Current issues in Antibiotic Use:the Continued Evolution of Antimicrobial Resistance

Bert K. Lopansri, MDDivision of Infectious Diseases and Clinical Epidemiology

Associate Professor, University of UtahMedical Director, Intermountain Central Laboratory

DISCLOSURES

• Research support from:– Nanosphere, Inc.– Ansell, Inc.– Catheter Connections, Inc.

Objectives

• Discuss emerging issues related to antimicrobial resistance

• Discuss methods to control antimicrobial resistance

• Encourage healthcare workers to think about how antibiotics are used

Fleming in reference to Penicillin

• The public will demand [the drug and]…then will begin an era… of abuses. The microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed to other individuals…In such a case the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with penicillin-resistant organism. I hope the evil can be averted.

Fleming A. Penicillin’s finder assays its future. New York Times. 1945; 21

Outpatient antibiotic prescriptions per 1000 Persons, 2010

LA Hicks. NEJM. 368;15. April 11, 2013

Trends in outpatient antibiotic use in U.S. (per 1000 persons)

AGENT 1999 2010 % Change 2010 (UT)ALL CLASSES 966 801 -17 791Penicillins 352 248 -30 293Macrolides 209 211 NC 176Cephalosporins 117 114 -35 129Fluoroquinolones 83 94 +14 69Tetracyclines 71 67 73TMP/Sulfa 74 66 51Other (vanco, linezolid, dapto, polymyxins, carbapenems)

0.33 1.0 +200 0.7

Data from www.cddep.org (Center for Disease Dynamics, Economics & Policy)

Outpatient ABX Use: US vs. Sweden

U.S.(2010)

SWEDEN (2012)

ABX/1000 persons 833 388TOP ANTIBIOTICS AZITHROMYCIN

PENICILLINSPCN VK

DOXYCYCLINEFLOXACILLIN

PIVMECILLINAMNITROFURANTOIN

LA Hicks. NEJM. 368;15. April 11, 2013A Ternhag. NEJM. 369;12. Sept 19, 2013

CASE #1

• 76 y/o man presented to ED with abrupt onset of chills, nausea, vomiting, dysuria and difficulty urinating.

• In usual state of health prior to admission.• Other than constipation, ROS negative• No hospitalizations in past 12 months

CASE #1• PMHx:

– DM– Recurrent DVT– HTN– Factor V Leiden Deficiency

• MEDICATIONS (HOME):– Glipizide– Metformin– Lipitor– Coumadin– Lisinopril/HCTZ– Diltiazem

• SOCIAL HISTORY:– Retired landscaper– No ETOH, Illicits, Tobacco– Exercises weekly

CASE #1

• VITALS: Temp 39.2, HR 108, BP 111/52, Sat 92%

• ABDOMEN: Soft/slightly distended/non-tender

• BACK: No CVA tenderness

• LABS:– Cr 1.41 (Baseline

1.25)– WBC 3.7, HGB 14.2,

PLT 85– Urinalysis: Cloudy,

Large Leuk Esterase, >30 WBC

Question #1

• Patient was diagnosed with urosepsis. What antibiotic regimen would you start?

a) Cefepimeb) Ceftriaxonec) Imipenem or meropenemd) Ertapeneme) Ciprofloxacinf) Piperacillin/Tazobactam

CASE #2

• 79 y/o woman with HPV, cirrhosis, DM admitted with fever and diarrhea.

• Multiple episodes of daily, non-bloody diarrhea and abdominal pain x 1 month.

• 1 week PTA, developed regular fevers to 101 • +urinary frequency without dysuria or

urgency.• Recently returned from a 3 month stay in India

CASE #2• PMHX

– Breast CA s/p lumpectomy 4/2013. On tamoxifen.

– DM– HTN– Hep B with cirrhosis– Choledocholithiasis

• PSHX– Lumpectomy– Cholecystectomy– R TKA

• EXAM:– Temp 38.4, RR 25, HR 120,

BP 138/71– Non-toxic– ABD distended with diffuse

tenderness. Liver and spleen unable to be palpated

• LABS:– WBC 13.0 (PMN 81.4%),

HGB 8.2, PLT 275– BUN 36, Cr 3.17– Urine: Cloudy, + Nitrite,

Large Leuk Esterase, >30 WBC

QUESTION #2

Patient was diagnosed with urosepsis. What antibiotic regimen would you start?

a) Cefepimeb) Ceftriaxonec) Imipenem/meropenemd) Ertapeneme) Ciprofloxacinf) Piperacillin/Tazobactam

Hospital Course

E coli susceptibilities: CASE #1 AND #2Susceptible Carbepenems

Nitrofurantoin

Resistant All cephalosporinsPip/TazobactamCipro/levaquinAmox/ClavAmpicillinTobramycinGentamicinBactrim

• Blood + urine cultures: for ESBL E. coli

• Case #1– Started on Cefepime– Switched to

MEROPENEM on Day #3 of hospitalization

• Case #2– Started on Ciprofloxacin

and ceftriaxone– Switched to

MEROPENEM on Day #3

QUESTION #3

• Carbapenem-resistant Enterobacteriaceae (CRE) is:

a) An overhyped, story that is unlikely to be a significant problem where I practice medicine.

b) A global problemc) A U.S. problemd) A problem only in certain parts of the worlde) Europe’s faultf) What in the world is a CRE?

Emerging Antibiotic Resistant Organisms

Ceftriaxone Resistant

NG

FQR NG

FQRCampy

Penicillin resistant

Staph aureus

MRSA

PCN Res Strep

pneumoVRE

ESBL CRABFQR E. coli

MDRO P. aerugCRE

FQR= fluoroquinolone resistantMDRO=multidrug resistantMRSA=methicillin resistant Staph aureusNG=Neiserria gonorrheaPCN=penicillin

CRAB=carbapenem resistant Acinetobacter baumaniiCRE=carbapenem resistant EnterobacteriaceaeESBL=extended spectrum β-lactamaseVRE=vancomycin resistant Enterococcus

http://wellcommons.com/users/jestevens/photos/2011/apr/10/211822/

Fluorquinolone-resistant E. coli (%) RESISTANT (2009)

Turkey

Spain

Germany

United States

UK

Iceland

0% 10% 20% 30% 40% 50% 60%

http://www.cddep.org/ResistanceMap/bug-drug/EC-FQ#.Ui0G-Ra3CRI

US Mountain Region=18%

Mechanisms of FQ Resistance

• Alterations in target enzymes– DNA gyrase (GyrA and GyrB)– Topoisomerase IV (ParC and ParE)

• Alterations in permeation of drug to reach target– Porin reduction– Eflux pumps

Plasmid Mediated FQ Resistance

• Discovered in 1994• Plasmid = pMG252

– Encodes QnrA protein– Carries multiple resistance determinants

• Binds to DNA gyrase and Topoisomerase IV• May be carried with other resistance genes

Risk Factors for Acquisition of FQ Resistance in LTCF

• Prospective, cohort study• 47.5% LTCF residents became colonized• Time to colonization=57 days

HR 95% CIFecal Incontinence 1.78 1.04, 3.06Receipt of amox/clavulanate 6.48 1.43, 29.4Presence of urinary catheter 3.81 1.06, 13.8

JH Han, JID. 2013 Aug 28

Risk Factors for Acquisition of Community-Acquired FQREC

• Nested case-control study– FQREC=51, Controls=369

• Resistance to multiple antibiotics present

HR 95% CIHospitalization within previous 6 months

2.03 0.96-4.31

Receipt of FQ 17.5 6.0-50.7Presence of urinary catheter 3.14 0.85-11.6

WE van der Starre. JAC. 2011;66 650-656

Number of β-lactamase enzymes described during age of antibiotics

1973 2013

Num

ber o

f Uni

que

Enzy

mes

900

Julian Davies. Micro biol and Molecular Bio Rev. Sept. 2010, p. 417-433

• Enzymes that mediate resistance to extended-spectrum cephalosporins (third generation) and monobactams but do not affect cephamycins (cefoxitin/cefotetan) or carbapenems.

• Activity is reversed by clavulanic acidAntibiotic Resistance Threats in the U.S., 2013. CDC

ESBL (CLASS A) AmpC (CLASS C)Location of gene Plasmid Chromosomal

Inhibited by clavulanic acid

YES NO

Cefepime useful NO YESCephamycin

resistantNO YES

Pathogens Klebsiella pneumoniaeEscherichia coli

Proteus mirabilisEnterobacter cloacae

Salmonella

E. cloacaeS. marcescens

C. freundiiM. MorgagniiP. Aeruginosa

Y. EnterocoliticaHafnia alvei

Common ESBLs

blaTEM/blaSHV blaCTX-MEpidemiology Associated with HAIs Community-associated

infectionsPreferential targets

Ceftazidime Cefotaxime

Number of types

>100 >50

Distribution Global Global

Risk Factors for ESBL Infections

• Length of hospital stay• Severity of illness• Time in ICU• Mechanical ventilation• Urinary catheterization• Previous antibiotic exposure

Bradford PA. Clin Microbiol Rev. 2001;14:933-951

M. McKenna. Nature. Vol 499. 25 July 2013

MECHANISMS OF CARBAPENEM RESISTANCE

• ESBL or AmpC with porin loss• Efflux pump• Carbapenemase• Common organisms

– Pseudomonas aeruginosa– Acinetobacter spp.– Enterobacteriaceae

CRE = Enterobacteriaceae resistant to one of the carbepenems (Doripenem, imipenem or meropenem) and third generation cephalosporins (ceftriaxone, cefotaxime, ceftazidime)

Guidance for Control of Carbapenem-resistant Enterobacteriaceae – 2012 CRE Toolkit, CDC. Antibiotic Resistance Threats in the U.S., 2013. CDC

CarbapenemasesAmbler Classification

Enzyme Organisms

Class A KPC, SME, IMI, NMC, GES

Enterobacteriaceae

Class B (metallo-β-lactamase)

NDM-1, IMP, VIM Enterobacteriaceae, Acinetobacter sp, P. aeruginosa

Class D OXA Acinetobacter sp

Emergence of carbapenem resistant Enterobacteriaceae

M. McKenna. Nature. Vol 499. 25 July 2013

Global Distribution of Klebsiella pneumoniae carbapenemase

LS Munoz-Price. LANCET INFECT DISEASES. Vol 13:785. Sept 2013.

Regional spread of KPC CRE

S.Y. Won. CID. 2011;53(6):532-540

1. DELAYED RECOGNITION OF KPC

2. AMPLIFICATION IN LTACHS AND NH

3. DESPITE INVOLVEMENT OF A SINGLE LTACH, KPC QUICKLY BECAME A REGIONAL PROBLEM

4. COORDINATED, REGIONAL EFFORTSAMONG HOSPITALS, LTACHS, ANDPUBLIC HEALTH DEPT

From www.medicaltourismmag.com

Outbreak of NDM-1 K. pneumo in Denver, CO

• 8 cases between Jan-Oct 2012 at acute care hospital– 3 infections – 5 identified by active surveillance

• K pneumoniae – Susceptible to tigecycline with colisitin MIC≤2 μg/mL– Highly related by PFGE

• Multiple transmission events in 3 units• Not all patients overlapped• Source not identified

MMWR. Feb. 15, 2013. 62(06);108

Antibiotic Susceptibilities for NDM-1UK (n=37) Chennai (n=44) Haryana (n=26)

Imipenem 0% 0% 0%

Meropenem 3% 3% 3%

Piperacillin-tazobactam 0% 0% 0%

Cefotaxime 0% 0% 0%

Ceftazidime 0% 0% 0%

Cefpirome 0% 0% 0%

Aztreonam 11% 0% 8%

Ciprofloxacin 8% 8% 8%

Gentamicin 3% 3% 3%

Tobramycin 0% 0% 0%

Amikacin 0% 0% 0%

Minocycline 0% 0% 0%

Tigecycline 64% 56% 67%

Colistin 89% 94% 100%

KK Kumarasamy. Lancet ID. Vol 10. September 2010

Why are CREs clinically important?

KPC NDM-1

Gene Location Highly transferable plasmids

Treatment options Limited

Outcomes Infections associated with high mortality

Reporting required in Utah

Outbreaks Mostly clonal Mostly polyclonal

Asymptomatic carriage plays an key role

in transmission

Seven Ways to Preserve Antibiotics

• US database for antibiotic use and resistance• Restrict use of antibiotics in agriculture• Prevent selected nosocomial infections• Practice antimicrobial stewardship• Promote use of new diagnostic tests (POC)• Reduce FDA antibiotic barrier• Facilitate public-private partnerships for

antibiotic development

Bartlett, JG. CID. 2013:56 (15 May)

CDC’s Four Core Actions

• Prevent infections, prevent spread• Track resistance patterns• Improve use of antibiotics• Develop new antibiotics and diagnostic tests

Antibiotic Resistance Threats in the U.S., 2013. CDC

Mechanism of Resistance: Horizontal Gene Transfer

INFECTION CONTROL MEASURES TO PREVENT SPREAD OF CRE

• Awareness• HAND HYGIENE• Use glove and gowns

for every encounter• Use equipment

dedicated• Communicate with

facilities for transfers• Limit HCW exposure

“Emerging Antibiotics”

Antibiotic Pipeline

PRODUCT STATUS WT P aerug ESBL KPC NDM-1

Ceftolozane/taxobactama Phase 3 Y Y N NCeftazidime-avibactama Phase 3 Y Y Y N

Ceftaroline-avibactama Phase 2 N Y Y N

Imipenem/MK-7655a Phase 2 Y Y Y N

Plazomicinb Phase 2 N Y Y ?

Eravacyclinec Phase 2 N Y Y ?

Brilacidind Phase 3 ? Y ? ?

HW Boucher. CID. 2013;56(12):1685-94

WT=wild typeESBL=Extended spectrum beta lactamaseKPC=Klebsiella pneumoniae carbapenemaseNDM-1=New Delhi metallo-β-lactamase

a. Β-lactamase inhibitorb. Aminoglycosidec. Fluorocycline (targets ribosome)d. Peptide defense protein mimetic

FDA approved rapid diagnostic platformsMethod ADVANTAGES DISADVANTAGES

MALDI-TOF Mass spectrometry Rapid speciation of micro-organisms

Requires growth in solid media

No resistance markers

PNA FISHQuick FISH

Nucleic acid hybridization

Rapid speciation of Staphylococcus sp,

Enterococcus sp, GNR, Candida sp directly out of blood culture

No resistance markers

Verigene BC-GP

Microarray-based nucleic acid

hybridization

Rapid speciation of most common gram positive cocci

and resistance markers (mecA, Van A, Van B) directly out of

blood culture

No gram negatives rods or Candida sp

yet

Film Array BCID panel

Multiplex PCR Gram positive, gram negative, yeast, resistance markers

(VanA, Van B, mecA) directly out of blood culture

No gram negative resistance markers

SUMMARY

• Antibiotic resistance in gram negative organisms is increasing rapidly

• Preventing spread of organisms in healthcare settings is critical

• We need to be wiser about how we use antibiotics

• While essential, waiting for new antibiotics is not the solution for combating antibiotic resistance

THANK YOU FOR YOUR ATTENTION!