedtomography,andmag-
neticresonanceimaging)canbeusedadjunctivelyinmaking(orexcluding)thediagnosisanddeterminingitsextent.
THERAPY• Smalllesionsmaybetreatedsuccessfullywithsurgicalexcisionalone.• Actinomycetomaistypicallytreatedwithmedicaltherapyalone.• Eumycetomacommonlyrequirescombinedmedicalandsurgicaltherapy.• Nosingletherapyhasprovedmosteffectiveforeitherformofmycetoma.• Mostactinomycetomaregimensincludeparenteralaminoglycosidesandoralsulfadrugs.
389C
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ents o
f Myceto
ma
• Less severe actinomycetoma may be treated with 6 to 24 months of trimethoprim-sulfamethoxazole.
• Eumycetomaistypicallytreatedwitharegimenofanoralazoleantifungaldrugfor6to24monthscombinedwithdebulkingsurgery.
PREVENTION• Novaccineisavailable.• Useoffootwearandproperprotectiveclothingshouldprotectagainstthisinfection.
390
191 Cryptococcosis (Cryptococcus neoformans and Cryptococcus gattii )John R. Perfect
HISTORY• Thelifecyclerepresentsbothasexual(clinical)andsexual(recombination)cycleswiththe
impactofsexualcycleonpathogenesis.
TAXONOMY• There are 19 cryptococcal species with two major pathogenic species, C. neoformans and
C. gattii.• Atpresent,thefollowingtaxonomicdivisionshavebeenproposed:Cryptococcus neoformans
var.grubii(serotypeA),withthreegenotypes(VNI,VNII,VNB);Cryptococcus neoformansvar.neoformans (serotypeDorVNIV);andfiveothercrypticspecies:Cryptococcus gattii, Cryptococcus bacillisporus, Cryptococcus deuterogattii, Cryptococcus tetragattii, andCryptococcus decagattii(serotypesB/CorVGl-lV).
IDENTIFICATION• Biochemicaltests,includingurease,melaninproduction,andappearanceofcapsule• CulturesorDNA-basedtests
ECOLOGY• C. neoformans(serotypesAandD)foundinpigeonguanotorottingtrees• C. gattiifoundineucalyptustoconiferoustrees(landscapeofnichemaybechanging)
EPIDEMIOLOGY• Notroutineconstituentofhumanbiotabutcancolonizehumanswithoutdisease• Widespreadasymptomaticinfectionsintheexposedpopulations• Risk factors for disease (acquired immunodeficiency syndrome [AIDS], corticosteroid
treatment, transplantation, cancer, monoclonal antibodies, sarcoidosis, autoantibodies togranulocyte-macrophagecolony-stimulatingfactor,idiopathicCD4lymphocytopenia);pri-marilycell-mediatedimmunitydefect(seeTable191-1)
• Antiretroviraltherapy(ART)impactonclinicalcryptococcosisisimpressiveinpatientswithAIDS.
• Amillionnewcasesofcryptococcosisperyear,withmorethan600,000deathsworldwideat thepeakof thehuman immunodeficiencyvirus (HIV)epidemicandprobablyreducedwithARTavailability
PATHOGENICITY• Virulencefactors(capsule,melanin,hightemperaturegrowth,urease,phospholipase)• Understandingatthegeneticandmolecularlevel
HOST RESPONSES• Efficientprotectionrequiresintactcell-mediated,innate,andhumoralimmunity.
391C
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ccosis (C
rypto
coccu
s neo
form
ans an
d C
rypto
coccu
s gattii)
PATHOGENESIS• Threefactors:(1)hostdefenses,(2)virulenceofstrain,and(3)sizeofinocula• Cryptococcosisconsideredprimarilyareactivationdisease
CLINICAL MANIFESTATIONS (SEE TABLE 191-2)• Majorsitesarethecentralnervoussystemandlung.• Othersiteswithuniqueconsiderationsaretheskin,prostate,peritoneum,andeye.• Cryptococcicaninfectanyorganofthehumanbody.• Diseaseprimarilydependsonhostimmunity(eitherfromtoolittleortoomuch[immune
reconstitutioninflammatorysyndrome,IRIS]).
LABORATORY DIAGNOSIS• Microscopy(Indiainkandhistopathologicstainsincludingmucicarmine)• Cultureofcerebrospinalfluid(CSF),blood,bronchoalveolarlavage• CryptococcalantigenonCSFandserumissensitiveandspecificasdetectedbylatexagglu-
tination,enzyme-linkedimmunosorbentassay,andlateralflow
MANAGEMENT• TheInfectiousDiseasesSocietyofAmericanGuidelinesin2010establishedroadmapsfor
therapiesandstrategies(www.idsociety.org/Organism/#Fungi).• Directantifungaldrugresistanceuncommonlyarisesduringtherapy.• TreatmentisbeststudiedforcryptococcalmeningitisinHIV-infectedpatients(2013guide-
lines at http://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/333/cryptococcosis).TreatmentisinitiatedwithamphotericinB,pref-erablywiththeliposomalformulationat3to4mg/kgdaily,thealternativesbeingthelipidcomplexat5mg/kgorconventionalamphotericinBat0.7mg/kg/day.Anyoneofthesecanbeusedplusflucytosine25mg/kgevery6hours(100mg/kgperday) forat least2weeksanduntilclinicallyimproved.Inseverelyillpatientsorthosewithhighintracranialpressure,delaying ART during these 2 weeks may prevent IRIS from complicating management.PatientswhorespondtoamphotericinBmaybeswitchedtofluconazole,400to800mg/day,for8to10weeksasaconsolidationphase.Finally,asuppressivephaseisbegunwithfluco-nazole200mgoncedaily.Antifungaltherapycanbestoppedafter1to2yearsinpatientswhorespondtoARTwithaCD4countabove100/µLforatleast3months,anondetectableviralload,andanegativeorlowserumcryptococcalantigen.
TABLE 191-1 Conditions Known or Possibly Associated with Predisposition to Cryptococcus neoformans InfectionsHIV infectionLymphoproliferative disordersSarcoidosisCorticosteroid therapyHyper-IgM syndromeHyper-IgE syndrome
Autoantibodies to GM-CSFMonoclonal antibodies (e.g., infliximab intercept, adalimumab, alemtuzumab)Systemic lupus erythematosus*HIV-negative CD4+ T-cell lymphocytopeniaDiabetes mellitus†
Organ transplantation*Peritoneal dialysisCirrhosis
GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus.*Immunosuppressive therapy may account for the predisposition.†Diabetes mellitus has historically been considered a risk factor for cryptococcal infection. However, diabetes is a
common disease, and it is unclear whether this condition is truly a specific risk factor for cryptococcosis.Modified from Casadevall A, Perfect JR. Cryptococcus neoformans. Washington, DC: ASM Press; 1998:410.
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• Complicationsofcryptococcalmeningitisrequiringspecialattentionare(1)increasedintra-cranialpressure,whichcan leadtoblindness,permanentdementia,anddeath;(2)hydro-cephalus, which may require placement of a ventriculoperitoneal shunt; and (3) immunereconstitutionsyndrome,whichmaybemistakenfortherapeuticfailure.
TABLE 191-2 Clinical Manifestations of Cryptococcosis
Central Nervous SystemAcute, subacute, chronic meningitis
Cryptococcomas of brain (abscesses)
Spinal cord granuloma
Chronic dementia (from hydrocephalus)
LungNodules (single or multiple)
Lobar infiltrates
Interstitial infiltrates
Cavities
Endobronchial masses
Endobronchial colonization
Acute respiratory distress syndrome
Mediastinal adenopathy
Hilar adenopathy
Pneumothorax
Pleural effusions/empyema
Miliary pattern
SkinPapules and maculopapules
Subcutaneous abscess
Vesicles
Plaques
Cellulitis
Purpura
Acne
Draining sinuses
Ulcers
Bullae
Herpetiformis-like
Molluscum contagiosum–like
EyePapilledema
Extraocular muscle paresis
Keratitis
Chorioretinitis
Endophthalmitis
Optic nerve atrophy
Genitourinary TractProstatitis
Renal cortical abscess
Positive urine culture from occult source
Genital lesions
Bone and JointsOsteolytic lesion (single or multiple sites)
Arthritis (acute/chronic)
MuscleMyositis
Heart, Blood VesselsCryptococcemia
Endocarditis (native and prosthetic)
Mycotic aneurysm
Myocarditis
Pericarditis
Infected vascular graft
Gastrointestinal TractEsophageal nodule
Nodular or ulcerated lesions in stomach or intestines (may resemble Crohn’s disease)
Hepatitis
Peritonitis
Pancreatic mass
BreastBreast abscess
Lymph nodes
Lymphadenopathy
ThyroidThyroiditis
Thyroid mass
Adrenal GlandAdrenal insufficiency
Adrenal mass
Head and NeckGingivitis
Sinusitis
Salivary gland enlargement
Modified from Casadevall A, Perfect JR. Cryptococcus neoformans. Washington, DC: ASM Press; 1998:409.
393
192 Histoplasma capsulatum (Histoplasmosis)George S. Deepe, Jr.
DEFINITION• Histoplasmosis is themost frequentcauseof fungal respiratory infectionandhasabroad
spectrumofclinicalmanifestationsrangingfromaself-limited,acute,influenza-likeillnesstoaprogressivedisseminatedinfectionthatislifethreatening.
EPIDEMIOLOGY• The fungus is typically found in the midwestern and southeastern United States and in
CentralandSouthAmerica.• Indigenouscaseshavebeenreportedworldwide.• Thefungusthrivesindecayingbirdguano(starlingsandblackbirds)andbatguano.• Patientswithacquiredimmunodeficiencysyndrome(AIDS)orreceivingimmunosuppres-
sive drugs, including tumor necrosis factor-α inhibitors, are predisposed to disseminatedinfection.
MICROBIOLOGY• Thefungusexistsinthemycelialforminnature.• The mycelia produce two sizes of conidia—micro and macro. The former are thought to
inducediseasebecausetheyaresmallenoughtoreachthebronchiolesandalveoli.• Conversiontotheyeastphaseisdrivenbytemperature.
DIAGNOSIS• SerologyisusefulforallbutAIDSpatients.Complement-fixationtitersof1:32orgreater
areindicativeofactivedisease.ThepresenceoftheHimmunodiffusionbandsignifiesactivedisease.AnMbanddoesnotdiscriminatebetweencurrentorremoteinfection.
• TheHistoplasmaantigentesteitherfromurineorserumisparticularlyusefulindiagnosisofextrapulmonarydisease.Itisalsousefulforfollowingresponsetotherapy.
• Tissueandbuffycoatexaminationisusefulfordetectingtheorganism.• SeeTable192-1fordiagnostictests.
THERAPY• Pulmonaryhistoplasmosis:mildtomoderate—notreatmentoritraconazole200mg3times
daily,followedby200mgtwiceadayfor6to12weeks;moderatetosevere—lipid-formulatedamphotericin B, 3 to 5mg/kg or deoxycholate amphotericin B, 0.7 to 1mg/kg, for 1 to 2weeks, followed by itraconazole for total of 10 to 11 weeks; cavitary—itraconazole asdescribedabove.
• Disseminateddisease:moderatetosevere—sameasmoderate-to-severepulmonarydisease;inchildrencanusedeoxycholateamphotericinB,1mg/kgfor4to6weeks.
• Rheumatologicmanifestations—nonsteroidals• Mediastinal lymphadenitis—no treatment or, if symptomatic, itraconazole as described
above• SeeTable192-2fortreatmentoptions.
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PREVENTION• Prophylaxisforimmunosuppressedpatients—itraconazole200mgdaily• Avoid construction sites, spelunking, and remodeling of unoccupied homes or farm
habitats.
TABLE 192-1 Diagnostics for Histoplasmosis
INFECTION SITE DISEASE SEVERITY DIAGNOSTICLung
Acute Mild-moderate H and M bands and complement fixation.
Moderate to severe As above. Serum or urine antigen, or both, also may be positive in up to 70%. Bronchoalveolar fluid antigen may be useful. Culture of bronchoalveolar lavage fluid and silver stain of concentrated lavage fluid. Sputum culture.
Chronic cavitary H and M bands and complement fixation. Culture of bronchoalveolar lavage fluid and silver stain of concentrated lavage fluid. Sputum cultures.
Disseminated
Acute Serum or urine antigen, or both. H and M bands and complement fixation. These are not useful in AIDS patients. Examination of the buffy coat for yeast cells in phagocytes. Biopsy of bone marrow or liver with silver stain and culture. Blood culture.
Chronic Serum or urine antigen, or both. H and M bands and complement fixation. Biopsy of tissue with silver stain and culture.
Central nervous system Serum or urine antigen, or both. CSF antigen. Culture of CSF. H and M bands and complement fixation are not as useful.
Mediastinal
Lymphadenitis H and M bands and complement fixation.
Granuloma H and M bands and complement fixation.
Fibrosis H and M bands and complement fixation.
Rheumatologic Arthralgias H and M bands and complement fixation.
Pericarditis H and M bands and complement fixation.
Endocarditis/Endovascular H and M bands and complement fixation. Serum or urine antigen, or both. Culture and silver stain of valve.
AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid.
395C
hap
ter 192 Histo
plasm
a capsu
latum
(Histo
plasm
osis)
TABLE 192-2 Treatment of Histoplasmosis
INFECTION SITE DISEASE SEVERITY TREATMENTLung
Acute Mild-Moderate None or itraconazole 200 mg 3 times daily for 3 days followed by 200 mg twice a day for 6-12 wk.
Moderate-Severe Lipid-formulated amphotericin B, 3-5 mg/kg, or deoxycholate amphotericin B, 0.7-1 mg/kg, daily for 1-2 wk followed by itraconazole 200 mg 3 times a day for 3 days followed by 200 mg twice a day for a total duration of 12 wk. For children, itraconazole 5-10 mg/kg or deoxycholate amphotericin B, 1 mg/kg daily.
Chronic cavitary Itraconazole 200 mg 3 times a day for 3 days followed by twice daily for at least 1 yr and as long as 2 yr.
Disseminated
Acute Lipid-formulated amphotericin B, 3-5 mg/kg, or deoxycholate amphotericin B, 0.7-1 mg/kg, daily for 1-2 wk followed by itraconazole 200 mg 3 times a day for 3 days followed by 200 mg twice a day for at least 12 mo. For children, deoxycholate amphotericin B (1 mg/kg) daily for 4-6 wk or 2-4 wk followed by itraconazole 5-10 mg/kg daily. Total duration = 3 mo.
Chronic Itraconazole 200 mg 3 times a day for 3 days followed by 200 mg twice a day for at least 1 yr. Serum levels should be monitored to ensure adequate concentrations.
Central nervous system
Liposomal amphotericin B, 5 mg/kg daily for 4-6 wk followed by itraconazole administered as above for at least 1 yr and resolution of symptoms and negative cerebrospinal fluid antigen.
Mediastinal
Lymphadenitis No treatment. If symptomatic (e.g., dysphagia), itraconazole 200 mg twice daily for 12 wk. Corticosteroids (60 mg with a rapid taper) may be used to diminish lymph node size.
Granuloma Same as lymphadenitis. Corticosteroids are not necessary.
Fibrosis Surgical intervention with stents. Antifungals are not useful.
Rheumatologic Arthralgias, etc. Nonsteroidals
Pericarditis Nonsteroidals or corticosteroids. If the latter, treat with itraconazole (200 mg × 3 for 3 days and then once a day) until corticosteroids have been discontinued.
Endocarditis/Endovascular
Surgical removal of the valve combined with lipid-formulated amphotericin B, 5 mg/kg daily for 6 wk. Lifelong suppression may be considered in some who are not surgical candidates with itraconazole 200 mg once or twice a day.
Data from Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45:807-825.
396
193 BlastomycosisRobert W. Bradsher, Jr.
DEFINITION• InfectionbyBlastomycesdermatitidis
MICROBIOLOGY AND EPIDEMIOLOGY• Broad-basedsinglebuddingyeast• Blastomyces dermatitidis:dimorphic;grows25°to28°Casamoldandat37°Casyeast• Visible in wet preparations of potassium hydroxide or calcofluor white by fluorescent
microscopy• PrimarilyinNorthAmerica—Mississippi,Ohio,andSt.LawrenceRiverValleysandGreat
Lakesregions• Point source outbreaks, often around lakes or rivers with recreational or occupational
exposures• Endemicorsporadiccasesmostcommonlyinnormalhosts,althoughimmune-suppressed
hostscanbeinfectedandcouldreactivateinfectionfrompriorsubclinicalinfection• Cellularimmunityistheprimaryhostdefensetocontroltheinfection
CLINICAL MANIFESTATIONS• Pulmonaryportalofinfectionwithpneumoniathemostcommonfinding• Extrapulmonary infection to skin and subcutaneous tissue most common but also bone,
prostate,centralnervoussystem(CNS),oressentiallyanyorgan
DIAGNOSIS• Diagnosis by visualization of organism with fungal stains or by culture of specimens. No
colonizationorcontaminationwiththisfungus• Antibodytestslackofsensitivity• Antigentestingofurinemaybeuseful fordiagnosis,butcross-reactionsoccurwithother
dimorphicfungalinfections
TREATMENT (SEE TABLE 193-1)• Itraconazoleisthedrugofchoiceformild-to-moderatepulmonaryornon-CNSextrapul-
monaryinfection• AmphotericinB(usuallylipid)isthetreatmentforsevereinfectionuntilimprovementand
thenitraconazole• CNSinfectionwithlipidamphotericinB,followedbyvoriconazoleorfluconazole
397C
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myco
sis
TABLE 193-1 Treatment of Blastomycosis*
INDICATION THERAPYModerately severe or severe pulmonary blastomycosis or immunosuppressed patients
Liposomal amphotericin B 3-5 mg/kg or conventional amphotericin B 0.7-1 mg/kg once daily for 6-8 wk.After improvement, consider switching to itraconazole 200 mg PO once or twice daily.†
Pregnant Liposomal amphotericin B 3-5 mg/kg or conventional amphotericin B 0.7-1 mg/kg once daily for 6-8 wk.
Brain abscess or meningitis Amphotericin B as above until improved. For step-down treatment, consider itraconazole 200 mg PO 2-3 times daily, fluconazole 800 mg daily, or voriconazole 6 mg/kg for 2 doses, then 4 mg/kg q12h, IV or PO.
Mild-to-moderate pulmonary blastomycosis Itraconazole 200 mg PO once or twice daily.†
IV, intravenous; PO, by mouth.*Total duration of therapy at least 6 months. Disseminated, central nervous system, osteoarticular, or cavitary
pulmonary manifestations may require longer treatment.†Consider monitoring trough levels of native drug in patients not responding to itraconazole. Levels above
1 µg/mL by high-performance liquid chromatography are considered desirable, although data are scant.
398
194 Coccidioidomycosis (Coccidioides Species)John N. Galgiani
DEFINITION• Thedimorphicfungi,Coccidioides immitisandCoccidioides posadasii,causeasystemicfungal
infection,coccidioidomycosis,alsoknownasSan Joaquin Valley fever.
EPIDEMIOLOGY• CoccidioidomycosisisendemictoaridregionsoftheWesternHemisphere.• Approximately150,000newU.S.infectionsoccurannuallywith60%originatinginArizona
and30%inCalifornia.Ofthese,50,000producesignificantillness.• Infectionsmostfrequentlyoccurduringdryseasons,andtheincubationperioduntilfirst
symptomsrangesfrom1to3weeks.• The most common illness is a community-acquired pneumonia, lasting weeks to months
whether treated or not with antifungal agents. Progressive pneumonia or hematogenousdisseminationtootherorgansisaseriouscomplicationthatrequirestreatment.
• Patientswithdiabetesaremorelikelytosufferpulmonarycomplications.• Disseminationisfrequentinpatientswithimpairedcellularimmunity.
MICROBIOLOGY• Coccidioideshasbeenfoundindesertsoilandassociatedwithanimalburrowsbutissparsely
distributed,evenwithinthemosthighlyendemicregions.• Throughout the 20th century, coccidioidomycosis was recognized as caused by a single
fungalspecies,C. immitis.Thispopulationcontainstwogeneticallyandgeographicallydis-tinctclades,nowrecognizedasseparatespecies:C. immitispredominantlyfoundinCaliforniaandC. posadasiiinallotherendemicregions.
• Onmostlaboratorymedia,growthbyapicalmycelialelongationisvisiblewithinaweek.• Alternatehyphalcellsautolyze,leavingbehindsingle3-to5-µmcells(arthroconidia)that
canbecomeairborneandcapableofbeinginhaleddeepintoairways.• Inmammaliantissue,anarthroconidiumremodelsintoasphericalcellthatenlargesisotro-
picallytoformlargematurespheruleswithscoresofendosporesdevelopingwithin.• Endospores,whenreleasedduringspherulerupture,candevelopintoanewspherulewithin
hosttissueorreverttomycelialgrowthifremovedfromtheinfection.• A sexual phase has not been observed, but population genetics suggest that one exists.
SequenceanalysisindicatesthatCoccidioidesisanascomycete.
DIAGNOSIS• IsolationofCoccidioidesinculturefromaclinicalspecimenisdiagnosticofinfection.• Recognizing endospore-containing spherules in wet mounts or histologic sections is also
definitive.• Diagnosisinmostpatientsismadepresumptivelybydetectinganticoccidioidalantibodies
inserumorcerebrospinalfluid.
399C
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ccidio
ido
myco
sis (Co
ccidio
ides Sp
ecies)
• Complement-fixinganticoccidioidal antibodiesarequantitatedby serialdilution titration.Moreextensiveinfectionsarefrequentlyassociatedwithhighertiters,andclinicalimprove-mentisassociatedwithdecreasingtiters.
• Immunodiffusion techniques are routinely used to provide a qualitative mimic of thecomplement-fixing antibody test and also to detect other Coccidioides-specific antibodies,oftenIgM,whichoccurearlier.
• ProprietaryenzymeimmunoassaykitsthatmeasureanticoccidioidalIgMandIgGantibodiesareinwideuse.Theyaremoresensitiveindetectingearlycoccidioidalinfectionsbutmaynotbeasspecific.
• Atestforcoccidioidalantigensiscommerciallyavailableandismostfrequentlypositiveinpatientswithextensiveinfection.
THERAPY• Healthypatientswithuncomplicatedcoccidioidalpneumoniausuallyimprovewithgeneral
supportivemanagementwhetherornotantifungaldrugsareused.Ifantifungaltreatmentisinitiatedforsuchpatients,itusuallyconsistsoffluconazolegivenorallyatadoseof400mgperdayforperiodsrangingfrom3monthsto1year.
• PatientswithsevereearlypneumoniasufficienttorequireintensivecarehospitalizationareoftentreatedwithintravenousamphotericinBinitiallyuntiltherespiratorystatusstabilizesorimproves.
• Wheninfectionresults inchronicfibrocavitarypneumoniaorextrapulmonarydissemina-tion,antifungal therapyinvolvesoralfluconazole(400mgdailyorhigher)or itraconazole(200mgtwiceorthreetimesdaily).Treatmentwouldnormallybecontinuedforatleast1year.Insuchpatients,itisnotinfrequentfortreatmenttocontinueforseveralyearsbecauserelapseofftreatmentiscommon.
• Insomepatients,surgeryisessentialinadditiontoantifungaldrugstocontrolinfection.• Treatmentofcoccidioidalmeningitis ismost frequentlymanagedwithoralfluconazole in
dosesof400to800mgdaily.Thistreatmentislifelongforallpatients.Patientswhodevelophydrocephalususuallyrequiretheplacementofaninternalventricularshunt.
PREVENTION• Apreventivevaccineforcoccidioidomycosisisnotavailable.
400
195 Dermatophytosis (Ringworm) and Other Superficial MycosesRoderick J. Hay
DEFINITION• Dermatophyteinfectionsaresuperficialinfectionsofthestratumcorneumoftheskinorof
keratinizedappendages,suchashairornails,arisingfromit.OthersuperficialinfectionsarecausedbyCandidaandMalasseziaspp.orlesscommonorganisms(e.g.,Piedraia).
EPIDEMIOLOGY• Globally,thesuperficialfungalinfectionsoftheskinaffectmorethan900,000millionindi-
viduals.Mosthavenounderlyingabnormality,althoughindividualconditionssuchassebor-rheicdermatitisandoropharyngealcandidiasismaybeearlysignsofhumanimmunodeficiencyvirusinfection.
MICROBIOLOGY• ThemainfungiinvolvedaredermatophytespeciesofthegeneraTrichophyton, Microsporum,
andEpidermophytonandyeastssuchasCandidaorMalasseziaspp.Lesscommonly,othermoldfungi(e.g.,Scytalidium)areimplicated.
DIAGNOSIS• Directmicroscopyoftheskinandcultureisdiagnostic.Moleculardiagnostictechniquesare
indevelopment.
THERAPY• Topicaltreatmentsincludeazoleantifungalagentsandterbinafine.Seleniumsulfideandzinc
pyrithione have specific activity against Malassezia. Oral therapies are itraconazole andfluconazole;oralterbinafineisusedmainlyfordermatophyteinfections(seeTable195-1).
PREVENTION• There are no major preventive programs, although early identification of infection limits
spreadincommunities,suchasschools.
401C
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ter 195 Derm
atop
hyto
sis (Rin
gw
orm
) and
Oth
er Sup
erficial M
ycoses
TABLE 195-1 Treatment of Dermatophytosis
DERMATOPHYTOSIS, CLINICAL DISEASE PATTERN TREATMENTTinea pedis
Interdigital Topical cream/ointment: terbinafine, imidazoles (miconazole, econazole, clotrimazole, etc.), undecenoic acid, tolnaftate
“Dry type” Oral: terbinafine, 250 mg/day for 2-4 wk; itraconazole, 400 mg/day for 1 wk per month (repeated if necessary); fluconazole 200 mg weekly for 4-8 wk
Tinea corporis
Small, well-defined lesions Topical cream/ointment: terbinafine, imidazoles (e.g., miconazole, econazole, clotrimazole)
Larger lesions Oral: terbinafine, 250 mg/day for 2 weeks; itraconazole, 200 mg/day for 1 wk; fluconazole, 250 mg weekly for 2-4 wk
Tinea capitis Griseofulvin, 10-20 mg/kg/day for minimum 6 wk
Terbinafine
<20 kg: 62.5 mg/day
20-40 kg: 125 mg/day
>40 kg: 250 mg/day
Itraconazole, 4-6 mg/kg pulsed dose weekly
Onychomycosis Fluconazole, 3-8 mg/kg pulsed dose weekly
Fingernails Terbinafine, 250 mg daily for 6 wk
Itraconazole, 400 mg/day for 1 wk each month, repeated for 2-3 mo
Fluconazole, 200 mg weekly for 8-16 wk
Toenails Terbinafine, 250 mg daily for 12 wk
Itraconazole, 400 mg/day for 1 wk each month, repeated for 2-4 mo
Fluconazole, 200 mg weekly for 12-24 wk
402
196 ParacoccidioidomycosisAngela Restrepo, Angela María Tobón, and Luz Elena Cano
MICROBIOLOGY AND EPIDEMIOLOGY• Paracoccidioidomycosis iscausedbyParacoccidioides brasiliensis,whichcontains fourdif-
ferentphylogeneticlineages(S1,PS2,PS3,andPS4).Anewspecies,Paracoccidioides lutzii,hasbeenrecognizedwithinP. brasiliensisandalsocausesparacoccidioidomycosis.
• Paracoccidioides spp. are thermally dimorphic fungi, identified by multiple-budding yeastcells(pilot’swheel).
• Thesefungiexhibitslowmycelialgrowthformorethan20daysat22°to24°C.Theyeastformappears±10daysat36°to37°C.
• Directmicroscopyandhistopathologyallowpromptdiagnosis.• ThesefungiarerestrictedtoLatinAmericancountriesinunknownhabitats.• ThelargestendemicareasarefoundinBrazil.• Mostpatientsaremalesandwork(orhaveworked)inagriculturewithintheendemicareas.• Twoprogressivediseaseformsexist:(1)acute/subacuteinchildren,adolescents,andimmu-
nocompromisedindividualsand(2)chronicinadultsatleast30yearsofage.
CLINICAL MANIFESTATIONS• In theacute/subacute form,a severedisease, there is fever,weight loss, lymphadenopathy
andhepatosplenomegaly.Multipleskinandmucosallesionsoccurinhalfofthecases.• Inthechronicform,therearepulmonaryinfiltratesonchestradiographs(>90%ofthecases)
andlesionsinmucousmembranesandskin.Adrenallesionswithadrenalinsufficiencyarecommon.
• Specificdiagnosisisusuallylateduetoconfusionwithothermoreprevalentdiseases(e.g.,tuberculosis).Lackofphysicians’awarenessisaproblem.
• Lung imaging studies are essential in adult patients. Healing by fibrosis creates seriouscomplications.
• Intissues,granulomaformationisan importantcluetodiagnosis.Buddingyeastcellsarefoundinlesions.
• Serologyshowsthatanti–P. brasiliensisantibodiesaredetectableinmostpatients.Quantitativetestsallowtreatmentfollow-up.Antigendeterminationalsoisusefulincertainpatients.
• Humanimmunodeficiencyviruscomorbidityisuncommon.
TREATMENT (SEE TABLE 196-1)• Itraconazole is the treatment of choice for most patients, at 200 to 400mg/day for 9 to
12months.• AmphotericinBdeoxycholateisreservedforseverecases,at1mg/kg/dayuntilachievinga
2-gtotaldose.Thisshouldbefollowedbyoralmedications.• Trimethoprim-sulfamethoxazole(TMP-SMX)isgivenasTMP,160to240mg,andSMX,800
to1200mgperdayfor12to24months,dependingondiseaseseverity.• Regularfollow-upobservations(clinical,laboratoryoriented)aremandatory.
403C
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ioid
om
ycosis
TABLE 196-1 Antifungal Therapy for ParacoccidioidomycosisA
NTI
FUN
GA
L PR
ESC
RIB
ED
(AD
MIN
ISTR
ATI
ON
R
OU
TE)
MIN
IMA
L TR
EATM
ENT
DU
RA
TIO
N B
ASE
D
ON
OR
GA
N
INV
OLV
EMEN
T*
DO
SE
AD
VER
SE E
FFEC
TS
RES
PON
SE (
%)
REL
APS
ES (
%)
TMP-SMX (PO/IV)
Minor: 12 moModerate: 18-24 mo
AdultsTMP: 160-240 mg/daySMX: 800-1200 mg/dayDivided into two doses per dayChildrenTMP: 8-10 mg/kgSMX: 40-50 mg/kgDivided into two doses per day
LeukopeniaHypersensitivity-reactions, such as rash
80 20
Amphotericin B deoxycholate (IV)
Until patient improves and can be treated by the oral routeAchieve a total dose of 2 g†
1 mg/kg/day NephrotoxicityHypokalemiaNausea/vomitingFeverAnemia
70 25
Ketoconazole (PO)
9-12 mo 200-400 mg/day Hormonal alterationsIncrease in hepatic enzymesNausea/vomiting
90 11
Itraconazole (PO)
6-9 mo Adults600 mg/day for 3 days; continue 200 mg/dayChildren (<30/kg and >5 yr)5-10 mg/kg/day
Nausea/vomiting↑ Hepatic enzymesDrug interactions
94-98 3-5
Voriconazole (PO/IV)
6 mo Initial dose: 400 mg each 12 hr for one day, then 200 mg each 12 hrDiminish the dose to 50% if weight is <40 kg
Visual alterations↑ Hepatic enzymesSkin rashPhotosensitivityHallucinationsPeriostitis
88 No data
IV, intravenous; PO, orally; TMP-SMX, trimethoprim-sulfamethoxazole.*Shown only with the aim of guiding therapy. Total duration must be defined in accordance with clinical and
immune-based tests, as well with the mycosis clinical form.†Should always be continued with TMP-SMX or itraconazole oral therapy, once clinical improvement has been
obtained.
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197 Uncommon Fungi and Related SpeciesDuane R. Hospenthal
PSEUDALLESCHERIA BOYDIIDefinition• Infection of the lungs, bones and joints, or central nervous system (CNS); may be
disseminated• Alsocausesmycetoma
Epidemiology• Typicallyoccursintheimmunocompromisedorfollowingtrauma• CNSinfectioninimmunocompetentpersonsafternear-drowning• Organismcanbefoundinsoilandfreshwater,especiallystagnantorpolluted
Microbiology• P. boydii (Scedosporium apiospermum)isagroupofatleastfivespecies.• Identificationistypicallymadebyidentificationofmicroscopicstructuresfromculture.
Diagnosis• Diagnosisismadebyculturerecoveryfrominfectedsite.• BecauseP. boydiimaycolonizeairways,sputumculturesmaynotreflectinfection.
Therapy• Voriconazoleislikelythemosteffectiveagent.
SCEDOSPORIUM PROLIFICANSDefinition• Disseminatedinfectionandboneandjointinfectionsaremostcommon.• S. prolificansmaycauseonychomycosisandinfectionsoftheeyeandwounds.
Epidemiology• Disseminatedinfectioncommonlyoccursintheseverelyimmunocompromised.• Localizedinfectionoccursinimmunocompetentindividualsaftertrauma.• Theorganismcanbefoundinsoilandcolonizingtherespiratorytract.
Microbiology• Identificationismadebyculture.
Diagnosis• Diagnosisismadebyculturerecoveryfromtheinfectedsite.• BecauseS. prolificansmaycolonizeairways,sputumculturesmaynotreflectinfection.
Therapy• Noeffectivetherapy.ConsidervoriconazolewithamphotericinB.
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DARK-WALLED FUNGI (BIPOLARIS, EXOPHIALA, EXSEROHILUM, PHIALOPHORA, CURVULARIA, OTHERS)Definition• Thisinfectioninvolvesfungithathavemelaninintheircellwallandmayappeardarkwalled
intissue.• Infectionisoftentermedphaeohyphomycosisandtypicallypresentsaslocalizedskinandsoft
tissueinfections,CNSinfections,orallergicsinusitis.• Dark-walledfungithatcausechromoblastomycosisandmycetomaarenotincludedinthe
agentsofphaeohyphomycosis.
Epidemiology• Infectioniscommonlyacquiredfromminortraumaorinhalation.• Fungiarefoundinsoil,organicmaterial,plants,andair.• Theymaybespreadthroughcontaminatedproducts(e.g.,injectablesteroids).
Microbiology• ThemostcommonagentsofphaeohyphomycosisareAlternaria, Bipolaris, Cladophialophora,
Curvularia, Exophiala, Exserohilum,andWangiella
Diagnosis• Diagnosisismadebyrecoveryoftheseorganismsinculturefromthesiteofinfection.• Cell walls may appear dark brown or golden on histopathology (hematoxylin and eosin).
UseofaFontana-Massonstainmayalloweasieridentificationofthesefungi.
Therapy• Surgicaldébridementoflesionsorcolonizingfungiinthecaseofallergicfungalsinusitis• AmphotericinBinlife-threateninginfections• Voriconazoleanditraconazolearetypicallyeffectivebutprolongedtherapyneeded
FUSARIUM SPP.Definition• Cancausedisseminatedinfectioninimmunocompromisedpatients• Commoncauseofkeratitisandothereyeinfectionsincontact lenswearersandfollowing
trauma• Skinandsofttissueinfectionaftertrauma,onychomycosis;cancausemycetoma
Epidemiology• Commonplantpathogens;foundinsoilandorganicdebris• Hasbeenrecoveredinhospitalwatersupplies
Microbiology• F. solaniisthemostcommonpathogen,althoughotherspeciesmayalsocauseinfection.• Fusariumproducesbanana-(orcrescent)-shapedmulticellularmacroconidiainculture.
Diagnosis• Recoveryofthefungusfromcultureofanotherwisesterilesite• Oneofthefewmoldsthatarecommonlyrecoveredfrombloodculture
Therapy• Optimumtherapyisnotknown.• Recoveryfromneutropeniaisessentialinresponsetotherapyofdisseminatedinfection.• AmphotericinBorvoriconazoleissuggested.
TRICHOSPORON SPP.Definition• Mostcommonlypresentsasdisseminatedinfection
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Epidemiology• Typicallyaninfectionoftheimmunocompromised;maybeassociatedwithcentralvenous
catheter• Fungifoundcolonizingtheskin,gastrointestinal,respiratory,orgenitaltract• Foundinsoilandwater• Breakthroughinfectionsinpatientsreceivingechinocandins
Microbiology• MostcommonpathogenisT. asahii.• Trichosporonareidentifiedbytheiruniqueabilitytoproduceseptatehyphae,arthroconidia,
andbuddingyeast.• Appearsyeastlikeoninitialculture
Diagnosis• Byrecoveryoftheorganismfromthebloodorlesionbiopsy
Therapy• Azoleantifungal(voriconazole,itraconazole,isavuconazole,posaconazole,orfluconazole)
MALASSEZIA FURFURDefinition• Catheter-relatedbloodstreaminfection• Alsocausespityriasisversicolor
Epidemiology• Typicallyassociatedwithparenterallipidinfusion• Commonlyreportedinneonates
Microbiology• Maybedifficulttogrowfrompositivebloodcultureswithoutlipidsupplementation
Diagnosis• Recoveryoffungusfrombloodculture
Therapy• Catheterremovalanddiscontinuationofparenterallipids• Susceptibletomostantifungals(voriconazole,fluconazole,oramphotericinB)
Prevention• Limitinguseofparenterallipids
OTHER UNCOMMON YEASTSDefinition• Otherlesscommonyeastsmayalsocausecatheter-relatedbloodstreaminfection.
Epidemiology• Typicallyassociatedwithuseofcentralvenouscathetersandimmunocompromise
Microbiology• Include Saprochaete capitata (Blastoschizomyces capitatus), Pichia anomala, Rhodotorula
species,andSaccharomyces cerevisiae
Diagnosis• Madebyrecoveryoftheyeastinbloodculture
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Therapy• Removalofcentralvenouscatheter• Antifungalsbasedonrecoveredyeast
PENICILLIUM MARNEFFEIDefinition• Acute disseminated infection of persons infected with human immunodeficiency virus
(HIV)inSoutheastAsia• Infectionsimilartoacutedisseminatedhistoplasmosis inpatientswithacquiredimmuno-
deficiencysyndrome• Rarely,localizedinfectioninapparentlyimmunocompetentpersons
Epidemiology• LimitedtoSoutheastAsia.Morecommoninrainyseason,inyoungadultmaleswithHIV
infection,typicallywithlowCD4cellcounts
Microbiology• TypicalPenicillium-likestructuresonmicroscopicexaminationofculture• Culturesproduceredpigmentthatdiffusesintotheagar.
Diagnosis• Typicallymadefromrecoveryoftheorganisminblood• Mayalsoberecoveredincultureofskinlesions,lymphnodes,orbonemarrowaspirates• Serologictestingmaybeavailableinendemicregions.
Therapy• AmphotericinBinlife-threateningpresentations• Itraconazoleorvoriconazoleininitialtherapy(notlife-threatening)• ItraconazolesecondaryprophylaxisinHIV-infectedpatients
LACAZIA LOBOIDefinition• Chronicnodularorkeloidalskininfection,commonlyoftheearsorface
Epidemiology• LimitedtoCentralandSouthAmerica• Infectionalsofoundindolphins
Microbiology• Hasnotbeenrecoveredinculture• IdentifiedascloselyrelatedtoParacoccidioides brasiliensisbymoleculartechniques
Diagnosis• Basedonclinicalpresentationandfindingtypicalstructuresonhistopathology• Globose(yeast)cellsend-to-endinshort“strings”
Therapy• Surgicalremoval
AGENTS OF ADIASPIROMYCOSIS (EMMONSIA SPP.)Definition• Disease secondary to host immune response to nonreplicating fungal conidia, termed
adiaspores• Chieflyapulmonarydisease;mayrangefromasymptomatictorapidlyleadingtorespiratory
failureandoccasionallydeath• Mayalsopresentasocularnodules
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Epidemiology• Seenwithoccupationalinhalationtodustsinmen,averageage40• OutbreakinBrazilianchildreninassociationwithdivingandfreshwatersponges
Microbiology• SecondarytoEmmonsiaspecies,usuallyE. crescens• DimorphicfungicloselyrelatedtoBlastomyces dermatitidis
Diagnosis• Identificationislimitedtoobservationoftypicalstructuresonhistopathologyshowingadia-
spores,upto500µmindiameter,nondividing,andsurroundedbygranulomatacomposedofepithelioidandgiantcells.
Therapy• Corticosteroidsappeartobeuseful.
EMMONSIA PASTEURIANADefinition• DisseminatedinfectionmostcommonlyafflictingHIV-infectedpersons
Epidemiology• Severelyimmunocompromisedpersons• LargestreportfromSouthAfrica
Microbiology• Emmonsia pasteurianaorcloselyrelatedfungus• Thermallydimorphicfungus
Diagnosis• Recoveryofthedimorphicfungusfromskinbiopsyorbloodculture
Therapy• ResponsestoamphotericinBandtriazoleantifungalshavebeenreported
PROTOTHECA SPP.Definition• Localizedskinorsubcutaneousinfectioncausedbyalgalpathogen• Rarereportsofdisseminatedordeepinfection
Epidemiology• Likelycauseinfectionaftertraumaticinoculation• Organismscolonizeskin,gastrointestinalandrespiratorytract
Microbiology• DiseaseistypicallyduetoP. wickerhamiiorP. zopfii.• Unicellularalgaelackchlorophyll.• Protothecaspp.growonfungalculturemediawithyeastlikecolonialmorphology.• Microscopicappearanceintissueisdiagnostic.
Diagnosis• Recoveryofalgaeincultureisdiagnostic.• YeastbiochemicalpanelscommonlyidentifyPrototheca.
Therapy• SurgicalexcisionwithamphotericinBoritraconazole
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PYTHIUM SPP.Definition• Vascular infectionsinpersonswithironoverloadsuchasthalassemiaorocularinfections
followingtrauma• Skinandsubcutaneousanddisseminatedinfectionpossible
Epidemiology• Worldwidedistribution,butmostcommonlyreportedfromThailand• Riskfactors:thalassemia-hemoglobinopathysyndromeandtrauma• Presumedassociationwithworkinswampy(e.g.,ricepaddy)environment• Highmorbidity(eyeorlimbloss)andmortality
Microbiology• Fungus-likeprotist,Pythium,growsrapidlyasmoldonfungalculture.
Diagnosis• Recoveryoftheorganismfromcultureisdiagnostic.• Localserologictestingmaybeavailable.
Therapy• Canperformsurgicalresectionoramputation.• Nosatisfactorymedicaltherapyisknown.• Doxycycline,minocycline,tigecycline,linezolid,andmacrolideshaveactivityinvitro.
RHINOSPORIDIUM SEEBERIDefinition• Localizedpolypoidalinfection,chieflyofthenose,upperairway,andconjunctiva
Epidemiology• Worldwidedistribution,butmostcommonlyreportedfromsouthernIndiaandSriLanka
Microbiology• Hasnotbeengrowninculture• Identifiedasaprotistbymolecularmethods
Diagnosis• Madebymicroscopicobservationoftypicalstructures—thick-walledcysts(100to350µm)
filledwithnumerousspores
Therapy• Surgicalexcisionwithelectrocauteryoflesionbase
410
198 Pneumocystis SpeciesPeter D. Walzer, A. George Smulian, and Robert F. Miller*
DEFINITION• Pneumocystis spp. are genetically distinct, host-specific opportunistic fungal pathogens
widelyfoundinnature.• Pneumocystis jirovecii,foundinhumans,causespneumonia(“Pneumocystispneumonia”or
“PCP”)inimmunocompromisedpatients.
EPIDEMIOLOGY• Infectionisacquiredbyinhalationofthecystformoftheorganism.• Primaryinfectionoccursinthefirst2yearsoflifeinmostpeople.• Person-to-persontransmissionandoutbreaksofPCPin immunosuppressedpatientshave
beenreported.• EnvironmentalfactorsinfluencePCPhospitalizations.• Colonizationiscommon,associatedwithobstructiveairwaydisease.
DIAGNOSIS• PCP in patients with human immunodeficiency virus (HIV): slow development, milder
disease,10%to12%mortality• PCPinnon-HIVpatients:rapiddevelopment,severedisease,30%to50%mortality• Gold standard: microscopic demonstration of organism in respiratory tract specimens by
immunofluorescenceorspecialstains• Othermethods(polymerasechainreaction,β-D-glucanlevels)arepromisingbutarecon-
sideredinvestigational
TREATMENT• Trimethoprim-sulfamethoxazole(TMP-SMX)15to20mg/kg/day(TMP)and75to100mg/
kg/day(SMX)IVorPOindivideddosesevery6to8hoursfor14to21daysisthetreatmentofchoiceformild,moderate,orseverePCP.
• Mild-to-moderate PCP:OraldosecanbegivenasTMP-SMXdoublestrength2tabletsorallythreetimesaday.
• SeveralalternativeregimensareavailabledependingontheseverityofPCP.• Prednisone40mgPOtwicedailyondays1to5,40mgPOeverydayondays6to10,and
20mgPOeverydayondays11to21aregivenasadjunctivetherapyformoderate-to-severePCP(PaO2≤70mmHg,oralveolar-arterialO2gradient>35mmHg).
• Startprednisoneassoonaspossibleorwithinthefirst3daysafterbeginningantimicrobialtherapy.
• PrednisoneismainlyindicatedforHIV-positivepatients.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
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PREVENTION• TMP-SMX1DStabletorallyeverydayor1SStabletorallyeverydayisthedrugofchoice
forprimaryandsecondaryprophylaxis.• Alternativeregimensareavailable.• Strongevidencesupports isolationofPCPpatientsfromcontactwithotherimmunocom-
promisedhosts.
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199 MicrosporidiosisLouis M. Weiss
DEFINITION• Microsporidiaareobligateeukaryoticintracellularpathogensrelatedtofungi.• Taxonomyofthephylumisbasedonultrastructuraldescriptionsofthesporesandlifecycle.• Molecularphylogeny,basedonrRNAsequences,isalsoutilizedforclassification.
EPIDEMIOLOGY• The phylum Microsporidia contains at least 1200 species distributed into more than 190
genera.• Several different genera and species of microsporidia cause disease in humans, including
Nosema, Vittaforma, Pleistophora, Encephalitozoon, Enterocytozoon, Trachipleistophora, Anncaliia, Tubulinosema, Endoreticulatus,andMicrosporidium.
• Microsporidiosisoccursinbothimmunocompromisedandimmune-competenthosts.• Thesepathogenscanbetransmittedbyfoodorwaterandarelikelyzoonotic.• Diarrheaorkeratoconjunctivitisarethemostcommonpresentingmanifestationsofinfec-
tion,butinfectioncanoccurinanyorgansystem.
DIAGNOSIS• Diagnosis can be made by finding characteristic spores in body fluids (e.g., stool, urine,
conjunctivalscraping,etc.,usingstains,suchaschromotrope2RorUvitex2B).• Definitiveidentificationofthemicrosporidiacausinganinfectioncanbedoneusingultra-
structuralexaminationormoleculartechniques.• Patientswithdiarrheaorkeratoconjunctivitisshouldhaveurineexaminedtolookfordis-
seminatedinfection.• Species-specificdiagnosisisusefulforguidingtreatment.
THERAPY• Systemic albendazole and fumagillin are active therapeutic agents for the treatment of
microsporidiosis.• Topicalfumagillinisusefulformicrosporidiankeratoconjunctivitis.• Immunerestorationsuchascombinationantiretroviraltreatmentinpatientswithacquired
immunodeficiencysyndromeoftenresultsinresolutionofinfection.
PREVENTION• Therearelimiteddataoneffectivepreventivestrategiesformicrosporidiosis,butthemost
effectiveprophylaxisisrestorationofimmunefunctioninimmunocompromisedhosts.• Theusualsanitarymeasuresthatpreventcontaminationoffoodandwaterwilldecreasethe
chanceofinfection.• Handwashingandgeneralhygienichabitsreducethechanceofcontaminationofthecon-
junctivaandcorneawithmicrosporidianspores.
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H Protozoal Diseases
200 Entamoeba Species, Including Amebic Colitis and Liver AbscessWilliam A. Petri, Jr., and Rashidul Haque
DEFINITION• Amebiasis is defined as human infection by Entamoeba species, including E. histolytica,
whichisthecauseofamebiccolitis,liverabscess,and,rarely,brainabscess;E. moshkovskii,whichcausesdiarrhea;andE. dispar,whichisnonpathogenic.
EPIDEMIOLOGY• Amebiasisisspreadbyfecal-oraltransmission,andinadditiontopersontopersoncanbe
waterborneandfoodborne.• Mostinfectionsareinimpoverishedcommunitiesinthedevelopingworld.• Amebic colonization, diarrhea, and colitis are most common in infants through the pre-
schoolyears.• Amebicliverandbrainabscessoccur90%ofthetimeinyoungmen.• E. histolyticaisacommoncauseofdiarrheainreturninginternationaltravelers.• Men who have sex with men (MSM) are at risk of both human immunodeficiency virus
(HIV)andamebiasis,andoneshouldconsiderthepossibilityofHIVinthesettingofamebia-sisinMSM.
MICROBIOLOGY• Cystformisinfectious,environmentallystable,andresistanttochlorination.• Trophozoiteisthetissue-invasivestage.
DIAGNOSIS• Stoolovaandparasiteexamshouldnotbeusedbecausetheyareinsensitiveandnonspecific.
Instead, diagnosis is best accomplished in the laboratory through a combination of fecalantigendetectionorquantitativepolymerasechainreactionforfecalparasiteDNA,incombi-nationwithserologictestsforantiamebicantibodies(whichcanbenegativeearlyinillness).
• Colonoscopyandabdominal imagingtechniques(ultrasound,computedtomography,andmagneticresonanceimaging)areusefuladjunctsfordiagnosisofintestinalandextraintes-tinaldisease,respectively.
THERAPY (SEE TABLE 200-1)• Noninvasive infection is treatedwithparomomycin:30mg/kg/dayorally in threedivided
dosesperday×5to10days.• Invasiveinfectionistreatedwithtinidazole2goncedailyfor5days,followedbyparomo-
mycin(topreventrelapsefromgutlumenparasites).• Considerpercutaneousdrainageforliverabscessesof5cmorgreaterindiameterorifthey
areintheleftlobe.
PREVENTION• Preventionisaccomplishedbysanitationandcleanwater.• Vaccineisunderdevelopment.
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TABLE 200-1 Drug Therapy for Treatment of Amebiasis
DRUG ADULT DOSAGE SIDE EFFECTS
Amebic Liver Abscess*Metronidazole† 750 mg PO tid × 10 days Primarily GI side effects: anorexia, nausea,
vomiting, diarrhea, abdominal discomfort, or unpleasant metallic taste; disulfiram-like intolerance reaction to alcoholic beverages; neurotoxicity, including seizures, peripheral neuropathy, dizziness, confusion, irritability
or
Tinidazole 2 g PO once daily × 5 days Primarily GI side effects and disulfiram-like intolerance reaction to alcoholic beverages for 5 days
Followed by a luminal agent
Paromomycin 30 mg/kg/day PO in three divided doses per day × 5-10 days
Primarily GI side effects: diarrhea, GI upset
or
Diloxanide furoate 500 mg PO tid × 10 days Primarily GI side effects: flatulence, nausea, vomitingPruritus, urticaria
Amebic Colitis‡
Tinidazole 2 g PO once daily × 5 days Same as for amebic liver abscess
Plus a luminal agent (same as for amebic liver abscess)
Asymptomatic Intestinal ColonizationTreatment with luminal agent as for amebic liver abscess
GI, gastrointestinal; PO, by mouth.*Amebic liver abscess may necessitate antiparasitic treatment plus percutaneous or surgical drainage. Nitazoxanide
may be effective therapy as well, but clinical experience is limited.†Drug of choice for treatment of amebic liver abscess.‡Amebic colitis may necessitate antiparasitic treatment plus surgical treatment.Modified from Haque R, Huston CD, Hughes M, et al. Current concepts: amebiasis. N Engl J Med. 2003;348:
1565-1573.
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201 Free-Living AmebaeAnita A. Koshy, Brian G. Blackburn, and Upinder Singh
MICROBIOLOGY AND EPIDEMIOLOGY• Free-livingamebaeareprotiststhatarecommonintheenvironmentworldwidebutrarely
causerecognizedhumaninfections.Thetrophozoitestagesoftheseorganismsfeedonbac-teriaanddebrisintheenvironment.• Naegleria fowleri iswidelydistributedgloballyandhasbeen isolated fromfreshwater,
mostcommonlyinwarmenvironments.• Acanthamoebaspp.areubiquitousmembersoftheenvironmentandarefoundworldwide
insoilandfreshwater.• Balamuthia mandrillaris is also likely widely distributed and has been isolated
fromsoil.
CLINICAL MANIFESTATIONS AND DIAGNOSIS• N. fowleritypicallycausesafulminantmeningoencephalitisinhealthy,immunocompetent
young patients, in association with swimming in warm fresh water. The disease is nearlyalwaysfatal.• Thecerebrospinalfluid(CSF)profileofpatientswithN. fowleriprimaryamebicmenin-
goencephalitis (PAM) is similar to that seen inbacterialmeningitis (highwhitebloodcellcount,lowglucose,highprotein),butwithanegativeGramstainandculture.MotiletrophozoitescansometimesbeseenonwetmountoftheCSF.
• NeuroimagingstudiesinpatientswithPAMareusuallynonspecific.• Acanthamoebaspp.andB. mandrillariscausethesubacuteonsetoffocalneurologicdeficits
and mental status changes (granulomatous amebic encephalitis [GAE]) related to centralnervous system mass lesions. Acanthamoeba is mostly seen in immunocompromised anddebilitated individuals, whereas Balamuthia occurs in both immunocompromised andimmunocompetentpatients.Thecase-fatalityratefortheseinfectionsisalsohigh.• IntheUnitedStates,BalamuthiaGAEmaybemorecommoninmaleHispanicpatients
thaninothergroups.• CSFstudiesofpatientswithGAEareusuallynonspecific,anditisraretoisolateorgan-
ismsfromtheCSF.• Neuroimagingstudiesgenerallyrevealmultiplespace-occupyinglesionsinthebrain,with
orwithoutcontrastenhancement.• Biopsyofinvolvedtissues(skin,brain,etc.)canbediagnostic,usuallyviahistopathologic
examination/immunohistochemicalstainingorpolymerasechainreaction(PCR).• Acanthamoebaspp.andB. mandrillariscaninvolveothersites(lungs,sinuses,adrenals,and
skin).• Acanthamoebaspp.alsocausesight-threateningkeratitisinotherwisehealthyindividualsin
associationwithcontactlensuse.Diagnosisdependsonahighclinicalsuspicion,inconjunc-tionwithinvivoconfocalmicroscopyordemonstrationofAcanthamoebaincornealscrap-ingsorbiopsyspecimensbyhistopathologicexamination,culture,orPCR.
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THERAPY• Therapeuticregimensforfree-livingamebicinfectionsofhumansarenotwelldefined.• TreatmentforN. fowleriPAMshouldincludehigh-doseintravenousamphotericinproducts;
intrathecalamphotericinmayalsoprovidesomebenefit,andtheadditionofazoles,rifampin,miltefosine,orotherantimicrobialsshouldbeconsidered.
• Acanthamoebakeratitisshouldbetreatedwithtopicalchlorhexidineorpolyhexamethylenebiguanide;adjunctivesurgicaltherapymayalsobenecessary.
• AcanthamoebaGAEshouldbe treatedwithcombinationantimicrobial regimens,possiblyincludingpentamidine,anazole,asulfonamide,miltefosine,andflucytosine.However,themostefficaciousregimenisnotcurrentlyknown.
• B. mandrillarisGAEshouldbetreatedwithcombinationantimicrobialregimens,possiblyincluding pentamidine, flucytosine, a sulfonamide, albendazole, an azole, a macrolide,amphotericin, and/or miltefosine. However, the most efficacious regimen is not currentlyknown.
• SurgicaldébridementmayplayanadjunctiveroleinthemanagementofbothformsofGAE.
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202 Malaria (Plasmodium Species)Rick M. Fairhurst* and Thomas E. Wellems
DEFINITION• Thehistoryoftravelandexposureinamalaria-endemicareaistypical.• Uncomplicatedmalariaisoftenconfusedwiththe“flu”:fever,accompaniedbyheadaches,
bodyaches,andmalaise.• Severemalariacanpresentwithanyoneofthefollowing:diminishedconsciousness,convul-
sions, respiratory distress, prostration, hyperparasitemia, severe anemia, hypoglycemia,jaundice,renalinsufficiency,hemoglobinuria,shock,cessationofeatinganddrinking,repeti-tivevomiting,orhyperpyrexia.
EPIDEMIOLOGY• Malaria is endemic in tropical and subtropical areas of Africa, South America, Asia, and
Oceania.• MalariaistransmittedbythebiteofafemaleAnophelesmosquito.• Transmissioncanalsooccurbybloodtransfusion,importedmosquitoes,orautochthonous
mosquitoesinfectedbyimmigrants.
MICROBIOLOGY• PlasmodiaareparasiticprotozoaoftheApicomplexaphylum.• Plasmodium falciparum,Plasmodium vivax,Plasmodium ovale,Plasmodium malariae, and
Plasmodium knowlesiarethemajorhumanmalariaparasites.
LABORATORY DIAGNOSIS• IdentificationofparasitesisthroughGiemsa-stainedthickandthinbloodsmears.• Rapiddiagnostictestsareavailable(e.g.,BinaxNOWintheUnitedStates).
THERAPY• Treatmentdependsprimarilyondiseaseseverity,drug-resistanceepidemiology,patientage,
andpregnancystatus.• Uncomplicatedmalariadueto:
• Chloroquine-sensitiveP. falciparum(Mexico,CentralAmericawestofthePanamaCanal,Haiti, the Dominican Republic, and most areas of the Middle East), P. vivax, P. ovale,P. malariae,andP. knowlesi,aswellasuncomplicatedmalaria,dueto:• Oraltreatmentwithchloroquinephosphate
• Chloroquine-resistant P. falciparum (most areas of the world) or chloroquine-resistantP. vivax(PapuaNewGuineaandIndonesia)• Oral treatment with atovaquone-proguanil, artemether-lumefantrine, quinine plus
doxycycline,ormefloquine(dihydroartemisinin-piperaquineisregisteredandavail-ableinsomecountriesoutsidetheUnitedStates)
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
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• PreventrelapsingP. vivaxandP. ovalemalariawithprimaquinephosphate(contraindi-cated in pregnant/breast-feeding women and glucose-6-phosphate dehydrogenase[G6PD]-deficientpersons)
• Severemalaria• Intravenoustreatmentwithquinidinegluconate(onlydrugcommerciallyavailableinthe
United States), artesunate (available only from the Centers for Disease Control andPreventionintheUnitedStates),orquininedihydrochloride(notavailableintheUnitedStates)
PREVENTION• Chemoprophylaxisdecisionsshouldbebasedondrug-resistanceepidemiology,patientage,
andpregnancystatus.• Areaswithchloroquine-sensitivemalaria:chloroquinephosphate• Areaswithmefloquine-sensitivemalaria:mefloquine• Allareas:atovaquone-proguanilordoxycycline• AreaswithmostlyP. vivax:primaquine(contraindicatedinpregnantwomenandG6PD-
deficientpersons)• Mosquitorepellentsandavoidancemeasures
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203 Leishmania Species: Visceral (Kala-Azar), Cutaneous, and Mucosal LeishmaniasisAlan J. Magill
DEFINITION• Leishmaniasis is infection with Leishmania species of protozoa acquired by the bite of a
PhlebotomusorLutzomyiasandfly.
CLINICAL MANIFESTATIONS• The syndrome classifications of leishmaniasis are cutaneous, mucosal (mucocutaneous),
and visceral (kala-azar). Uncommon skin manifestations are diffuse cutaneous leish-maniasis,post–kala-azardermal leishmaniasis, leishmaniasisrecidivans,anddisseminatedleishmaniasis.
DIAGNOSIS• Giemsastain,culture,andpolymerasechainreactionassayareperformed.
TREATMENT• Treatmentofskinlesionsincludestopical,oral,andsystemicregimens.Visceralleishmani-
asis andNewWorldmucosal leishmaniasis are treatedparenterallybyanamphotericinBformulation,pentavalentantimony,andmiltefosine.
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204 Trypanosoma Species (American Trypanosomiasis, Chagas’ Disease): Biology of TrypanosomesLouis V. Kirchhoff*
DEFINITION• Chagas’disease,orAmericantrypanosomiasis,isaninfectioncausedbythesingle-cellpro-
tozoanparasiteTrypanosoma cruzi.
MICROBIOLOGY• T. cruziisspreadamongitsvariousmammalianhosts,includingdomesticandwildanimals
as well as humans, by bloodsucking triatomine insects, also called cone-nosed or kissingbugs.
• Theparasitesmultiplyinthegutoftheseinsects,andtheirfecescontainformsthatcaninfectmammals.Whencontaminatedfecestouchvulnerablemammaliantissuessuchasthecon-junctivae,oralandnasalmucosalsurfaces,orskinabrasions,transmissioncantakeplace.
• Oncetheparasitesgainafootholdinamammalianhost,theyalternatebetweenmultiplyingintracellularformsandfree-swimmingformsinthebloodstreamthatspreadtheinfectioninternallyorgetsweptupbyfeedingvectors,thuscompletingthecycle.
• T. cruzicanalsobetransmittedfrommothertofetus,throughbloodproductsandorgansobtainedfrominfecteddonors,andinlaboratoryaccidents.
• InfectionwithT. cruziinhumansislifelong.
EPIDEMIOLOGY• Chagas’diseaseisendemicinallSouthandCentralAmericancountriesandalsoinMexico.• TheinfectionisnotendemicinanyoftheCaribbeanislands.• About8millionpersonsarechronicallyinfectedwithT. cruzi,roughly56,000newinfections
occureachyear,andabout12,000personsdieoftheillnessannually.Anestimated300,000immigrantswithChagas’diseasecurrentlyliveintheUnitedStates.
• Duringrecentdecades,largenumbersofpeopleintheendemiccountrieshavebeenmigrat-ingfromruralareastothecities,andatthesametimemanymillionsofpeoplehaveemi-grated from the endemic countries to industrialized regions, particularly the EuropeanUnionandtheUnitedStates,thusurbanizingandglobalizingthedisease.
CLINICAL MANIFESTATIONS• Between 10% and 30% of persons who are chronically infected with T. cruzi ultimately
developcardiacorgastrointestinalsymptomsthatarecausedbypathologicprocessesrelatedtothepersistentpresenceoftheparasite.
• ChroniccardiacChagas’diseasetypicallyinvolvesrhythmdisturbancesandcardiomyopathy.• Gastrointestinalproblemscanincludemegaesophagusandmegacolon.• ImmunosuppressionofpersonswhoharborT. cruzichronicallycanresultinlife-threatening
reactivationoftheinfection.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofborrowedfigures.
421C
hap
ter 204 Trypan
oso
ma Sp
ecies (Am
erican Tryp
ano
som
iasis, Ch
agas’ D
isease): Bio
log
y of Tryp
ano
som
es
DIAGNOSIS• ThediagnosisofacuteorcongenitalChagas’diseaseismadebyparasitologicmethods,typi-
callydirectmicroscopicexaminationofblood,hemoculture,orpolymerasechainreaction–basedassays.
• ChronicT. cruziinfectionisdiagnosedserologically,andmanyenzyme-linkedimmunosor-bent assays, immunofluorescence assays, and chemiluminescence tests are available com-merciallyforthispurpose.
THERAPY• NifurtimoxandbenznidazolearetheonlytwodrugsavailablefortreatingT. cruziinfections
(availablefromtheCentersforDiseaseControlandPreventionDrugService).• Parasitologic cure rates for these drugs are high for acute and congenital infections but
unfortunatelyverylowinpersonswithlong-standinginfections.• Therearenoconvincingdatafromrandomizedcontrolledtrialsindicatingthattreatmentof
chronically infected persons with either drug significantly delays pathogenesis or affectslong-termoutcomes.
PREVENTION• NovaccineorprophylacticdrugsareavailableforreducingtransmissionofT. cruzi.• In the endemic countries, reducing transmission depends primarily on educating at-risk
populations, housing improvement, and spraying insecticides to eliminate vectors indwellings.
• SerologicscreeningofbloodandorgandonorsisalsoakeyelementinthecontrolofChagas’disease.
• Inmanyoftheendemiccountries,enormousprogresshasbeenmadeinbothvectorcontrolandbloodscreeningand in theUnitedStates,Canada,and theEuropeanUnionwith thelatter.
422
205 Agents of African Trypanosomiasis (Sleeping Sickness)Louis V. Kirchhoff*
DEFINITION• HumanAfricantrypanosomiasis(HAT),alsoknownassleepingsickness,iscausedbytwo
protozoanparasitesubspecies:Trypanosoma brucei gambiense(WestAfricantrypanosomia-sis)andTrypanosoma brucei rhodesiense(EastAfricantrypanosomiasis).
MICROBIOLOGY• ThetrypanosomesthatcauseHATaretransmittedamongtheirmammalianhostsbytsetse
flies.Thefliesbecomeinfectedwhentheytakeabloodmealfromaninfectedmammal.Thereisadevelopmentalcycle intheflies,afterwhichinfectiveparasitesmigratetothesalivaryglandsandareinjectedintoanewhostwhenthefliestakesubsequentbloodmeals.IntheirmammalianhostsAfricantrypanosomesarefoundprimarilyinthebloodstreamand,toalesserextent,inperivascularareasofthebrainandothertissues.IncontrasttoTrypanosoma cruzi,theparasitethatcausesChagas’disease,Africantrypanosomesdonothaveanintracel-lular phase. They avoid immune destruction by antibodies by periodically changing theirglycoproteincoatsthroughamolecularprocesscalledantigenic variation.
EPIDEMIOLOGY• HAT occurs only in sub-Saharan Africa, where endemic foci are found in about 20
countries.• HAT is much less of a problem today than in the past. Fewer than 10,000 new cases are
reportedannuallytotheWorldHealthOrganization.Althoughthisnumberreflectssubstan-tial underreporting, there is no doubt that control efforts implemented in many endemiccountriesduringthepast15yearshaveachievedconsiderablesuccess.Eachyearinindus-trializedcountriesHATisdiagnosedinasprinklingofpersonswhohavetraveledtoendemicareas,butgiventhe largenumbersofpersonswhomakesuchtrips, the incidenceofsuchcasesisextremelylow.
CLINICAL MANIFESTATIONS• Twoclinicalstagesexist.Stage1(hemolymphaticdisease)ischaracterizedbyfever,adenopa-
thy,andheadache.Stage2(centralnervoussystemorencephaliticdisease)involvesmainlyneuropsychiatricsignsandsymptoms.
• TheprimarydifferencebetweentheclinicalpatternsofgambienseandrhodesienseHATisthatthelatterfollowsamuchmorerapidcourseandcanleadtodeathinamatterofmonths,whereasgambienseHATtypicallydevelopsachronicpatternthatcanlastforyears.
• UntreatedHATalmostinevitablyendsindeath.• Itisimportantforcaregiversattendingtotravelerswithfeverandothernonspecificsymp-
tomswhohavebeeninendemicareastoincludeHATinthedifferentialdiagnosis.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofborrowedfigures.
423C
hap
ter 205 Ag
ents o
f African
Trypan
oso
miasis (Sleep
ing
Sickness)
DIAGNOSIS• Given the life-threatening nature of untreated HAT, a high index of suspicion should be
maintainedwithpersonswhohavebeeninareasendemicforHAT.• Numerousotherillnessescommoninthetropicscausesymptomssimilartothoseseenin
boththeearlyandlatestagesofsleepingsickness.• A definitive diagnosis of African trypanosomiasis requires demonstration of the parasite.
ExaminationofbloodsmearsandcerebrospinalfluidforparasitesisthecornerstoneofHATdiagnosis.
• ThereisagrowingroleforpolymerasechainreactionandrelatedmolecularmethodsinthediagnosisofHAT.
• DiagnosticapproachesandtreatmentshouldbediscussedindetailwithappropriatestaffattheCentersforDiseaseControlandPrevention.
THERAPY• Treatmentiscomplicatedbecauseitvariesaccordingtotheclinicalstageofthediseaseand
thetrypanosomesubspeciescausingtheinfection.• ToxicityofthedrugsusedtotreatHATisamajorproblem.
PREVENTION• Individuals can reduce their risk of acquiring infections with African trypanosomes by
avoidingareasknowntoharborinfectedinsects,wearingclothingthatreducesthebitingoftheflies,andusinginsectrepellent.
• Chemoprophylaxis isnotrecommendedbecauseof thehightoxicityof thedrugs thatareactiveagainstAfricantrypanosomes,andnovaccineisavailabletopreventtransmissionoftheparasites.
424
206 Toxoplasma gondiiJosé G. Montoya, John C. Boothroyd, and Joseph A. Kovacs
DEFINITION• Toxoplasma gondii is a ubiquitous coccidian protozoan that usually causes asymptomatic
infection inhumansbut cancause significantdisease incongenitally infected infantsandimmunodeficientpatientsandoccasionallyinimmunocompetentindividuals.
EPIDEMIOLOGY• Toxoplasmosisisaworldwidezoonosisthatcaninfectawiderangeofanimalsandbirds.• Transmissiontohumansismainlybyingestionofviabletissuecystsinmeatoroffoodor
watercontaminatedwithoocysts.Lesscommonly,thereiscongenitaltransmissionortransplantationofaninfectedorgan.
• PositiveimmunoglobulinG(IgG)representingpriorinfectionincreaseswithage;seroprevalenceis≈11%intheUnitedStatesandupto≈78%inotherpartsoftheworld.
• Congenital transmission occurs almost exclusively when the mother becomes infectedduringpregnancy.Retinochoroiditiscanoccuraftercongenitalinfectionorrecentlyacquiredinfection.Infectioninhumanimmunodeficiencyvirus(HIV)/acquiredimmunodeficiencysyndromepatientsalmostalwaysresultsfromreactivationoflatentinfection.Amongorgantransplantpatients,diseasecanresultfromeithernewlyacquiredinfectionfromthetransplantedorganorfromreactivationoflatentinfection.
MICROBIOLOGY• Toxoplasma organisms are exclusively intracellular. The sexual phase occurs in felines.
Excretedoocystsrequire1to5daystobecomeinfectious.Tachyzoitesactivelyreplicateinessentiallyallcelltypes.Tissuecystswithintracysticbradyzoitesmaintainorganismviabilityduringlatentinfection.
• Tachyzoites replicate well in tissue culture and are responsible for clinical manifestationsduringprimaryinfectionorreactivationoflatentinfection.
• Multiplestrainsareidentifiedbygenotyping.Strainsdifferinvirulence,withthemostvirulentstrainssofarreportedbeingfoundinSouthAmerica.
DIAGNOSIS• Direct detection of the organism is by polymerase chain reaction (PCR) assay, histopa
thology with immunoperoxidase staining, or, less commonly, by tissue culture or mouseinoculation.
• Serologicassayscanhelpdistinguishacutefromchronicinfectionandcanidentifypatientsatriskforreactivation.ImmunoglobulinM(IgM)positivetestresultsshouldbeconfirmedat a reference laboratory (e.g., the Palo Alto Medical Foundation–Toxoplasma SerologyLaboratory[PAMFTSL];www.pamf.org/serology/).
• Maternalinfectionisoftenasymptomatic;serologyshowsacuteinfection,andIgMpositivetestresultsmustbeconfirmedatareferencelaboratory.Congenitalinfectionmaybeasymptomaticorappearwithneurologicorocularmanifestations;thisformisdiagnosedinuterobyPCRofamnioticfluidorafterbirthbyserologyorPCR.
425C
hap
ter 206 Toxo
plasm
a go
nd
ii
• Chorioretinitismaybeasymptomaticorshowvisualloss;ophthalmologicexaminationandPCRofvitreousoraqueousfluidareperformed.TheGoldmannWitmercoefficient(antiToxoplasma IgG/total IgG in aqueous fluid divided by antiToxoplasma IgG/total IgG inserum)canbehelpful.
• HIVinfectedpatientsusuallypresentwithfocalneurologicsymptoms.PatientsareusuallyIgGpositiveandIgMnegative,computedtomographyormagneticresonanceimagingmayshow one or more contrastenhancing lesions, cerebrospinal fluid PCR is specific but notsensitive,brainbiopsysensitivityisimprovedbyimmunoperoxidasestaining,anddiagnosisisoftenpresumptiveandextendstoaresponsetoempiricaltherapy.
• Immunodeficient patients present with encephalopathy, seizures, pneumonia, and fever.DiagnosisisbasedonpositivePCRorhistopathology.Hematopoieticstemcelltransplantation(HSCT)requirespretransplantserology;solidorgantransplantationrequirespretransplantserologyinthedonorandrecipient.
THERAPY• Immunocompetentpatients:Thesepatientsusuallyrequirenotherapyifasymptomatic;they
maybenefitfromtreatmentifsymptomsaresevereorpersist.• Immunocompromised patients: The therapy dosage is pyrimethamine (200mg load,
then50 to75mg/day)plus sulfadiazine (1000 to1500mgevery6hours)plus leucovorin(10to20mg/day).Thedosageisthendecreasedtomaintenancedosingofpyrimethamine(25 to 50mg/day) plus sulfadiazine (500 to 1000mg every 6 hours) plus leucovorin (10to 20mg/day) after 3 to 6 weeks if a clinical response occurs. Alternatives include pyrimethamine,asabove,plusleucovorinpluseitherclindamycin(intravenous[IV]ororal[PO];600mg every 6 hours) or atovaquone (1500mg every 12 hours). Another alternative istrimethoprimsulfamethoxazole(TMPSMX)(IVorPO;5mg/kgofTMPevery12hours).Corticosteroidsaregivenonlyforclinicallysignificantedemaormasseffect,andanticonvulsantsaregivenonlyafteraseizure.
• HIV patients: Start antiretroviral therapy (ART) after 2 to 3 weeks; stop antiToxoplasmamedicationsiftheCD4countisgreaterthan200cells/mm3formorethan6months.HighrelapserateoccurswithoutARTandmaintenancetherapy.
• Acuteinfectioninpregnantwomenlessthanorequalto18weeksofgestation:Givespiramycin (1g every 8 hours; available at no cost through the PAMFTSL and the U.S. FoodandDrugAdministration)untildelivery.Ifinfectioninthefetusisdocumentedorsuspected,or ifatgreaterthan18weeksofgestation,givepyrimethamine(50mgevery12hoursfor2days,then50mg/day)plussulfadiazine(initialdose75mg/kg,followedby50mg/kgevery12hours;maximum,4g/day),plusfolinicacid(10to20mg/day).Before14to18weeksofgestation,givenopyrimethamineorleucovorin.
• Congenitallyinfectedinfant:Givepyrimethamine(1mg/kgevery12hoursfor2days,then1mg/kg/day for 2 or 6 months); then this dose is given every Monday, Wednesday, andFriday; plus sulfadiazine (50mg/kg every 12 hours) plus folinic acid (10mg three timesweekly)foratleast12months.
• Chorioretinitis patients: If therapy is clinically indicated, give pyrimethamine (100mgloadingdoseover24hours,then25to50mg/day)plussulfadiazine(1gevery6hours)plusleucovorin(10to20mg/day)for4to6weeks.TMPSMX,onedoublestrengthtabletevery3days,canpreventrelapse.
PREVENTION AND PROPHYLAXIS• Avoidundercookedmeatandpotentiallycontaminatedfoodorwater;cleancatlitterdaily.• Immunocompromised patients: Give TMPSMX, one doublestrength or singlestrength
tablet daily. An alternative is dapsone (50mg/day) plus pyrimethamine (50mg/wk) plusleucovorin (25mg/wk). If the patient has HIV, start if the CD4 count is less than 100 to200 cells/mm3; discontinue if the patient is on ART and the CD4 count is greater than200cells/mm3foratleast3months(primaryprophylaxis)or6months(secondaryprophylaxis).ForHSCTrecipients,startTMPSMXafterengraftment.Ifthepatientisasolidorgantransplantrecipient,startattransplantationifclassifiedasD+orR+.
426
207 Giardia lambliaDavid R. Hill and Theodore E. Nash
DEFINITION• Giardiasis,causedbytheprotozoanGiardia lamblia,isacommoncauseofsporadic,endemic,
andepidemicdiarrheathroughouttheworld.• Infected persons can have acute diarrhea with malaise, cramping and bloating, chronic
diarrhea with malabsorption, or asymptomatic infection. Asymptomatic infection is mostcommon in children, particularly in low-income settings, and may contribute to poornutrition.
EPIDEMIOLOGY• Giardiaisoneofthemostwidelydistributedentericparasites.• IntheUnitedStates,thereareapproximately20,000documentedinfectionsannually,with
estimatedinfectionsofmorethan100,000;itismostfrequentlyreportedinchildrenaged1to9yearsandadultsaged35to45years.
• Inlow-incomecountries,Giardiainfectsnearlyallchildrenbytheageof10years.• Transmissionofthisfecal-oralparasiteismostcommonthroughpersontopersontransmis-
sionandthroughuntreatedorinadequatelytreatedsurfacewater.• Although specific human genotypes (assemblages A and B) are found in some animals,
epidemicsofgiardiasiscausedbyanimalshavenotbeenreliablyobserved.Animalstypicallyharborotherassemblages.
DIAGNOSIS• Aclinicalsyndromeofdiarrhealasting7to10days,andoftenassociatedwithweightloss,
ishelpfulindistinguishinggiardiasisfromotherentericinfections.• Usefulepidemiologicrisk factorsareahistoryof travel,drinkinguntreatedsurfacewater,
having young children in daycare, or engaging in sexual practices with the potential forfecal-oraltransmission.
• Stoolexaminationforovaandparasitesisthetraditionalmethodofdiagnosis.• Antigendetectioniswidelyavailableandismoresensitiveandspecificthanstoolexamina-
tionforovaandparasites.Polymerasechainreactionassayisbecomingmorewidelyusedandcanidentifytheassemblage.
THERAPY• Tinidazoleisthedrugofchoice,takeninasingledose(seeTable207-1).• Alternativesaremetronidazole,nitazoxanide,andalbendazole.• Potentialadverseeventsassociatedwithtreatmentshouldbediscussedwiththepatient.• Treatmentduringpregnancyrequiresspecialconsiderations.• Post-Giardialactoseintoleranceshouldbeconsiderediftreatmentappearstofail.Ifparasites
arepresent,thenre-treatmentwithadrugofadifferentclassisusuallysuccessful.
427C
hap
ter 207 Giard
ia lamb
lia
PREVENTION• Preventionofgiardiasisrequirestheproperhandlingandtreatmentofdrinkingandrecre-
ational water supplies, good personal hygiene, and protection of food supplies fromcontamination.
• Bringingwatertoaboil,filtration,andcarefulhalogenationcanbeeffectivemeasurestotreatsmallvolumesofwater.
TABLE 207-1 Treatment of Giardiasis
Drug (FDA Pregnancy Category)*
DOSAGE
Adult PediatricTinidazole (C) 2 g, single dose 50 mg/kg, single dose (maximum, 2 g)
Metronidazole† (B) 250 mg tid × 5-7 days 5 mg/kg tid × 7 days
Nitazoxanide (B) 500 mg bid × 3 days Age 12-47 mo: 100 mg bid × 3 days
Age 4-11 yr: 200 mg bid × 3 days
Albendazole† (C) 400 mg qd × 5 days 15 mg/kg/day × 5-7 days (maximum, 400 mg)
Paromomycin† (NC) 500 mg tid × 5-10 days 30 mg/kg/day in 3 doses × 5-10 days
Quinacrine‡ (C) 100 mg tid × 5-7 days 2 mg/kg tid × 7 days
Furazolidone‡ (C) 100 mg qid × 7-10 days 2 mg/kg qid × 10 days
FDA, U.S. Food and Drug Administration; NC, not categorized.*FDA pregnancy categories: B, Animal reproduction studies have failed to demonstrate a risk to the fetus, and
there are no adequate and well-controlled studies in pregnant women. C, Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
†Not an FDA-approved indication.‡No longer produced in the United States; may be obtained from some compounding pharmacies.
428
208 Trichomonas vaginalisJane R. Schwebke
MICROBIOLOGY AND EPIDEMIOLOGY• Trichomonas vaginalisisaflagellatedparasite.• Infectionisthroughsexualtransmission.• Susceptibilitytohumanimmunodeficiencyvirus(HIV)infectionmaybeincreased.
DIAGNOSIS• Infection causes vaginitis in women and may cause urethritis in men; it is often
asymptomatic.• Inwomen,mostcasesarediagnosedusingwetprepmicroscopyofvaginalfluidasthepoint
ofcaretest,butthislackssensitivity.• Goldstandardfordiagnosisisnucleicacidamplificationtesting.
THERAPY• Metronidazoleistheusualtherapy.• Resistancetometronidazolemayoccur.• Tinidazolemaybemoreeffective.
PREVENTION• Sexualpartnersshouldbetreated.• Condomspreventinfection.
429
209 Babesia SpeciesJeffrey A. Gelfand and Edouard G. Vannier
DEFINITION• Babesiosisisanemerginginfectiousdiseasecausedbyhemoprotozoanparasitesofthegenus
Babesia.
EPIDEMIOLOGY AND MICROBIOLOGY• ThemainetiologicagentofbabesiosisintheUnitedStatesisBabesia microti,aparasitetypi-
callyfoundinwhite-footedmiceandprimarilytransmittedtohumansduringthebloodmealofaninfectedIxodes scapularisnymphaltick.
• B. microticanalsobetransmittedviatransfusionofbloodproducts,primarilypackedredbloodcells.Transplacentaltransmissionisrare.
• Babesiosis is a nationally notifiable disease in seven highly endemic states (Connecticut,Massachusetts, Minnesota, New Jersey, New York, Rhode Island, and Wisconsin) and 12otherjurisdictions.
• Risk factors for severe babesiosis include age older than 50 years, splenectomy, humanimmunodeficiencyvirusinfection,malignancy,andimmunosuppressiontherapiesfortrans-plantationorcancer.
DIAGNOSIS• Feveristhesalientsymptom.Chillsandsweatsarecommon.Lessfrequentsymptomsinclude
headache,myalgia,anorexia,arthralgia,andnausea.• DiagnosisismadeonGiemsa-stainedthinbloodsmears.Trophozoitesoftenappearasrings.
Tetradsofmerozoitesarepathognomonic.Other features thatdistinguishbabesiosis frommalariaincludethelackofbrownishdepositinrings,theabsenceofgametocytes,andthepresenceofextracellularmerozoites.
• Ifparasitesarenotvisualizedonasmearandbabesiosisissuspected,polymerasechainreac-tionassay–basedamplificationofparasiteDNAshouldbeperformed.Serologyconfirmsthediagnosis.
• Laboratory findings are consistent with hemolytic anemia and include low hematocrit,low hemoglobin, elevated lactate dehydrogenase level, and elevated reticulocyte count.Thrombocytopeniaandelevatedliverenzymevaluesarecommon.
THERAPY (SEE TABLE 209-1)• MildB. microtiillnessshouldbetreatedwithasingle7-to10-daycourseoforalatovaquone
(750mg orally every 12 hours) plus oral azithromycin (500mg orally once, then 250mgdaily). Symptoms should be expected to abate within 48 hours and to resolve within3months.
• Severe B. microti illness requires hospitalization. Initial therapy should consist of a 7-to10-daycourseofclindamycin(300to600mgintravenouslyevery6hoursor600mgorallyevery 8 hours) plus oral quinine (650mg orally every 8 hours). Despite therapy, half ofhospitalizedpatientsdevelopcomplicationsandabout10%die.
430Part
II
Infe
ctio
us
Dis
ease
s an
d t
hei
r Et
iolo
gic
Ag
ents
• Ifsymptomspersistorrelapse,antimicrobialtherapyshouldlast6weeks,including2weeksduringwhichparasitesarenolongerseenonbloodsmear.
• Partialorcompleteredbloodcellexchangetransfusionisrecommendedwhenhigh-gradeparasitemia (≥10%) or severe anemia (≤10g/dL) occurs, or when pulmonary, renal, orhepaticsystemsarecompromised.
PREVENTION• Novaccineisavailable.Individualsatriskshouldavoidhighlyendemicareas.
TABLE 209-1 Treatment of Human Babesiosis
ORGANISM SEVERITY ADULTS CHILDRENBabesia microti* Mild† Atovaquone 750 mg
q12h PO plus azithromycin 500 mg PO on day 1 and 250 mg/day PO from day 2 on
Atovaquone 20 mg/kg q12h PO (maximum 750 mg/dose) plus azithromycin 10 mg/kg PO on day 1 (maximum 500 mg/dose) and 5 mg/kg/day PO from day 2 on (maximum 250 mg/dose)
Severe‡§ Clindamycin 300-600 mg q6h IV or 600 mg q8h PO plus quinine 650 mg q8h PO
Clindamycin 7-10 mg/kg q6-8h IV or 7-10 mg/kg q6-8h PO (maximum 600 mg/dose) plus quinine 8 mg/kg q8h PO (maximum 650 mg/dose)
Babesia divergens* Immediate complete RBC exchange transfusion plus clindamycin 600 mg q6-8h IV plus quinine 650 mg q8h PO
Immediate complete RBC exchange transfusion plus clindamycin 7-10 mg/kg q6-8h IV (maximum 600 mg/dose) plus quinine 8 mg/kg q8h PO (maximum 650 mg/dose)
Note: Monitor patients on quinine with electrocardiography; monitor quinine serum levels in the setting of hepatic or renal disease.
IV, intravenously; PO, orally; RBC, red blood cell.*Treatment for 7 to 10 days, but duration may vary.†Atovaquone (750 mg twice daily) combined with higher doses of azithromycin (600 to 1000 mg/day) has been
used in immunocompromised patients. With this regimen, symptoms and parasitemia resolve faster.‡Consider partial or complete RBC exchange transfusion in cases of high-grade parasitemia (≥10%), severe anemia
(<10 g/dL), or pulmonary, renal, or hepatic compromise. Even when parasitemia is less than 10%, consider exchange transfusion if acute respiratory distress syndrome or syndrome resembling a systemic inflammatory response syndrome is present.
§In asplenic individuals and in immunocompromised patients, persistent or relapsing babesiosis should be treated for at least 6 weeks, including 2 weeks during which parasites are no longer detected.
431
210 Cryptosporidiosis (Cryptosporidium Species)A. Clinton White, Jr.
DEFINITION• CryptosporidiosisiscausedbyinfectionwithoocystsofCryptosporidiumspecies.
EPIDEMIOLOGY• Cryptosporidiosis has a global distribution with a higher prevalence in resource-poor
countries.• Cryptosporidiosis is amajorcauseofprolongeddiarrheaandmalnutrition inchildren in
resource-poorcountries.• Cryptosporidiosis is a major cause of diarrhea in adults infected by human immunodefi-
ciencyvirus(HIV).• Cryptosporidiosis is associated with person-to-person and waterborne transmission in
wealthycountries.• Themajorspecies,Cryptosporidium hominis,primarilyinfectshumans.• Zoonoticspecies,includingCryptosporidium parvum,arealsocommoninhumans.
MICROBIOLOGY• Cryptosporidiumspeciesareapicocomplexanprotozoanparasites.
CLINICAL MANIFESTATIONS• Mostpatientspresentwithdiarrheathatisfrequentlyprolonged.
DIAGNOSIS• Diagnosisdependsondemonstrationoftheorganisminstoolbyantigendetection,nucleic
acidamplification,ormicroscopywithacid-fastorfluorescentstains.
MANAGEMENT• Forimmunocompromisedhosts,thereisnoeffectivetherapy,butreversalofimmunedefects
iscritical(e.g.,treatingunderlyingHIVwithantiretroviraltherapy).• Nitazoxanidealoneiseffectiveinimmunocompetenthostsbutnotinseverelyimmunocom-
promisedpatients.
PREVENTION• Watertreatmentandhandhygienearekeymeasurestopreventinfection.
432
211 Cyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis SpeciesKathryn N. Suh, Phyllis Kozarsky, and Jay S. Keystone
CYCLOSPORA AND CYSTOISOSPORA (ISOSPORA)Epidemiology• Bothareopportunisticpathogens in immunocompromisedhostsbutalso infectnoncom-
promisedpatients.• Cyclospora:distributionisworldwideandisendemicindevelopingareas,withoutbreaksin
developedareas.• Cystoisospora: occurrence is primarily in tropical and subtropical climes, especially South
America,Africa,andSoutheastAsia.• Contaminatedfoodandwaterareprimarysources.• Oocystscansurviveinenvironmentformonthsbutmustsporulatetobecomeinfective.
Diagnosis• Acuteorchronicdiarrheaoccurswithotherconstitutionalandgastrointestinalsymptoms.• Oocystsinstoolmaybevisualizedusingmodifiedacid-faststain.• Multiplestoolexaminationsmayberequired.
Therapy• Trimethoprim-sulfamethoxazole, 1 double-strength tablet twice daily for 7 to 10 days,
or ciprofloxacin, 500mg orally twice daily for 7 days, is effective (see Tables 211-1 and211-2).
SARCOCYSTIS SPECIESEpidemiology• Distributionismainlytropicalandsubtropical,especiallyinSoutheastAsiaandMalaysia.• Infectioniswidelydistributedinvariousanimals;humandiseaseisveryrareafterconsump-
tionofinfectedraworundercookedanimalflesh.• Sarcocystis suihominisandSarcocystis hominisarethemaincausesofhumandisease.
Diagnosis• Infectionisgenerallyasymptomatic.• Rarely,self-limitedgastrointestinalillnessormyositis(fever,myalgias)occursafterexposure
inendemicareas.• Sporocystsoroocystsmaybevisibleinstool;musclebiopsymayberequired.
Therapy• None;albendazolehasbeenused.
BALANTIDIUM COLIEpidemiology• Distribution is worldwide, with infections in Latin America, Southeast Asia, Papua New
Guinea,andtheMiddleEastmostcommon.
433C
hap
ter 211 Cyclo
spo
ra cayetanen
sis, Cysto
isosp
ora (Iso
spo
ra) belli, Sarco
cystis Species, B
alantid
ium
coli, an
d B
lastocystis Sp
ecies
• Pigsareprimaryreservoirsandshedcystsinstool.• Cystsincontaminatedfoodorwaterareinfective.
Diagnosis• Theinfectionisgenerallyasymptomatic;occasionallyadiarrhealillnessisreported.• Trophozoitesarevisibleinstool.
Therapy• Tetracycline,metronidazole,oriodoquinolisused(seeTable211-3).
BLASTOCYSTIS SPECIESEpidemiology• Distribution is worldwide, primarily in developing countries, but prevalence varies
markedly.
Diagnosis• Roleinhumandiseaseisunclear;diarrhea,flatulence,andabdominaldiscomfortaremost
commonlyreportedsymptoms.• Microscopicdiagnosisischallenging;trichromestainisthemostsensitive.• Polymerasechainreactionassayismoresensitiveandspecificbutnotwidelyavailable.
Therapy• Therapyisoftenunsatisfactory.• Trimethoprim-sulfamethoxazole,metronidazole,oriodoquinolisused(seeTable211-4).
TABLE 211-1 Therapy (Adult) for Cyclosporiasis
DRUG* THERAPEUTIC DOSAGE PROPHYLACTIC DOSAGETrimethoprim-sulfamethoxazole One DS tablet† PO bid for 7-10 days One DS tablet PO three times weekly
Ciprofloxacin 500 mg PO bid for 7 days 500 mg PO three times weekly
Nitazoxanide 500 mg PO bid for 7 days
DS, double strength; PO, orally.*Drugs are listed in order of preference.†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole.
TABLE 211-2 Therapy (Adult) for Cystoisosporiasis
DRUG* THERAPEUTIC DOSAGE PROPHYLACTIC DOSAGETrimethoprim-sulfamethoxazole One DS tablet† PO bid for 10 days One DS tablet PO daily or three times
weekly
Ciprofloxacin 500 mg PO bid for 7 days 500 mg PO daily or three times weekly
DS, double strength; PO, orally.*Drugs are listed in order of preference.†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole.
TABLE 211-3 Therapy (Adult) for Balantidiasis
DRUG* DOSAGETetracycline 500 mg PO qid for 10 days
Metronidazole 750 mg PO tid for 5 days
Iodoquinol 650 mg PO tid for 20 days
PO, orally.*Drugs are listed in order of preference.
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TABLE 211-4 Therapy (Adult) for Blastocystosis
DRUG* DOSAGEMetronidazole 750 mg PO tid or 1.5 g daily, for 10 days
Trimethoprim-sulfamethoxazole One DS tablet† bid or two DS tablets daily for 7 days
Iodoquinol 650 mg PO tid for 20 days
Nitazoxanide 500 mg bid for 3 days
Paromomycin 25-35 mg/kg divided tid for 7 days
DS, double strength; PO, orally.*Drugs are listed in order of preference.†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole.
435
I Diseases Due to Toxic Algae
212 Human Illness Associated with Harmful Algal BloomsJ. Glenn Morris, Jr.
DEFINITION• Illnessesofprimaryconcerncausedbypreformedtoxinsproducedbyalgalspeciesinclude
ciguaterafishpoisoning,paralyticshellfishpoisoning,andamnesicshellfishpoisoning.
EPIDEMIOLOGY AND MICROBIOLOGY• Dependingontheagent,illnessiscausedbyingestionoftoxinsinseafoodorbyinhalation
orskincontact.• Occurrenceofillnessisusuallylinkedwithbloomsofspecifictoxicalgalspecies(seeTable
212-1).Harmfulalgalbloom–relatedillnessesintheUnitedStateshavebeenreportedfromAtlantic,Pacific,andGulfCoasts,HawaiiandAlaska,andtheCaribbean(seeFig.212-1).
DIAGNOSIS• Diagnosisisbasedonclinicalpresentation(seeTable212-1).
THERAPY• Therapy is supportive. The syndrome of hypotension/bradycardia seen in severe cases of
ciguaterafishpoisoningmayrequireatropine;respiratorysupportmaybenecessaryinseverecasesofparalyticshellfishpoisoning.
PREVENTION• Prevention is based on avoidance of fish or shellfish that contain toxins. Environmental
monitoringofshellfishfortoxinsresponsibleforparalytic,amnesic,andneurotoxicshellfishpoisoningisconductedbystateandlocalhealthdepartments.
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TABLE 212-1 Human Illness Associated with Harmful Algal Blooms
SYNDROMECAUSATIVE ORGANISMS
TOXIN PRODUCED CLINICAL MANIFESTATIONS
Ciguatera fish poisoning
Gambierdiscus spp. and others
Ciguatoxin Acute gastroenteritis, followed by paresthesias and other neurologic symptoms
Paralytic shellfish poisoning
Alexandrium spp. and others
Saxitoxins Acute paresthesias and other neurologic manifestations; may progress rapidly to respiratory paralysis
Neurotoxic shellfish poisoning
Karenia brevis Brevetoxins Gastrointestinal and neurologic symptoms; formation of toxic aerosols by wave action can produce respiratory irritation and asthma-like symptoms
Diarrhetic shellfish poisoning
Dinophysis spp. Okadaic acid and others
Acute gastroenteritis, abdominal pain
Amnesic shellfish poisoning
Pseudonitzschia spp.
Domoic acid Gastroenteritis, followed by memory loss, neurologic manifestations; may progress to amnesia, coma, and death
Azaspiracid shellfish poisoning
Azadinium spp. and others
Azaspiracid Acute gastroenteritis, abdominal pain
Lyngbya or Cyanobacteria exposure syndromes
Lyngbya spp. Lyngbyatoxin A, debromaplysiatoxin
“Swimmers’ itch,” particularly in inguinal area; sore eyes, ears; headache; possibly gastrointestinal symptoms
Microcystis spp. Microcystins (??)
Pfiesteria-associated syndrome
Pfiesteria spp. (?) Unidentified to date
Deficiencies in learning and memory; acute respiratory and eye irritation; acute confusional syndrome
FIGURE 212-1 Sites and types of harmful algal blooms along the U.S. coast. ASP, amnesic shellfish poisoning; CFP, ciguatera fish poisoning; CyanoHABs, cyanobacterial harmful algal bloom; DSP, diarrhetic shellfish poisoning; NSP, neurotoxic shellfish poisoning; PSP, paralytic shellfish poison-ing. (From U.S. National Office for Harmful Algal Blooms/Woods Hole Oceanographic Institution.)
Puerto Rico
HawaiiAlaska
Harmful algae blooms
PSP
ASP
CFP
NSP
Brown tide
CyanoHABs
Golden algae
DSP
Karlodinium and Pfiesteria
437
J Diseases Due to Helminths
213 Intestinal Nematodes (Roundworms)James H. Maguire
DEFINITION• Intestinalnematodesorroundwormsarehelminthicparasitesofthehumangastrointestinal
tract(seeTable213-1).• AscarisandTrichuris(whipworm)areacquiredbyingestionofcontaminatedsoil.• Strongyloidesandhookworms(Ancylostoma, Necator)areacquiredbyexposuretolarvaein
soil.• OnlyEnterobius(pinworm)istransmittedfrompersontopersonbyingestionofeggsorby
contactwithfomites.
EPIDEMIOLOGY• Soil-transmittedhelminthscalledStrongyloidesareprevalentintropicsandsubtropics.They
infectmorethan1billionpersons,primarily thosewith limitedaccess tocleanwaterandsanitation.
• In temperate areas and industrialized countries, Strongyloides are found primarily amongimmigrantsandtravelersreturningfromthetropicsandsubtropics.
MICROBIOLOGY• Ascarisnematodes,hookworms,andTrichuriswhipwormscannotreplicateinahumanhost;
hence,thereisnoperson-to-persontransmission.Thedurationofinfectionisthelifespanofadultworms,usuallylessthanafewyears.
• Strongyloidescanreplicateinhumanhosts;hence,infectionisacquiredviaperson-to-personcontactandcontactwithlarvaeonsoil.Infectionpersistsfordecades,andnumbersofwormscanincreasewithoutexogenousreinfection,especiallyinpersonsreceivingcorticosteroidsorwithhumanT-celllymphotropicvirus-1infection.
• Pinwormsarecommoninallpartsoftheworld,particularlyinchildren.• Pinworms spread readily by person-to-person contact and ingestion of eggs shed in the
environment,andinfectedpersonsfrequentlyreinfectthemselvesandothersinfamily.• Hookworms,Ascaris,andStrongyloidesmigratethroughthelung,butwhipwormsandpin-
wormsdonot.
DIAGNOSIS• Intestinalparasiteinfections:usuallycauselight,few,ornosymptomsbutoftenelicitperiph-
eralbloodeosinophilia• Soil-transmitted helminths: in children with moderate infections and those at risk of
malnutrition• Suggestive clinical syndromes: Ascaris: intestinal or biliary obstruction; hookworm: iron-
deficiencyanemia;Trichuris: intestinalprolapse,dysentery;Strongyloides:abdominalpain,diarrhea, larva currens, disseminated infection (immune compromised); pinworm: analitching
• Ascaris nematodes, hookworms, and Trichuris whipworms: readily diagnosed by micro-scopicexaminationofthestoolforcharacteristiceggs
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• Strongyloides:serologymoresensitivethanstoolexamination• Pinworm:cellophanetapemethod
THERAPY• Soil-transmittedhelminthsandpinworms;albendazole,mebendazole,orpyrantel• SingledoseeffectiveforAscaris,hookworm;multipledosesforTrichuris;repeatsingledose
after2weeksforpinworm• Strongyloides: two daily doses of ivermectin; prolonged therapy for hyperinfection or dis-
seminatedinfection
PREVENTION• Sanitation,provisionofcleanwater,wearingshoes,handwashing• Periodicmassdrugadministrationforsoil-transmittedhelminths• Strongyloides:suspect,diagnose,andtreatbeforeimmunosuppressivetherapy
TABLE 213-1 Features of Major Intestinal NematodesN
EMA
TOD
E
TRA
NSM
ISSI
ON
DIR
ECT
PER
SON
-TO
-PER
SON
TR
AN
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N
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DU
RA
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F IN
FEC
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)
TREA
TMEN
T*
Ascaris lumbricoides
Ingestion of infective eggs
No Warm, humid areas; temperate zones in warmer months
1-2 yr Free in lumen of small bowel, primarily jejunum
Albendazole MebendazolePyrantel Ivermectin Levamisole Piperazine
Trichuris trichiura (whipworm)
Ingestion of infective eggs
No Warm, humid areas; temperate zones in warmer months
1-3 yr Anchored in superficial mucosa of cecum and colon
Albendazole Mebendazole
Necator americanus, Ancylostoma duodenale (hookworm)
Penetration of skin by filariform larvae
No Warm, humid areas; temperate zones in warmer months
3-5 yr (Necator); 1 yr (Ancylostoma)
Attached to mucosa of mid to upper portion of small bowel
Albendazole Mebendazole LevamisolePyrantel
Strongyloides stercoralis
Penetration of skin or bowel mucosa by filariform larvae
Yes Primarily warm, humid areas, but can be worldwide
Lifetime of host
Embedded in mucosa of duodenum, jejunum
Ivermectin† Albendazole Thiabendazole
Enterobius vermicularis (pinworm)
Ingestion of infective eggs
Yes Worldwide 1 mo Free in lumen of cecum, appendix, adjacent colon
Albendazole MebendazolePyrantel Ivermectin Levamisole Piperazine
*Nitazoxanide has been shown to be effective in the treatment of ascariasis, trichuriasis, and enterobiasis in several trials in Mexico. Tribendimidine, which is licensed in China, was shown to be efficacious against Ascaris and had moderate efficacy against Strongyloides in a randomized trial.
†Drug of choice.
439
214 Tissue Nematodes (Trichinellosis, Dracunculiasis, Filariasis, Loiasis, and Onchocerciasis)James W. Kazura
DEFINITION• Tissuenematodeinfectionscauseaspectrumofdiseasemanifestationsrangingfromasymp-
tomaticcasestochronicpathologicprocessesand,occasionally,severeillnessanddeath.
EPIDEMIOLOGY• Infectionswithtissuenematodesoccurthroughouttheworldandhavethehighestpreva-
lenceintropicalregionswhereobligatoryinsectvectorsarepresent.• Trichinellosis• Dracunculiais• Filariases
MICROBIOLOGY• Thelifecyclesoftheseparasitesarecomplexwithfivedistinctstagesthatinvolvetheirhuman
hostand,whereapplicable,insectvectors.• Trichinellosis• Dracunculiais• Filariases
DIAGNOSIS• Parasitesareidentifiedmicroscopicallyinbodyfluids,ordiagnosticassaysareusedtodetect
parasiteantigens.
THERAPY• Anthelminticdrugsareavailableformanyinfections.• Fortrichinellosis,nodrugsareavailablefortreatmentofnewbornlarvaeormaturingfirst-
stage larvae. Corticosteroids and mebendazole are sometimes utilized in severe disease.Duringtheenteralstageofinfection(1to2weeksaftereatingcontaminatedmeat),meben-dazoleoralbendazolecanbeusedtoeliminateadultwormsfromthesmallintestine.
• Forlymphaticfilariasis,diethylcarbamazineismoreactiveagainstWuchereria bancroftithanBrugia malayi.
• Diethylcarbamazineisalsousedtotreattropicalpulmonaryeosinophiliaandloiasis.• Ivermectinisusedtotreatonchocerciasis.
PREVENTION• Controllinginsectvectorsandmassadministrationofanthelminticdrugstoendemicpopu-
lations reduces and may potentially eliminate transmission of medically significant tissuenematodeinfections.
440
215 Trematodes (Schistosomes and Liver, Intestinal, and Lung Flukes)James H. Maguire*
DEFINITION• Trematodesorflukesareflatworms that live inbloodvessels,biliary tract, intestines, and
lungsofhumansandloweranimals.• Included are the schistosomes and the foodborne trematodes—liver flukes (Fasciola,
Clonorchis, Opisthorchis),intestinalflukes(variousspecies),andlungfluke(Paragonimus).
EPIDEMIOLOGY• Schistosomes are prevalent in tropical and subtropical Africa, the Middle East, Southeast
Asia,EastAsia,thePhilippines,andlimitedareasintheCaribbeanandSouthAmericainareaswithinadequatesanitationoraccesstocleanwater.
• FoodbornetrematodesaremostprevalentinSoutheastandEastAsiabutalsoinotherpartsoftheworldwherepersonsingestraworundercookedfish,crayfish,orplantsproducedinfreshwatercontaminatedwithhumanoranimalfecesor(forParagonimus)sputum.
MICROBIOLOGY• Persons become infected with schistosomes when the larval parasites (cercariae) shed by
freshwatersnails(intermediatehosts)penetratebareskin.• Personsbecomeinfectedwithfoodbornetrematodesbyingestingthelarvalparasites(meta-
cercariae)encystedinfish,aquaticvegetation,orcrustaceans(secondintermediatehost)thatwereinfectedwithcercariaeshedfromsnails(firstintermediatehost).
DIAGNOSIS• Trematodeinfectionsarefrequentlylightandmaycausefewornosymptomsbutoftenelicit
peripheralbloodeosinophilia.• Suggestive clinical syndromes during the first weeks after initial infection include acute
illnesswithfever,urticaria,eosinophilia,andothersymptomswhenlarvalflukesaremigrat-ing through the body and maturing; ectopic migration can lead to disease of the centralnervoussystem,theskin,andotherpartsofthebody.
• Suggestive clinical syndromes during chronic infections include intestinal schistosomes(diarrhea,intestinalpolyps,portalhypertension),urinaryschistosomes(hematuria,bladdercancer),liverflukes(biliaryobstruction),intestinalflukes(diarrhea,abdominaldiscomfort),andlungflukes(cough,hemoptysis,cavitarylunglesions).
• Diagnosis is made by microscopic identification of characteristic eggs in stool, urine, orsputumorbyidentificationoflarvaloradultwormsintissue.
• Serology,availableforsometrematodeinfections,maybemoresensitivethanmicroscopicexamination,especiallyduringacuteinfections.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
441C
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des (Sch
istoso
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Flukes)
THERAPY• Praziquantelisthedrugofchoiceforalltrematodeinfectionsexceptfascioliasis,forwhich
triclabendazoleispreferred(seeTable215-1).
PREVENTION• Forschistosomiasis,preventivemethods includesanitation,provisionofcleanwater, snail
control,andavoidanceofcontactwithcontaminatedfreshwater.• Forfoodbornetrematodes,preventionofinfectionincludesmaintainingfreshwaterbodies
freeofcontaminationbyhumansandloweranimals,snailcontrol,andpropercookingofaquaticfish,plants,andcrustaceans.
• Periodic screening and treatment or mass drug administration for populations at risk forinfectionareessential.
TABLE 215-1 Features of Schistosomes and Other Important Trematodes
PAR
ASI
TE
SNA
IL
INTE
RM
EDIA
TE
HO
ST (
GEN
US)
SEC
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D
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HO
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TMEN
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Schistosomes*Schistosoma mansoni
Biomphalaria None South America, Africa, Caribbean, Arabian peninsula
Mesenteric venules
Praziquantel, 40 mg/kg/day in 1 or 2 doses × 1 dayOxamniquine†
Schistosoma japonicum
Onchomelania None China, Philippines, Indonesia, Thailand
Mesenteric venules
Praziquantel, 60 mg/kg/day in 3 doses × 1 day
Schistosoma mekongi
Neotricula None Cambodia, Laos
Mesenteric venules
Praziquantel, 60 mg/kg/day in 3 doses × 1 day
Schistosoma intercalatum, Schistosoma guineensis
Bulinus None Central and West Africa
Mesenteric venules
Praziquantel, 40 mg/kg/day in 1 or 2 doses × 1 day
Schistosoma haematobium
Bulinus None Africa, Middle East
Venules of lower urinary tract
Praziquantel, 40 mg/kg/day in 1 or 2 doses × 1 dayMetriphonate†
Liver FlukesClonorchis sinensis
Bithynia, Parafossarulus
Freshwater fish
China, Taiwan, Korea, Japan, Vietnam
Bile, pancreatic ducts
Praziquantel, 75 mg/kg/day in 3 doses × 1-2 daysAlbendazole,‡ 10 mg/kg/day × 10 days
Opisthorchis viverrini
Bithynia Freshwater fish
Thailand, Laos, Cambodia
Bile, pancreatic ducts
Praziquantel, 75 mg/kg/day in 3 doses × 1-2 daysAlbendazole,‡ 10 mg/kg/day × 10 days
Opisthorchis felineus
Bithynia Freshwater fish
Eastern Europe, former Soviet Union
Bile, pancreatic ducts
Praziquantel, 75 mg/kg/day in 3 doses × 1-2 daysAlbendazole,‡ 10 mg/kg/day × 10 days
Fasciola hepatica
Lymnaea Watercress, other aquatic plants
Americas, Europe, Asia, western Pacific, North Africa
Bile ducts Triclabendazole,§ × 10 mg/kg × 1 dayNitazoxanide¶
Continued
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PAR
ASI
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SNA
IL
INTE
RM
EDIA
TE
HO
ST (
GEN
US)
SEC
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D
INTE
RM
EDIA
TE
HO
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GEO
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DIS
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TREA
TMEN
T
Intestinal FlukesFasciolopsis buski
Segmentina Aquatic plants
Far East, India Small intestine
Praziquantel, 25 mg/kg/day × 1 dayNiclosamide,‡ 1 g × 1 dayTriclabendazole¶
Heterophyes heterophyes
Pirenella, Cerithidea
Freshwater fish
Far East, Egypt, Middle East, southern Europe
Small intestine
Praziquantel, 25 mg/kg/day × 1 dayTriclabendazole¶
Metagonimus yokogawai
Semisulcospira Freshwater fish
Far East, Russia, southern Europe
Small intestine
Praziquantel, 25 mg/kg/day × 1 dayTriclabendazole¶
Lung FlukesParagonimus westermani; other species
Semisulcospira, Onchomelania, Thiara
Freshwater crabs, crayfish
Far East, South Asia, Philippines, West Africa, South and Central America
Lungs Praziquantel, 75 mg/kg/day in 3 doses × 2 daysTriclabendazole,‡ 10 mg/kg day × 3 days
*Some experts recommend higher doses (e.g., praziquantel 60 mg/kg/day in divided doses for all species), multiple doses (e.g., for 2 or 3 days), or a repeated dose at 4 to 6 weeks to achieve higher rates of cure in persons not exposed to reinfection.
†Not available or limited availability.‡Alternative drug.§In the United States it is available (from the manufacturer, Novartis, from Victoria Pharmacy in Zurich, Switzerland)
for compassionate use after approval of patient Investigational New Drug (IND) by the U.S. Food and Drug Administration.
¶Limited data.
TABLE 215-1 Features of Schistosomes and Other Important Trematodes—cont’d
443
216 Tapeworms (Cestodes)Charles H. King and Jessica K. Fairley
DEFINITION• Cestodesareflatworms(platyhelminths)thatcausehumanparasiticinfectionintheformof
intestinaltapewormsorinvasivelarvalcysts(i.e.,neurocysticercosisorechinococcosis)(seeTable216-1).
EPIDEMIOLOGY• Diphyllobothrium latum,fishtapeworm,isassociatedwitheatingundercookedfresh-water
fishandendemicworldwide.• Hymenolepis nana is the most common tapeworm worldwide and transmitted person to
person.• Taenia saginata(beeftapeworm)occursincattle-breedingareasoftheworld.• Taenia solium(porktapeworm),andconsequentlyneurocysticercosis,isendemictoresource-
limitedareas,includingMexico,CentralandSouthAmerica,Asia,andAfrica.• Echinococcus granulosusinfectionoccursworldwideinlivestock-raisingareasandprimarily
isassociatedwithdomesticdogs.• Echinococcus multilocularishasalifecyclethatinvolveswildcaninesandisendemiconlyin
theNorthernHemisphere.
MICROBIOLOGY• Maturetapewormsresideinintestinesofcarnivorousanimals.• Eggsareshedandthenpasstoanintermediatehost,causingcysticinfectionviadissemina-
tionofoncospheresintohosttissues.• Definitive carnivore host ingests cyst-infected tissue, and tapeworm then develops in
intestines.
DIAGNOSIS• Diagnosis of intestinal tapeworms relies on examination of stool for evidence of eggs or
tapewormsegments(proglottids).• Neurocysticercosisisdiagnosedbytypicalappearanceonimagingscansandsupportedby
clinicalsymptomsandserologictesting.• Echinococcosisisdiagnosedbytypicalscanimageryandsupportedbyserology.
THERAPY• Mainstayoftherapyforintestinaltapewormsispraziquantelorniclosamide.• Neurocysticercosistherapydependsonthelocationandstageofthecyst.• Parenchymal neurocysticercosis is generally treated with a combination of anthelmintic
agentsandcorticosteroids(albendazoleorpraziquantel).• Echinococcosis,dependingonthestageandspecies,oftenrequiressurgeryincombination
withanthelminticagents.
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PREVENTION• Improvedsanitationisessential.• Educationprogramsonsymptomsofinfectionandkeepinglivestockincorralsawayfrom
humansshouldbeimplemented.• Livestockatmarketorslaughterhouseshouldbescreenedforcysts.• DogsshouldbescreenedandtreatedtoeliminateEchinococcus granulosus.• Prolongedfreezingorthoroughcookingwillkillcystsintissue.
TABLE 216-1 Common Cestode Parasites of Humans, Their Typical Vectors, and Their Usual Symptoms
PARASITE SPECIES
DEVELOPMENTAL STAGE FOUND IN HUMANS
COMMON NAME
TRANSMISSION SOURCE
SYMPTOMS ASSOCIATED WITH INFECTION
Diphyllobothrium latum
Tapeworm Fish tapeworm Plerocercoid cysts in freshwater fish
Usually minimal; with prolonged or heavy infection, vitamin B12 deficiency
Hymenolepis nana
Tapeworm, cysticercoids
Dwarf tapeworm
Infected humans Mild abdominal discomfort
Taenia saginata Tapeworm Beef tapeworm Cysts in beef Abdominal discomfort, proglottid migration
Taenia solium Tapeworm Pork tapeworm Cysticerci in pork Minimal
Taenia solium (Cysticercus cellulosae)
Cysticerci Cysticercosis Eggs from infected humans
Local inflammation, mass effect; if in central nervous system, seizures, hydrocephalus, arachnoiditis
Echinococcus granulosus
Larval cysts Hydatid cyst disease
Eggs from infected dogs
Mass effect leading to pain, obstruction of adjacent organs; less commonly, secondary bacterial infection, distal spread of daughter cysts
Echinococcus multilocularis
Larval cysts Alveolar cyst disease
Eggs from infected canines
Local invasion and mass effect leading to organ dysfunction; distal metastasis possible
Taenia multiceps Larval cysts Coenurosis, bladder worm
Eggs from infected dogs
Local inflammation and mass effect
Spirometra mansonoides
Larval cysts Sparganosis Cysts from infected copepods, frogs, snakes
Local inflammation and mass effect
445
217 Visceral Larva Migrans and Other Uncommon Helminth InfectionsTheodore E. Nash*
VISCERAL LARVA MIGRANSDefinition• Visceral larva migrans (toxocariasis) is caused by Toxocara canis and less frequently by
Toxocara catiandotherhelminths.Itcommonlyoccursinchildrenandmaybemanifestedbyfever,wheezing,hepatomegaly,andothergeneralizedsymptoms.
Diagnosis• Diagnosis is based on the finding of larvae in affected tissues and the presence of
eosinophilia.
Treatment• Mostpatientsrecoverwithouttherapy.• Anti-inflammatorydrugsmaybeconsidered,andalbendazole,mebendazole,anddiethyl-
carbamazinehavebeentriedbutareofuncertainefficacy.
OCULAR LARVA MIGRANSDefinition• OcularlarvamigransiscausedbyToxocara canislarvaeintheeyeandresultsinachorio-
retinalgranulomaoroccasionallyinpanuveitis.Retinaldetachmentmayalsooccur.Thereisnospecifictherapy.
OTHER UNCOMMON HELMINTHS• Otherhelminthicinfectionsdiscussedinthechapterareanisakiasis,cutaneouslarvamigrans,
eosinophilic meningitis, gnathostomiasis, angiostrongyliasis, eosinophilic gastroenteritis,dirofilariasis,capillariasis,nanophyetiasis,andswimmer’sitch.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
446
K Ectoparasitic Diseases
218 Lice (Pediculosis)James H. Diaz
DEFINITION• Pediculosisisacomplexofthreedifferenthumaninfestations(headlice,bodylice,andpubic
lice)with twospeciesofbloodsucking lice:Pediculus humanusvar.capitisorcorporis andPhthirus pubis.
EPIDEMIOLOGY• Headlice,orpediculosiscapitis,aretransmittedprimarilybyhead-to-headcontactrather
thanbyfomites.• Headliceafflictmillionsofpeopleannually,mostlyschool-agedchildren.• Bodylice,orpediculosiscorporis,aretransmittedprimarilybybodilycontactratherthan
byfomites.• Bodyliceareassociatedwithpoorhygieneandprimarilyinfesttheindigent,institutional-
ized,homeless,refugees,andimmunocompromised.• Pubic lice infestations (phthiriasis) are transmitted primarily during sexual contacts and
oftencoexistwithothersexuallytransmitteddiseases.
MICROBIOLOGY• Body lice can transmit several bacterial diseases, including (1) relapsing fever caused by
Borrelia recurrentis,(2)trenchfevercausedbyBartonella quintana,and(3)epidemictyphuscausedbyRickettsia prowazekii. B. quintanahasbeen isolated inhead lice fromhomelesspersonsintheUnitedStates,establishingthepotential fortransmissionoftrenchfeverbyheadliceinadditiontobodylice.
DIAGNOSIS• Liceinfestationsarediagnosedbyclinicalinspectiondemonstratingliveadultlice,nymphs,
andviableeggs,ornits,intheirprecisehumananatomicniches.• Recently,dermoscopyhasbeenused to immediatelydistinguishviablenits fromhatched,
emptynits.• Dermoscopy may provide a more sensitive screening tool for head lice infestations than
inspectionalone.
THERAPY• Acombinationofpharmacologictherapywithtopicalororal(ivermectin)pediculicidesand
physicalremovalofviablenitsbywetcombingisrequired.• Pharmacotherapyshouldbeginwiththeleasttoxicpediculicides,suchaspyrethrins.• Topicalororalivermectinpreparationsshouldbereservedforpyrethrin-resistantcases.
447C
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losis)
PREVENTION• Combinationsofsanitizingtheenvironmentandeliminatingallhumanreservoirsofhead
lice in households, apartments, housing complexes, homeless shelters, classrooms, andschoolsarerecommended.
• Preventionstrategiesforpubiclicearesimilartothepreventionstrategiesforbodyliceandshouldincludehotcyclewashinganddryingofallclothingandbedding;institutionofbasicpersonalhygieneandsanitationmeasures;andtreatmentofsexualcontactswithactivebodyorpubicliceinfestations.
448
219 ScabiesJames H. Diaz
DEFINITION• Scabies is an infestation by the itch or scabies miteSarcoptes scabiei var.hominis and has
become a significant reemerging ectoparasitosis in its most severe form as crusted orNorwegianscabiesamongthehomeless,institutionalizedolderadults,thementallyretarded,andtheimmunocompromised.
EPIDEMIOLOGY• Theworldwideannualprevalenceofscabieshasbeenestimatedtobeabout300millioncases.• Scabiesoccursworldwideinbothgenders,atallages,andamongallethnicandsocioeco-
nomicgroups.Scabiesishyperendemicthroughoutthedevelopingworld,especiallyinsub-SaharanAfrica, India, theAboriginalregionsofnorthernAustralia,andtheSouthPacificIslands,especiallytheSolomonIslands.
• CrustedorNorwegianscabiesishighlytransmissibleinthehospitalenvironment.
MICROBIOLOGY• Thehumanscabiesmiteisanobligateparasiteandcompletesitsentirelifecycleonitshuman
hostsasfemalesburrowintradermallytolayeggsandlarvaeemergeandmaturetoreinfestthesameornewhosts.Theentireincubationperiodfromeggstofull-grownmiteslasts14to15days.
• The human incubation period from initial infestation to symptom development is 3 to 6weeksininitialinfestationsandasshortas1to3daysinreinfestationsasaresultofpriorsensitizationtomiteantigens.
DIAGNOSIS• The diagnosis of scabies is made by epidemiologic considerations and clinical
observations.• Aclinicaldiagnosismaybeconfirmedbylow-powermicroscopicexaminationofaburrow
skinscrapingthatexcavatesthefemalemite.• Skinbiopsymayhelpconfirmthediagnosisinatypicalcases.• Newerdiagnosticmethodsforscabiesincludeenhancedmicroscopictechniques(dermos-
copy),immunologicdetectionofspecificscabiesantibodies,andmolecularidentificationofscabiesDNA.
THERAPY• Bothtopical5%permethrinandoralivermectinappearmosteffectiveforindividualclassic
scabies.• Themanagementofcrusted(Norwegian)scabiesmayrequirecombined,intensescabicidal
therapieswithbothtopical5%permethrinandoralivermectin,especiallyinhigh-riskcom-munityandinstitutionaloutbreaks.
449C
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PREVENTION• Aggressivetreatmentof infestedpatientsandallclosehousehold, institutional,andsexual
contacts,especiallyincasesofhighlyinfectiouscrusted(Norwegian)scabies,isrequired.• Disposalorhotwash-drysterilization(bymachinewashinganddryingat60°C[140°F]or
higher)ofallcontaminatedclothingandbeddingofindexcasesisessential.• Provisionofimprovedaccessforpersonalhygieneandhealthcareforalldisplaced,homeless,
orinstitutionalizedpersonsshouldbeimplemented.
450
220 Myiasis and TungiasisJames H. Diaz
MYIASISDefinition• Myiasisisanectoparasiticinfestationofviableornecrotictissuesbythedipterouslarvaeof
higherflies.Furuncularmyiasisisthemostcommonclinicalmanifestationofmyiasisandoccurswhenoneormoreflylarvaepenetratetheskin,causingpustularlesionsthatresembleboilsorfuruncles.
Epidemiology• Myiasisisanopportunisticinfestationthatoccursintravelersreturningfromtropicaljungles
andinvulnerablepopulationslivinginendemicareasofthetropics.
Microbiology• Inhumanbotflyfuruncularmyiasis,botflylarvaerapidlyburrowintotheskinwithsharp
mandiblestobegintheirdevelopmentalinstarstages,whichcanlast6to12weeksandcausedraining,boil-likelesions,orfuruncles.
Diagnosis• Thediagnosisofmyiasisisusuallybyclinicalinspectionandexamination,oftenwithmicros-
copy. Some immunodiagnostic tests have been developed to detect the antibodies to theantigensofspecificflyspeciescausingmyiasis.
Therapy• Furuncularmyiasismaybetreatedconservativelybycoaxingembeddedlarvaefromfurun-
clesbysmotheringtheirrespiratoryspiracleswithocclusivecoatingsofpetrolatum(Vaseline),clearfingernailpolish,tobaccotar,porkfat,rawbeefsteak,orbaconstrips.However,unsuc-cessful occlusive therapy may asphyxiate larvae and necessitate their surgical or vacuumextraction.Alongwithlarvalremoval,myiasiswoundsshouldbecleansedandconservativelydébrided,tetanusprophylaxisadministered,andbacterialsecondaryinfectionstreatedwithantibiotics.
Prevention• Methodsincludecontrolofdomesticandlivestockanimallarvalinfestations;sanitarydis-
posal of animal carcasses and offal to deny flies their preferred breeding grounds; propermanagementofanyopenhumanwoundsorcutaneousinfections;cementingfloorstodenyfloor maggot flies their preferred egg-laying surfaces; sleeping on raised beds or cots inscreenedhutsor tents;wearing long-sleevedshirtsandpants,whichcanbepyrethrin-orpyrethroid-impregnated;sprayingexposedskinwithdiethyltoluamide(N,N-diethyl-meta-toluamide[DEET])–containingrepellents;andironingbothsidesofallclothesanddiapersleftoutsidetodryintumbuflyhabitats.
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d Tu
ng
iasis
TUNGIASISDefinition• Tungiasis isapainful,cutaneous infestationwiththegravidfemale jiggerfleathatusually
occursonthefeetbutmayoccuranywherewherebareskintouchessoilcontaininggravidfemalefleas.
Epidemiology• Intravelersreturningtoaccessiblehealthcareinfrastructuresindevelopednations,tungiasis
isanexotic infestation,withaminimalparasiteburdenandasimplesurgicalcure,but intheimpoverishedandunderservedcommunitiesofdevelopingtropicalnations,tungiasisisarecurrentinfestationofthefeetwithahighparasiteburdencausingsignificantmorbidity,includingautoamputation.
Microbiology• Intungiasis, thegravidfemale jigger(chigoe)fleapenetratesbareskinusuallyonthe feet
(orheels),underornearthetoenailsorintheinterdigitalwebspaces,tofeedonbloodandtissuejuicesandtoincubatehundredsofdevelopingeggswithindays;itswellsto2000timesits sizeand thenexpelseggsoveraperiodof3weeksor lessbeforedyingand leaving itsshriveledcarcassinacontaminatedwoundtract.
Diagnosis• The diagnosis of tungiasis is usually by clinical inspection and examination, often with
microscopy.
Therapy• Tungiasis is treated by extracting all embedded fleas immediately with sterile needles or
curets, administering tetanus prophylaxis, and treating secondary wound infections withappropriatetopicalororalantibiotics.
Prevention• Methodsincludewearingshoes,whichcanbesprayedwithpyrethroidordiethyltoluamide–
containingsolutions;notsittingnakedonbareground;insecticidetreatmentofflea-infesteddomesticandstrayanimalsandpetswith10%pyrethrinorpyrethroidsprays,or1%to4%malathion powder; bathing the feet of domestic and stray dogs and pigs with insecticidesolutions,suchas2%trichlorfon(Neguvon);andsprayingordustinghouseholds,especiallythosewithdirtfloors,with1%to4%malathion.
452
221 Mites, Including ChiggersJames H. Diaz
DEFINITION• Mites are among the smallest arthropods, with more than 3000 species, only about 25 of
which,mostlychigger,animal,plant,andscabiesmites,areofanymedicalimportance.
EPIDEMIOLOGY• Mostmitesaresimplybitingnuisancesthatcancausehighlysymptomaticmaculopapular
eruptionsanddonottransmitinfectiousdiseases.
MICROBIOLOGY• Only biting larvae of Asian scrub typhus chiggers (Leptotrombidium spp.) can transmit
scrubtyphuscausedbyOrientia tsutsugamushi(formerlyRickettsia tsutsugamushi),andonlybitinghousemousemites(Liponyssoides sanguineus)cantransmitrickettsialpoxcausedbyRickettsia akari.
DIAGNOSIS• Clinicaldiagnosesarehighlysensitiveandspecificinthepresenceofamite-biteoutbreak.• Mite-transmittedscrubtyphusandrickettsialpoxpresentclinicallyinasimilarfashionwith
fever,biteeschar,regionallymphadenopathy,conjunctivalinjection,centralnervoussystemsymptomsinseverescrubtyphus(e.g.,confusion,delirium,coma,ortransienthearingloss),andcentrifugalrashinscrubtyphus.
THERAPY• Treatmentofchiggerbitesissupportivewithsoapandwatercleansing,warmwatersoaks,
andtopicalandlocalanestheticsandantihistamines.Impetigoandsecondaryinfectionsarepotentialcomplicationsthatwouldnecessitateantibiotictreatment.
• Bothscrubtyphusandrickettsialpoxrespondtotreatmentwithoraldoxycycline.
PREVENTION• Chiggerbitescanbepreventedwithcampsitesprayingofpyrethrinorpyrethroid-containing
insecticides;bysprayingorimpregnatingpyrethrinandpyrethroid-containingrepellentsonclothingandsleepingbags;andbyapplyingdiethyltoluamide–containinginsectrepellents(N,N-diethyl-meta-toluamide[DEET])toexposedskin.
• Rickettsialpox can be prevented by improving rodent reservoir control in campgrounds,homes,apartments,barns,sheds,and,especially,crowdedpublichousing.
• Therearenovaccinesforscrubtyphusorrickettsialpox.• Weeklydosesof200mgofdoxycyclinecanpreventO. tsutsugamushiinfectionsinendemic
regions.
453
222 Ticks, Including Tick ParalysisJames H. Diaz
DEFINITION• Tickscantransmitthebroadestrangeofinfectiousmicrobesamongallarthropods,including
bacteria,viruses,andparasites.• Gravidticksmayalsotransmitparalyticsalivarytoxinsduringblood-feeding.
EPIDEMIOLOGY• Ticks are among the most competent and versatile of all arthropod vectors of infectious
diseases.• Tick-transmitted Lyme borreliosis or Lyme disease is now the most common arthropod-
borneinfectiousdiseaseintheUnitedStatesandEurope.• Mosttick-borneinfectiousdiseasescanalsobetransmittedtohumansbybloodtransfusions
andorgantransplants,andbabesiosiscanbetransmittedcongenitally.
MICROBIOLOGY• Ticksofallagesandbothgendersmayremaininfectiousforgenerationswithouthavingto
reacquireinfectionsfromhostreservoirs.• Newtick-transmittedpathogenicspeciesareconstantlybeingdescribedintheUnitedStates.
DIAGNOSIS• Tickscantransmitseveralpathogensduringoneblood-feeding,resultingincoinfectionsthat
cancomplicatedifferentialdiagnosisandtreatment.• Thediagnosisof tick-transmittedinfectiousdiseases isbasedoncombinationsoftick-bite
historyandcharacteristiclesions,suchaserythemamigransandeschars,microscopiciden-tificationofpathogensinbloodandtissuebiopsyspecimens,serologicandimmunocytologictests,andnucleicacidserotyping.
THERAPY• Most tick-transmitted bacterial diseases remain sensitive to doxycycline, amoxicillin, and
chloramphenicol.• Thetick-transmittedviraldiseasescanbemanagedonlysupportively.• Babesiosis is caused by a malaria-like parasite and must be treated with combinations of
antimalarialagentsandazithromycinorclindamycin.
PREVENTION• Combinations of immunization, prophylactic antibiotics, personal protective measures,
landscapemanagement,andwildlifemanagementarealleffectivestrategiesforthepreven-tionandcontroloftick-borneinfectiousdiseases.
• Asingle200-mgdoseofdoxycyclineadministeredwithin72hoursofatickbiteismorethan80%effectiveinpreventingLymedisease.
454
L Diseases of Unknown Etiology
223 Kawasaki DiseaseJane C. Burns
DEFINITION• Kawasakidisease(KD)isanacute,self-limitedpediatricvasculitisthatisthemostcommon
causeofacquiredheartdiseaseinchildren.Coronaryarteryaneurysmsdevelopin25%ofuntreatedpatients.
EPIDEMIOLOGY• KDaffectschildrenofallethnicitiesworldwide.ChildrenofAsianandAfrican-American
descentaredisproportionatelyaffected.Thereisnoevidenceforperson-to-persontransmis-sion.Temporospatialclusteringofcaseshasbeenobserved.
ETIOLOGY• ThecauseofKDisunknown.Accordingtothecurrentparadigm,KDistriggeredingeneti-
callysusceptiblechildrenafterexposuretoawidelydispersedagent.
DIAGNOSIS• Thediagnosisisestablishedbyfulfillmentoffouroffiveclinicalcriteriainachildwithfever
and no other apparent cause. Clinical criteria include bilateral conjunctival injection;a polymorphous rash; oropharyngeal changes including erythematous, fissured lips, ery-thematousoropharynxwithoutdiscretelesions,andstrawberrytongue;extremitychangesincluding edema of the dorsa of the hands and feet, palm and sole erythema, and peri-ungual desquamation during the convalescent phase; and a cervical lymph node massmeasuring at least 1.5cm. Coronary artery abnormalities are detected by transthoracicechocardiography.
THERAPY• High-doseintravenousimmuneglobulin(IVIG,2g/kg)plusaspirinisthestandardtherapy
forKD.Ifadministeredwithinthefirst10daysafterfeveronset,theincidenceofcoronaryarteryaneurysms is reduced from25% to5%.A subsetofpatients (10% to20%)mayberelativelyresistanttoIVIGandrequireadditionalanti-inflammatorytherapy.
PREVENTION• ThereisnoknowninterventionthatcanpreventKD.
PART III
Special Problems
456
A Nosocomial Infections
224 Infections Caused by Percutaneous Intravascular DevicesSusan E. Beekmann and David K. Henderson*
DEFINITION• Infections caused by peripheral and central intravenous catheters, including nontunneled
centralcathetersandtunneled(HickmanorBroviac)catheterswithorwithouttheGroshongtip,peripherally insertedcentralvenouscatheters(PICCs), totally implantedintravascularaccessdevices(ports),pulmonaryarterycatheters,andarteriallines
EPIDEMIOLOGY• Ratesofcentralline–associatedbloodstreaminfections(CLABSIs)in2009rangedfrom1.05
(pooledmeanhemodialysisrate)to1.14(pooledmeaninpatientwardrate)to1.65(pooledmeanintensivecareunitrate)bacteremiasper1000centralvenouscatheter(CVC)days.
• These rates reflect a 58% reduction in total estimated CLABSIs from 2001 to 2009; thereduction in incidence of Staphylococcus aureus CLABSIs was greater than for any otherpathogen.
• ThemajorityofCLABSIsnowoccurininpatientwardsandoutpatienthemodialysiscenters.
MICROBIOLOGY• Staphylococcipredominateasthemostfrequentlyencounteredpathogensindevice-related
infections; coagulase-negative staphylococci are the single most common cause of theseinfections,whereasS. aureusbacteremiashavedecreased.
• CLABSIsincreasinglyarecausedbymultiresistantgram-negativerods.
DIAGNOSIS• Clinicalmarkersshowapoorcorrelationwithintravenousdevice–relatedbacteremia.• Blood culture results positive for coagulase-negative staphylococci, S. aureus, or Candida
spp.,intheabsenceofanyotheridentifiablesourceofinfection,increasethepossibilityofintravenousdevice–relatedbacteremia.
• Quantitativeorsemiquantitativecultureofthecathetercombinedwithtwobloodcultures(one peripheral and one through the catheter) is most accurate for short-term centralcatheters.
• Pairedquantitativebloodculturewasdeterminedtobethemostaccuratediagnosticmethodforlong-termdevices,includingtunneledandtotallyimplantedcatheters.
• Differentialtimetopositivity(betweenculturesdrawnthroughthecatheterandperipher-ally)comparesfavorablywithquantitativebloodculturesforthediagnosisofCLABSIs.
PREVENTION• ManyCLABSIscanbepreventedusingsimultaneousimplementationofanarrayofpractice
improvements(i.e.,“bundles”).
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
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ns C
aused
by Percu
taneo
us In
travascular D
evices
• Allhealthcarepersonnelinvolvedincatheterinsertionandmaintenanceshouldcompleteaneducationalprogramregardingcatheter-associatedinfections.
• Chlorhexidinesolutionsshouldbeusedforskinpreparationbeforecatheterinsertion.• MaximalsterilebarriersshouldbeusedduringinsertionofCVCs.• DonotroutinelyreplaceCVCs,PICCs,hemodialysiscatheters,peripheralarterialcatheters,
orpulmonaryarterycatheterstopreventinfection.• Antimicrobial-impregnatedcatheters,ifused,shouldonlybeusedaspartofacomprehensive
nosocomialbacteremiapreventionstrategy.
458
225 Nosocomial PneumoniaMichael Klompas
DIAGNOSIS• Classic clinical signs for ventilator-assisted pneumonia (VAP) include fever, leukocytosis,
purulentsecretions,worseningoxygenation,infiltrates,andpathogeniccultures.Thesesignsareneithersensitivenorspecific.PaucityofneutrophilsorlackoforganismsonGramstainmakeVAPunlikely,buttheirpresenceisnotspecific.Stableoxygenation/ventilatorsettingsargueagainstclinicallysignificantdisease.
• Quantitativebronchoalveolarlavage(BAL)culturesare51%sensitive,are77%specific,andhaveapositivepredictivevalueof67%forhistologicallyconfirmedVAP.
• RandomizedcontrolledtrialsofquantitativeBALculturesversusendotrachealaspiratesfordiagnosis have found no difference in duration of mechanical ventilation, length of stay,mortality,superinfection,oracquiredresistancerates.Endotrachealaspiratesarethereforepreferred.
• Obtaindiagnosticstudiestoguidetherapy:bloodandendotrachealaspiratecultures,urinepneumococcalandlegionellaantigens,±viralstudies.
MICROBIOLOGY• Most common pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella sp.,
andAcinetobactersp.Drugresistanceiscommon:50%ofS. aureusisolatesaremethicillin-resistant,25%to30%ofPseudomonasandKlebsiella isolatesareceftazidimeandcefepimeresistant,and60%ofAcinetobacterisolatesarecarbapenemresistant.
• Risk factors for methicillin-resistant S. aureus (MRSA) and multidrug-resistant gram-negative pathogens include recent broad-spectrum antibiotics, prolonged hospitalization,poorfunctionalstatus,hemodialysis,andsevereillness.
TREATMENT• Initiatebroad-spectrumantibioticsassoonaspneumoniaissuspected.Usevancomycinor
linezolidplustwoantipseudomonalagentsforempirictherapy.Consideraloadingdoseofvancomycin25to30mg/kgforseriouslyillpatients.Includeanaerobiccoverageifthereisfrankaspiration.
• Reassessthelikelihoodofpneumoniadaily;ifthediagnosisnolongerseemslikely,thenstopantibiotics.
• Narrowtreatmentassoonassusceptibilitiesareavailable.Avoiddoublecoverage.Ifculturesarenegativeandthepatientisimproving,trimorstopantibiotics.
• Vancomycin and linezolid are similarly effective for MRSA. Dose vancomycin 15 to20mg/kgevery8to12hours.Thegoaltroughis15to20mg/L.Thereisanincreasedriskofclinicalfailureifthevancomycinminimalinhibitoryconcentrationisgreaterthan1mg/L.
• Treat7 to8days,but shorter forpatientswith rapidclinical improvementand longer forpatientswhoareslowtoimproveorwhohavecomplicationssuchasbacteremia,abscess,orempyema.Dailyprocalcitoninmonitoringcansafelyshortenthedurationofantibiotics.
• Adjunctiveaerosolizedantibioticsinadditiontointravenoustherapyenhanceclearanceofpulmonaryculturesbuthavenoimpactonclinicalcureratesorpatientoutcomes.Vibrating
459C
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soco
mial Pn
eum
on
ia
meshplateispreferredfordelivery.Aerosolizationmaybeaseffectiveasintravenousdrugdelivery,butnephrotoxicityisequallylikely.Dataaresparse.
PREVENTION• VAPratesaresubjectiveandnonspecific.Therefore,preferentiallyselectinterventionsproven
toimproveconcreteoutcomes.• Noninvasivepositivepressureventilation,continuousaspirationofsubglotticsecretions,and
ventilator-weaningprotocols(especiallypaireddailyspontaneousawakeningandbreathingtrials)shortentheaveragedurationofmechanicalventilation.
• Digestive decontamination decreases mortality, but there are ongoing concerns about thepotential impactonantibioticresistancerates,especially inunitswithhighbaselineresis-tancerates.
460
226 Nosocomial Urinary Tract InfectionsThomas M. Hooton
DEFINITION• Nosocomialurinarytractinfection(UTI)referstoUTIacquiredinanyinstitutionalsetting
providinghealthcare.• Catheter-associated(CA)-bacteriuriaiscomposedmostlyofCA-asymptomaticbacteriuria
(CA-ASB).• CA-ASBshouldbedistinguishedfromCA-UTIbecausetreatmentisusuallyindicatedonly
forthelatter.• Significantbacteriuria:≥103CFU/mLinasymptomaticpersonisanindicatorofCA-UTI,
whereas≥105CFU/mLinanasymptomaticpersonisanindicatorofCA-ASB.
EPIDEMIOLOGY• NosocomialUTIs,97%ofwhicharecatheterassociated,accountforupto40%ofnosocomial
infectionsinU.S.hospitalseachyear.• Approximately15%to25%ofpatientsingeneralhospitalshaveacatheterinsertedatsome
timeduringtheirstay.• About 5% to 10% of long-term care facility residents are managed with urethral
catheterization.• Theincidenceofbacteriuriaassociatedwithindwellingurethralcatheterizationwithaclosed
drainagesystemisapproximately3%to8%perday.• ThedurationofcatheterizationisthemostimportantriskfactorforCA-bacteriuria.• CA-bacteriuriacomprisesalargereservoirofantibiotic-resistantorganismsandisafrequent
targetforinappropriateantimicrobialtherapy.
MICROBIOLOGY• A broad range of bacteria can cause nosocomial UTI, and many are resistant to multiple
antimicrobialagents.• CA-bacteriuria is caused by a broad range of bacteria, including Escherichia coli, other
Enterobacteriaceae, nonfermenters such as Pseudomonas aeruginosa, and gram-positivecocci,includingcoagulase-negativestaphylococciandEnterococcusspp.
• Funguria,mostlycandiduria,isreportedin3%to32%ofcatheterizedpatients.
DIAGNOSIS• The majority of patients with CA-bacteriuria are asymptomatic, and signs and symptoms
commonlyassociatedwithUTI,suchasfever,dysuria,urgency,flankpain,orleukocytosis,arenonspecific.
• In the catheterized patient, pyuria does not differentiate CA-ASB from CA-UTI, but itsabsencesuggeststhatCA-UTIisnotthecauseofsymptoms.
THERAPY (SEE TABLE 226-1)• ScreeningandtreatmentofASBarenotrecommendedexceptinpregnantwomenandsome
patientswhoundergogenitourinarysurgery.
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mial U
rinary Tract In
fection
s
• UrineculturesshouldbeobtainedbeforetreatmentofnosocomialUTI.• RecommendedtreatmentdurationforCA-UTIrangesfrom7to21days,dependingonthe
severity.• Asymptomaticnosocomialcandiduriararelyrequirestreatment.
PREVENTION• Reducing exposure to urinary catheterization is the most effective way to prevent
CA-bacteriuria.• IndwellingurethralcatheterizationplacesthepatientatgreaterriskforCA-bacteriuriathan
condomorintermittentcatheterization.• Aclosedcatheterdrainagesystemisindicatedinallcatheterizedpatients.• Routineuseofantimicrobial-coatedurinarycathetersisnotsupportedbyavailabledata.• Routine use of systemic antimicrobial agents to prevent CA-bacteriuria should be
discouraged.• Use of multiple infection control techniques and strategies simultaneously (bundling) is
recommendedtopreventCA-bacteriuria.
TABLE 226-1 Empirical Management of Catheter-associated Urinary Tract Infection
Antimicrobial Agent* and Dosing
Mild to Moderate, Afebrile (Dosage Duration: 5-7 Days)
Ciprofloxacin 500 mg PO twice daily or 1 g (extended release) PO once daily†
Levofloxacin 750 mg PO once daily†
Severe Illness or Febrile, or Both (Dosage Duration: 5-14 Days)
Ciprofloxacin 400 mg IV twice daily†
Levofloxacin 500-750 mg IV once daily†
Ceftriaxone 1-2 g IV once daily‡
Cefepime 1 g IV twice daily‡
Piperacillin-tazobactam 3.375 g IV q6h‡
Meropenem 500 mg–1 g IV q8h‡
Imipenem-cilastatin 500 mg IV q6-8h†
Doripenem 500 mg IV q8h‡
Ertapenem 1 g IV once daily‡
Gentamicin 5-7 mg/kg IV once daily† ± ampicillin 1-2 g IV q6h§
In Choosing an Empirical Agent, Consider the FollowingSeverity of illness and comorbiditiesAntimicrobial susceptibility of prior urinary tract infection strainsLocal resistance dataExposure to same class in past 3-6 mo—choose alternative agentConsider adding vancomycin if Gram stain shows gram-positive cocciUse a carbapenem (meropenem, imipenem, doripenem, or ertapenem) if an extended-spectrum β-lactamase
strain is known or suspectedTailor regimen based on susceptibility data, and transition to oral medications (usually a fluoroquinolone), as
soon as condition allows
*If resistance to the antimicrobial agent is a concern because of the prevalence of resistance in the community, especially in a severely ill patient, an initial intravenous dose of a broader-spectrum agent, such as meropenem, should be given.
†Pregnancy category C—animal studies have shown an adverse effect on the fetus; use only if potential benefit justifies the potential risk to the fetus.
‡Pregnancy category B—no clear risk to fetus based on animal or human studies, or both.§Pregnancy category D—associated with human fetal risk; use only if the potential benefit justifies the potential
risk to the fetus.Modified from Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med. 2012;366:
1028-1037.
462
227 Health Care–Acquired HepatitisKent A. Sepkowitz
DEFINITION• Viralhepatitiscanbeacquiredbypatientsorhealthcareworkers(HCWs)duringtheprocess
ofhealthcaredelivery.
EPIDEMIOLOGY• TransmissionbetweenpatientsandHCWsisrare,buttheriskremains.• DialysispatientsandworkersareatparticularriskforhepatitisCvirus(HCV)and,ifunvac-
cinated,forhepatitisBvirus(HBV).• Increasingly,transmissionstopatientsareseeninlong-termcareandcanbetracedtounsafe
injectionpractices.
DIAGNOSIS• Identificationofanoutbreakisdifficultunlessaclusterofcasesoccurs.• Mostinvestigationsareidentifiedinconjunctionwithpublichealthauthorities.• Useofagenotypetodeterminehomologyisusefulininvestigation.
POSTEXPOSURE TREATMENT• HepatitisA:BothimmuneglobulinandhepatitisAvaccinehavebeenusedeffectively.• HepatitisB:Treatallexposednonimmunepersons.IfexposedbutwithoutHBVantibody,
administerhepatitisBimmuneglobulinwithorwithoutinitiationofvaccineseries.Theroleofantiviralshasnotbeendetermined.Useasimilarapproachforexposedpatients.
• HepatitisC:Treatonlyiftheexposedpersonhasevidenceofacuteinfection.Useofcurrentlyapprovedtherapieshasnotbeenstudiedinthiscontextbutislikelyeffective.
VACCINATION• HepatitisAvaccineisnotroutinelyrecommendedforHCWs.• HepatitisBvaccineorformaldeclinationismandatedforHCWs.• NovaccineisavailableforHCV.
463
228 Transfusion- and Transplantation-Transmitted InfectionsMatthew J. Kuehnert and Sridhar V. Basavaraju*
DEFINITION• Transfusion-andtransplant-transmittedinfectionsoccurwhenapathogenisspreadfrom
thedonortorecipientsthroughblood,organs,orothertissue.
EPIDEMIOLOGY• Transfusion-andtransplant-transmittedinfectionsareunusualbutoccurwhenadonorhas
aninfectionbutscreeningisnoteffectiveorwhenapathogenisnotscreened.Theriskofinfectiontransmittedthroughorgantransplantationislikelygreaterthanthroughbloodortissue,duetothelackofinclusioncriteriafororgandonors.
MICROBIOLOGY• Transfusionofbloodproducthastransmittedinfectionsbybacteria,viruses,parasites,and
prions.• Solid organ transplantation has transmitted infections caused by viruses, bacteria, fungi,
mycobacteria,andparasites.• Encephalitis followingsolidorgan transplantationhasresulted fromtransmissionofWest
NileVirus,lymphocyticchoriomeningitisvirus,rabies,andBalamuthia mandrillaris.
DIAGNOSIS• Diagnosis isdependentonclinicalrecognitionthatarecipienthasaninfectionthatcould
havebeenfromatransfusionortransplant.
THERAPY AND PREVENTION• Betterdonorscreening,orpromptrecognitionwhentransfusion-ortransplant-transmitted
infectionoccurs,canimproverecipientoutcomes.
*ThefindingsandconclusionsinthischapterarethoseoftheauthorsanddonotnecessarilyrepresenttheofficialpositionoftheCentersforDiseaseControlandPrevention.
464
B Infections in Special Hosts
229 Prophylaxis and Empirical Therapy of Infection in Cancer PatientsElio Castagnola, Małgorzata Mikulska, and Claudio Viscoli
RISK FACTORS FOR INFECTIONS IN CANCER PATIENTS• Neutropeniaisthemostimportant,particularlyifsevere(<100polymorphonuclearneutro-
phils)andprolonged(7to10days).• Otherriskfactorsincludemucositis;underlyingdiseaseanditsstatus;intensityofchemo-
therapy; theuseofbiologicresponsemodifiers,especiallymonoclonalantibodies, suchasalemtuzumaborrituximab;presenceofcentralvenouscatheter;andgeneticfactors.
EPIDEMIOLOGY AND ETIOLOGY• Epidemiology of bloodstream infections in neutropenia is constantly changing, and after
yearsofthepredominanceofgram-positivecocci,gram-negativerodshavebeenemerginginmanycentersasthemostfrequentpathogens.
• This shift has been accompanied by an increasing rate of resistant pathogens, suchas extended-spectrum β-lactamase–producing Enterobacteriaceae, carbapenem-resistantgram-negative pathogens, methicillin-resistant Staphylococcus aureus, methicillin-resistantStaphylococcus epidermidis,orvancomycin-resistantenterococci.
• Themainchallengeisthemanagementofmultidrug-resistant(MDR)gram-negativebacteriaforwhichfewtherapeuticoptionsexist.
• Invasivefungaldiseases(IFDs)inhematologypatientsarecausedmainlybyAspergillus,inturncausedbyawidespreaduseofCandida-activefluconazoleprophylaxis(theemergenceoffluconazole-resistantstrainsisthenaturalconsequence),whereasinsolid-organtumors,candidemiaremainsthemostfrequentIFD.
PROPHYLAXIS (SEE TABLE 229-1)• Ingeneral,antibacterial,antifungal,andantiviralprophylaxisisindicatedinpatientsreceiv-
inginductionchemotherapyforacutemyelogenousleukemia(AML).• Influenza and varicella vaccination of household contact and health care workers is
recommended.• Influenzaandpneumococcalvaccinationofpatients,especiallyduringlessaggressivetreat-
mentphases,isrecommended.• Fluoroquinolonesarerecommendedonlyforpatientswithprolonged(7to10days)neutro-
peniaincenterswhereresistancetofluoroquinolonesislessthan20%.• Primaryantifungalprophylaxisincancerpatientsisusuallyrecommendediftheincidence
ofIFDishigherthan15%.• Fluconazole is recommended as yeast-active prophylaxis in AML patients receiving
anthracyclineregimens.• Posaconazoleasmold-activeprophylaxisisrecommendedforpatientsreceivingchemo-
therapyforAMLormyelodysplasticsyndrome.• SecondaryantifungalprophylaxisshouldbeadministeredtopatientswithpreviousIFDwho
receivehigh-intensitychemotherapyoratransplant.• Prophylaxis against Pneumocystis jirovecii (usually with trimethoprim-sulfamethoxazole
three times per week) is beneficial in patients with deficits of T-cellular immunity,
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TABLE 229-1 Suggested Prophylaxis for Infections in Cancer Patients
DRUG SCHEDULE COMMENTSAntibacterial Ciprofloxacin 500 mg bid Adults receiving chemotherapy for acute
leukemia or autologous HSCT; starting with chemotherapy and continuing until resolution of neutropenia or initiation of empirical antibacterial therapy for febrile neutropenia
Levofloxacin 500 mg once daily
Amoxicillin-clavulanate
25 mg/kg (max., 1000 mg) bid
Children receiving chemotherapy for acute leukemia
Antifungal Posaconazole Oral solution 200 mg tid orally with a (fatty) meal
Patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome
Fluconazole 400 mg once daily Patients receiving chemotherapy for acute myelogenous leukemia with cytarabine plus anthracycline regimens (administered for 7 and 3 days, respectively) and high-dose cytarabine-containing regimens
Other Secondary prophylaxis according to isolated pathogen and/or clinical presentation
Pneumocystis jirovecii
Trimethoprim-sulfamethoxazole
One-double strength tablet (160/800 mg) three times weekly, or25 mg/kg of TMP-SMX (5 mg/kg of TMP), max., 1920 mg (two double-strength capsules) in 2 divided doses for 3 consecutive days/wk
All patients receiving chemotherapy with steroids, including those with solid tumors (e.g., brain cancer)
Dapsone 2 mg/kg/day (max., 100 mg), on alternate days three times/wk
In patients who cannot tolerate TMP-SMX
Aerosolized pentamidine
300 mg once a month with nebulizer
In patients who cannot tolerate TMP-SMX; effective, but it is more difficult to administer
Atovaquone 750 mg twice daily or 1500 mg once daily
In patients who cannot tolerate TMP-SMX
Antiviral Acycloviror
2000 mg (40 mg/kg in children) in 4-5 divided doses or in adult >40 kg: 800 mg twice daily
Patients with positive anti-HSV antibodies and severe mucositis or receiving treatment for acute leukemia
Valacyclovir 500 mg twice daily for HSV prophylaxisFor VZV exposure 1 g three times daily
VZV-susceptible patients exposed to chickenpox who did not receive prompt administration of specific immunoglobulins
Lamivudine 100 mg once daily Patients with chronic inactive HBV infection (HBsAg-positive, HBV DNA low level or negative)Patients with resolved HBV infection (HBsAg-negative and HBcAb-positive) if receiving rituximab or allogeneic HSCT
Tuberculosis Isoniazid 300 mg once daily Patients with latent tuberculosisEfficacy not specifically evaluated in cancer patients
Central venous catheter
None Good skin preparation and the use of sterile technique at time of device insertionGood maintenance procedures
All patients with indwelling central venous catheter
Continued
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DRUG SCHEDULE COMMENTSOthers Growth factors Filgrastim 300 µg/day (in
children: 5 µg/kg/day) either subcutaneously or as an intravenous infusion over at least 1 hr, or pegylated filgrastim, 6 mg every 14 days
For the prevention of febrile neutropenia in patients who have a high risk of this complication based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimenSecondary prophylaxis with G-CSFs is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose of chemotherapy may compromise disease-free or overall survival or treatment outcomeEfficacy not fully demonstrated for pegylated filgrastim
Immunoglobulins Polyclonal immunoglobulins: 400 mg/kg every 21-28 days
Patients with chronic lymphocytic leukemia after the second episode of severe bacterial infectionPatients with leukemia or lymphoma with hypogammaglobulinemia (<400 mg/dL) and severe bacterial infections (reasonable, but not proved)
Specific anti-VZV (VariZIG) 125 IU for every 10 kg of body weight (max., 625 IU)
In high-risk contact with a negative history of varicella within 96 hours after exposure to chickenpox
Vaccines InfluenzaVaricella
Influenza and varicella (negative contacts) vaccination of household contact and health care workersInfluenza vaccination of patients, especially during less aggressive treatment phases
Pneumococcus Conjugated-polysaccharide 13-valent antipneumococcal vaccine
Isolation procedures
Perform hand hygiene with an alcohol-based hand rub or by washing hands with soap and water if soiled, before and after all patient contacts or contact with the patients’ potentially contaminated equipment or environmentUse contact precautions (gowns and gloves)Ensure adherence to standard environmental cleaning with an effective disinfectant
Patients colonized or infected with multidrug-resistant pathogens (such as VRE, KPC, etc.) or infected with other pathogens for which contact isolation precautions are advisable (Clostridum difficile, norovirus, etc.); of note, alcohol-based hand rubs are not sporicidal
G-CSFs, granulocyte colony-stimulating factors; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; IU, international unit; KPC, Klebsiella pneumoniae carbapenemase; max., maximum; TMP-SMX, trimethoprim-sulfamethoxazole; VRE, vancomycin-resistant enterococci; VZV, varicella-zoster virus.
TABLE 229-1 Suggested Prophylaxis for Infections in Cancer Patients—cont’d
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particularlywithchroniclymphocyticleukemia,orinthosereceivinghigh-dosecorticoste-roidsoralemtuzumab.
• Antiherpesprophylaxiswithacyclovirorvalacyclovirshouldbeofferedtopatientswithacuteleukemiaorreceivingalemtuzumab.
• Varicella postexposure prophylaxis with specific immunoglobulins or acyclovir is recom-mendedforhigh-riskvaricella-zostervirus–susceptiblepatients.
• LamivudineisrecommendedforcancerpatientswithchronicinactivehepatitisBreceivinghigh-dosechemotherapy,particularlyifcontainingrituximab,andforselectedpatientswitharesolvedhepatitisBvirusinfection.
MANAGEMENT OF FEBRILE NEUTROPENIA (SEE FIGS. 229-1 AND 229-2)• Bloodcultures• Assessment of the risk of severe infection (e.g., Multinational Association for Supportive
CareinCancerscore;seeTable229-2)• Assessmentoftheriskofinfectioncausedbyresistantpathogens;riskishighincaseof
• Colonizationorpreviousinfectioncausedbyresistantbacteria• Localepidemiologywithhighincidenceofinfectionscausedbyresistantpathogens
• Choiceoftheappropriatetherapy• Oralversusintravenous• Inpatientversusoutpatientsetting
FIGURE 229-1 Possible initial approach to a patient with febrile neutropenia.
At onset of febrile neutropenia consider: 1. Type of patient: underlying disease, time from chemotherapy, previous history of
infectious complications, particularly caused by resistant pathogens. 2. Type of center: knowledge of epidemiology of infections and susceptibility patterns.If available, use a risk stratification system. For antibiotic choice, consider the local resistance patterns. Perform blood cultures (at least 3) and other cultures from sites of suspected infection.
Yes
No
Yes
Clinical signs ofa localizedinfection
Signs of septic shockStart empirical therapy activeagainst gram-negatives (considercombination of β-lactam +aminoglycoside), AND gram-positives(according to local epidemiology andsusceptibility patterns) AND considerantifungal therapy (an echinocandin).
Use antibiotics active againstgram-negatives AND add otheragents according to the mostprobable pathogen (if different)AND the site of infection.
Start empirical therapy according to risk stratification(consider oral therapy) AND local epidemiologic patterns.In any case, use antibiotics active against gram-negatives.
Discontinue anti–gram-positive and antifungal drugs if these infections are not confirmed.Discontinue aminoglycoside if gram-negatives are not isolated or susceptible to the chosen β-lactam.Adjust treatment according to isolated pathogens and the site of infection.
Revise anti-infective regimen usually after 72 hours of treatment:
Consider chest computed tomography scan or other imaging according to clinical features.
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FIGURE 229-2 Management of persistently febrile neutropenic patient.
infection or colonization by resistant
Signs or cultures suggesting a “new”bacterial infection or a viral infection
Treat accordingly Treat accordingly
No
Patient at high risk of invasive fungal disease
Wait and see Availability ofdiagnostic workup
Yes NoYes
YesNo
YesNo
YesNo
Septic shock or rapid worsening
Diagnostic workup1. Lung computed tomography scan (repeat at least 1/wk, unless clinical signs or
acute deterioration) 2. Serum galactomannan testing for 3 consecutive days3.4. Blood cultures5. Other imaging and/or invasive diagnostic procedures, with culture, microscopic
examination and antigen search, according to clinical features
Positive result of any
Patient at high risk of infection caused by resistant pathogens (e.g., previous
bacteria)
Start antifungal therapy
All negative
Persistent fever andneutropenia in spite of
broad-spectrum antibiotics
Empirical antifungaltherapy
Empirical antifungaltherapy AND
Do not start antifungalsor discontinue
empirical antifungal therapy
Serum (1,3)-�-D-glucan testing for 3 consecutive days
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• Escalationversusdeescalationstrategy• Escalationstrategyusuallystartswithanti-Pseudomonasβ-lactammonotherapy.• Deescalationstrategystartswithacombinationofanti-Pseudomonasβ-lactamplus
otheragentscoveringthemostprobableresistantpathogens;theseotheragentsshouldbediscontinuedifnoresistantpathogenisisolated.
• Empiricalantifungaltherapy(addingantifungalagentinpatientspersistentlyfebriledespitebroad-spectrumantibiotics) couldbe replacedbydiagnostic-driven strategybasedon theuseofdiagnostictools,suchasachestcomputedtomographyscanandfungalserummarkers(galactomannanandβ-D-glucan).
• IntheeraofincreasingantibioticresistanceandfewagentsactiveagainstMDRpathogens,antimicrobialstewardshipincancercentersismandatoryandshouldinclude• Infection-controlpractices• Local surveillance of antibiotic resistance, antibiotic consumption, and patient
outcomes• Promotingappropriateantibioticuse(timelydeescalation,appropriatedosing)• Establishing antibiotic regiments for empirical therapy appropriate for local
epidemiology
TABLE 229-2 Factors Associated with Low Risk of Severe Infection or Associated with an Uncomplicated Clinical Course in Febrile Neutropenic Cancer Patients
MASCC SCORE
Clinical Parameters ScoreClinical data available at onset of febrile neutropenia or soon after admission
1. Burden of illness: no or mild symptoms 5
2. No hypotension 5
3. No chronic obstructive pulmonary disease 4
4. Solid tumor or no previous fungal infection 4
5. No dehydration 3
6. Outpatient status 3
7. Burden of illness: moderate symptoms 3
8. Patient’s age <60 yr 2
MASCC, Multinational Association for Supportive Care in Cancer.Points attributed to the variable “burden of illness” are not cumulative. The maximal theoretical score is therefore
26.Low-risk patient: score ≥21.
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230 Infections in Recipients of Hematopoietic Stem Cell TransplantsJo-Anne H. Young and Daniel J. Weisdorf
TYPES OF DONORS OF STEM CELLS FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)• Syngeneic:donorisanidenticaltwinsibling• Autologous:therecipientdonatestoself• Allogeneic:thedonatedmaterialcomesfromadifferentindividualthantherecipient
SPECIFIC TYPES OF ALLOGENEIC DONORS• Matchedrelatedorpartiallymatchedrelateddonor,suchasasiblingwiththesameorsimilar
humanleukocyteantigen(HLA)type• Unrelateddonorormatchedunrelateddonor• Haploidentical:parent,cousin,sibling,orchildisthedonor;oneHLAhaplotypematched.
AlthoughhaploidenticalorotherHLAmismatchedtransplantsmayleadtoahighincidenceof graft-versus-host disease (GVHD), administration of cyclophosphamide early post-transplantandT-celldepletionofthegraftsmaylimitrisksofGVHD.
• Cord: umbilical cord blood usually partially HLA matched, not matched for blood type;sometimestwocordsusedtoprovidebloodwithsufficientcells
• Haplo-cord: haploidentical peripheral blood stem cells plus cord blood cells; haplo-cordengraftsrapidlybutmaynotbesustainedyetprovidesneutrophilproductionuntilthecordengrafts
TYPES OF CELLS USED IN HSCT• Peripheralbloodstemcells,usuallyfilgrastim(granulocytecolony-stimulatingfactor)mobi-
lized;maybeCD34selectedforT-celldepletion• Umbilicalcordblood:usuallyassociatedwithdelayedengraftmentbutlessGVHD• Bonemarrow:collectedbyaspirationharvest frommatchedrelatedormatchedunrelated
donor;associatedwithlesschronicGVHD• Donorlymphocyteinfusion:donorcellssortedforlymphocytes;givenafterengraftmentor
afterrelapseforantitumororantiviraleffectbutcanstimulateGVHD
PREPARATION OF PATIENT FOR CELL INFUSION (“CONDITIONING REGIMEN”)• Myeloablative: total-body irradiation plus cyclophosphamide or busulfan; can be without
irradiation• Nonmyeloablative(reducedintensity):usinglower-dosetotal-bodyirradiationorwithanti-
thymocyteglobulin,mostoftenwithfludarabine
OUTCOMES• Engraftment:absoluteneutrophilcountrisestomorethan500cells/µLbyday42• Primarygraftfailure:noengraftmentbyday42• Mixedchimerism:persistenceofhostanddonorhematopoiesis• Relapse:returnoftheunderlyingmalignantcondition
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COMPLICATIONS• Mucositis:mucosalinflammationthatservesasaportalofentryfororalorintestinalinfec-
tions;commonwithmethotrexate-containingregimens.Paliferminmayreducemucositis.• Hemorrhagiccystitis:oftenoccursinconjunctionwithcyclophosphamideearlyaftertrans-
plant,despite theuseofmesnaand forceddiuresis;viral causesmorecommon lateraftertransplant,includingadenovirusorBKvirus
• Engraftmentsyndrome(immunereconstitutionsyndrome):feverwithorwithoutrashand/orpulmonaryinfiltratesatengraftment
• Veno-occlusive disease, also called sinusoidal obstruction syndrome: triad of jaundice,weightgain,andascites leadingtomultiorganfailure,usuallyoccurring in thefirst3 to4weeksaftertransplantation
• Diffusealveolarhemorrhage:bleedingintoalveoli,usuallyduringthesecondorthirdweekafter transplant;diagnosedbyprogressivebloody returnson lung lavageand treatedwithcorticosteroids
• Graft-versus-hostdisease:inflammationandcelldeath(apoptosis)inskin,liver,gut,orlung.Acuteformusuallyoccursuntilday100.Chronicformgenerallyoccurslaterandhasfeaturesresemblingbutdistinctfromscleroderma.Theriskishigherintheelderlyandwithgraftsfrompartiallymatcheddonors.Calcineurininhibitors(cyclosporine,tacrolimus),lessoftensirolimus,andmycophenolatemofetilarestartedsoonaftertransplanttodecreasetheinci-denceandseverityofGVHD.High-dosecorticosteroids(andotheragents)areusedtotreatGVHD.
• Posteriorreversibleencephalopathysyndrome:neurotoxicityfromhypertension,calcineurininhibitors,orfludarabine
• Bronchiolitisobliteransorganizingpneumoniaandobliterativebronchiolitis:pneumonitisassociatedwithsmallairwayinjury,sometimesassociatedwithchronicGVHD
ANTIMICROBIAL AGENTS FOR PROPHYLAXIS• Acyclovir: low dose for herpes simplex virus, high dose for cytomegalovirus (see
Table230-1)• Levofloxacin:usedforpreventionofbacterialinfections,untilfeversorinfectiondevelop• Fluconazole:forpreventionofcandidiasis,startingwithneutropenia• Trimethoprim-sulfamethoxazole:agentofchoiceforPneumocystis;alsocoversToxoplasma
andsomebacteria,suchasNocardia.Alternativesincludeaerosolizedpentamidine,atova-quone,anddapsone.
• PenicillinVK:preventionagainstStreptococcus pneumoniaeduringactivechronicGVHD.Regionalpenicillinresistancemayleadtotheuseoflevofloxacinforthisindication.
• Voriconazoleorposaconazole:giveninplaceoffluconazoletopreventmoldinfections• Echinocandins(micafunginorcaspofungin):intravenouslyadministeredagentsthatmaybe
substitutedforazoles• Lamivudine:preventionofhepatitisBvirusreactivationinanti–hepatitisBcoreantibody–
positive, hepatitis B surface antigen–negative, and hepatitis B DNA–negative patient withhepatitisB–positivedonors.Entecavirortenofovirmaybesubstitutedforlamivudine.
• Entecavir or tenofovir: prevention of hepatitis B virus reactivation in hepatitis B surfaceantigen–positivepatient
• Ivermectin:twodosesforpatientsfromcountrieswithhighriskforStrongyloidesinfestation
PREEMPTIVE THERAPY• Ganciclovir, valganciclovir, or foscarnet: given to patients with cytomegalovirus reactiva-
tion based on polymerase chain reaction assay of blood or pp65 neutrophil antigen (seeTable230-1)
EMPIRICAL ANTIBACTERIAL THERAPY DURING FEVER AND NEUTROPENIA WITH NEGATIVE WORKUP• Designatedbroad-spectrumagentsuchasceftazidime,piperacillin-tazobactam,orcefepime• Addition of an aminoglycoside possibly required for institutional antibiotic resistance
patterns
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TABLE 230-1 Suggestions for Management of Possible CMV Infection after HSCT
INDICATION STRATEGY* COMMENT
Prevention
Allogeneic Transplant
Seropositive recipient Preemptive ganciclovir† induction for subclinical viremia, 5 mg/kg bid for 7-14 days, followed by 5 mg/kg daily until the end of maintenanceorGanciclovir prophylaxis‡ at engraftment
Some cases of CMV disease may occur shortly after ganciclovir discontinuation.
CMV reactivation might be delayed, occurring later after HSCT.
Seronegative recipient with seropositive donor
Preemptive ganciclovir induction for subclinical viremia, 5 mg/kg bid for 7-14 days, followed by 5 mg/kg daily until the end of maintenanceandSeronegative or filtered blood products
Prophylaxis at engraftment is not recommended because of the low incidence of post-transplantation infection.
Seronegative recipient with seronegative donor
Seronegative or filtered blood products
Autologous Transplant
Seropositive recipient Early ganciclovir induction of subclinical viremia, 5 mg/kg ganciclovir bid for 7 days, followed by 5 mg/kg daily for 14 days of maintenance
Because of the very low risk in some settings, monitoring is not uniformly advocated.
Seronegative recipient Seronegative or filtered blood products
Treatment of DiseaseCMV pneumonitis Ganciclovir induction, 5 mg/kg bid for 14-21
days, followed by 5 mg/kg daily for at least 3-4 wk of maintenanceplusIVIG every other day for the duration of induction
Extended maintenance throughout periods of severe immunosuppression (i.e., GVHD treatment) may be considered.
Gastrointestinal disease Ganciclovir induction, 5 mg/kg bid for 14-21 days, followed by 5 mg/kg daily for at least 3-4 wk of maintenance
If deep ulcerations are present, maintenance may be required for a longer time.
Marrow failure Foscarnet, 90 mg/kg bid for 14 days, followed by 90 mg/kg daily for 2 wkplusG-CSF
Ganciclovir plus IVIG has also been used.
Retinitis Ganciclovir, 5 mg/kg bid for 14-21 days, followed by 5 mg/kg daily for at least 3-4 wk
Extended maintenance may be required.
CMV, cytomegalovirus; G-CSF, granulocyte colony-stimulating factor; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; IVIG, intravenous immune globulin; PCR, polymerase chain reaction.
*Regimens should be accompanied by weekly monitoring with antigenemia or PCR-based nucleic acid testing.†Oral 900-mg doses of valganciclovir produce blood levels that are similar to those for the standard intravenous
dose (5 mg/kg) of ganciclovir. Foscarnet and cidofovir are acceptable alternatives. Renal dose adjustment is required for all antiviral agents.
‡Foscarnet, high-dose acyclovir, or valacyclovir are acceptable alternatives. Renal dose adjustment required for all antiviral agents.
• Vancomycin if any cellulitis, dysfunction with an indwelling catheter, or hemodynamicinstabilityorcolonizedwithmethicillin-resistantStaphylococcus aureus.
VIRAL DISEASES IN THE TRANSPLANT RECIPIENT• Herpessimplexvirus:oral,esophageal,vaginalulcers;autoinoculatonofotherskinsites• Varicella-zostervirus:dermatomalzoster;maydisseminate;rarelyseverehepatitisorvisceral
zoster• Cytomegalovirus: fever, viremia, cytopenias, pneumonitis, gastrointestinal disorders (e.g.,
hepatitis,esophagealulcers,mucosalchangesintheduodenumorcolon),retinitis
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• Humanherpesvirus6:viremia,pneumonitis,encephalitis;maybeassociatedwithdelayedneutrophilrecoveryorprolongedthrombocytopenia
• Adenovirus:hemorrhagiccystitis,pneumonitis,hepatitis• BKpolyomavirus:hemorrhagiccystitis• HepatitisBandC:hepatitis• Majorrespiratoryviruses:influenza,respiratorysyncytialvirusinthewinter;parainfluenza
virusandrhinovirusyear-round.• JCpolyomavirus:progressivemultifocalleukoencephalopathy• Epstein-Barrvirus:viremiaorpost-transplantlymphoproliferativedisorder
OTHER INFECTIONS• Clostridium difficile diarrhea: stool toxin polymerase chain reaction assay considered the
besttest• Intravascularcentralcatheter–relatedbacteremiaortunnelinfection• Typhlitis:abdominalpainandcecaledemaduringneutropenia• Pneumocystisinfection:diffusepneumonitisamongthosenottakingprophylaxis• Candidiasis:candidemiaoriginatingfromthegut• InfectionwithAspergillusandothermolds:lungfieldabnormalities,sinusitis• Toxoplasmosis:brainlesions
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231 Infections in Solid-Organ Transplant RecipientsNina Singh and Ajit P. Limaye
EPIDEMIOLOGY• Infectionsinorgantransplantrecipientstypicallyrepresentopportunisticinfections,reacti-
vation of latent organisms, and complications related to surgery, health care–associatedinfections,orboth.Infectionsmayalsobedonorderived.
• Advancesinmedicalpracticesandpreventivestrategieshavemodifiedtherisksandtimelineofmanyinfectionsinthecurrentera.
TYPES OF INFECTIONS• Bacterialinfectionsarethemostfrequentlyoccurringinfections.Bacteremiaoccursin5%
to25%oftransplantrecipients.• Fungalinfectionsoccurin0.7%to23%ofpatients.AmajorityoftheseareduetoCandida
orAspergillus spp.,withCryptococcus,endemicmycoses,andothernon-Aspergillusmoldsaccountingformostoftheothers.
• Cytomegalovirus(CMV)isamajorviralinfection.Intheeraofroutineantiviralprophylaxis,CMVdiseasetypicallyoccursinthelatepost-transplantperiod.Otherherpesviruses(herpessimplexvirus,varicella-zostervirus,Epstein-Barrvirus,humanherpesvirus6)arealsoseenwithgreaterfrequencyandseverityintransplantpatients.
• Influenzaandotherrespiratoryvirusesareamajorcauseofmorbidityandmortality,espe-ciallyinlungtransplantrecipients.
• BKvirusnephropathyhasemergedasanimportantcauseofallograftdysfunctionandlossinkidneytransplantpatients.
MANAGEMENT• Asageneralprinciple,serologicassays,althoughvaluableintheassessmentofpastexposure,
arenotreliableforthediagnosisofacuteinfections.• Quantitativemolecularassayshaveprovedtobevaluabletoolsfordiagnosis,guidingpre-
emptivetherapy,andmonitoringresponsetotreatmentforseveralviralpathogens(CMV,BKvirus).
• ProphylaxisagainstPneumocystisandToxoplasma(hearttransplantrecipients)isconsideredstandard.PreventiveapproachesarealsoroutinelyusedforCMV,BKvirus,fungalinfections,andherpessimplexvirusinselectedtransplantpatients,basedonriskfactors.
• Evaluation should take into consideration the time elapsed since transplant, exposures,receiptofpriorantimicrobialprophylacticagents,graftfunction,andtheoverallimmuno-suppressivestateofthetransplantrecipient.
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232 Infections in Patients with Spinal Cord InjuryRabih O. Darouiche
DEFINITION• Spinalcordinjury(SCI)resultsfrommechanicalcompression,vascularinsult,orboth.
PREVALENCE AND ETIOLOGY• SCIaffectsalmost1per1000persons.• CausesofSCIincludevehicularaccidents,falls,violence,sports,andinfection.• InfectioncancauseorresultfromSCI.
URINARY TRACT INFECTION• Urinary tract infection (UTI) is the most common infection and leading cause of
rehospitalization.• UTIs are mostly caused by usual bowel microbiota (gram-negative bacteria and
enterococci).• Intermittentcatheterizationispreferredtoindwellingbladdercatheters.• Preventionisineffective.• FrequentunnecessarytherapyisundertakenforfailuretodistinguishbetweenclinicalUTI
andasymptomaticpyuria.
PNEUMONIA• Pneumoniahasthehighestinfection-relatedmortality.• Itoccursmostlyinpatientswithtetraplegia.• Community-andhospital-acquiredmicrobesarecomparabletothosefoundinthegeneral
population.
INFECTION OF PRESSURE SORES AND BONE• Thisdiagnosisisveryproblematic.• The broadest microbial etiology includes gram-positive cocci, gram-negative bacilli, and
anaerobes.• Multidisciplinarymanagementisdifficultandrequireslongandrepeatedhospitalstays.
MULTIRESISTANT ORGANISMS IN SPINAL CORD INJURY UNITS• Multiresistant organisms include methicillin-resistant Staphylococcus aureus, vancomycin-
resistantEnterococcus, Clostridium difficile,andmultiresistantgram-negativebacteria.• TheseorganismsaremoreprevalentinSCIunitsthaningeneralhospitalwards.• Properinfectioncontrolmeasuresreducebothcolonizationandinfection.
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233 Infections in the ElderlyKent B. Crossley* and Phillip K. Peterson
GENERAL CONSIDERATIONS• Peoplelivingpast65yearsofagearerapidlyincreasinginnumber.• Individuals older than age 65 years have a higher incidence of most infections than do
youngerpeople.• Fornearlyallinfections,clinicalmanifestationsaremoresubtleintheelderly.
URINARY TRACT INFECTION• Asymptomaticbacteriuriashouldnotbetreated.• SymptomaticinfectionisoftencausedbyorganismsotherthanEscherichia coli.• Extended-durationtherapy(i.e.,>7days)ofsymptomaticinfectionisnotneededineither
menorwomen.
PNEUMONIA• Pneumoniaiscommonandoftenfollowedbydeathintheyearafterapneumonicillness.• Nonbacterial causes (e.g., metapneumovirus, respiratory syncytial virus) are relatively
frequent.• Managementofnursinghome–associatedpneumoniaremainscontroversial.• Immunizationwithinfluenzaandpneumococcalvaccinesisofsignificantbutlesserbenefit.
BACTEREMIA AND ENDOCARDITIS• Botharemorecommonintheelderly.• Multidrug-resistantgram-negativeorganismsarecommonlyrecoveredfrombloodcultures
ofresidentsinlong-termcarefacilities.
CENTRAL NERVOUS SYSTEM INFECTIONS• Viralmeningitisisuncommoninelderlyindividuals.• WestNilevirusinfectionhasrecentlyincreasedinfrequencyandismorecommonandmore
severeintheaged.
IMMUNIZATIONS• Immunizationwithaserialcombinationofbothpneumococcalvaccinesissuggestedforall
individualsaged65yearsandolder.• Ahigh-doseinfluenzavaccineisavailablefortheelderly.• Yellow fevervaccine isassociatedwithprolongedviremiaanddelayedantibodyresponse,
withmoresevereadverseeffectsafterimmunization.• Immunizationagainstherpeszosterhasbeenshowntoreducetheincidenceofdiseaseand
ofpostherpeticneuralgia.Recentstudieshavevalidatedthesafetyofthevaccine.
*Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanyborrowedfiguresortables.
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234 Infections in Asplenic PatientsJanet R. Gilsdorf
EPIDEMIOLOGY• Infectionoccursinpatientswithcongenitalasplenia(rare),acquiredaspleniasecondaryto
splenectomyorsicklecellanemia,andacquiredhypospleniasecondarytoinflammatoryorautoimmune disorders or human immunodeficiency virus–acquired immunodeficiencysyndrome.
• Theincidenceisseventoeightsevere infectionsper100person-years inpostsplenectomyadults.
• Riskfactorsforinfectionincludeyoungoroldage,lessthan1yearaftersplenectomy,indica-tionforsplenectomy(immunecytopenias>trauma> incidental),lackofappropriatevac-cines,andlackofprophylacticantibioticsinyoungchildren.
MICROBIOLOGY• Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria
meningitidis)aretheclassicalpathogensofpostsplenectomysepsis.• Withwidespreaduseofvaccinesagainstencapsulatedbacteria,Staphylococcus aureus and
gram-negativeentericbacteriaareseenmorecommonly.• Asplenic patients are at risk for increased severity of malaria, babesiosis, and
anaplasmosis.
DIAGNOSIS• Blood culture is the most important test to identify postsplenectomy sepsis and must be
obtainedattheearliestsignofinfection.• Whitebloodcellcountmaybeelevatedordepressed.• Cerebrospinalfluidexaminationmaybeindicatedinseveresepsis.• Evidence of disseminated intravascular coagulation or vascular collapse may accompany
sepsis.
TREATMENT• Immediateempiricalantibiotictherapyiskeytopreventingfulminantbacterialinfection.• Self-administered,oralantibiotics(amoxicillin-clavulanate,cefuroxime,orfluoroquinolone)
maybeusedbyasplenicpatientsathomeatfirstsignofinfection,followedbyimmediatevisittoanemergencyfacility.
• Empirical systemic antibiotics (vancomycin + ceftriaxone or fluoroquinolone) must bestartedimmediatelyatanemergencyfacility(afterbloodculturebutbeforeotherdiagnostictests).
• Definitiveantibiotictherapywilldependontheidentificationandantibioticsusceptibilityoftheinfectingpathogen.
PREVENTION• Patienteducation,repeatedlyreinforced,istheresponsibilityofallhealthcareproviders.• Avoidsplenectomyifpossible.
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• Administerappropriatevaccines(Hib,PCV13,PPSV23,MCV4,MenB,influenza),asrecom-mendedbytheAdvisoryCommitteeonImmunizationPracticesoftheCentersforDiseaseControlandPrevention.
• Prophylacticantibioticsarerecommendedforchildrenyounger than5yearsofage, thosewhoareimmunocompromised,orpatientswithpasthistoryofsepsis.
• Avoidvectorsthatcarrytheparasitescausingmalaria,babesiosis,andanaplasmosis.
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235 Infections in Injection Drug UsersDonald P. Levine and Patricia D. Brown
HOST DEFENSES• Direct effects of opioids on the immune system include impairment of chemotaxis,
phagocytosis, cytokine and chemokine production, natural killer cell activity, lymphocyteproliferationinresponsetomitogens,andantigenpresentationbyBlymphocytes.Indirecteffects through the neuroendocrine system and the autonomic nervous system are alsopostulated.
• IgMandIgGlevelsareoftenelevated,givingrisetoahighfrequencyofautoantibodiesaswellasantibodiesagainstvariousmicroorganisms;thismaycausediagnosticconfusion(e.g.,ininterpretationofsyphilisserology).
• Morphine-mediateddepressionofmonocytefunctionsimportanttoantiviraldefensemaycontributetothehighefficiencyoftransmissionofvirusessuchashepatitisBandCvirusesandhumanimmunodeficiencyvirus(HIV).
SKIN AND SOFT TISSUE INFECTIONS• Location of infection is related to the preferred location of injection; abscesses are most
common,followedbycellulitisandskinulcers.• InfectionwithStaphylococcus aureus(particularlycommunity-acquiredmethicillin-resistant
S. aureus[MRSA])ismostcommon,followedbystreptococci,eitheraloneorincombinationwith other pathogens; infection with Eikenella corrodens occurs in injection drug users(IDUs)wholicktheirneedlesorcontaminatetheirdrugswithsaliva;anaerobesandgram-negativebacilliarefoundinmixedinfections.
• Incisionanddrainageisthemainstayoftherapyforabscesses;forcellulitis,antibioticselec-tionandneedforhospitalizationmustbeindividualizedbasedonseverityofillness;ahighindexofsuspicionfornecrotizingfasciitisshouldbemaintainedinthesettingofseverepainorseveresignsofsystemictoxicityorboth.
BONE AND JOINT INFECTIONS• Theseinfectionsarecommon,mainlyaffecttheaxialskeleton,andoccurbythehematoge-
nousroute;contiguousspreadfromadjacentskinandsofttissueinfectionalsooccurs.• Bacterial infection with S. aureus and group A and G streptococci are most common;
infectionwithPseudomonas isalsoreported; infectionwithEikenellaoccurs inIDUswholicktheirneedles;andinfectionwithCandidaspeciesisincreasinglyreported.
• Joint infections typically involve the extremities (most commonly the knee), althoughinvolvementofunusualsites(costochondralandsternoclavicularjoints,pubicsymphysis)isfrequent;thereisahighincidenceofcervicalspineinvolvementinpersonswithvertebralosteomyelitis.
• Microbiologicdiagnosisshouldbeconfirmedinallcases;theuseofhighbioavailabilityoralantibiotictherapyforprolongedtreatmentisincreasing.
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INFECTIVE ENDOCARDITIS• IncidenceamongIDUsappearstobeincreasing,perhapsowingtoincreasedmethamphet-
amine use (increased number of injections); IDUs with HIV are at even higher risk forinfectiveendocarditis(IE).
• InfectionwithS. aureus ismostcommon(theincidenceofMRSAisincreasing),followedbygroupsA,B,andGstreptococci;outbreaksofgram-negative IE(causedbySerratiaorPseudomonas)arewelldescribed;andinfectionwithCandidaspecies(mainlynon-C. albi-cans)havebeenreported.
• TricuspidvalveIE isassociatedwith injectiondruguse,but the incidenceof left-sidedIEnowexceedsthatofright-sidedinfectioninsomeseries;multiplevalvesmaybeinvolved;infectionofthepulmonaryvalveisrare.
• IDUstendtopresentacutely inthefirstweekof illness;diagnosis isusuallyeasytomakebasedontheclinicalsignsandsymptomsandsupportedbytheresultsofbloodculturesandcardiacimaging.
• InitialempiricaltherapyshouldbedirectedagainstS. aureus(withvancomycinornafcillininsettingswhereMRSAisknowntoberare);optimaltherapyforMRSAisolateswithvan-comycin minimal inhibitory concentration of 2.0µg/mL is not yet defined; many expertsrecommenddaptomycin.
• Cefepimeplushigh-dosetobramycinhasbeenusedsuccessfullyinthetreatmentofpseudo-monalIE;surgicaltherapyalongwithamphotericinplusflucytosineisthestandardrecom-mendationforcandidalIE;theroleofazolesandechinocandinsisnotyetdefined;indefinitesuppressive therapy with oral azoles is recommended if the patient is not a candidate forsurgery.
NONCARDIAC VASCULAR INFECTIONS• InfectionwithS. aureusmostcommon;infectionwithPseudomonasisalsoreported;poly-
microbialinfectionsarecommon.• Septic thrombophlebitis presents as local pain, swelling, and fever, with bacteremia and
sepsis;septicpulmonaryembolimayoccur;antibiotictherapyshouldbegivenforatleast4weeks;theroleofanticoagulationremainscontroversial—short-termanticoagulationwhilethepatientishospitalizedmaybesufficient.
• Mycoticaneurysmsfrequentlyinvolvethefemoralveinsandpresentasatender,enlargingandpulsatilemass;Dopplerultrasonography,computedtomography(CT),ormagneticreso-nanceangiography(MRA)canbeusedfordiagnosis;surgicalmanagementisrequired,alongwithantibiotictherapyfor4to6weeks.
PULMONARY INFECTIONS• Community-acquired pneumonia caused by common respiratory pathogens is most
common;patientsareatriskforbacteremia,parapneumoniceffusions,andempyema.• PulmonarytuberculosisisamajorproblemamongIDUs,especiallythoseinfectedwithHIV;
treatment for latent tuberculous infection is challenging; material incentives and directlyobservedtherapycanincreaseadherence.
HEPATITIS• Cocaine,methamphetamine,andbuprenorphine(injectedorsublingual)canbehepatotoxic;
heroinisnot.• IDUs are at risk for hepatitis B virus infection and should be vaccinated if nonimmune;
spontaneousreactivationofinfectioncanoccur.• InnonendemicareassuchastheUnitedStates,hepatitisDvirusoccursalmostexclusively
inIDUs;althoughtheoverallprevalenceofhepatitisDvirushasdecreased,theprevalenceamongthosewithchronichepatitisBvirusinfectionhasincreased.
• SuperinfectionofhepatitisDvirusonchronichepatitisBvirusismostcommon;however,simultaneousinfectionoccursinIDUsandcanresultinfulminanthepatitis.
• IDUsaccount for themajorityofhepatitisC infections in theUnitedStates,although theoverallprevalenceofinfectionsinthispopulationisdecreasing;chronicinfectiondevelops
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in60%to80%ofpatients;treatmentischallengingandshouldbecoupledwithtreatmentforsubstanceabuse.
• IDUs are at increased risk for infection with hepatitis A virus, but socioeconomic factorsratherthandrugusearethelargerrisk;nonimmuneIDUsshouldbevaccinated.
SPLENIC ABSCESS• Splenic abscess occurs most commonly as a complication of IE; secondary infection of a
cocaine-inducedsplenicinfarctorinfectionoccurringaftertraumaalsoisreported;staphy-lococciandstreptococciarethemostcommoncausativeagents.
• Ultrasonography, CT, and magnetic resonance imaging can all be utilized for diagnosis;althoughsplenectomyisgenerallyconsideredthemanagementofchoice,especially inthesetting of IE necessitating valve replacement, there is an increasing role for percutaneousdrainage.
CENTRAL NERVOUS SYSTEM INFECTION• InfectionofthecentralnervoussystemoccursmostcommonlyasacomplicationofIE(e.g.,
meningitis,brainabscess,mycoticaneurysms).• MycoticaneurysmmaybediagnosedbyCT,CTangiography,orMRA;optimalmanagement
isnotdefined;manyaneurysmshealwithantibiotic therapy; rupturedaneurysmsrequiresurgeryoranendovascularprocedure.
• Thedifferentialdiagnosisofbrainabscessisbroad,especiallyinIDUswithHIVinfection;microbiologicdiagnosisshouldalwaysbeconfirmed.
• SpinalepiduralabscessshouldbesuspectedinIDUswhopresentwithbackpainaccompa-niedbyradicularsymptomsorneurologicfindings;S. aureusisthemostcommonetiologicagent.
• IDUsareatincreasedriskfortetanusandwoundbotulism.
OCULAR INFECTIONS• Bacterialandfungalendophthalmitisareseen,frequentlyasacomplicationofIE;Aspergillus
endophthalmitisisalsoreported.• Intravitrealantimicrobialagentswithorwithoutparsplanavitrectomymayberequired.
HUMAN IMMUNODEFICIENCY VIRUS INFECTION• IncidenceofHIVinfectionamongIDUsintheUnitedStateshassteadilydeclined;however,
injectiondruguseremainsamajorriskfactorforHIVacquisitioninotherpartsoftheworld.• NeedleexchangeprogramsareeffectiveatreducingHIVtransmissionbutshouldideallybe
coupled with access to voluntary counseling and testing, opioid substitution therapy, andcombinationantiretroviraltherapyforthosealreadyinfected.
• Injection drug use is associated with delayed entry into care and receipt of antiretroviraltherapy;periodsofincarcerationareassociatedwithvirologicfailure,buttheprevalenceofdrugresistanceisnohigherthaninnon-IDUs.
SEXUALLY TRANSMITTED DISEASES• Injectiondruguseisassociatedwithhigh-risksexualbehavior,andreductioninriskysexual
behaviorismoredifficulttoachievethanreductionsinriskyinjectionbehavior.• Theprevalenceofcommonsexuallytransmittedinfectionsappearstobenohigherthanin
thegeneralpopulation,butbecause theyplaya role in the transmissionofHIV, reducinginfections in this population could reduce the transmission of HIV from IDUs to sexualpartners.
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236 Surgical Site Infections and Antimicrobial ProphylaxisThomas R. Talbot
BACKGROUND• Surgical site infections (SSIs) are a common and unwanted outcome from most types of
surgicalprocedures.• The development of an SSI depends on patient-related, procedure-related, and pathogen-
relatedfactors,aswellastheapplicationofevidence-basedpreventionmethods.• CausativeorganismsofSSIarepredominantlytheflorapresentattheincisionsite.
RISK FACTORS FOR SURGICAL SITE INFECTIONS (SEE TABLE 236-1)• Patientfactorsincludecomorbidillness,colonizationwithpathogenicbacteria,perioperative
hyperglycemia,andtobaccouse.• Proceduralfactorsincludebreaksinsteriletechnique,operatingroomventilation,andtraffic.• Proceduralistfactorsincludesurgicaltechnique,improperapplicationofskinantisepsis,and
providerimpairment.
PREVENTION OF SURGICAL SITE INFECTIONS (SEE TABLE 236-2)• Practices to reducebacterial inoculation intowounds includeantisepticuse, sterile attire,
decolonizationstrategies,andproperhairremoval.• Practicestoimprovehostcontainmentofintroducedbacteriaincludemaintenanceofnor-
mothermia,minimizingtissuehypoxia,glucosecontrol,andantimicrobialprophylaxis.
SURGICAL ANTIMICROBIAL PROPHYLAXIS• Keyprinciples:
• Maintaintissueconcentrationofdrugaboveminimalinhibitoryconcentration(MIC)ofcommonflora(seeFig.236-1).
• Provide“right”drug:thus,targetfloraatsurgicalsite,penetratesurgicalincisionsite,andachieveminimaladverseevents.
• Provide“right”doseatthe“right”time:providedoseinthewindowbeforeincisiontoallowpenetrationintotissues(seeFig.236-2);considerhigherdoseforobesepatients;redoseinprolongedprocedures.
• Provide“right”durationofdrug:stoponceincisionclosedorby24hoursatthelatest.• Prophylaxistargetingresistantorganismsmaybewarrantedinselectsituations(e.g.,known
colonizationwithorganism).• Adherencetokeyprinciplesofantimicrobialprophylaxisisusedtoassessoverallqualityof
careandreimbursementfromthird-partypayers.
SSI SURVEILLANCE• SSIsurveillancerequiresstandardizeddefinitions.• PostdischargesurveillanceofSSIsmayleadtovariabilityinreportedoutcomesandmustbe
addressedaspartofanysurveillancesystem.
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TABLE 236-1 Selected Factors Associated with an Increased Risk for Surgical Site Infection
Patient FactorsDiabetes mellitus/perioperative hyperglycemiaConcurrent tobacco useRemote infection at time of surgeryObesityLow preoperative serum albuminMalnutritionConcurrent steroid useProlonged preoperative stay*Prior site irradiationColonization with Staphylococcus aureus
Procedural FactorsShaving of site the night before procedureUse of razor for hair removalImproper preoperative skin preparation/use of non–alcohol-based skin preparationImproper antimicrobial prophylaxis (wrong drug, wrong dose, wrong time of administration)Failure to timely redose antibiotics in prolonged proceduresInadequate OR ventilationIncreased OR trafficPerioperative hypothermiaPerioperative hypoxia
Proceduralist FactorsSurgical technique (poor hemostasis, tissue trauma)Lapses in sterile technique and asepsisGlove micropenetrationsBehavioral factors/proceduralist impairment
OR, operating room.*Likely a surrogate marker for severity of underlying illness and comorbidities.Modified from Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection,
1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. 1999;20:250-278; quiz 279-280.
TABLE 236-2 Interventional Maneuvers of Proven or Theoretical Benefit in Diminishing the Risk of Surgical Site Infection
Maneuvers to Diminish Inoculation of Bacteria into Wound
Preoperative Factors
Avoid preoperative antibiotic use (excluding surgical prophylaxis)Minimize preoperative hospitalizationTreat remote sites of infection before surgeryAvoid shaving or razor use at operative siteDelay hair removal at operative site until time of surgery and remove hair (only if necessary) with electric
clippers or depilatoriesEnsure timely administration (including appropriate dose) of prophylactic antibioticsConsider elimination of Staphylococcus aureus nasal carriage via decolonization techniquesUse standardized checklist for implementation at preprocedural time-out
Intraoperative and Postoperative Factors
Carefully prepare patient’s skin with antiseptic + alcohol-based skin preparation agent (e.g., povidone-iodine-alcohol or chlorhexidine-alcohol–containing solution)
Rigorously adhere to aseptic techniquesIsolate clean from contaminated surgical fields (e.g., reglove and change instruments used to harvest
saphenous vein before working in intrathoracic field)Maintain high flow of filtered airRedose prophylactic antibiotics in prolonged proceduresMinimize operative personnel trafficMinimize immediate use steam sterilization of surgical instrumentsMinimize use of drainsBring drains, if used, through a separate stab wound
Continued
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FIGURE 236-1 Tissue antibiotic concentration over time. Dynamics of tissue antibiotic con-centration during the course of a surgical procedure. After an initial dose of antibiotic (noted on the far left of the x axis), tissue concentrations reach their peak rapidly, with a subsequent decline over time. As illustrated, the goal of antibiotic prophylaxis is to have tissue concentrations above the minimal inhibitory concentration (MIC) for the specific pathogens of concern at the time of the inci-sion and throughout the procedure. Antibiotics should be redosed in prolonged procedures to prevent a period with tissue levels below the MIC (light blue arrow). Failure to redose antibiotics appropriately (dark blue arrow) may result in a period during which the wound is vulnerable.
Antibi
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TABLE 10-2 Initial Empirical Antimicrobial Regimens for Suppurative Infections of the Head and Neck—cont’d
Maneuvers to Improve Host Containment of Contaminating Bacteria
Preoperative Factors
Resolve malnutrition or obesityDiscontinue tobacco use for at least 30 days preoperativelyMaximize diabetes control
Intraoperative and Postoperative Factors
Minimize dead space, devitalized tissue, and hematomasConsider use of supplemental oxygen therapyMaintain perioperative normothermia (core temperature at or above 36.0° C)Maintain adequate hydration and nutritionIdentify and minimize hyperglycemia (through 48 hours postprocedure)
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FIGURE 236-2 Timing of administration and infection rate. Relationship between timing of administration of prophylactic antibiotics and surgical site infection rate from two large studies. A, Data from 2847 elective surgical patients. B, Data from 3656 cardiac, orthopedic, and gynecologic surgical patients. (A from Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med. 1992;326:281-286. B from Steinberg JP, Braun BI, Hellinger WC, et al. Timing of antimicrobial prophylaxis and the risk of surgical site infections: results from the Trial to Reduce Antimicrobial Prophylaxis Errors. Ann Surg. 2009;250:10-16.)
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237 BurnsClinton K. Murray*
DEFINITIONS• Annually,500,000burninjuriesreceivemedicaltreatment,andapproximately40,000require
hospitalization,ofwhichapproximately55%areadmittedtospecializedburncenters.• Theprimaryinsultfromaburnisthewounditself.
EPIDEMIOLOGY• Burnpatientpopulation:almost70%ofpatientsaremen,withmeanage32years,with19%
ofpatientsyoungerthan5years,and12%age60yearsorolder.Thetotalburnsizeistypi-callylessthan10%oftotalbodysurfacearea(TBSA)in72%ofcases.
*TheopinionsorassertionscontainedhereinaretheprivateviewsoftheauthorandarenottobeconstruedasofficialorreflectingtheviewsoftheU.S.DepartmentoftheArmy,theU.S.DepartmentofDefense,orthefederalgovernment.TheauthorisanemployeeoftheU.S.government,andthisworkwasperformedaspartofofficialduties.Allmaterialinthischapterisinthepublicdomain,withtheexceptionofanybor-rowedfiguresortables.
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238 BitesEllie J. C. Goldstein and Fredrick M. Abrahamian
DEFINITION• Bitewoundsarecommoninjuriescausedbyawidevarietyofdomesticandwildanimals,as
wellashumans.
EPIDEMIOLOGY• Bitesoccurin4.7millionAmericansyearlyandaccountfor800,000medicalvisits,including
approximately1%ofallemergencydepartmentvisits.
MICROBIOLOGY• Thebacteriaassociatedwithbite infectionsmaycome fromtheenvironment, thevictim’s
skinflora,ormostfrequently,theoralfloraofthebiter,whichcanalsobeinfluencedbythemicrobiomeoftheiringestedpreyandotherfood.
DIAGNOSIS• Thediagnosisismadebythepatient’sreportedhistoryofevents.Ultimatelyamicrobiologic
assessmentofinfectedwoundsisperformedthroughaerobicandanaerobiccultures.• Plainradiographsshouldbeobtainedifthereisahighlikelihoodofbonyinjury.
THERAPY• Irrigatewoundswithcopiousamountsofnormalsaline.• Cautiouslydébridedevitalizedornecrotictissue.• Primarywoundclosure isnotusuallyadvocated;delayedprimaryclosureorallowing the
woundtoclosebysecondaryintentionisrecommended.• Looseapproximationofwoundedgeswithadhesivestripsorsuturesmaybenecessaryfor
selected,fresh,uninfectedwounds.Closureoffacialwoundsmaybeconsideredifcoupledwithcopiousirrigationandantimicrobialpreemptivetherapy.
• Inmostcasesofterrestrialanimalbites,antimicrobialtherapywhenindicatedshouldincludecoverageforPasteurella(Eikenellainhumanbites),Streptococcus, Staphylococcus,andanaer-obesincludingFusobacterium, Porphyromonas, Prevotella,andBacteroidesspecies.
• Oralantimicrobialchoicescanincludethefollowing(seeTable238-1):• Amoxicillin/clavulanicacid875/125mgonetabletbymouthtwicedaily• Clindamycin300mgbymouthfourtimesdailyplusciprofloxacin500mgbymouthtwice
daily• Clindamycin300mgbymouthfourtimesdailyplustrimethoprim-sulfamethoxazoleone
double-strengthtabletbymouthtwicedaily• Moxifloxacin400mgbymouthdaily• Doxycycline100mgbymouthtwicedaily
• Intravenousantimicrobialchoicescanincludethefollowing:• Ampicillin/sulbactam1.5to3gIVevery6hours• Cefoxitin1to2gIVevery6to8hours
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TABLE 238-1 Management of Bite Wounds
HistoryAnimal bite: Ascertain the type of animal, whether the bite was provoked or unprovoked, and the situation/
environment in which the bite occurred. Follow rabies guidelines for details on management of bites that carry a risk of rabies.
Patient: Obtain information on antimicrobial allergies, current medications, splenectomy, mastectomy, liver disease, or immunosuppressive conditions.
Physical ExaminationIf possible record a diagram of the wound with the location, type, and approximate depth of injury; range of
motion; possibility of joint penetration; presence of edema or crush injury; nerve and tendon function; signs of infection; and odor of exudate.
CultureAerobic and anaerobic cultures should be taken from infected wounds.
IrrigationCopious amounts of normal saline should be used for irrigation.
DébridementDevitalized or necrotic tissue should be cautiously débrided.
RadiographsPlain radiographs should be obtained if bony penetration is possible and to provide a baseline for future
evaluation of osteomyelitis.
Wound ClosurePrimary wound closure is not usually advocated. Wound closure may be necessary for selected, fresh,
uninfected wounds, especially large facial wounds. For larger wounds, edges may be approximated with adhesive strips in selected cases.
Antimicrobial TherapyEarly presenting (uninfected) wounds: Provide antimicrobial therapy for (1) moderate-to-severe injuries less
than 8 hours old, especially if edema or significant crush injury is present; (2) bone or joint space penetration; (3) deep hand wounds; (4) immunocompromised patients (including those with mastectomy, advanced liver disease, asplenia, or chronic steroid therapy); (5) wounds adjacent to a prosthetic joint; and (6) wounds in close proximity to the genital area. In most cases, coverage should include Pasteurella (Eikenella in human bites), Staphylococcus, Streptococcus, and anaerobes including Fusobacterium, Porphyromonas, Prevotella, and Bacteroides species.
Infected wounds: Cover Pasteurella (Eikenella in human bites), Staphylococcus, Streptococcus, and anaerobes including Fusobacterium, Porphyromonas, Prevotella, and Bacteroides spp. The following antimicrobials can be considered for most terrestrial animal and human bites in adults:• First choice: Amoxicillin/clavulanic acid 875/125 mg one tablet bid with food.• Penicillin allergy: No alternative treatment for animal bites has been established for penicillin-allergic
patients. The following regimens can be considered for adults:• Clindamycin 300 mg PO qid plus either ciprofloxacin 500 mg PO bid or levofloxacin 500 mg PO daily
or trimethoprim-sulfamethoxazole one double-strength tablet PO bid• Doxycycline 100 mg PO bid• Moxifloxacin 400 mg PO daily• In highly penicillin-allergic pregnant patients, macrolides have been used, but because of poor
antimicrobial coverage against anaerobic pathogens, the wounds must be closely followed.• In cases where intravenous antibiotics are deemed necessary, single antimicrobial choices can include
ampicillin/sulbactam, cefoxitin, ertapenem, or moxifloxacin.• Empirical regimens for marine- and freshwater-acquired infection should also cover Vibrio and
Aeromonas species, respectively, with agents such as third-generation cephalosporins (e.g., cefotaxime) and fluoroquinolones.
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HospitalizationIndications include signs and symptoms of systemic toxicity and worsening infection.
ImmunizationsProvide tetanus and rabies immunization, if indicated.
ElevationElevation may be required if any edema is present. Lack of elevation is a common cause of therapeutic
failure.
ImmobilizationFor significant injuries, immobilize the extremity, especially the hands, with a splint.
Follow-upPatients should be reminded to follow up within 48 hours or sooner for worsening or unresolved infections
and continuous pain.
ReportingReporting the incident to a local health department may be required.
bid, two times a day; PO, orally; qid, four times a day; tid, three times a day.
• Moxifloxacin400mgIVdaily• Ertapenem1gIVdaily
• Empiricalregimensformarine-andfreshwater-acquiredinfectionsshouldcoverVibrioandAeromonasspecies,respectively,withagentssuchasthird-generationcephalosporins(e.g.,cefotaxime)andfluoroquinolones.
PREVENTION• Asaroutine,antimicrobialsarenotadvocatedforeveryuninfectedanimalbiteinjury.• In general, antimicrobial preemptive therapy is advocated for 3 to 5 days for uninfected
animalbites(e.g.,<24hoursafterinjury)inmoderate-to-severeinjuries,especiallythosetothehandorface,deepinjuriespenetratingbonystructures,inthepresenceofedema,andinimmunocompromisedhosts.
• Providetetanusandrabiesimmunization,asindicated.
TABLE 238-1 Management of Bite Wounds—cont’d
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D Zoonoses
239 ZoonosesW. Ian Lipkin
DEFINITION• Azoonosisisaninfectiousdiseaseofhumansthatoriginatesinanimals.
EPIDEMIOLOGY• Zoonosesaccountformorethanhalfofallemerginginfectiousdiseasesandincludesuch
variedexamplesashumanimmunodeficiencyvirus/acquiredimmunodeficiencysyndrome(HIV/AIDS),Ebolavirus,severeacuterespiratorysyndrome,plague,rabies,influenza,andnew-variantCreutzfeldt-Jakobdisease.
DIAGNOSIS• Themajorityofzoonoticdiseasesarediagnosedusingmolecularmethods.Manyappearin
unexpectedcontexts;thus,acomprehensivetravelandexposurehistorycanbecritical.
TREATMENT• WiththenotableexceptionofHIV/AIDSandinfluenza,mostviralzoonoseshavenotbeen
a focus for drug development. Thus, treatment is primarily supportive. In contrast, manybacterialzoonosescanbetreatedwithantibiotics.
PREVENTION• Vaccinesareestablished foronlyaminorityofzoonoticdiseases.Thus,prevention isbest
achievedbylimitingexposuretoreservoirsandvectorsfortransmissionofinfection.
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E Protection of Travelers
240 Protection of TravelersDavid O. Freedman
The pretravel office visit with an adult traveler to the developing world should follow a structured approach.
PERFORM RISK ASSESSMENT• Exact itinerary, including regions within each country to be visited, dates of travel to assess
risk of seasonal diseases, age, past vaccination history, underlying illness(es), current medica-tions, pregnancy status, allergies, purpose of trip, risk exposures—blood, body fluids, adven-ture or extensive outdoor exposures, urban versus rural travel, type of accommodations, level of aversion to risk, and financial limitations that may necessitate prioritization of interventions
ADMINISTER IMMUNIZATIONS• Routine vaccinations that are not up to date, including measles-mumps-rubella (MMR),
tetanus-diphtheria–acellular pertussis (Tdap), pneumococcal, varicella, zoster• Indicated routine travel vaccines, including hepatitis A, hepatitis B, typhoid, and
influenza• Indicated specialized vaccines, including yellow fever, rabies, polio, meningococcal, and, in
certain countries, tick-borne encephalitis and cholera
PROVIDE MALARIA PREVENTION (IF INDICATED)• Several equally effective drugs of choice may be indicated, including atovaquone/proguanil,
mefloquine, and doxycycline. Ascertain which is best suited to the individual patient and itinerary.
• Educate on personal protection against arthropods.
TRAVELER’S DIARRHEA• Recommend food and water precautions.• Prescribe and educate on standby therapy with a quinolone antibiotic or azithromycin, and
advise on use of loperamide and oral hydration if needed.
TEACH ESSENTIAL PREVENTIVE BEHAVIORS• Most travel-related health problems, including vaccine-preventable diseases, can be avoided
through simple behaviors initiated by the traveler.• Educate on appropriate strategies in the following categories (some topics are not applicable
to all destinations): blood-borne and sexually transmitted diseases, safety and crime avoid-ance, injury prevention, swimming safety, rabies, skin/wound care, tuberculosis, packing for healthy travel, and obtaining health care abroad.
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DISCUSS OTHER APPLICABLE HEALTH ISSUES• Advise and prescribe for altitude illness, motion sickness, or jet lag.• Discuss prevention of specific travel-related infections that are of some risk to the traveler
and have a possible preventive strategy not included in the strategies given above.• Discuss any minimal-risk conditions (e.g., hemorrhagic fevers) that are a frequent cause of
patient anxiety.
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241 Infections in Returning TravelersDavid O. Freedman
MAJOR SYNDROMES IN RETURNED TRAVELERS• Fever,diarrhea(acuteorpersistent),skinproblems,eosinophilia
TROPICAL DISEASES WITH POSITIVE PERIPHERAL BLOOD FILMS• Malaria,babesiosis,filariasis,Africantrypanosomiasis,Americantrypanosomiasis,relapsing
fever,bartonellosis
INCUBATION PERIODS OF TROPICAL DISEASES• Short (<10 days):arboviralinfectionsincludingdengueandyellowfever,hemorrhagicfevers,
respiratoryvirusinfections,typhoid,infectionwithgastrointestinalpathogens,spottedfeverrickettsioses,relapsingfever,leptospirosis
• Intermediate (10 to 20 days):malaria,hemorrhagicfever,Qfever,typhus,typhoid,brucellosis,Africantrypanosomiasis,rabies,tick-borneencephalitis,Japaneseencephalitis
• Prolonged (>21 days):viralhepatitis,malaria,rabies,tuberculosis,schistosomiasis,filariasis,amebicabscess,Qfever,Epstein-Barrvirusinfection
EVALUATION OF SIGNIFICANT TROPICAL FEVER• Any hemorrhagic manifestations?Ifviralhemorrhagicfeverispossible,isolateandcallpublic
healthauthorities;considermeningococcemia,rickettsiosis,sepsis,dengue.• Is malaria possible?Ifthereisend-organdamage,initiateempiricaltherapy.• Utilize a “rule out malaria protocol,” and use empirical therapy if no local expertise is
available.• Aretherelocalizingfindings?Gotosyndromicapproachanddifferentialdiagnosis.• Aretherenolocalizingfindings?Considertyphoid,dengue,rickettsiosis,humanimmuno-
deficiencyvirusinfection,leptospirosis,schistosomiasis(eosinophilia),amebicdisease.• ConsultTable241-1forconstellationsofexposuresandclinicalpresentationssuggestiveof
particulardiagnosesinreturnedtravelers.• Eosinophilia iscausedbytissue-invasivehelminthsandisproportionaltodegreeoftissue
invasion.
494Part
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TABLE 241-1 Constellations of Exposures and Clinical Presentations Suggestive of Particular Diagnoses in Returned Travelers*
EXPOSURE SCENARIO DISTINCTIVE FINDINGS DIAGNOSISAny exposure in any area with documented malaria transmission
Fever with or without any other finding
Malaria
Most tropical countries Fever and altered mental status Malaria, meningococcal meningitis, rabies, West Nile virus
Budget travel to India, Nepal, Pakistan, or Bangladesh
Insidious-onset, high unremitting fever, toxic patient, paucity of physical findings
Enteric fever due to Salmonella Typhi or Salmonella Paratyphi
Freshwater recreational exposure in Africa Fever, eosinophilia, hepatomegaly, negative malaria smear
Acute schistosomiasis (Katayama fever)
Bitten by Aedes aegypti in Central America, Southeast Asia, or the South Pacific
Fever, headache, myalgia, diffuse macular rash, mild to moderate thrombocytopenia
Dengue
Bitten by A. aegypti or Aedes albopictus in India, Malaysia, Singapore, the Caribbean, or an island in the Indian Ocean
Fever, headache, myalgia, diffuse macular rash, arthralgia, tenosynovitis often followed by chronic polyarthritis after the fever resolves
Chikungunya fever
Hunting or visiting game reserves in southern Africa
Fever, eschar, diffuse petechial rash African tick typhus due to Rickettsia africae
Travel to Southeast Asia Fever, eschar, diffuse petechial rash Scrub typhus due to Orientia tsutsugamushi
Hiking, biking, swimming, rafting with exposure to fresh surface water
Fever, myalgia, conjunctival suffusion, mild to severe jaundice, variable rash
Leptospirosis
Cruise, elderly traveler Influenza-like illness Influenza A or B
Outdoor exposure anywhere in the Americas
Large, single furuncular lesion anywhere on body, with sense of movement inside
Myiasis due to Dermatobia hominis (botfly)
Clothing washed or dried out of doors in Africa
Multiple furuncular lesions around clothing contact points with skin
Myiasis due to Cordylobia anthropophaga (tumbu fly)
New sexual partner during travel Fever, rash, mononucleosis-like illness Acute human immunodeficiency virus infection
Travel to any developing country or to Western Europe
Coryza, conjunctivitis, Koplik spots, rash
Measles
Longer visit to humid areas of Africa, the Americas, or Southeast Asia
Asymptomatic eosinophilia or with periodic cough or wheezing
Strongyloidiasis
Sand fly bite in either New or Old World tropical area
Painless skin ulcer with clean, moist base in exposed area
Cutaneous leishmaniasis
Resort hotel in southern Europe, ± exposure to whirlpool spas
Pneumonia Legionnaires’ disease
Explored a cave in the Americas Fever, cough, retrosternal chest pain, hilar adenopathy
Histoplasmosis
Ingestion of unpasteurized goat cheese Chronic fever, fatigue Brucella melitensis
Long trip to West/Central Africa Afebrile, intensely pruritic, evanescent truncal maculopapular rash
Onchocerciasis
Long trip to West/Central Africa Migratory localized angioedema or swellings over large joints, eosinophilia
Loiasis
Safari to game parks of East Africa Fever, nongenital chancre, fine macular rash
East African trypanosomiasis
Travel to Australia Fever, fatigue, polyarthritis Ross River virus
Farming areas of India and Southeast Asia Fever, altered mental status, paralysis Japanese encephalitis
Forested areas of central and eastern Europe and across Russia
Fever, altered mental status, paralysis Tick-borne encephalitis
495C
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EXPOSURE SCENARIO DISTINCTIVE FINDINGS DIAGNOSISRodent exposure in West Africa Fever, sore throat, jaundice,
hemorrhagic manifestationsLassa fever
Ingestion of sushi, ceviche, or raw freshwater fish
Migratory nodules in truncal areas with overlying erythema or mild hemorrhage
Gnathostomiasis
Returning Hajj pilgrim or family contact Fever, meningitis Meningococcal meningitis
Ingestion of snails, fish, or shellfish in Asia or Australia
Eosinophilic meningitis Angiostrongyliasis, gnathostomiasis
Diabetic or compromised host with exposure to moist terrain in Asia or Australia
Fever, sepsis, pneumonia or multifocal abscesses
Melioidosis
Summertime exposure to rodent droppings in Scandinavia
Fever with decreased renal function Puumala virus
Ingestion of undercooked meat of any animal in any country
Fever, facial edema, myositis, increased creatine phosphokinase, massive eosinophilia, normal erythrocyte sedimentation rate
Trichinosis
Unvaccinated, returning from sub-Saharan Africa or forested areas of Amazonia
Fever, jaundice, proteinuria, hemorrhage
Yellow fever
Exposure to farm animals Pneumonia, mild hepatitis Q fever
Possible tick exposure almost anywhere Fever, headache, rash, conjunctival injection, hepatosplenomegaly
Tick-borne relapsing fever
Poor hygienic conditions with possible body louse exposure in Ethiopia or Sudan
Fever, headache, rash, conjunctival injection, hepatosplenomegaly
Louse-borne relapsing fever
*The table includes illnesses of travelers (listed first) as well as less common diseases with presentations that should suggest the possibility of the appropriate diagnosis. Many diseases have a spectrum of presentation, and the table describes the most common presentations of these diseases. Many diseases have a spectrum of geographic origins, and the table describes the most common exposures seen in daily practice.
TABLE 241-1 Constellations of Exposures and Clinical Presentations Suggestive of Particular Diagnoses in Returned Travelers*—cont’d
496
Index
AAbacavir, for human immunodeficiency virus infection,
150t-151tAbdominal imaging techniques, in amebiasis, 413Abiotrophia, 287Abscess
brain, 84-85caused by Streptococcus anginosus group, 289epidural, 86-87intraperitoneal, peritonitis and, 42-47liver, 48lung, bacterial, 30pancreatic, 49, 50tsplenic, 54
in injection drug users, 481Acalculous cholecystitis, 48Acanthamoeba spp., 415-416Acid, hepatitis A virus and, 240Acinetobacter baumannii, 323Acinetobacter nosocomialis, 323Acinetobacter pittii, 323Acinetobacter species, 323Acquired immunodeficiency syndrome (AIDS), 138-139
histoplasmosis and, 393tuberculosis and, 365zoonoses and, 490
Acquired immunodeficiency syndrome (AIDS)-related opportunistic infections, 155
treatment of, 156t-168tActinomycetoma, 388Actinomycosis, agents of, 380Acute appendicitis, 55Acute bacterial sinusitis, 14Acute bronchitis, 22Acute diverticulitis, 56Acute exacerbations, of chronic obstructive pulmonary
disease, 23Acute fluid collection, 50tAcute illness, in HCV infection, 212Acute laryngitis, 10Acute laryngotracheobronchitis, 11Acute mediastinitis, 72
causes of, 73t
Acute meningitis, 75-77Acute necrotizing ulcerative gingivitis, antimicrobial
regimens for, 18t-19tAcute otitis media (AOM), 12Acute pancreatitis, 49, 50t
definitions derived from the International Symposium on, 50t
severe, 50tAcute pharyngitis, microbial causes of, 7tAcute pneumonia, 25-26Acute postcataract endophthalmitis, 125-126Acute poststreptococcal glomerulonephritis (APSGN)
definition of, 279diagnosis of, 279treatment of, 280
Acute pseudocyst, 50tAcute pulmonary exacerbations, in cystic fibrosis, 33, 36tAcute respiratory disease, adenoviruses and, 192Acute retinal necrosis (ARN), treatment of, 156t-168tAcute retroviral syndrome, 140
symptoms and signs of, 141tAcute rheumatic fever (ARF)
anti-inflammatory therapy for, 280, 280tdefinition of, 279diagnosis of, 279prevention of, 280, 280t
Acute simple gingivitis, antimicrobial regimens for, 18t-19t
Acute transient disease, 300Acute uncomplicated diverticulitis, 56-57Acutely ill patient, with fever and rash, 3-4Acyclovir
for HSV conjunctivitis, 123for infections
in cancer patients, 465t-466t, 467in HSCT, 471
Adefovir, for chronic hepatitis B, 200tAdenoviruses, 81t-83t, 192-193
human, 192Adiaspiromycosis, 407-408Adiaspores, 407β2-adrenergic receptor agonists, 34t-36tAdult epiglottitis, 15
clinical manifestations of, 15therapy for, 16
Adult T-cell leukemia (ATL), lymphoma type of, 235Advisory Committee on Immunization Practices, 77Aeromonas hydrophila, 318
Page numbers followed by f indicate figures and t indicate tables.
497In
dex
Aerosolized pentamidine, for infections in cancer patients, 465t-466t
Aerosolized ribavirin, for respiratory syncytial virus, 218African trypanosomiasis, 422-423Age, burn and, 486Albendazole
for cestodes, 443for giardiasis, 427tfor microsporidiosis, 412for tissue nematodes, 439
Algal blooms, harmfulillness associated with, 435, 436tsites and types of, 436f
Alkhurma hemorrhagic fever virus (AHFV), 210Allergic bronchopulmonary aspergillosis, 381Allogeneic donors, for HSCT, types of, 470Alphavirus encephalitis, 207Alphaviruses, 207-208Alveolar hemorrhage, diffuse, in HSCT, 471Amebae, free-living, 415-416Amebiasis, 413
treatment of, 414tAmebic colitis, 413
treatment of, 414tAmebic liver abscess, 48, 413
treatment of, 414tAmerican trypanosomiasis, 420-421Aminoglycoside, for bacterial keratitis, 124Aminotransferase levels, hepatic, in murine typhus,
264Amnesic shellfish poisoning, harmful algal blooms and,
436tAmoxicillin
for bites, 487for group A streptococcal pharyngitis, 9t
Amoxicillin-clavulanate, for infections in cancer patients, 465t-466t
Amphotericin Bfor entomophthoramycosis and mucormycosis, 385liposomal, for aspergillosis, 381, 384tfor Sporothrix schenckii, 386
Amphotericin B deoxycholate, for paracoccidioidomycosis, 402, 403t
Ampicillinfor bites, 487for listeriosis, 293
Anaplasma phagocytophilum, 266-267Anaplasmataceae, 266-267Ancylostoma, 437, 438tAnidulafungin, for aspergillosis, 384tAnopheles mosquito, malaria transmitted by, 417Anterior uveitis, 127, 128tAnthelmintic agents
for cestodes, 443for tissue nematodes, 439
Anthrax, 296-297, 297tAnthrax meningitis, 296Anti-HBV agents, 199Antibiotic prophylaxis, of infective endocarditis,
regimens for, 68tAntibiotic susceptibility testing, for gram-negative and
gram-variable bacilli, 350
Antibiotic therapyfor leptospirosis, 354, 355tfor melioidosis, 322tfor tularemia, 334t
Antibiotics, 34t-36tbroad-spectrum, for pneumonia, 458-459for infections, in asplenic patients, 477intravitreal, for endophthalmitis, 126for myiasis, 450for septic bursitis, 110for shigellosis, 325for tungiasis, 451for zoonoses, 490
Anticholinergics, 34t-36tAntifungal therapeutic agents, for microbial keratitis, 124Antigen detection, in Giardia lamblia, 426Antigenic variation, of African trypanosomiasis, 422Antimicrobial agents
for Capnocytophaga, 345for fever of unknown origin, 2for foodborne disease, 105guide to empirical choice of, for treating adult patients
with community-acquired pneumonia or health care-acquired pneumonia, 26t-27t
for plague, 337Antimicrobial prophylaxis, 288, 482
for Pasteurella species, 336surgical, 482, 484f-485f
Antimicrobial therapyfor bites, 487, 488t-489t, 489for CSF shunt infections, 88-89empirical, for brain abscess, 85tfor epidural abscess, 86-87for group A streptococcal pharyngitis, 9tfor microbial keratitis, 124for osteomyelitis, 112tfor Salmonella gastroenteritis, 324for suppurative intracranial thrombophlebitis, 87
Antiretroviral therapy (ART)for cryptococcosis, 390for human immunodeficiency virus infection, 149
entry inhibitors for, 154tintegrase inhibitor for, 154tnon-nucleoside reverse-transcriptase inhibitors for,
152tnucleoside and nucleotide reverse-transcriptase
inhibitors for, 150t-151tprotease inhibitors for, 152t-153t
for human immunodeficiency viruses, 236for toxoplasmosis, 425
Antistaphylococcal antibiotics, 34t-36tAntiviral chemotherapy
for herpes simplex virus infection, 180t-182tfor influenza, 229t
Antiviral drugsfor chronic hepatitis B, 133tfor influenza, 228
Antiviral therapyfor infectious mononucleosis, 187for influenza, 228for Kaposi’s sarcoma-associated herpesvirus, 189
Aphthous ulceration, esophagitis from, 99t
498In
dex
Apnea, bronchiolitis and, 24Appendicitis, 55Appendix, vermiform, 55Arenaviruses, 232-233ART. see Antiretroviral therapy (ART).Arthritis
bacterial, 108fungal, 109gonococcal, 108infectious, of native joints, 108-110
empirical therapy for, 109treactive, foodborne diseases and, 105viral, 108
Ascaris, 437-438, 438tAsialoglycoprotein receptor, 305Asian scrub typhus chiggers, larvae of, in scrub typhus,
452Aspergilloma, 381Aspergillosis, pulmonary, in human immunodeficiency
virus infection, 143Aspergillus, 59t, 381-382
characteristics of, 383tdefinition of, 381diagnosis of, 381epidemiology of, 381, 382tmicrobiology of, 381prevention of, 382therapy for, 381, 384t
Aspirin, for KD, 454Asplenic patients, infections in, 477-478Asthma, rhinovirus and, 243Astroviruses, 246Asymptomatic bacteriuria, 37
of pregnancy, 38Asymptomatic infection, of reoviruses, 203Atazanavir, for human immunodeficiency virus infection,
152t-153tAtovaquone
for Babesia microti, 429-430, 430tfor infections, in cancer patients, 465t-466tfor malaria prevention, in travelers, 491
Atropine, for hypotension/bradycardia, syndrome of, 435
Attenuated mumps virus vaccine, immunization with, 217
Atypical pneumonia, 255Avian influenza, 228Azaspiracid shellfish poisoning, harmful algal blooms
and, 436tAzithromycin
for Babesia microti, 429-430, 430tfor babesiosis, 453for chancroid, 326for conjunctivitis, 123for diarrhea, in travelers, 491for donovanosis, 348with P. aeruginosa, 34t-36tfor pertussis, 339for SFG rickettsioses, 258for trachoma, 250without P. aeruginosa, 34t-36t
Aztreonam, 34t-36t
BBabesia divergens, treatment of babesiosis from, 430tBabesia microti, 429
treatment of babesiosis from, 430tBabesia species, 429-430Babesiosis, 429
treatment of, 430t, 453Bacillary angiomatosis, from Bartonella henselae, 346Bacillary dysentery, 325Bacillary peliosis, from Bartonella henselae, 346Bacilli
gram-negative, 349-350brain abscess and, 84
gram-variable, 349-350Bacillus anthracis, 296-297
related genera to, 298Bacillus species, 298Bacteremia, 56
from Clostridium, 362in elderly, 476non-catheter-related S. maltophilia, 318-319
Bacteriawith bite infections, 487chronic pneumonia and, 31conjunctivitis from, 122encapsulated, in postsplenectomy sepsis, 477inflammatory enteritides from, 102-103mucous membrane lesions, 116noninflammatory gastroenteritis from, 100prostatitis from, 120
Bacterial arthritis, acute, 108Bacterial diseases, body lice and, 446Bacterial infection
in injection drug users, 479in solid-organ transplant recipients, 474
Bacterial lung abscess, 30Bacterial lymphadenitis, 95t-96tBacterial meningitis, Streptococcus pneumoniae in, 281Bacterial pneumonia, in human immunodeficiency virus
infection, 142Bacterial respiratory diseases, treatment of, 156t-168tBacterial sinusitis, acute, 14Bacteriuria, asymptomatic, 37
of pregnancy, 38Bacteroides, 364
brain abscess and, 84definition of, 364diagnosis of, 364epidemiology of, 364microbiology of, 364therapy for, 364, 364t
BAL. see Bronchoalveolar lavage (BAL).Balamuthia mandrillaris, 415-416Balantidiasis, therapy for, 433tBalantidium coli, 432-433Banna virus (BAV), 204Bartonella bacilliformis, 346Bartonella henselae, 346Bartonella quintana, 346Bartonella spp., 58, 59tBasidiobolomycosis, 385Basidiobolus ranarum, 385
499In
dex
Bat rabies, 226BAV. see Banna virus (BAV).Benzathine penicillin
for S. pyogenes infections, 278for syphilis, 352
Benzathine penicillin G, for group A streptococcal pharyngitis, 9t
Benznidazole, for T. cruzi, 421Benzodiazepines, for tetanus, 360Biliary tract infections, from Clostridium, 362Biliary tree, disorders of, from human immunodeficiency
virus infection, 144-145Binary toxin, from Clostridium difficile, 358Biopsy, for cutaneous warts and genital warts, 194Bioterrorism, anthrax for, 296Birds, psittacosis from, 253Bites, 487-489
dog, Capnocytophaga from, 344management of, 488t-489tPasteurella infection from, 335
BK virus (BKV), 196-197in solid-organ transplant recipients, 474
Blastocystis species, 432-433Blastocystosis, therapy for, 434tBlastomyces dermatitidis, 396Blastomycosis, 396
clinical manifestations of, 396definition of, 396diagnosis of, 396microbiology and epidemiology of, 396treatment for, 396, 397t
Bleb-related endophthalmitis, 125Blepharitis, marginal, 129Blood, donors of, transfusion- and transplantation-
transmitted infections in, 463Blood culture
for enteric fever, 104in postsplenectomy sepsis, 477
Blood films, positive peripheral, tropical diseases with, in returning travelers, 493
Blood stem cells, peripheral, in HSCT, 470Bloodstream infections, in cancer patients, 464Boceprevir, for hepatitis C virus, 136fBody lice, 446-447Bone fractures, internal fixation-associated infection and,
115Bone infection
in injection drug users, 479SCI and, 475
Bone marrow, in HSCT, 470Bone marrow cultures, for enteric fever, 104Bordetella pertussis, 339-340Borrelia afzelii, 357Borrelia burgdorferi, Lyme disease due to, 357Borrelia garinii, 357Borrelia species, relapsing fever caused by, 356Botfly furuncular myiasis, 450Botulism, 361Brain abscess, 84-85Bronchiolitis, 24
posterior, in HSCT, 471Bronchitis, acute, 22
Bronchoalveolar lavage (BAL), 458Brucella species, 59t, 328Brucellosis, 328
treatment of, 329tBullous lesions, in acutely ill patients, 3-4Bunyavirus hemorrhagic fevers, 231Burkholderia cenocepacia, 318Burkholderia cepacia, 318-319Burkholderia mallei, 320-322Burkholderia multivorans, 318Burkholderia pseudomallei, 320-322Burns, 486Bursitis, septic, 110
CCA-asymptomatic bacteriuria (CA-ASB), 460CA-UTI. see Catheter-associated urinary tract infection
(CA-UTI).Caliciviruses, 244-245California encephalitis, 231Campylobacter jejuni, and related species, 314Campylobacter spp., inflammatory enteritides from, 102Canaliculitis, 129Candida, esophagitis from, 99tCandida endophthalmitis, 125Candidiasis
esophageal, treatment of, 156t-168tmucocutaneous, treatment of, 156t-168toropharyngeal, treatment of, 156t-168tvulvovaginal, 118
treatment of, 156t-168tCapnocytophaga, 344-345Capsular polysaccharides, of Staphylococcus aureus,
270t-271tCardiac disease, from human immunodeficiency virus
infection, 140Cardiomyopathy, trypanosomiasis and, 420Cardiovascular devices, nonvalvular, infections of,
65-66Cardiovascular implantable electronic device (CIED)
infections, 65Caspofungin, for aspergillosis, 384tCat-scratch disease, 346-347Catheter-associated (CA)-bacteriuria, 460-461Catheter-associated urinary tract infection (CA-UTI),
460-461management of, 461t
Catheterization, in CA-bacteriuria, 460Catheters, infections caused by, 456-457Cats, parturient, Q fever from, 260Cefazolin, for bacterial keratitis, 124Cefepime, for infective endocarditis, in injection drug
users, 480Cefotaxime, for H. influenzae type b meningitis, 326Cefoxitin, for bites, 487Ceftazidime, for melioidosis, 322Ceftriaxone
for brucellosis, 329tfor conjunctivitis, 123for H. influenzae type b meningitis, 326for Salmonella gastroenteritis, 324
Cell infusion, preparation of patient for, 470
500In
dex
Cell wall fatty acid analysis, for gram-negative and gram-variable bacilli, 349
Cellular immunity, in rotaviruses, 206Cellulitis, 90-91Centers for Disease Control and Prevention (CDC), 75
for human immunodeficiency virus, 138, 139tCenters for Disease Control and Prevention/National
Institutes of Health consensus conference, definition of chronic fatigue syndrome, 172, 173t
Central line-associated bloodstream infections (CLABSIs), 456
Central nervous system (CNS)infection of
in elderly, 476in injection drug users, 481
mass lesions in, human immunodeficiency virus and, 146
prion diseases of, 248Cephalosporin, for Capnocytophaga, 345Cerebrospinal fluid (CSF)
of patients with N. fowleri, 415shunt and drain infections of, 88-89
Cervicitis, 118from Chlamydia trachomatis, clinical characteristics of,
251t-252tCervicofacial actinomycosis, initial empirical
antimicrobial regimens for, 20t-21tCestodes, 443-444, 444tCFS. see Chronic fatigue syndrome (CFS).Chagas’ disease, 420-421Chalazion, 129Chancroid, 326-327Chemicals, causing foodborne illnesses, 105Chemoprophylaxis
for acute meningitis, 76-77for influenza, 229tfor Neisseria meningitidis, 303, 303t
Chickenpox, 183-184Chiggers, mites and, 452Chikungunya virus, 81t-83tChildren
croup in, 11cryptosporidiosis in, 431human immunodeficiency virus infection in, 147KD in, 454visceral larva migrans in, 445
Chlamydia pneumoniae, 254Chlamydia psittaci, 59t, 253Chlamydia trachomatis, 249-250
clinical characteristics of, 251t-252tepididymitis from, 120urethritis from, 117
Chlamydial conjunctivitis, neonatal, 123Chlamydial lymphadenitis, 95t-96tChloramphenicol
for louse-borne typhus, 262for murine typhus, 264for Rocky Mountain spotted fever, 258
Cholangitis, 48Cholecystitis, 48Cholera, caused by Vibrio cholerae, 308Chorioretinitis, 125, 425
Chromoblastomycosis, 387Chronic airway infection, 33Chronic airway inflammation, 33Chronic fatigue syndrome (CFS), 172
CDC/NIH consensus conference definition of, 172, 173t
proposed infectious causes of, 173tChronic fibrocavitary pneumonia, 399Chronic hepatitis B, 198
approved agents for treatment of, 200tChronic infection, with hepatitis C, 212Chronic infectious arthritis, 109Chronic mediastinitis, 72Chronic obstructive pulmonary disease (COPD)
acute exacerbations of, 23Haemophilus influenzae and, 326Moraxella catarrhalis causing, 307
Chronic pneumonia, 31-32Chronic postcataract endophthalmitis, 125Chronic prostatitis/chronic pelvic pain syndrome (CP/
CPPS), 120Chronic pulmonary therapies, for patients with cystic
fibrosis, 34t-36tCIED infections. see Cardiovascular implantable
electronic device (CIED) infections.Cierny and Mader classification, of osteomyelitis, 111Ciguatera fish poisoning, harmful algal blooms and, 436tCiprofloxacin
for bites, 487for Cyclospora and Cystoisospora, 432, 433tfor infections, in cancer patients, 465t-466tfor tularemia, 334t
Cirrhosis, HCV-associated, 134Citrobacter spp., 316Cladophialophora carrionii, 387Clarithromycin
for pertussis, 339for SFG rickettsioses, 258
Clindamycinfor Babesia microti, 429, 430tfor babesiosis, 453for bites, 487for S. pyogenes infections, 278
Clonorchis sinensis, 441t-442tClostridial myonecrosis, 92, 362Clostridium difficile infection, 358-359
definition of, 358diagnosis of, 358epidemiology of, 358microbiology of, 358prevention of, 359therapy for, 358-359
Clostridium perfringensand clostridial myonecrosis, 362food poisoning by, 362myonecrosis from, 92toxins produced by, 363t
Clostridium spp.characteristics of, 362, 363tother diseases associated with, 362
Clostridium tetani, 360CMV. see Cytomegalovirus (CMV).
501In
dex
CMV colitis, treatment of, 156t-168tCMV esophagitis, treatment of, 156t-168tCMV retinitis, treatment of, 156t-168tCoagulase-negative staphylococci, 275-276Cobicistat, for human immunodeficiency virus infection,
150t-151tCoccidioides immitis, 398Coccidioidomycosis, 398-399
diagnosis of, 398epidemiology of, 398in human immunodeficiency virus infection, 143microbiology of, 398prevention of, 399prophylaxis of, 168t-171ttherapy for, 399treatment of, 156t-168t
Colchicine, with NSAIDs, for pericarditis, 70Cold
common, 5rhinovirus and, 243
Colonoscopy, in amebiasis, 413Colorado tick fever virus (CTFV), 204Coltiviruses, 204Common cold, 5Common respiratory pathogens, frequency of laryngitis
associated with, 10tCommunity, MRSA from, 268Community-acquired CoV infections, 215Community-acquired pneumonia, guide to empirical
choice of antimicrobial agent for treating adult patients with, 26t-27t
Complement-fixing anticoccidioidal antibodies, 399Complicated diverticulitis, 56Computed tomography (CT)
for brain abscess, 85for empyema, 28
Comvax, 201tCondom
for gonorrhea prevention, 306urethritis and, 117
Confirmatory assay, for human immunodeficiency virus, 138-139, 139t
Congenital asplenia, patients with, infections in, 477Congenital rubella, 209Conidiobolomycosis, 385Conidiobolus coronatus, 385Conidiobolus incongruus, 385Conjunctivitis
from Chlamydia trachomatis, clinical characteristics of, 251t-252t
microbial, 122-123Contact lens, keratitis and, 124Contamination, of food, 105Continuous ambulatory peritoneal dialysis (CAPD),
polymicrobial peritonitis in, 44Continuous ambulatory peritoneal dialysis (CAPD)
peritonitis, 42, 44, 47indications for catheter removal, 47t
Convalescent human plasma, for arenaviruses, 232Cornea, inflammatory condition of, 124Coronary artery aneurysm, KD and, 454Coronaviruses (CoVs), 215
Corticosteroids, 34t-36tfor cestodes, 443for infectious mononucleosis, 187for tissue nematodes, 439for toxoplasmosis, 425
Corynebacterium diphtheriae, 290-291Corynebacterium ulcerans, 290Corynebacterium urealyticum, 292Coryneform bacteria, 292Cough, Bordetella pertussis and, 339CoVs. see Coronaviruses (CoVs).Coxiella burnetii, 59t, 260-261Coxsackieviruses, 238Craniotomy, for subdural empyema, 86-87Croup, in children, 11Crusted, 448-449Cryptococcal meningitis, treatment of, 156t-168tCryptococcosis, 390-392
clinical manifestations of, 391, 392tcomplications of, 392conditions associated with, 391tepidemiology of, 390history of, 390laboratory diagnosis for, 391management of, 391-392pathogenesis of, 391risk factors for, 390treatment of, 156t-168t
Cryptococcus gattii, 390-392Cryptococcus neoformans, 390-392Cryptosporidiosis, 431Cryptosporidium species, 431CTFV. see Colorado tick fever virus (CTFV).Culture
from cerebrospinal fluid shunt, 88for herpes B virus, 190for management of bite wounds, 488t-489t
Culture-negative endocarditis, causes of, 59tCutaneous anthrax, 296Cutaneous disease, from human immunodeficiency virus
infection, 140Cutaneous leishmaniasis, 419Cutaneous warts, 194Cyclospora cayetanensis, 432-433Cyclosporiasis, therapy for, 433tCystic fibrosis (CF), 33-36
caused by Burkholderia species, 318chronic pulmonary therapies for patients with, 34t-36t
Cystitis, hemorrhagic, in HSCT, 471Cystoisospora (Isospora) belli, 432-433Cystoisosporiasis, therapy for, 433tCysts, thick-walled, from Rhinosporidium seeberi, 409Cytomegalovirus (CMV), 185
esophagitis from, 99tin solid-organ transplant recipients, 474
Cytomegalovirus (CMV) disease, treatment of, 156t-168tCytotoxins, of Staphylococcus aureus, 270t-271t
DDacryoadenitis, 129Dacryocystitis, 129Dapsone, for infections, in cancer patients, 465t-466t
502In
dex
Daptomycin, 284Dark-walled fungi, 405Darkfield microscopy, for treponemes, 351Darunavir, for human immunodeficiency virus infection,
152t-153tDébridement
for management of bite wounds, 488t-489tfor necrotizing infections, 91
Decontamination, for prevention of norovirus infection, 245
Definitive antibiotic therapy, for infections, in asplenic patients, 477
Delavirdine, for human immunodeficiency virus infection, 152t
Deltavirus, 134Dengue, 210Dermatophytosis, 400
definition of, 400diagnosis of, 400epidemiology of, 400microbiology of, 400prevention of, 400therapy for, 400, 401t
Dermoscopy, in lice, 446Desquamative inflammatory vaginitis, 118Detergents, hepatitis A virus and, 240Dexamethasone, for H. influenzae type b meningitis, 326Diabetes mellitus, osteomyelitis and, 112Diagnostic laboratory testing, for poxviruses, 178Dialysis, in hepatitis, 462Diarrhea
caused by Campylobacter spp., 314cryptosporidiosis in, 431enteropathy and, 107Giardia lamblia in, 426microsporidiosis and, 412noninflammatory, with nausea and vomiting, 100-101in travelers, 491
Diarrhetic shellfish poisoning, harmful algal blooms and, 436t
Didanosine, for human immunodeficiency virus infection, 150t-151t
Diethylcarbamazine, for tissue nematodes, 439Diffuse alveolar hemorrhage, in HSCT, 471Diloxanide furoate, for amebiasis, 414tDiphtheria, 290-291Diphtheria antitoxin (DAT), 290Diphtheroids, in CSF shunt infections, 88Diphyllobothrium latum, 443, 444tDisseminated disease, with human immunodeficiency
virus (HIV) infection, 373Disseminated Mycobacterium avium complex (MAC)
disease, 373prophylaxis of, 168t-171ttreatment of, 156t-168t
Diverticulitis, 56-57Dog bite, Capnocytophaga from, 344Dolutegravir, for human immunodeficiency virus
infection, 150t-151t, 154tDonors, transfusion- and transplantation-transmitted
infections in, 463“Donovan bodies,” 348
Donovanosis, 348Dornase alfa, 34t-36tDoxycycline
for Anaplasmataceae infection, 267for Bartonella infection, 347for bites, 487chemoprophylaxis with, for leptospirosis, 354for louse-borne typhus, 262for lymphogranuloma venereum, 250for malaria prevention, in travelers, 491for murine typhus, 264for plague, 337for Q fever, 261for rickettsialpox, 259for Rocky Mountain spotted fever, 258for scrub typhus, 265
and rickettsialpox, 452with streptomycin, for brucellosis, 328, 329tfor syphilis, 352for ticks, 453for tularemia, 334t
Dracunculiasis, 439Drain infections, of cerebrospinal fluid, 88-89Drainage, infections of, in injection drug users, 479Drug users, injection of, infections in, 479-481Drugs, toxicity of, for HAT, 423DTaP, for pertussis, 340Duodenal biopsy, for Whipple’s disease, 300Dysenteric syndromes, acute, 102Dysentery, bacillary, 325
EEbola hemorrhagic fevers, 227Ebola viral diseases, 227EBV. see Epstein-Barr virus (EBV).Echinocandins, for infections, in HSCT, 471Echinococcosis, 443Echinococcus granulosus, 443, 444tEchinococcus multilocularis, 443, 444tEchoviruses, 238Efavirenz, for human immunodeficiency virus infection,
150t-151tEhrlichia chaffeensis, 266-267Ehrlichia ewingii, 266Ehrlichia muris, 266Elderly, infections in, 476Elevation, for management of bite wounds, 488t-489tElvitegravir, for human immunodeficiency virus
infection, 150t-151tEmmonsia pasteuriana, 408Empirical antibiotic therapy, 41t
for infections, in asplenic patients, 477Empirical antifungal therapy, for febrile neutropenia, 469Empirical regimens, for bites, 489Empirical therapy, for suspected tuberculous meningitis,
78Empyema, 28
source of, 28subdural, 86-87
Emtricitabine, for human immunodeficiency virus infection, 150t-151t
Encapsulated bacteria, in asplenic patients, 477
503In
dex
Encephalitic disease, African trypanosomiasis and, 422Encephalitic rabies, 225Encephalitis, 80
alphavirus, 207comparison of encephalopathy and, 81tToxoplasma gondii
prophylaxis of, 168t-171ttreatment of, 156t-168t
Encephalopathy, comparison of encephalitis and, 81tEndemic treponematoses, 353Endocarditis, 58-59
Bartonella, 346caused by S. gallolyticus group, 284causes of culture-negative, 59tin elderly, 476infective
in injection drug users, 480preexisting cardiac conditions associated with, 68tprevention of, 67prophylaxis of, 67regimens for antibiotic prophylaxis of, 68t
prosthetic valve, 63-64caused by staphylococci, therapy for, 64tindications for consideration of surgical
intervention, 64tsummary of treatment options for, 60t-62t
Endocrine abnormalities, from human immunodeficiency virus infection, 140
Endogenous bacterial endophthalmitis, 125Endophthalmitis, 125-126
categories of, 126tEnfuvirtide, for human immunodeficiency virus
infection, 154tEngerix-B, 201tEngraftment syndrome, in HSCT, 471Entamoeba histolytica, amebiasis and, 413Entamoeba species, including amebic colitis, liver abscess
and, 413, 414tEntecavir
for chronic hepatitis B, 200tfor hepatitis B virus, 132for infections, in HSCT, 471
Enteric fever, 104Enteritides, bacterial inflammatory, 102-103Enterobacteriaceae, 316
prostatitis from, 120Enterobius, 437, 438tEnterococcus faecalis, 283Enterococcus faecium, 283Enterococcus species, 283-284Enterocolitis
from human immunodeficiency virus infection, 145tneutropenic, 56
Enteropathy, 107HIV-associated, 145
Enteroviruses, 75-76Entomophthoramycosis, agents of, 385Entry inhibitors, for human immunodeficiency virus
infection, 154tEnzymes, of Staphylococcus aureus, 270t-271tEosinophilia, in returning travelers, 493Epidemic keratoconjunctivitis, 192
Epidermophyton, 400Epididymitis, 120
from Chlamydia trachomatis, clinical characteristics of, 251t-252t
Epidural abscess, 86-87Epiglottitis, 15-16
empirical therapy for, 16Epstein-Barr virus (EBV), 186-187Ertapenem, for bites, 489Erysipelas, 90Erysipeloid, 299Erysipelothrix rhusiopathiae, 299Erythromycin, 314
for chlamydial conjunctivitis, 123for group A streptococcal pharyngitis, 9tfor pertussis, 339
Eschar, vesicular fever with, 259Escherichia coli, 316
enteroinvasive, 325inflammatory enteritides from, 102urinary tract infections and, 37-38
Esophageal candidiasis, treatment of, 156t-168tEsophageal perforation, acute mediastinitis and, 73tEsophageal rupture, 72Esophagitis, 98
in herpes simplex virus, 180treatment of, 99t
Esophagusdisorders of, from human immunodeficiency virus
infection, 144inflammation of, 98
Ethambutol, for tuberculosis, 369t-370tEumycetoma, 388Exanthem subitum, 188Excretory urography, 38Extensively drug-resistant tuberculosis (XDR-TB), 365Extragenital lesions, in herpes simplex virus, 179Eye infections, 122-123Eyedrops, for conjunctivitis, 123Eyelid
infections of, 129inner, inflammation of, 122
FFasciitis, necrotizing, 90-91Fasciola hepatica, 441t-442tFasciolopsis buski, 441t-442tFebrile neutropenia, management of, 467-469, 467f-468fFecal microbiota transplant, for Clostridium difficile
infections, 359Fecal-oral transmission, of adenoviruses, 192Female genital tract infections, from Clostridium, 362Female jigger flea, gravid, 451Fever
acutely ill patient with, 3-4enteric, 104Pontiac, 342-343rat-bite, 341relapsing, caused by Borrelia species, 356tropical, evaluation of, in returning travelers, 493,
494t-495tFever/arthralgia/rash syndrome, 207
504In
dex
Fever of unknown origin (FUO), 2from Bartonella henselae, 346definition of, 2diagnosis of, 2etiology and epidemiology of, 2prognosis of, 2therapy of, 2
Fibrinolytic therapy, for pleural effusion and empyema, 28
Fibrosing mediastinitis, 72Fidaxomicin, for Clostridium difficile infections, 359Filariasis, 439Filoviruses, 227First-generation cephalosporins, for group A
streptococcal pharyngitis, 9tFish, harmful algal blooms in, 435Flaviviruses, 210-211Fleas, murine typhus from, 264Flies, Francisella tularensis from, 330Fluconazole, for infections
in cancer patients, 464, 465t-466tin HSCT, 471
Flukes. see Trematodes.Fluorescent antibody assay, indirect, for scrub typhus,
265Fluorescent in situ hybridization, for Coxiella burnetii,
260Fluoroquinolones
for atypical pneumonia, 255for Salmonella gastroenteritis, 324
Flying fox, 222Flying squirrels, Rickettsia prowazekii in, 262Folate, for enteropathy, 107Folliculitis, 90Follow-up, for management of bite wounds, 488t-489tFonsecaea monophora, 387Fonsecaea nubica, 387Fonsecaea pedrosoi, 387Food poisoning, 298
due to Clostridium perfringens, 362Foodborne botulism, 361Foodborne disease, 105-106Foodborne trematodes, 440-441Foreign bodies, swallowed, acute mediastinitis and,
73tFosamprenavir, for human immunodeficiency virus
infection, 152t-153tFoscarnet
for human herpesvirus types 6 and 7, 188for infections, in HSCT, 471
Fracture, open, contaminated, osteomyelitis after, 111Francisella tularensis, 330-333
characterization of, 331tsubspecies of, 330, 331t
Free-living amebae, 415-416Fruit bat, Pteropus species of, 222Fulminant hepatitis, due to HCV infection, 212Fulminant meningoencephalitis, N. fowleri and, 415Fumagillin, for microsporidiosis, 412Fungal arthritides, 109Fungal infections, in solid-organ transplant recipients,
474
Fungal pneumonia, in human immunodeficiency virus infection, 143
Fungemia, 56Fungi
brain abscess and, 84chronic pneumonia and, 31mucous membrane lesions, 116noncandidal, 59t
Furazolidone, for giardiasis, 427tFuruncular myiasis, 450Fusarium spp., 405Fusobacterium necrophorum, pharyngitis and, 6Fusobacterium species, 364
definition of, 364diagnosis of, 364epidemiology of, 364microbiology of, 364therapy for, 364, 364t
GGalactomannan, 381Gallbladder, disorders of, from human
immunodeficiency virus infection, 144-145Ganciclovir
for cytomegalovirus infection, 185for human herpesvirus types 6 and 7, 188for infections, in HSCT, 471
Gangrenous stomatitis (noma), antimicrobial regimens for, 18t-19t
Gas gangrene, 362and Clostridium perfringens, 362
Gastric cancer, risk of, 315Gastric Helicobacter species, 315Gastroenteritis
from astroviruses, 246due to rotaviruses, 205noninflammatory, 100from noroviruses, 244from Salmonella, 324
Gastroesophageal reflux disease, esophagitis from, 98Gastrointestinal anthrax, 296Gastrointestinal problems, trypanosomiasis and, 420Gemella, 287Genital infections, chlamydial, 249-250Genital mycoplasmas, 256Genital (or mucosal) HPV infections, 194Genital skin, lesions of, 116Genital ulcers, caused by syphilis, 351Genome
of hepatitis C virus, 213fof rotaviruses, 205
Gentamicinfor listeriosis, 293for plague, 337for tularemia, 331, 334t
German measles, 209Giardia lamblia, 426-427Giardiasis, 426
prevention of, 427treatment of, 427t
Giemsa-stained blood smears, for malaria, 417Gingivostomatitis, in herpes simplex virus, 179
505In
dex
Glanders, 320-322Glaucomys volans, 262Glomerulonephritis
nonsuppurative poststreptococcal sequelae of, 279-280
from Streptococcus pyogenes, 277Glucocorticoids, for croup, 216Glucose nonfermenting gram-negative bacilli, 349Glycoconjugate vaccine, for group B streptococci, 285Gonorrhea, 305-306Graft-versus-host disease (GVHD), in HSCT, 470-471Gram-negative bacilli, 349-350
acute bacterial arthritis from, 108Gram-negative bacteria, peritonitis and intraperitoneal
abscesses and, 44Gram-negative cocci, 307Gram-negative species, in CSF shunt infections, 88Gram-positive organisms, acute bacterial arthritis from,
108Gram-positive spore-forming bacilli, 298Gram-variable bacilli, 349-350Granulicatella, 287Granuloma inguinale, 348Granulomatous amebic encephalitis (GAE), 415Gravid female jigger flea, 451Gravid ticks, 453Group A streptococcal pharyngitis
antimicrobial therapy for, 9tclinical and epidemiologic findings associated with,
8tsigns and symptoms of, 6
Group A Streptococcus (GAS), 6Group B Streptococcus (GBS), 76, 285Groups C and G streptococci, 287-288Growth factors, for infections, in cancer patients,
465t-466tGuillain-Barré syndrome, foodborne diseases and,
105
HHACEK spp., 59tHAdVs. see Human adenoviruses (HAdVs).Haemophilus ducreyi, 326-327Haemophilus influenzae, 326-327Haemophilus species, 326-327Hand hygiene, 299Handwashing
human parechoviruses and, 239for prevention of norovirus infection, 245
Hantavirus pulmonary syndrome, 231HAT. see Human African trypanosomiasis (HAT).HAV. see Hepatitis A virus (HAV).HBoVs. see Human bocaparvoviruses (HBoVs).HBV. see Hepatitis B virus (HBV).HCMV. see Human cytomegalovirus (HCMV).HCV. see Hepatitis C virus (HCV).HDV. see Hepatitis D virus (HDV).Head, infections of, 17-18
initial empirical antimicrobial regimens for suppurative, 20t-21t
Head lice, 446-447Health care, MRSA from, 268
Health care-acquired hepatitis, 462Health care-acquired pneumonia
antibiotic treatment for, 26guide to empirical choice of antimicrobial agent for
treating adult patients with, 26t-27tHealth care-associated intra-abdominal infections,
42Health care workers (HCWs), hepatitis in, 462Heat, hepatitis A virus and, 240Helicobacter pylori, 315Helminth infections, 445Helminthic lymphadenitis, 95t-96tHematogenous osteomyelitis, acute, 112Hematopoietic stem cell transplantation (HSCT)
cell infusion in, preparation of, 470cells used in, types of, 470complications of, 471donors of, types of, 470outcomes of, 470prophylaxis of, antimicrobial agents for, 471, 472trecipients of
infections in, 470-473viral diseases in, 472-473
Hemolymphatic disease, African trypanosomiasis and, 422
β-hemolytic streptococci, 285Hemorrhagic cystitis, in HSCT, 471Hemorrhagic fever, evaluation of, in returning travelers,
493Hendra virus, 81t-83t, 222Hendra virus subunit vaccine, 223Hepacivirus, 134Hepadnavirus, 130Hepatitis, 130-137
acute, 130chronic, 130diagnostic approach for, 131tHAV, 130HBV, 130-134HCV, 134-136, 135f-136f, 137tHDV, 134health care-acquired, 462HEV, 136-137in injection drug users, 480-481viruses causing, 130-137, 131t
Hepatitis A virus (HAV), 130, 240-241infection, prophylaxis of, 168t-171tpostexposure prophylaxis for, 242tvaccine for, 241t
Hepatitis B vaccines, doses and schedules of, 201tHepatitis B virus (HBV), 130-134, 198-199, 462
chronic, 198diagnosis of, 131, 132tepidemiology of, 130global seroprevalence rates and modes of transmission
of, 199tinfection, prophylaxis of, 168t-171tinterpretation of serologic tests in, 199tprevention of, 134replication of, 198treatment of, 131-134, 132t-133tvirology of, 130
506In
dex
Hepatitis C virus (HCV), 134-136, 212-214, 462genome and viral polyprotein organization of, 213ftreatment-naïve patients in, 213ttreatment of, 135f-136f, 137t
Hepatitis D virus (HDV), 134, 198-199Hepatitis E virus (HEV), 136-137, 247Hepatovirus, 130Hepevirus, 136-137, 247Heptavalent botulinum antitoxin, 361Herpes B virus, 190
postexposure prophylaxis for, 191tHerpes labialis, in herpes simplex virus, 179Herpes simplex encephalitis, 180Herpes simplex virus (HSV), 179-180
esophagitis from, 99tinfection, therapy for, 116
Herpes simplex virus (HSV)-1, 179Herpes simplex virus (HSV)-2, 179Herpes simplex virus (HSV) disease, treatment of,
156t-168tHerpes zoster, 183-184
treatment of, 156t-168tHeterophile antibodies, in infectious mononucleosis, 186Heterophyes heterophyes, 441t-442tHEV. see Hepatitis E virus (HEV).HGA. see Human granulocytotropic anaplasmosis
(HGA).HHV-8. see Human herpesvirus 8 (HHV-8).High-dose intravenous immune globulin, for KD, 454Higher-order bacteria, chronic pneumonia and, 31Histoplasma capsulatum, 393-394
infection, prophylaxis of, 168t-171tHistoplasmosis, 393-394
definition of, 393diagnosis of, 393, 394tepidemiology of, 393in human immunodeficiency virus infection, 143microbiology of, 393prevention of, 394therapy for, 393, 395ttreatment of, 156t-168t
History, for management of bite wounds, 488t-489tHIV. see Human immunodeficiency virus (HIV).HME. see Human monocytotropic ehrlichiosis (HME).hMPV. see Human metapneumovirus (hMPV).Hookworms, 437-438, 438tHordeolum, 129Hospitalization, for management of bite wounds,
488t-489tHost defenses, infections of, in injection drug users, 479House mouse mites, in rickettsialpox, 452HPeVs. see Human parechoviruses (HPeVs).HPV. see Human papillomavirus (HPV).HSV. see Herpes simplex virus (HSV).HTIG. see Human tetanus immune globulin (HTIG).HTLV. see Human T-lymphotropic virus (HTLV).HTLV antibodies, 234HTLV-associated myelopathy (HAM), therapy for, 235Human adenoviruses (HAdVs), 192Human African trypanosomiasis (HAT), 422-423Human bocaparvoviruses (HBoVs), 202
infections of, 202
Human botulinum immune globulin (BabyBIG), 361Human cowpox virus infection, 176Human cytomegalovirus (HCMV), 185Human granulocytotropic anaplasmosis (HGA), 266-267Human herpesvirus
type 6, 188type 7, 188
Human herpesvirus 8 (HHV-8), 189Human immunodeficiency virus (HIV), 81t-83t, 236
cryptosporidiosis in, 431infected patients, with disseminated disease, 373patient with, PCP and, 410and Penicillium marneffei, 407type 1, neurologic diseases caused by, 146zoonoses and, 490
Human immunodeficiency virus (HIV) infection, 138-139
antiretroviral therapy for, 149entry inhibitors for, 154tintegrase inhibitor for, 154tnon-nucleoside reverse-transcriptase inhibitors for,
152tnucleoside and nucleotide reverse-transcriptase
inhibitors for, 150t-151tprotease inhibitors for, 152t-153t
clinical manifestations of, 140gastrointestinal manifestations of, 144-145, 145thepatobiliary manifestations of, 144-145in injection drug users, 481management of opportunistic infections associated
with, 155-156pancreatic manifestations of, 144-145pediatric, 147-148primary, EBV and, 186pulmonary manifestations of, 142-143, 143ttoxoplasmosis and, 424Trichomonas vaginalis and, 428
Human metapneumovirus (hMPV), 219Human monocytotropic ehrlichiosis (HME), 266-267Human or animal bites, initial empirical antimicrobial
regimens for, 20t-21tHuman papillomavirus (HPV), 194
and human immunodeficiency virus infection, 145two main groups of, 194
Human parechoviruses (HPeVs), 239Human parvoviruses, 202Human T-lymphotropic virus (HTLV), 234-235Human T-lymphotropic virus (HTLV)-1, 234Human T-lymphotropic virus (HTLV)-2, 234Human tetanus immune globulin (HTIG), 360Humoral immunity, in rotaviruses, 206Hydrocephalus, from cryptococcosis, 392Hygiene, conjunctivitis and, 123Hymenolepis nana, 443, 444tHypertonic saline aerosols, for bronchiolitis, 24Hypochlorite, hepatitis A virus and, 240Hypopyon, in endophthalmitis, 125
IIbuprofen, 34t-36tIgM antibodies, of arenaviruses, 232IgM viral capsid antigen (VCA) antibodies, 186
507In
dex
Immobilization, for management of bite wounds, 488t-489t
Immune reconstitution, of JC virus, 196Immune reconstitution syndrome
from cryptococcosis, 392from human immunodeficiency virus infection, 140
Immunity, of rotaviruses, 206Immunization
in elderly, 476with live, attenuated mumps virus vaccine, 217for management of bite wounds, 488t-489tfor opportunistic infections associated with human
immunodeficiency virus infection, 155-156for pertussis, 340for rotaviruses, 206for travelers, 491
Immunodiffusion, 399Immunofluorescence assay
indirect, for Rocky Mountain spotted fever, 257for murine typhus, 264of respiratory secretions, 219
Immunofluorescent serologic test, indirect, for Q fever, 260
Immunoglobulin G (IgG)passive immunization with, in measles, 221positive, toxoplasmosis and, 424
Immunoglobulin M (IgM), positive test results of, in toxoplasmosis, 424
Immunoglobulins, for infections, in cancer patients, 465t-466t, 467
Immunohistochemical detectionof Rickettsia prowazekii, 262of Rickettsia typhi, 264of SFG rickettsiae, 257
Immunosuppression, reduction in, in BK virus, 197Impetigo, 90Implant, orthopedic, infections associated with, 113-115Inactivated vaccines
for influenza, 228of poliovirus, 237
Incision, infections of, in injection drug users, 479Indinavir, for human immunodeficiency virus infection,
152t-153tInfant botulism, 361Infants, amebiasis in, 413Infected embryologic cysts, initial empirical
antimicrobial regimens for, 20t-21tInfections
see also specific infectionin asplenic patients, 477-478in cancer patients, 464-469
epidemiology and etiology of, 464prophylaxis of, 464-467, 465t-466trisk factors for, 464, 469t
cardiovascular implantable electronic device, 65caused by nontuberculous mycobacteria, 375-377
definition of, 375diagnosis of, 376epidemiology of, 375microbiology of, 375-376prevention of, 377therapy for, 376-377
caused by P. aeruginosa, 317in elderly, 476head and neck, acute mediastinitis and, 73thuman immunodeficiency virus, 236human metapneumovirus, 219in injection drug users, 479-481internal fixation-associated, 113-115intravascular, 58-59left ventricular assist device, 65of liver and biliary system, 48of nonvalvular cardiovascular devices, 65-66of oral cavity, neck, and head, 17-18orthopedic implant-associated, 113-115pancreatic, 49
incidence and mortality rate in controlled trials with antibiotics and meta-analyses, 51t-53t
in patients with spinal cord injury, 475of pelvis, female, 119periprosthetic joint, 113, 114fprosthetic vascular graft, 65-66rate of, administration and, timing of, 485fin recipients of hematopoietic stem cell transplants,
470-473in returning travelers, 493, 494t-495tfrom rhinovirus, 243rotaviruses, 205-206shunt and drain, of cerebrospinal fluid, 88-89in solid-organ transplant recipients, 474of subcutaneous tissue, 90-91in surgical site, 482transfusion- and transplantation-transmitted, 463uncomplicated, 42urinary tract, 37-38
recommendations for initial therapy of, 39tInfectious arthritis, of native joints, 108-110
empirical therapy for, 109tInfectious mononucleosis, 186Infective endocarditis, 58
preexisting cardiac conditions associated with, 68tprevention of, 67prophylaxis of, 67regimens for antibiotic prophylaxis of, 68t
Infective peritonitis, 42Inflammation, pelvic, in female, 119Inflammatory enteritides, bacterial, 102-103Influenza, 81t-83t, 228Influenza A, prophylaxis of, 168t-171tInfluenza B, prophylaxis of, 168t-171tInfluenza vaccines, 228, 230tInfluenza viruses, 228Inhalational anthrax, 296Inhaled hypertonic saline, 34t-36tInjection drug users, infections in, 479-481Integrase inhibitor, for human immunodeficiency virus
infection, 154tInterferon-γ release assays, 365-366Intermediate uveitis, 127, 128tInternal fixation, infection associated with, 113-115
clinical manifestations of, 115diagnosis of, 113-114microbiology in, 114
Infections (Continued)
508In
dex
pathogenesis of, 114treatment of, 115
Intestinal flukes, 440-441features of, 441t-442t
Intestinal nematodes, 437-438, 438tIntra-abdominal infections, complicated
organisms causing, 44trecommended agents for treatment of, 45t
Intraepithelial neoplasia, human papillomavirus and, 194
Intramuscular regimens, for group A streptococcal pharyngitis, 9t
Intrapartum antibiotic prophylaxis, for group B streptococci, 285, 286t
Intraperitoneal abscesses, 42-47Intravascular devices, percutaneous, infections caused by,
456-457Intravascular infections, 58-59Intravenous acyclovir, for herpes B virus, 190Intravenous catheters, infections caused by, 456Intravenous gamma globulin, for human
metapneumovirus, 219Intravenous ganciclovir, for herpes B virus, 190Intravenous immunoglobulin
for chronic anemia or pure red aplasia, 202for parainfluenza virus, 216
Intravenous pyelography, 38Invasive fungal diseases (IFDs), in cancer patients, 464Iodoquinol
for balantidiasis, 433tfor blastocystosis, 434t
Irrigation, for management of bite wounds, 488t-489tIrritable bowel syndrome, foodborne diseases and, 105Isolation procedures, for infections, in cancer patients,
465t-466tIsoniazid
for infections, in cancer patients, 465t-466tfor tuberculosis, 366, 369t-370t
Itraconazolefor aspergillosis, 384tfor chromoblastomycosis, 387for paracoccidioidomycosis, 402, 403tfor Penicillium marneffei infections, 407for Sporothrix schenckii, 386
Ivacaftor, 34t-36tIvermectin
for infections, in HSCT, 471for lice, 446for scabies, 448for tissue nematodes, 439
Ixodes ricinus, 357
JJapanese encephalitis, 81t-83tJapanese encephalitis (JE) virus, 210Jarisch-Herxheimer reactions, in relapsing fever, 356JC virus infections, treatment of, 156t-168tJC virus (JCV), 81t-83t, 196JCV. see JC virus (JCV).JE virus, 210Jigger flea, gravid female, 451
Joint infections, in injection drug users, 479Joints, native, infectious arthritis of, 108-110
empirical therapy for, 109tJones criteria, 279
KKaposi sarcoma, pulmonary, in human
immunodeficiency virus infection, 143Kaposi’s sarcoma-associated herpesvirus (KSHV), 189Kawasaki disease (KD), 454KD. see Kawasaki disease (KD).Keratitis
associated with viral conjunctivitis, 123microbial, 124
Keratoconjunctivitis, microsporidiosis and, 412Ketoconazole, for paracoccidioidomycosis, 403tKFDV. see Kyasanur Forest disease virus (KFDV).Kidney, impaired function of, foodborne diseases and,
105Killed vaccine, for vesicular stomatitis virus, 224Kingella kingae, 307Klebsiella granulomatis, 348Klebsiella pneumoniae, 48Klebsiella spp., 316KSHV. see Kaposi’s sarcoma-associated herpesvirus
(KSHV).Kyasanur Forest disease virus (KFDV), 210
LLacazia loboi, 407Lacrimal system, infections of, 129β-lactam, for anthrax, 296-297, 297tβ-lactam antibiotics
for S. pneumoniae, 282for Streptococcus anginosus group, 289
Lagomorphs, Francisella tularensis from, 330Lamivudine
for chronic hepatitis B, 200tfor human immunodeficiency virus infection,
150t-151tfor infections
in cancer patients, 465t-466t, 467in HSCT, 471
Large intestine, disorders of, from human immunodeficiency virus infection, 145
Laryngitisacute, 10frequency of, associated with common respiratory
pathogens, 10tLaryngotracheobronchitis, acute, 11Lassa fever, 232-233Latency, in herpes simplex virus, 179Lateral pharyngeal or retropharyngeal space infections,
initial empirical antimicrobial regimens for, 20t-21t
LCMV. see Lymphocytic choriomeningitis virus (LCMV).Left ventricular assist device (LVAD) infections, 65Legionella spp., 59t, 342Legionellosis, 342Legionnaires’ disease, 342-343Leishmania species, 419Leishmaniasis, 419
Internal fixation, infection associated with (Continued)
509In
dex
Leprosy, 371-372clinical manifestations and immunologic spectrum of,
371diagnosis of, 371-372therapy for, 372, 372t
Leptospira species, 354, 355tdefinition of, 354diagnosis of, 354epidemiology of, 354microbiology of, 354prevention of, 354therapy of, 354, 355t
Leptospirosis, 354definition of, 354diagnosis of, 354epidemiology of, 354microbiology of, 354prevention of, 354in returning travelers, 493therapy of, 354, 355t
Lesions, of genital skin and mucous membrane, 116Leuconostoc species, 283-284Leukoencephalopathy, progressive multifocal
human immunodeficiency virus and, 146treatment of, 156t-168t
Leukotriene modifiers, 34t-36tLevofloxacin
for infectionsin cancer patients, 465t-466tin HSCT, 471
for plague, 337Lew and Waldvogel classification, of osteomyelitis, 111LGV. see Lymphogranuloma venereum (LGV).Lice, 446-447Linezolid, 284
for pneumonia, 458-459Listeria monocytogenes, 293-294Listeriosis
clinical settings for, 293, 294tfood safety recommendations for, 294, 295t
Live-attenuated measles vaccine, 221Live-attenuated oral vaccines, of poliovirus, 237Live-attenuated rubella vaccine, 209Live-attenuated vaccines
of arenaviruses, 233for influenza, 228
Live oral vaccines, for prevention of adenoviruses, 193Liver, disorders of, from human immunodeficiency virus
infection, 144Liver biopsies, 212Liver flukes, 440-441
features of, 441t-442tLoiasis, 439Loperamide, for diarrhea, in travelers, 491Lopinavir, for human immunodeficiency virus infection,
152t-153tLouping ill virus, 81t-83tLouse-borne typhus, 262Lower urinary tract localization test, for prostatitis, 121tLung abscess, bacterial, 30Lung flukes, 440-441
features of, 441t-442t
Lutzomyia sand fly, 419LVAD infections. see Left ventricular assist device
(LVAD) infections.Lyme borreliosis, 357
definition of, 357diagnosis of, 357epidemiology of, 357microbiology of, 357prevention of, 357therapy for, 357tick-transmitted, 453
Lyme disease, 357Lymph nodes, inflammation of, 94Lymphadenitis, 94
forms of, 95t-96tfrom Mycobacterium avium complex, 373
Lymphadenopathy, persistent generalized, from human immunodeficiency virus infection, 140
Lymphangitis, 94causes of, 97t
Lymphatic channels, inflammation of, 94Lymphocutaneous disease, from Sporothrix schenckii, 386Lymphocyte infusion, in HSCT, 470Lymphocytic choriomeningitis, 232-233Lymphocytic choriomeningitis virus (LCMV), 232Lymphocytic interstitial pneumonitis, in human
immunodeficiency virus infection, 143Lymphogranuloma venereum (LGV), 249-250
clinical characteristics of, 251t-252ttherapy for, 116
Lymphomaprimary CNS, human immunodeficiency virus and,
146pulmonary, in human immunodeficiency virus
infection, 143Lyngbya or Cyanobacteria exposure syndromes, harmful
algal blooms and, 436t
MMacrolides
for atypical pneumonia, 255for ureaplasmas, 256
Maculopapular eruptions, mites in, 452Maculopapular rashes, in acutely ill patients, 3-4Madurella mycetomatis, 388Magnetic resonance imaging (MRI)
for brain abscess, 84-85for subdural empyema, 86
Major commensal microorganisms, 41tMajor community-acquired pathogens, 41tMalaria, 417-418
prevention of, in travelers, 491in returning travelers, 493
Malassezia furfur, 406Male condoms, in human papillomavirus, 195Malignant otitis externa, 13Malnutrition, cryptosporidiosis in, 431Mandibular osteomyelitis, initial empirical antimicrobial
regimens for, 20t-21tMaraviroc, for human immunodeficiency virus infection,
154tMarburg hemorrhagic fevers, 227
510In
dex
Marburg viral diseases, 227Mass spectrometry, matrix-assisted laser desorption/
ionization time-of-flight, for Capnocytophaga, 344Mastoiditis, 12-13
definition of, 12diagnosis of, 13epidemiology of, 12microbiology of, 13prevention of, 13therapy of, 13
Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry
for Capnocytophaga, 344for diagnosis of Nocardia infection, 378for gram-negative and gram-variable bacilli, 349
Maxillofacial trauma, initial empirical antimicrobial regimens for, 20t-21t
Me Tri virus, 81t-83tMeasles, 220
vaccination, 220Measles virus, 220-221Mebendazole, for tissue nematodes, 439Median sternotomy, acute mediastinitis and, 73tMediastinitis, 72-74Mediastinum, anatomic boundaries and divisions of, 73fMefloquine, for malaria prevention, in travelers, 491Melioidosis, 320-322
antibiotic therapy for, 322tclinical presentations and outcomes of, 321tdefinition of, 320diagnosis of, 320epidemiology of, 320microbiology of, 320prevention of, 322risk factors for, 321ttherapy for, 322
Men, burn in, 486Menangle virus, 222Meningeal infections, treatment of, 156t-168tMeningitis
acute, 75-77anthrax, 296chronic, 78
diagnostic tests for, 79tdifferential diagnosis of, 79t
cryptococcal, treatment of, 156t-168tH. influenzae type b, 326
Meningococcal conjugate vaccine, 77Meningococcal disease, Neisseria meningitidis in, 301,
302fMeningococcal meningitis, antibiotic treatment for, 302tMeningococcemia
antibiotic treatment for, 302tNeisseria meningitidis in, 301
MERS. see Middle East respiratory syndrome (MERS).Metabolic abnormalities, from human immunodeficiency
virus infection, 140Metagonimus yokogawai, 441t-442tMethicillin-resistant Staphylococcus aureus (MRSA), 268,
269fdecontaminating scheme for, 274trisk factors for, 458
Methicillin-resistant Staphylococcus aureus pneumonia, treatment of, 156t-168t
Methicillin-susceptible Staphylococcus aureus (MSSA), evolution of, 269f
Metronidazolefor amebiasis, 414tfor balantidiasis, 433tfor blastocystosis, 434tfor Clostridium difficile infections, 358-359for giardiasis, 427tfor Trichomonas vaginalis, 428
Micafungin, for aspergillosis, 384tMicrobes, in appendicitis, 55Microbial conjunctivitis, 122-123Microbial keratitis, 124Microsporidiosis, 412Middle East respiratory syndrome (MERS), 215Milk, unpasteurized, Q fever from, 260Mite-borne rickettsiosis, 265Mites, 452
vesicular fever with eschar from, 259Mixtures of benzathine and procaine penicillin G, for
group A streptococcal pharyngitis, 9tMobile genetic elements (MGEs), Staphylococcus aureus
and, 268, 273t-274tMold endophthalmitis, 126Molluscum contagiosum infection, 178Monkeypox, 81t-83tMonkeypox virus, 176Monoclonal antibody prophylaxis, for bronchiolitis, 24Monotherapy, for bacterial keratitis, 124Moraxella catarrhalis, 307Morphine-mediated depression, in injection drug users,
479Mosquitoes, Francisella tularensis from, 330Mother-to-child transmission (MTCT), of human
immunodeficiency virus, 147Moxifloxacin, 319
for bites, 487, 489for genital mycoplasmas, 256
MTCT. see Mother-to-child transmission (MTCT).Mucocutaneous candidiasis, treatment of, 156t-168tMucormycosis, agents of, 385Mucosal leishmaniasis, 419Mucositis, in HSCT, 471Mucous membrane, lesions of, 116Multidrug-resistant tuberculosis (MDR-TB), 365Multifocal leukoencephalopathy, progressive, treatment
of, 156t-168tMultiresistant organisms, in SCI units, 475Mumps, 217Mumps virus, 81t-83t, 217Muriform cells, 387Murine typhus, 264Murray Valley encephalitis virus, 81t-83tMycetoma, 388-389Mycobacteria
intermediately growing, 375-376therapy for, 377
nontuberculous, infections caused by, 375-377rapidly growing, 375
therapy for, 376-377
511In
dex
slowly growing, 376therapy for, 377
Mycobacterial pneumonia, in human immunodeficiency virus infection, 142-143
Mycobacterium abscessus, 375Mycobacterium avium complex, 373-374
clinical manifestations and diagnosis of, 373microbiology and epidemiology of, 373prevention of, 374treatment of, 373, 374t
Mycobacterium avium complex (MAC) disease, disseminated
prophylaxis of, 168t-171ttreatment of, 156t-168t
Mycobacterium chelonae, 376Mycobacterium fortuitum, 376Mycobacterium genavense, 376Mycobacterium gordonae, 376Mycobacterium leprae, 371-372Mycobacterium marinum, 375Mycobacterium smegmatis, 376Mycobacterium tuberculosis, 69, 365-366
diagnosis of, 366drug regimens for, 367tepidemiology of, 365first-line tuberculosis medications for, 369t-370thuman immunodeficiency virus infection and,
142-143immunology and pathogenesis of, 365lymphadenitis from, 94microbiology of, 365prevention of, 366prophylaxis of, 168t-171ttherapy for, 366
latent infection, 366treatment of, 156t-168t
Mycoplasma genitalium, 256urethritis from, 117
Mycoplasma hominis, 256Mycoplasma pneumoniae, 255Mycoplasmas, genital, 256Mycoses, superficial, 400Mycotic aneurysms, in injection drug users, 480Mycotic lymphadenitis, 95t-96tMyelopathy, vacuolar, human immunodeficiency virus
and, 146Myiasis, 450Myocarditis, 69
infectious causes of, 70tMyonecrosis, 92-93Myositis, 92-93
NNAAT. see Nucleic acid amplification test (NAAT).Naegleria fowleri, 415-416Nafcillin, for Staphylococcus epidermidis, 275-276Narrow-spectrum therapy, for myonecrosis, 92-93Nausea, vomiting and noninflammatory diarrhea,
100-101Nebulized epinephrine, for croup, 216Necator, 437, 438t
Neck, infections of, 17-18initial empirical antimicrobial regimens for
suppurative, 20t-21tNecrosis
pancreatic, 50tsterile, 49
retinal, acute, 127Necrotizing fasciitis, 90-91Neisseria gonorrhoeae, 301, 305-306
epididymitis from, 120pelvic inflammatory disease from, 119urethritis from, 117
Neisseria meningitidis, 301-303Nelfinavir, for human immunodeficiency virus infection,
152t-153tNematodes
intestinal, 437-438, 438tin tissue, 439
Neoehrlichia mikurensis, 266Neonatal infections, in herpes simplex virus, 180Neonate, conjunctivitis in, 122Neurobrucellosis, treatment of, 329tNeurocognitive disorder, human immunodeficiency
virus and, 146Neurocysticercosis, 443Neurodegenerative diseases, transmissible, 248Neurologic diseases, caused by human
immunodeficiency virus, 146Neuropathy, nucleoside, human immunodeficiency virus
and, 146Neurotoxic shellfish poisoning, harmful algal blooms
and, 436tNeutralizing antibodies, in rotaviruses, 206Neutropenia, 464
febrile, management of, 467-469, 467f-468f, 469tNeutropenic enterocolitis, 56Nevirapine, for human immunodeficiency virus
infection, 152tNew World alphaviruses, 207Nifurtimox, for T. cruzi, 421Nipah virus, 81t-83t, 222Nitazoxanide
for blastocystosis, 434tfor cryptosporidiosis, 431for cyclosporiasis, 433tfor giardiasis, 427t
Nocardia brasiliensis, 388Nocardia species, 378-379
clinical manifestations of, 378definition of, 378diagnosis of, 378microbiology and epidemiology of, 378therapy and follow-up, 379, 379t
Nocardial brain abscess, 84Nodular lesions, in acutely ill patients, 3-4Non-nucleoside reverse-transcriptase inhibitors, for
human immunodeficiency virus infection, 152tNoncandidal fungi, 59tNoncardiac vascular infections, in injection drug users,
480Nongonococcal urethritis, clinical characteristics of,
251t-252t
Mycobacteria (Continued)
512In
dex
Noninfectious causes, of chronic pneumonia, 31Noninfectious respiratory disorders, in human
immunodeficiency virus infection, 143Noninflammatory diarrhea, with nausea and vomiting,
100-101Noninflammatory gastroenteritides, 100Noninvasive liver tests, 212Nonpharmacologic therapies, for chronic fatigue
syndrome, 172Nontreponemal antibody tests, for syphilis, 351Nontyphoidal salmonellosis, 324Nonvalvular cardiovascular devices, infections of, 65-66Noroviruses, 244-245Norwegian scabies, 448-449Nosocomial microorganisms, 41tNosocomial pneumonia, 458-459Nosocomial urinary tract infections, 460-461Nucleic acid amplification assays, for enteric fever, 104Nucleic acid amplification test (NAAT), for Chlamydia
pneumoniae, 254Nucleoside and nucleotide reverse-transcriptase
inhibitors, for human immunodeficiency virus infection, 150t-151t
Numbered enteroviruses (EV-D68), 238Nutritionally variant streptococci, 59t, 287-288
OOcular infections, in injection drug users, 481Ocular larva migrans, definition of, 445Odontogenic infections, initial empirical antimicrobial
regimens for, 20t-21tOld World alphaviruses, 207Onchocerciasis, 439Open reading frames (ORFs), in hepatitis E virus, 247Opioids, effects of, in injection drug users, 479Opisthorchis felineus, 441t-442tOpisthorchis viverrini, 441t-442tOpportunistic infections
acquired immunodeficiency syndrome (AIDS)-related, 155
treatment of, 156t-168tmanagement of, associated with human
immunodeficiency virus infection, 155-156Oral antipseudomonal antibiotics, 34t-36tOral cavity, infections of, 17-18Oral corticosteroids, 34t-36tOral disease, from human immunodeficiency virus
infection, 140Oral mucositis, in immunocompromised hosts,
antimicrobial regimens for, 18t-19tOral N-acetylcysteine, 34t-36tOral therapy, for cutaneous infections, 91Orbit, infections of, 129Orbiviruses, 203Orchitis, 120Organ donors, transfusion- and transplantation-
transmitted infections in, 463Orientia tsutsugamushi, 265Orofacial infections
antimicrobial regimens for various odontogenic and nonodontogenic, 18t-19t
in herpes simplex virus, 179
Oropharyngeal candidiasis, treatment of, 156t-168tOroya fever, 346Orthohepadnavirus, 130Orthopedic implant, infections associated with,
113-115Orthopoxviruses, 176-177Orthoreoviruses, 203Osteomyelitis, 111-112
antimicrobial therapy for, 112textension of, from prevertebral space infection,
initial empirical antimicrobial regimens for, 20t-21t
Otitis externa, 12-13definition of, 12diagnosis of, 13epidemiology of, 12microbiology of, 12prevention of, 13therapy of, 13
Otitis media, 12-13, 281-282definition of, 12diagnosis of, 13epidemiology of, 12Haemophilus influenzae and, 326microbiology of, 12Moraxella catarrhalis causing, 307prevention of, 13therapy of, 13
Otogenic infections, initial empirical antimicrobial regimens for, 20t-21t
Outbreak, of foodborne diseases, 105Oxacillin, for Staphylococcus epidermidis, 275-276
PPain
in eye, in endophthalmitis, 125internal fixation-associated infection and, 115
Palivizumab, for respiratory syncytial virus, 218Pancreas, disorders of, from human immunodeficiency
virus infection, 144-145Pancreatic abscess, 49, 50tPancreatic infection, 49
incidence and mortality rate in controlled trials with antibiotics and meta-analyses, 51t-53t
Pancreatic necrosis, 50tsterile, 49
Panuveitis, 127, 128tPap smear, for cervical cancer, 194-195Papillomaviruses, 194-195Paracoccidioides brasiliensis, 402Paracoccidioides lutzii, 402Paracoccidioidomycosis, 402
clinical manifestations of, 402microbiology and epidemiology of, 402treatment of, 402, 403t
Paragonimus westermani, 441t-442tParainfluenza viruses (PIV), 216Paralytic rabies, 225Paralytic shellfish poisoning, harmful algal blooms and,
436tParamyxoviruses, zoonotic, 222-223Parapoxvirus infections, 178
513In
dex
Parasiteschronic pneumonia and, 31Legionella spp. as, 342noninflammatory gastroenteritis from, 100
Parenteral therapyfor cutaneous infections, 91for gonorrhea, 305, 306t
Paromomycinfor amebiasis, 413, 414tfor blastocystosis, 434tfor giardiasis, 427t
Parvovirus B19 (B19V), 202infection of, 202
Passive immunization, with immunoglobulin G, in measles, 221
Pasteurella species, 335-336, 336tPathogenic vibrios, 312-313Pathogens
causing foodborne illnesses, 105causing microbial keratitis, 124
Patient factors, in surgical site infections, 482, 483tPatient population, of burn, 486PCP. see Pneumocystis pneumonia (PCP).PCR. see Polymerase chain reaction (PCR).Pediarix, 201tPediatric epiglottitis, 15
clinical manifestations of, 15therapy for, 16
Pediculosis, 446-447Pediculosis capitis. see Head lice.Pediculosis corporis. see Body lice.Pediculus humanus corporis, 262Pediococcus, 287Pegylated interferon-α (PEG IFN-α), for chronic
hepatitis B, 200tPelvic inflammatory disease
from Chlamydia trachomatis, clinical characteristics of, 251t-252t
in female, 119Pelvis, female, infections of, 119Penetrating trauma, clostridial myonecrosis and, 92Penicillin, 76, 285
for Pasteurella species, 335for S. pyogenes infections, 278
Penicillin-allergic patients, antimicrobial therapy for group A streptococcal pharyngitis in, 9t
Penicillin/β-lactamase inhibitor, for Capnocytophaga, 345
Penicillin G, for syphilis, 352Penicillin V, for group A streptococcal pharyngitis, 9tPenicillin VK, for infections, in HSCT, 471Penicillium marneffei, 407Pentamidine, aerosolized, for infections, in cancer
patients, 465t-466tPeptic ulceration, 315Percutaneous intravascular devices, infections caused by,
456-457Pericarditis, 69-70
infectious causes of, 71tpurulent, 70tuberculous, 70
Perinatal human immunodeficiency virus infection, 147
Perinatal infections, chlamydial, 249-250Periocular infections, 129Periodontitis, antimicrobial regimens for, 18t-19tPeripheral blood films, positive, tropical diseases with, in
returning travelers, 493Peripheral blood stem cells, in HSCT, 470Peripheral leukocytosis, in epiglottitis, 15Peripheral nervous system, human immunodeficiency
virus and, 146Periprosthetic joint infection (PJI), 113
treatment algorithm for, 113, 114fPeritoneal dialysis, antibiotic dosage for peritonitis
during, 46tPeritonitis, 42
antibiotic dosage for, during peritoneal dialysis, 46tprimary, 42, 44-45, 45t
prophylaxis, 47secondary, 42-43
causes of, 43ttertiary, 42
Permethrin, for scabies, 448Persistent generalized lymphadenopathy, from human
immunodeficiency virus infection, 140Person-to-person transmission, of arenaviruses, 233Pertussis, 339Pertussis toxin (PT), 339Pfiesteria-associated syndrome, harmful algal blooms
and, 436tPhaeohyphomycosis, 405Pharmacologic therapies, for chronic fatigue syndrome,
172Pharyngitis, 6-7
acute, microbial causes of, 7tin herpes simplex virus, 179modified Centor score and culture management
approach for, 8tstreptococcal, 277
Phialophora verrucosa, 387Phlebotomus sand fly, 419Phthiriasis, 446Physical examination, for management of bite wounds,
488t-489tPicobirnaviruses, 246Picornaviridae, 243Pinworm, 437-438, 438tPIV. see Parainfluenza viruses (PIV).Plague, 337
pneumonic, treatment, 338tPlasmodium falciparum, 417Plasmodium knowlesi, 417Plasmodium malariae, 417Plasmodium ovale, 417Plasmodium species, 417-418Plasmodium vivax, 417Pleconaril, 238Pleural effusion, 28
transudative, features differentiating exudative from, 29t
Pleural fluid, Pasteurella in, 335Pleuropulmonary infections, from Clostridium, 362PML. see Progressive multifocal leukoencephalopathy
(PML).
514In
dex
Pneumococcal polysaccharide-protein conjugate vaccine (PCV13), 282
Pneumocystis jirovecii, 410prophylaxis against, 464-467
Pneumocystis jirovecii pneumonia (PCP), 142Pneumocystis pneumonia (PCP), 410
prophylaxis of, 168t-171ttreatment of, 156t-168t
Pneumocystis species, 410-411definition of, 410diagnosis of, 410epidemiology of, 410prevention of, 411treatment of, 410
Pneumolysin, 281Pneumonia
acute, 25-26atypical, 255bacterial, in human immunodeficiency virus infection,
142from Chlamydia pneumoniae, 254from Chlamydia trachomatis, clinical characteristics of,
251t-252tchronic, 31-32community-acquired, Legionnaires’ disease and, 342in elderly, 476fungal, in human immunodeficiency virus infection,
143in injection drug users, 480melioidosis and, 320methicillin-resistant Staphylococcus aureus, treatment
of, 156t-168tmycobacterial, in human immunodeficiency virus
infection, 142nosocomial, 458-459Pneumocystis
prophylaxis of, 168t-171ttreatment of, 156t-168t
Pneumocystis jirovecii, 142Pseudomonas, treatment of, 156t-168tpsittacosis causing, 253SCI and, 475Streptococcus pneumoniae in, 281tularemia, 333fviral, in human immunodeficiency virus infection, 143
Pneumonic plague, treatment, 338tPoliomyelitis, 237Poliovirus, 237Polymerase chain reaction amplification, of rickettsial
nucleic acids, 257Polymerase chain reaction assay
for Coxiella burnetii, 260for human T-lymphotropic virus, 234reverse-transcriptase, for astroviruses, 246for Rickettsia prowazekii, 262for scrub typhus, 265
Polymerase chain reaction (PCR)for adenovirus diagnosis, 192for herpes B virus diagnosis, 190for treponemes diagnosis, 351for VZV diagnosis, 183
Polymorphonuclear leukocytes, urethritis and, 117
Polyneuropathy, distal sensory, human immunodeficiency virus and, 146
Polysaccharide vaccine, 10423-valent, 282
Polysaccharides, capsular, of Staphylococcus aureus, 270t-271t
Pontiac fever, 342-343Porphyromonas species, 364
definition of, 364diagnosis of, 364epidemiology of, 364microbiology of, 364therapy for, 364, 364t
Posaconazolefor aspergillosis, 384tfor chromoblastomycosis, 387for infections
in cancer patients, 464, 465t-466tin HSCT, 471
Positive immunoglobulin G (IgG), toxoplasmosis and, 424
Post-cardiac surgery mediastinitis, 72Post-Giardia lactose intolerance, 426Post-traumatic endophthalmitis, 125Posterior reversible encephalopathy syndrome, in HSCT,
471Posterior uveitis, 127, 128tPostexposure prophylaxis
for hepatitis A virus, 242tfor herpes B virus, 191tfor rabies, 225
Postinjection endophthalmitis, 125Postnatal rubella, 209Postsurgical wound infections, initial empirical
antimicrobial regimens for, 20t-21tPotassium iodide, for Sporothrix schenckii, 386Powassan virus, 81t-83tPoxviruses, infecting humans, 178Praziquantel
for cestodes, 443for trematodes, 441, 441t-442t
Prednisone, for PCP, 410Preexposure prophylaxis, for rabies, 226Pregnancy
hepatitis E virus during, 247syphilis during, 351toxoplasmosis in, 424
Preseptal cellulitis, 129Pressure sores, infection of, SCI and, 475Prevotella species, 364
brain abscess and, 84definition of, 364diagnosis of, 364epidemiology of, 364microbiology of, 364therapy for, 364, 364t
Primary amebic meningoencephalitis (PAM), patients with, 415-416
Primary genital infections, in herpes simplex virus, 179Primary lung abscess, 30Primary peritonitis, 42, 45t
prophylaxis, 47
515In
dex
Primary varicella infection (chickenpox), treatment of, 156t-168t
Prion diseases, of central nervous system, 248Prion protein (PrP), 248Prions, 248Procedural factors, in surgical site infections, 482, 483tProceduralist factors, in surgical site infections, 482, 483tProctitis, from Chlamydia trachomatis, clinical
characteristics of, 251t-252tProgressive multifocal leukoencephalopathy (PML), 196
treatment of, 156t-168tProgressive outer retinal necrosis (PORN), treatment of,
156t-168tProguanil, for malaria prevention, in travelers, 491Prophylactic antibiotics, for infections, in asplenic
patients, 478Prophylaxis
for hepatitis A virus, 242tfor human immunodeficiency virus, 139of infection, in cancer patients, 464-467, 465t-466tfor Pasteurella species, 336for pertussis, 340for preventing first episode of opportunistic disease,
168t-171tPropionibacterium acnes, in periprosthetic joint infection,
113Proptosis, orbital infections and, 129Prostatitis, 120
classification of, 121tProsthetic valve endocarditis, 63-64
caused by staphylococci, therapy for, 64tindications for consideration of surgical intervention,
64tProsthetic vascular graft infections (PVGIS), 65-66Protease inhibitors, for human immunodeficiency virus
infection, 152t-153tProtein-synthesis inhibitors, for infections associated
with toxic shock syndrome, 91Proteins, sortase-mediated cell wall-associated,
Staphylococcus aureus MSCRAMMs belonging to, 271t-272t
Proteus spp., 316Prototheca spp., 408Protozoa, noninflammatory gastroenteritis from, 100Protozoan lymphadenitis, 95t-96tPseudallescheria boydii, 404Pseudocyst, acute, 50tPseudomonas aeruginosa, 12, 317
cystic fibrosis and, 33Pseudomonas pneumonia, treatment of, 156t-168tPseudomonas species, 317Psittacosis, 253Pubic lice, 446-447Pulmonary disease
in human immunodeficiency virus infection, 142-143, 143t
from Mycobacterium avium complex, 373from Sporothrix schenckii, 386
Pulmonary infectionsfrom herpes simplex virus, 180in injection drug users, 480
Pulmonary tuberculosis, in injection drug users, 480
Purulent pericarditis, 70PVGIS. see Prosthetic vascular graft infections (PVGIS).Pyogenic liver abscess, 48Pyomyositis, 92Pyrazinamide, for tuberculosis, 366, 369t-370tPyrimethamine, for toxoplasmosis, 425Pyrogenic exotoxin B, 277Pythium spp., 409
QQ fever, 59t, 260-261Quaternary ammonium formulations, hepatitis A virus
and, 240Quellung reaction, 281Quinacrine, for giardiasis, 427tQuinine, for Babesia microti, 429, 430tQuinolones, for genital mycoplasmas, 256Quinupristin-dalfopristin, 284
RRabies, 225-226Radiographs, for management of bite wounds, 488t-489tRaltegravir, for human immunodeficiency virus
infection, 154tRapid molecular tests, for Capnocytophaga, 344Rash
acutely ill patient with, 3-4from murine typhus, 264Neisseria meningitidis in, 301from Rocky Mountain spotted fever, 257
Rat-bite fever, 341Recombivax HB, 201tRed blood cell, exchange transfusion of, for babesiosis,
430, 430tReinfection
in human metapneumovirus, 219in respiratory syncytial virus, 218in rotaviruses, 205
Relapsing fever, due to Borrelia species, 356Renal disease, from human immunodeficiency virus
infection, 140Reoviruses, 203Replication
in Kaposi’s sarcoma-associated herpesvirus, 189of rotaviruses, 205
Reporting, in management of bite wounds, 488t-489tRespiratory diseases, bacterial, treatment of, 156t-168tRespiratory droplets, transmission of adenoviruses, 192Respiratory syncytial virus (RSV), 218
bronchiolitis and, 24Respiratory tract colonization, of Burkholderia
cenocepacia, 319Respiratory viruses, in solid-organ transplant recipients,
474Retinal necrosis, acute, 127Retinochoroiditis, toxoplasmosis and, 424Reverse-transcriptase polymerase chain reaction
(RT-PCR), in diagnosis of Filovirus infection, 227Rhabdoviruses, 225-226Rheumatic fever
nonsuppurative poststreptococcal sequelae of, 279-280from Streptococcus pyogenes, 277
516In
dex
Rhinocladiella aquaspersa, 387Rhinogenic infections, initial empirical antimicrobial
regimens for, 20t-21tRhinosporidium seeberi, 409Rhinovirus, 243Rhodococci, 292Rhodococcus equi, 292Ribavirin
for arenaviruses, 232for Bunyavirus infections, 231for hepatitis C virus, 135for human metapneumovirus, 219monotherapy, for chronic hepatitis E, 247for parainfluenza virus, 216
Rickettsia akari, 259Rickettsia felis, 257Rickettsia prowazekii, 262Rickettsia rickettsii, 257-258Rickettsia typhi, 264Rickettsiae, lymphadenitis and, 95t-96tRickettsialpox, 259
house mouse mites in, 452Rickettsiosis
mite-borne, 265in returning travelers, 493
Rifabutin, for tuberculosis, 369t-370tRifampin
for brucellosis, 329tfor coagulase-negative staphylococcal infections, 276for tuberculosis, 366, 369t-370t
Rifapentine, for tuberculosis, 369t-370tRift Valley fever virus, 81t-83tRilpivirine, for human immunodeficiency virus infection,
150t-152tRing worm, 400Ritonavir, for human immunodeficiency virus infection,
152t-153tRMSF. see Rocky Mountain spotted fever (RMSF).RNA tests, of hepatitis C virus, 212Rocio virus, 81t-83tRocky Mountain spotted fever (RMSF), 257-258Rodents, Francisella tularensis from, 330Rose-Bengal card agglutination test, for brucellosis, 328Rotaviruses, 205-206Rothia, 287Roundworms, 437-438, 438tRSV. see Respiratory syncytial virus (RSV).RT-PCR. see Reverse-transcriptase polymerase chain
reaction (RT-PCR).Rubella
congenital, 209postnatal, 209
Rubella vaccine, 209Rubella virus, 81t-83t, 209Rubeola, 220-221
SSalmonella flagellin, inflammatory enteritides from,
102Salmonella species, 324Salmonellosis, 324
treatment of, 156t-168t
San Joaquin Valley fever, 398Sapoviruses, 244-245Saquinavir, for human immunodeficiency virus infection,
152t-153tSarcocystis species, 432-433Sarcoptes scabiei var. hominis, 448SARS. see Severe acute respiratory syndrome (SARS).Scabies, 448-449Scabies mite, 448Scedosporium prolificans, 404Schistosoma guineensis, 441t-442tSchistosoma haematobium, 441t-442tSchistosoma intercalatum, 441t-442tSchistosoma japonicum, 441t-442tSchistosoma mansoni, 441t-442tSchistosoma mekongi, 441t-442tSchistosomes, 440-441
features of, 441t-442tSchistosomiasis, in returning travelers, 493Scratches
Pasteurella infection from, 335rat-bite fever from, 341
Screeningof blood and organ donors, for Chagas’ disease,
421for Chlamydia trachomatis, 250of donor, for transfusion- and transplantation-
transmitted infections, 463test, for human immunodeficiency virus, 138-139,
139tScrub typhus, 265
Asian scrub typhus chiggers in, 452Seadornaviruses, 204Secondary peritonitis, 42-43
causes of, 43tSelenium sulfide, for dermatophytosis, 400Sennetsu neorickettsiosis, 266Sepsis, 40
from Capnocytophaga, 344Septic bursitis, 110Septic shock, 40
empirical antibiotic options for, 41tSeptic thrombophlebitis, in injection drug users, 480Sequential urine cultures, for prostatitis, 121tSerologic assays
for enteric fever, 104in toxoplasmosis, 424
Serologic tests, in hepatitis B, 199tSerology, for Chlamydia pneumoniae, 254Severe acute pancreatitis, 50tSevere acute respiratory syndrome (SARS), 215Severe sepsis, 40
empirical antibiotic options for, 41tSexually transmitted diseases, in injection drug users,
481Shellfish, harmful algal blooms in, 435Shigella, 325
inflammatory enteritides from, 102Shigellosis, 325Shunt infections, of cerebrospinal fluid, 88-89Sialadenitis, antimicrobial regimens for, 18t-19tSinusitis, 14
517In
dex
Skingenital, lesions of, 116infections of, 90-91
in injection drug users, 479lesions, in acutely ill patients, 3
Skin biopsy, for leprosy, 371Skin slit smear, for leprosy, 371Sleeping sickness, 422-423Small intestine, disorders of, from human
immunodeficiency virus infection, 145Snowshoe hare virus, 81t-83tSofosbuvir, for hepatitis C virus, 135Soft tissue infections, 90-91
in injection drug users, 479Solid-organ transplant recipients, infections in, 474Solvents, hepatitis A virus and, 240South American hemorrhagic fevers, 232-233Spinal cord, human immunodeficiency virus and, 146Spinal cord injury (SCI), infections in, 475Spinal epidural abscess, in injection drug users, 481Spirillum minus, 341Spirometra mansonoides, 444tSplenectomy, for splenic abscess, 54Splenic abscess, 54
in injection drug users, 481Spondylodiskitis, 111Spore-forming bacilli, gram-positive, 298Sporothrix schenckii, 386Spotted fever group (SFG) rickettsiae, 257-258Sprue, tropical, 107Sputum, Pasteurella in, 335Squirrels, flying, Rickettsia prowazekii in, 262St. Louis encephalitis (SLE) virus, 210Staphylococcal species, in CSF shunt infections, 88Staphylococcal toxic shock syndrome, 268-269Staphylococci
coagulase-negative, 275-276prosthetic valve endocarditis caused by, therapy for,
64tStaphylococcus aureus, 58, 268-269
brain abscess and, 84CLABSIs, incidence of, 456cystic fibrosis and, 33definition of, 268diagnosis of, 268epidemiology of, 268epidural abscess and, 86infection with, in injection drug users, 479-480lymphadenitis from, 94methicillin-resistant, 268, 269f
decontaminating scheme for, 274trisk factors for, 458
methicillin-susceptible, 269fmicrobiology of, 268mobile genetic elements in, 273t-274tMSCRAMMs, 271t-272tpathogenesis of, extracellular factors involved in,
270t-271tprevention of, 269pyomyositis from, 92response to global regulatory elements during
bacterial growth, 270t-271t
sinusitis and, 14superficial cutaneous infection from, 90therapy for, 268-269
Staphylococcus epidermidis, 275-276Staphylococcus haemolyticus, 275Staphylococcus lugdunensis, 275Staphylococcus saprophyticus, 275Stavudine, for human immunodeficiency virus infection,
150t-151tStenotrophomonas maltophilia, 318-319Sterile pancreatic necrosis, 49Stomach, disorders of, from human immunodeficiency
virus infection, 144Streptobacillus moniliformis, 341Streptococcal pharyngitis, 277Streptococcal toxic shock syndrome, 277Streptococci
brain abscess and, 84group A, 279
myonecrosis from, 92group B, 285
Streptococcus agalactiae, 285Streptococcus anginosus group, 289Streptococcus bovis group, 283Streptococcus gallolyticus group, 283-284Streptococcus iniae, 287Streptococcus pneumoniae, 281-282
infection, prophylaxis of, 168t-171tsinusitis and, 14
Streptococcus pyogenes, 277-278Streptococcus suis, 287Streptolysin O, 277Streptolysin S, 277Streptomycin
doxycycline with, for brucellosis, 328, 329tfor plague, 337for tularemia, 331, 334t
Strongyloides, 437-438, 438tStye, 129Subacute faucial infection, 290Subcutaneous tissue, infections of, 90-91Subdural empyema, 86-87Superantigens, of Staphylococcus aureus, 270t-271tSupportive therapy, for noroviruses, 244Suppurative cavernous sinus thrombosis, initial empirical
antimicrobial regimens for, 20t-21tSuppurative cervical adenitis, initial empirical
antimicrobial regimens for, 20t-21tSuppurative intracranial thrombophlebitis, 86-87Suppurative jugular thrombophlebitis, initial empirical
antimicrobial regimens for, 20t-21tSuppurative lymphadenitis, 94Suppurative orofacial odontogenic infections, initial
empirical antimicrobial regimens for, 20t-21tSuppurative parotitis, antimicrobial regimens for, 18t-19tSuppurative thyroiditis, initial empirical antimicrobial
regimens for, 20t-21tSupragingival dental plaque, and dental caries
prevention, antimicrobial regimens for, 18t-19tSurface proteins, of Staphylococcus aureus, 270t-271tSurgical antimicrobial prophylaxis, 482, 484f-485f
Staphylococcus aureus (Continued)
518In
dex
Surgical site infections (SSIs)antimicrobial prophylaxis and, 482prevention of, 482, 483t-484trisk factors for, 482, 483tsurveillance of, 482
Sustained virologic response (SVR), 135-136Swimmer’s ear, 13Swine influenza, 228Syphilis, 351-352
ocular, uveitis and, 127prophylaxis of, 168t-171ttherapy for, 116
Systemic antibiotics, for empyema, 28Systemic exertion intolerance disease, 172
IOM diagnostic criteria for, 173t
TTachyzoites, of Toxoplasma, 424Taenia multiceps, 444tTaenia saginata, 443, 444tTaenia solium, 443, 444tTapeworms. see Cestodes.TaqMan Array Card, 103Tdap, for pertussis, 340Telaprevir, for hepatitis C virus, 135fTelbivudine, for chronic hepatitis B, 200tTenofovir
for chronic hepatitis B, 200tfor hepatitis B virus, 132for human immunodeficiency virus infection, 150t-151tfor infections, in HSCT, 471
Terbinafine, for chromoblastomycosis, 387Tertiary peritonitis, 42Tetanospasmin, 360Tetanus, 360Tetanus prophylaxis
for myiasis, 450for tungiasis, 451
Tetracyclinefor atypical pneumonia, 255for balantidiasis, 433tfor conjunctivitis, 123for enteropathy, 107for ureaplasmas, 256
Therapeutics, for orthopoxvirus infections, 176Thrombophlebitis, suppurative intracranial, 86-87Tick-borne encephalitis (TBE) virus, 81t-83t, 210Ticks, 204
Francisella tularensis from, 330including tick paralysis, 453Rocky Mountain spotted fever from, 257
Tinidazolefor amebiasis, 413, 414tfor giardiasis, 426, 427tfor Trichomonas vaginalis, 428
Tipranavir, for human immunodeficiency virus infection, 152t-153t
Tissue antibiotic concentration, over time, 484fTissue nematodes, 439Tobramycin, 34t-36t
for infective endocarditis, in injection drug users, 480Toscana virus, 81t-83t
Total body surface area (TBSA), burn size in, 486Toxic shock syndrome
staphylococcal, 268-269streptococcal, 277
Toxocara canis, 445Toxocara cati, 445Toxocariasis. see Visceral larva migrans.Toxoplasma gondii, 424-425Toxoplasma gondii encephalitis
prophylaxis of, 168t-171ttreatment of, 156t-168t
Toxoplasmosis, 424human immunodeficiency virus and, 146
Trachoma, 124, 249-250Transesophageal echocardiography (TEE), for prosthetic
valve endocarditis diagnosis, 63Transfusion-transmitted infections, 463Transmissible neurodegenerative diseases, 248Transplant recipients, solid-organ, infections in, 474Transplantation, incidence of aspergillosis in, 381, 382tTransplantation-transmitted infections, 463Transplanted organ, toxoplasmosis in, 424Transudative pleural effusion, features differentiating
exudative from, 29tTrauma
acute mediastinitis and, 73tocular, keratitis and, 124penetrating, clostridial myonecrosis and, 92
Travelersprotection of, 491-492returning, infections in, 493, 494t-495t
Trematodes, 440-441features of, 441t-442t
Trench fever, from Bartonella quintana, 346Treponema pallidum, 351-353Treponemal tests, for syphilis, 351Treponematoses, endemic, 353Trichinellosis, 439Trichomonas vaginalis, 428Trichomoniasis, 118Trichosporon spp., 405-406Trichuris, 437-438, 438tTriclabendazole, for trematodes, 441, 441t-442tTricuspid valve, infective endocarditis, in injection drug
users, 480Trimethoprim-sulfamethoxazole
for bites, 487for blastocystosis, 434tfor Cyclospora and Cystoisospora, 432, 433tfor infections
in cancer patients, 464-467, 465t-466tin HSCT, 471
for Nocardia infection, 379for paracoccidioidomycosis, 402, 403tfor PCP, 410-411for S. maltophilia, 319for toxoplasmosis, 425
Tropheryma whipplei, 59t, 300Tropical diseases, in returning travelers, 493Tropical sprue, 107Trypanosoma brucei gambiense, 422Trypanosoma brucei rhodesiense, 422
519In
dex
Trypanosoma cruzi, 420-421Trypanosoma species, 420-421Trypanosomiasis, 420-421Tsetse flies, in African trypanosomiasis, 422Tube agglutination test, for brucellosis, 328Tuberculin skin testing, 365-366Tuberculous pericarditis, 70Tularemia, 330-333
clinical manifestations of, 330-331, 332f-333fdefinition of, 330diagnosis of, 331epidemiology of, 330microbiology of, 330prevention of, 333therapy for, 331, 334t
Tularemia pneumonia, 333fTungiasis, 451Twinrix, 201tTyphlitis, 56-57Typhoid, in returning travelers, 493Typhoid conjugate vaccines, 104Typhoid vaccine, 104Typhoidal fever, 104Typhus
epidemic, 262, 263tlouse-borne, 262murine, 264scrub, 265
Tzanck smears, of lesion scrapings, 183
UUlceration, aphthous, esophagitis from, 99tUlceroglandular tularemia, 332f-333fUmbilical cord blood, in HSCT, 470Uncomplicated infections, 42United States, pediatric HIV infection in, 147Ureaplasma parvum, 256Ureaplasma species, 256Ureaplasma urealyticum, 256Urethritis, 117, 117t
nongonococcal, clinical characteristics of, 251t-252tTrichomonas vaginalis of, in men, 428
Urinary tract infection (UTI), 37-38in elderly, 476nosocomial, 460-461recommendations for initial therapy of, 39tSCI and, 475
Urine antigen testing, for Legionella spp., 342U.S.-licensed vaccines, for flaviviruses, 211UTI. see Urinary tract infection (UTI).Uveitis, 127
infectious etiologies of, 128t
VVaccination
for hepatitis, 462with hepatitis B vaccine, 199for human papillomavirus, 195measles, 220poliovirus, 237with smallpox vaccine, 177for travelers, 491
Vaccinefor H. influenzae, 327for hepatitis A virus, 241, 241tfor hepatitis E virus, 247for infections
in asplenic patients, 478in cancer patients, 465t-466t
for invasive pneumococcal disease, 282for noninflammatory gastroenteritis, 101for norovirus, 245polysaccharide-conjugate, for Neisseria meningitidis,
303, 304tfor zoonoses, 490
Vaccinia, 81t-83tVaccinia Immune Globulin Intravenous (VIGIV), 176Vaccinia virus (smallpox vaccine), 176Vaginitis, Trichomonas vaginalis of, in women, 428Vaginosis, bacterial, 118Valacyclovir, for infections, in cancer patients, 465t-466t,
467Valganciclovir
for cytomegalovirus infection, 185for infections, in HSCT, 471
Vancomycinfor Clostridium difficile infections, 358-359for coagulase-negative staphylococcal infections,
275-276for infections, in HSCT, 472for pneumonia, 458-459
VAP. see Ventilator-assisted pneumonia (VAP).Varicella-zoster immune globulin (VariZIG), 184Varicella-zoster virus (VZV), 183-184
vaccine for, 184Varicella-zoster virus (VZV) disease
prophylaxis of, 168t-171ttreatment of, 156t-168t
Variola (smallpox), 176VariZIG. see Varicella-zoster immune globulin
(VariZIG).Vascular infections, noncardiac, in injection drug users,
480Vascular insufficiency, osteomyelitis and, 112Venereal exposure, bacterial inflammatory enteritides
and, 102Veno-occlusive disease, in HSCT, 471Ventilator-assisted pneumonia (VAP), 458Ventriculoperitoneal (VP) shunt infections, 88Vermiform appendix, 55Verruga peruana, 346Vertebral osteomyelitis, 111Vesicular fever, with eschar, 259Vesicular stomatitis virus (VSV), 224Vesiculoviruses, 224Veterinary vaccines, for alphaviruses, 208Vibrio cholerae, 308-310
clinical manifestations of, 308diagnosis of, 308management of, 309-310, 309tmicrobiology and epidemiology of, 308prevention of, 310, 310t
Vibrio parahaemolyticus, inflammatory enteritides from, 102
520In
dex
Vibrio vulnificus, 312Vibrios, pathogenic, 312-313Video-assisted thoracoscopy, for empyema, 28VIGIV. see Vaccinia Immune Globulin Intravenous
(VIGIV).Vincent’s angina, antimicrobial regimens for, 18t-19tViral arthritis, 108Viral encephalitis, important and emerging causes of,
81t-83tViral hepatitis, 130-137
acute, 130chronic, 130diagnostic approach for, 131tHAV, 130HBV, 130-134HCV, 134-136, 135f-136f, 137tHDV, 134HEV, 136-137viruses causing, 130-137, 131t
Viral lymphadenitis, 95t-96tViral pneumonia, in human immunodeficiency virus
infection, 143Viral polyprotein, of hepatitis C virus, 213fViridans streptococci, 287-288Virulence factors, of Pseudomonas aeruginosa, 317Virus
see also specific viruscausing microbial keratitis, 124conjunctivitis from, 122mucous membrane lesions, 116noninflammatory gastroenteritis from, 100orchitis from, 120
Visceral larva migrans, 445Visceral leishmaniasis, 419Vision, decreased, in endophthalmitis, 125Vitamin A, administration of, in measles, 220Vitrectomy, for endophthalmitis, 126Vomiting, with nausea and noninflammatory diarrhea,
100-101Voriconazole
for aspergillosis, 381, 384tfor infections, in HSCT, 471for paracoccidioidomycosis, 403t
VSV. see Vesicular stomatitis virus (VSV).Vulvitis, 118Vulvovaginal candidiasis, 118
treatment of, 156t-168tVulvovaginitis, 118VZV. see Varicella-zoster virus (VZV); Varicella-zoster
virus (VZV) disease.
WWater
contaminated, 105hepatitis E virus in, 247noroviruses, 244-245
sanitation of, for noninflammatory gastroenteritis, 101Weil-Felix test, for scrub typhus, 265West Nile virus (WNV), 210Whipple’s disease, 59t, 300Whipworm, 437, 438tWild-type poliovirus type 2, 237Wound botulism, 361Wound closure, for management of bite wounds,
488t-489tWound management, and tetanus prevention, 360
YYatapoxvirus infections, 178Yaws, 353Yeasts, uncommon, 406-407Yellow fever (YF), 210Yersinia enterocolitica, 337Yersinia pestis, 337Yersinia pseudotuberculosis, 337Yersinia species, 337YF. see Yellow fever (YF).Youth, aging HIV-infected, therapy for, 147-148
ZZidovudine, for human immunodeficiency virus
infection, 150t-151tZika virus (ZIKV) infections, 210Zinc pyrithione, for dermatophytosis, 400Zoonoses, 490Zoonotic paramyxoviruses, 222-223
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