TYPHOID FEVER

  Seventh International Symposium in Continuing Nursing Education/March

2014

Donald W. McLaren, MD

PURPOSE OF TALK To discuss epidemiology of typhoid To discuss myriad of ways Typhoid can

present To discuss challenges in diagnosis and

give some guidelines for diagnosis To discuss antibiotic resistance patterns

and treatment recommendations for Typhoid

INTRODUCTION Typhoid or Enteric fever is a systemic

illness with fever and abdominal symptoms

Caused by S. Typhi & paratyphi A, B, and C

Now known as Salmonella enterica serotypes Typhi and Paratyphi A,B and C

Typhi meaning “typhus like” according to one source. From Greek typhos - an ethereal smoke or cloud that was believed to cause illness and madness

SHORT HISTORY OF TYPHOID Known 2000 years ago - may have been cause

of Great Plague of Athens at end of Pelopennesian War 431-404 B.C.

1659 First description of epidemic typhoid 1837 first differentiated from typhus 1880 Carl Eberth discovered typhoid bacillus 1896 Widal test described by George Widal 1948 Antibiotic treatment became available Increasing drug resistance since emergence of

Multidrug resistance (MDR) 1984-1989

© Homeschool Freebie of the Day. .

http://quigleyscabinet.blogspot.com/2010/07/typhoid-mary.html

“TYPHOID MARY” Mary Mallon (born 1869)

Emigrated from Ireland at about age 15First healthy carrier identified in the U.S.Unfortunately worked as a cookHired by Charles Warren, investment

banker6 of 11 in his household became infectedHired civil engineer George Soper to

investigateSuspected Ms. Mallon but getting stool

and blood specimen proved to be a real challenge

“TYPHOID MARY” CONTINUED

She with knife in hand put up resistanceAfter unsuccessful attempts, 5 police officers

took 5 hours to find her hiding in a closetKnown infected 47 – maybe many more – 3

died Initially quarantined 3 years but released

upon promise never to cook again for othersReleased once but started cooking againLived in enforced quarantine for 23 more

yearsWas demonized and butt of jokesBecame term for disease carrier

ETIOLOGY/BACTERIOLOGY Salmonella species – Typhi, Paratyphi A,B,C. Typhi > Paratyphi: equal in severity now Highly specific to humans - infection means

contact with infected individual, chronic carrier or contaminated food or water

3 common antigens – O (body), H (flagella), Vi (virulence antigen – lacking in about 10%)

Resistance to Amp, chloramphenicol (CMP), TMP/SMX (Multidrug resistance or MDR) a worldwide problem since 1989; increasing resistance to fluoroquinolones (FLQ)

EPIDEMIOLOGY 200-300 cases / year in U.S. 314 in 2006

– about 0.42/100,000 travelers 80% have travelled (< 20% traced to

carrier) – 2/3 to India Almost none had gotten the vaccine. Most cases from India (47%), Pakistan,

Mexico, Bangladesh India area travel (>100 case / million

travelers); SE Asia and Africa 5-14/million Highest rate if visiting friends, relatives

© 2014 Top-10-List.com. All Rights Reserved. http://top-10-list.org/2010/02/27/top-10-epidemics-list/2/

EPIDEMIOLOGY Infects > 21 mil/yr, kills >200,000 worldwide Most prevalent in impoverished areas with

overcrowding and poor access to sanitation. Mortality 9-13% pre antibiotics – now < 1% Incidence

South-central and SE Asia, Southern Africa > 100 cases / 100,000 person years

Rest of Asia, Africa, Latin America, Oceana 10-100 cases/ 100,000 person years (but poor reporting)

Percentage of paratyphi rising Resistance increasing from <1% 1986-89 to

>12% Children < 1 more susceptible, more severe

© Society for Science & the Public 2000 - 2013. All rights reserved. https://www.sciencenews.org/article/cheap-shots-%E2%80%94-typhoid-vaccine-shows-broad-coverage

PATHOPHYSIOLOGY Greater dose - higher attack rate, shorter

incubation. About 30% of volunteers given 105 CFU, 10-20% with 103 CFU develop illness

Most cases get low dose with low attack rate and long incubation of 2-3 weeks.

Ingested - pass stomach to SB. Doesn’t tend to cause fulminant enteritis as do non–typhi salmonella; 10-20% get D at some point.

Phagocytic cells take to sub-mucosal region and proliferate – primarily at terminal ileum

PATHOPHYSIOLOGY Enter Peyer’s patches which hypertrophy -

lymphs and mononuclear cells recruited. Necrosis of sub-mucosal tissue leads to

abdominal pain, sometimes ileal perforation.

Dissemination from Peyer’s patches through lymphatic system, blood to replicate in the reticuloendothelial system

This is a major part of Typhoid which can leads to prostration, sepsis, H-S megaly. (Primary bacteremia often silent)

PATHOPHYSIOLOGY Remain in mononuclear cells in the liver,

spleen, LNs, bone marrow (Source of relapse, late complications)

Proliferate then break into bloodstream Need Fe for growth. Hemochromatosis carriers

and carriers of cystic fibrosis gene have decreased susceptibility (and to cholera and Tb)

Low stomach acid (PPIs) - more susceptibile

Evidence mixed whether immune def (HIV) leads to more severe or complicated typhoid as it does for other salmonella organisms, but fare worse

CLINICAL – GREAT IMITATOR HTTP://WWW.WORLDORTHO.COM/DEV/INDEX.PHP?OPTION=COM_CONTENT&TASK=VIEW&ID=1778&ITEMID=420

“A case of typhoid fever may present as a disease clinically indistinguishable from malaria, progress to a bacillary dysentery, mimic a case of acute bronchitis, simulate a fully fledged lobar pneumonia, cause an acute abdomen with perforation, and then finally in convalescence, with its evil spent, linger on as an orchitis, a myocarditis or a peripheral neuritis. The Seven Ages of Man are scarcely greater, or more diverse in their span, or the stage more prone to variety.”

CLINICAL – GREAT IMITATOR* “Typhoid fever usually presents

nonspecifically with abdominal pain, fever, chills and constitutional symptoms; as a result many other diagnoses may be entertained”

Hohmann EL. Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever. UpToDate 2010. UpToDate.com

CLINICAL Personal experience: one of hardest

common tropical diseases to dx early and accurately

Highly variable presentation Often nonspecific symptoms Many organs can be effected Can mimic many other diseases No good quick accurate test to diagnose Test most often used to diagnose in

third world is totally unreliable

CLASSIC PRESENTATION IF NOT TREATED

Starts 7-14 (5-21) days after ingestion Week 1 - stepwise fever increase. Chills

common. Abdominal pain. Bacteremia. (Constipation in some - Dry cough, HA, delirium and malaise)

Week 2 Fever plateaus: 103-4. Rose spots, abdominal pain. Relative bradycardia and dicrotic pulse. (abdominal distension and splenomegaly)

Week 3 – More toxic, anorexic. Tachycardia. Bowel perforation, other complications, death possible.

Week 4 Slow improvement/resolution over weeks-months, but can still get neuro, GI complications. Weight loss and debilitation can last for months.

CLINICAL HISTORY Can vary a lot from classic presentation. Tends to be insidious onset Only 12% have classic stepwise fever Can develop D instead of constipation

(especially in AIDS, children, but in 1/3 of normal persons, specific to some outbreaks)

Non-localizing abdominal pain Non specific flu like symptoms Many atypical presentations

CLINICAL HISTORY

Strickland, GT (ed). Hunter’s Tropical Medicine and Emerging Infectious Diseases, Eight Edition. Philadelphia: W. B. Saunders Company, 2000. p 477

CLINICAL FEATURES Fever most prominent feature and lasts

3-4 weeks untreated. Tends not to be sudden and high (unlike

Dengue or Malaria) Tends to be stepwise (think 2 steps

forward, and 1 step back each day) Relative bradycardia common – slower

than would be expected for degree of fever but not very helpful sign

17Strickland, GT (ed). Hunter’s Tropical Medicine and Emerging Infectious Diseases, Eight Edition. Philadelphia: W. B. Saunders Company, 2000. p 477

Magill AJ, et. Al. Hunter’s Tropical Medicine and Emerging Infectious Diseases. China: Saunders Elsevier, 2013. pp 568-576

CLINICAL – USEFUL PHYSICAL SIGNS Rose spots – small blanching 2-4

salmon-pink colored macules or M-P rash mainly on chest, abdomen and back. 30% at end of first week. Lasts 2-5 days. Organism grows from lesions which are clumps of bacteria, cells.

Coated tongue – varies from 50-95%. White, yellow or brown sparing edge of tongue.

Stepwise rise in temperature

ROSE SPOTS (HTTP://EN.WIKIPEDIA.ORG/WIKI/FILE:SALMONELLA_TYPHI_TYPHOID_FEVER_PHIL_2215_LORES.JPG

http://www.zipheal.com/typhoid/typhoid-fever-symptoms/3761

Copyright ©2004 Canadian Medical Association or its licensors

Bal, S. K. et al. CMAJ 2004;170:1095

Figure 1

CLINICAL – CLASSIC FEVER CURVE HTTP://WWW.WORLDORTHO.COM/DEV/INDEX.PHP?

OPTION=COM_CONTENT&TASK=VIEW&ID=1786&ITEMID=420

http://www.henriettes-herb.com - Copyright 1995-2014 Henriette Kress.

USEFUL S/S POINTING TO TYPHOID Must have high index of suspicion Insidious onset – not sudden high

fever If present classic fever curve Coated tongue Rose spots Often have abdominal findings. If malaria ruled out or already

treated, and fever continues > 1 week must consider typhoid.

FROM HUNTER’S – IN ENDEMIC AREA:

Must have high index suspicion Consider if > 3 days non-focal fever. Good hx, px, lab can R/O other

conditions Increased suspicion if: young age, T > 39oC,

ill appearance and any abdominal symptoms. Consider W/U if >3 days non-localizing fever

+ any of these features Likelihood this is typhoid increases with

length of fever: If > 7 days should be evaluated and treated

(Magill AJ, et. Al. Hunter’s Tropical Medicine and Emerging Infectious Diseases. China: Saunders Elsevier, 2013. pp 568-576

OTHER PRESENTATIONS Can present as pneumonia Massive rectal bleeding Delirium and coma Uncommon: hepato-biliary, CNS, CVS,

Respiratory, GU, MS system complications.

Severe presentation ill or toxic appearing, febrile > 1 week, moderate abdominal pain, constipation or diarrhea.

Death most likely from GI perf, hemorrhage, encephalopathy, seizures or pneumonia

OTHER USEFUL SIGNS Malaise, anorexia and lassitude are

prominent in many cases. HA is common Dry cough is common as is vague

abdominal discomfort is common, constipation

Less common in antibiotic era Much less splenomegaly (60 to 10%) Fewer have rose spots (30 to 1.5%) Much lower mortality (15 to < 1%) Diarrhea now more common than constipation

especially in children and varies with location.

LAB Not real helpful but Anemia (normocytic) common WBC normal or decreased (15-30%) but Tends to be increased in children, or if

perforation. Increased ESR Thrombocytopenia common LFTs (ALT, AST, bili) about double in

90+% LDH, CPK often elevated; Na, K can be

low

DIAGNOSIS Definitive diagnosis a + culture

Positive from different places at different timesBone marrow most consistently +

throughout disease – 90% sensitive up to 5 days after antibiotics started

Stool + 30-50% early; 20% 2nd week; higher with later increased shedding from GB. Urine less.

Blood 90% week 1, but less after first weekBlood overall 40-80%. Can increase with high

volume culture (10-15 cc) and multiple culturesRose spots – about 60% positive culture

DIAGNOSIS – SEROLOGICAL TESTING Widal - measures agglutinating antibodies

to H, O antigens of S. Typhi. Not specific, sensitive enough – no

longer considered acceptable for diagnosis.

Positive if prior infection or immunization.

Great lab to lab variability – most not reliable

O titer more specific, H more sensitive – > 1:160 (O titer) positive + in non-endemic area but 1:640 in endemic

DIAGNOSIS CONTINUED Fourfold increase in paired titers 2

weeks apart helpful in half of cases. Really not positive till 6-8 days (O)

and 10-12 days (H) and negative in up to 30% of culture proven cases. Peaks week 3-5

Newer tests probably not available on field; not that helpful acutely since antibodies not present at beginning of illness, not very available. Includes PCR

COMPLICATIONS Gross intestinal hemorrhage 21% Relapse 12.5% Pneumonia 11.4% Intestinal perforation 1.9% Psychosis 1.9% UTI 1.9% Toxic myocarditis 1.7% Transient deafness 1.4% Toxic hepatitis 0.6% Meningitis 0.3% Endocarditis 0.3% Transient paralysis – LE 0.3%Hegazi AM. An update on: Typhoid Fever. http://www. imbabafevers.com/.../An%20update

%20on%20typhoid%20fever/Epidemiology%20of%20typhoid%20fever.ppt

Magill AJ, et. Al. Hunter’s Tropical Medicine and Emerging Infectious Diseases. China: Saunders Elsevier, 2013. pp 568-576

COMPLICATIONS – MANY OTHERS Pancreatitis or abscess Empyema Renal complications Focal infections in many places Post salmonella enteritis reactive arthritis

3.4% Bed sores CNS and neuritis (even psychosis) Dehydration Muscle degeneration and DVT Hemolytic anemia Acute cholecystitis

INTESTINAL PERFORATION Rare in children but as high as 25% in

adults Classically in 3rd week (1-22 days) median 9 days Up to 3% in developing countries (1% in U.S.) Sx: worsening, sudden onset increased RLQ pain,

tachycardia, rebound fever, abdominal distention tenderness or rigidity, leukocytosis in 3rd week

80% single perforation May be masked by steroids Tx: Surgery and broaden antibiotic

coverage High mortality

ENCEPHALOPATHY AND PNEUMONIA Delirium, stupor and confusion Sometimes altered consciousness or coma Seizures most common in children with

increased mortality (usually < 35 cells in CSF)

Has been reported in up to 17% of patients. High mortality around 50%. Decreased

mortality to 10% if treated with dexamethasone in study out of Indonesia.

Pneumonia serious complication of severe typhoid more common in children

DIFFERENTIAL DIAGNOSIS Other salmonella species Malaria Influenza Shigella and other bacterial enteritis Dengue Typhus, Rickettsial infections Pulmonary or abdominal Tb Brucellosis Many others: Trypanosomiasis,

Leptospirosis, Amebic liver abscess, Acute HIV infections, Toxoplasmosis, Tularemia, leishmaniasis

PROGNOSIS 10-15% (as high as 30%) mortality prior to

CMP Now < 1%; 0.2% in U.S.; higher in developing

countries – 2% in hospitalized patients Higher in infants and elderly Higher if antibiotics delayed (3) Causes of death

Early shock, ARDS 27.4% Late perforation 14.1 Intestinal hemorrhage 25.9 Pneumonia 12.6 Other (myocarditis 4.4%) Hegazi AM. An update on: Typhoid Fever. http://www.

imbabafevers.com/.../An%20update%20on%20typhoid%20fever/Epidemiology%20of%20typhoid%20fever.ppt

TREATMENT - RESISTANCE Emergence of resistance to all first line drugs

(MDR) began late 1980s – Amp, TMX/SMX, CMP (plasmid mediated)

Subsequently nalidixic acid resistance (NARST) which is followed by FLQ (single point mutations)

NARST (NaR) considered marker for decreased fluoroquinolone susceptibility.

FLQ resistance common from India In 1996-1997 CDC reported 17% resistant to 5

drugs. (Now 13% MDR) Sporadic ceftriaxone resistance but not clinically

much of a problem anywhere yet (MIC creep)

TREATMENT - RESISTANCE U.S. 1999-2006 43% resistant to at least 1

antibiotic Resistance patterns change quickly –

Asia: increase NaR resistance from 5-50% (1993 – 2004) 2009 from Central India 98% NaR resistant Full quinolone resistance India, Korea Nepal from 0-13%

In Africa only about 5% resistant to FLQs. 3.7% Americas, 10.8% Middle East

(When not resistant to CMP – very good drug despite 1:20,000 aplastic anemia – quick response (3-5 days), inexpensive, widely available, broad spectrum)

With decreased usage, some reemergence sensitivity to older first line drugs – 2001-4 67% typhi and 80% paratyphi sensitive to CMP

TREATMENT - RESISTANCE Resistance has lead to favoring FLQs,

ceftriaxone, over 1st line drugs for initial treatment

NARST especially problem in Asia – 70-90% in some parts of India, Nepal and Vietnam.

Nalidixic acid resistant S. Typhi harbinger of fully quinolone – resistant S. Typhi.

NaR resistant typhoid have slower and less reliable response to quinolones.

Avoid FLQs as first line drugs in most of Asia and especially India

TREATMENT RESISTANCE Even if “sensitive” to FLQ, tx of NARST

with FLQ less effective especially for short course tx of 3-5 days. Defervesce slower (> 10 days vs. 3.5 days) and > rate of treatment failure

Better options Azithromycin, 3rd generation cephalosporins

Alternatives being investigated – include imipenen, newer or higher doses of old fluoroquinolones, combinations.

TREATMENT IF susceptible, Fluoroquinolones drug of

choice for fully susceptible organisms High levels in GI tract after oral treatment Bactericidal with good IC (intracellular)

penetration Oral and IV available; Not expensive Acts rapidly - Defervesce 3-4 days High cure rate; low failure rate with relapse rate

< 2% Concentrated in biliary tract – decreasing carrier

rate Cipro, ofloxacin, levofloxacin good – Not

Norfloxacin – poorly absorbed Several studies show safety in children

If resistant, Azithromycin also gets good intra-cellular levels (IC levels 50-100X > blood levels)

Azithromax as effective as FLQ and have lower failure rate and relapse rate than 3rd generation cephalosporins

3rd generation cephalosporins (i.e. Ceftriaxone or cefixime) compared to FLQs - longer to defervescence and higher relapse rate

ADULT TREATMENT EXCEPT FOR SOUTH (AND POSSIBLY SE) ASIA Ciprofloxacin 500 mg BID or Ofloxacin

400 mg BID po or IV X 7-10 days. Ceftriaxone 2-3 gm IV, IM daily or

Cefixime 20-30 mg/kg/day po divided BID X 7-14 days.

Alternatives if can’t take, resistant to FQsAzithromycin 1 gm orally then 500 daily for

5-7 days OR 1 gm po daily X 5 daysCMP 2-3 gm/day divided q6hr for 14 days

Hohmann EL. Treatment and prevention of typhoid fever. UpToDate 2010. UpToDate.com

TREATMENT IN CHILDREN (IN U.S.) A beta lactam

Ceftriaxone 100 mg/kg/day max 4 gm/day for 10-14 days (qD or BID)

Cefotaxime 150-200 mg/kg/day q6-8 hr max 12 g for 10-14 days

Cefixime 20 mg/kg/day q12 hours max 400 mg/day 10-14 days (po)

Fluoroquinolones Ciprofloxacin or Ofloxacin 30 mg/kg/day BID

max 1000 mg/day oral or IV for 7-10 days Ofloxacin 30 mg/kg daily max 800 mg/day po

or iv X 7-10 days

Hohmann EL. Treatment and prevention of typhoid fever. UpToDate 2010. UpToDate.com

TREATMENT (CHILDREN) CONT 10

Azithromycin 10-20 mg/kg to 1 g maximum once daily for 5-7 days

If fully susceptibleAmox 100 mg/kg/d q8hr max 4 g/day for 14

daysTMP-SMX 8-12 mg/kg TMP 40-60 mg/kg

SMX / day divided every 6 hours max 320 mg TMP/1600 mg SMX/day for 14 days.

CMP 75 mg/kg/d po q6hr max 3g/day: 14-21 days

Hohmann EL. Treatment and prevention of typhoid fever. UpToDate 2010. UpToDate.com

TREATMENT Outside U.S. Fluoroquinolones 1st

line in children and studies support they are ok if fluoroquinolones-sensitive.

Treat at least 5 days after fever resolution

If susceptible usually defervesce 3-5 days So much resistance from parts of S, SE

Asia fluoroquinolone should not be 1st choice– use Azithromax or 3rd generation cephalosporin

CMP, Amp, TMP-SMX ok if not resistant

CHILDREN CONTINUED FLQ – cartilage toxicity in immature

animals Large series show no evidence acute

adverse bone or joint events in humans. For serious infection if no other

options they are ok for children Optimal duration of cephalosporin

treatment not established – but need > 7 days

Ceftriaxone may be superior to cefotaxime so give ceftriaxone or cefixime 10-14 days

http://thedhakaproject.blogspot.com/2011/02/treatment-of-typhoid-fever.html

TREATMENT - OTHER Pay attention to nutrition, fluid and

electrolytes and monitor closely In complicated typhoid (critically ill -

shock, obtundation, delirium, stupor, coma) studies with CMP in past show 80% reduced mortality from 55% to 10% with corticosteroids.

Dexamethasone 3 mg/kg then 1 mg/kg q6hr for 48 hours.

Perforation (most - 80% single – ileum) – primary repair. Sometimes needs segmental resection and appropriate antibiotics. 14-34% mortality.

RELAPSE Common 2-3 wks after fever resolution

(1-10 weeks) after antibiotics stopped. Relapse usually milder than initial

infection. In past 10-25% but more recently 1-

6% - newer antibiotics seem to be more effective

Usually can treat with same drug vs. longer course with third generation cephalosporin. But culture to be sure sensitive.

CARRIER STATE Can shed normally up to 3 months in 10% Can be in stool or less commonly urine Chronic carrier = Excretion in stool (or

urine) > 12 months (Typhoid > Paratyphoid)

Incidence after Typhoid about 4 % (1-6%)

Increased with cholelithiasis Urine carriage more common with kidney

stones, urinary schistosomiasis or BPH Well but risk to others – esp. food preparers

TREATMENT OF CARRIER STATE In past Ampicillin for 6-12 weeks +

cholecystectomy. Now can treat try FLQ for 4 wks for

near 90% cure rate. If FLQ treatment fails, cholecystectomy

(for food handlers, day care workers, health care workers)Ciprofloxacin 500-750 mg BID for 4 weeksOfloxacin 400 mg BID for 4 weeks

CARRIERS Missouri: after typhoid 3 stool cultures

needed for (child care, food handlers, medical personnel) 24 hrs apart to see if carrier - If so repeat every month till 3 consecutive negative cultures.

For chronic carrier (> 1 year) must have 6 consecutive negative cultures collected 1 month apart to go back to work.

Missouri Depart. Of Health and senior Services Communicable Disease Investigation and Reference Manual. Typhoid fever. 7/03.

http://www.docstoc.com/docs/11383809/Spots-Typhoid-Fever © Docstoc® 2013. All rights reserved.

PREVENTION/VACCINATION CDC: “Boil it, cook it, peel it, or forget it” 2 vaccines – 50% effective at 3 years (85%

initially) Parenteral Vi polysaccharide vaccine (efficacy 55%) (>

2 yoa. Repeat 2 yrs); Oral S. Typhi vaccine strain Ty21a (efficacy 51%) (> 6

yoa. Repeat 5 years) About 1/6 of cases in travelers came after < 2 weeks

travel so recommended even for short travel. Neither 100% effective – no good against paratyphoid In U.S. 1994-99, ¾ of U.S. cases from travel; but only

4% vaccinated Though only approved for > 6, studies show 57%

protection with oral vaccine in ages 2-5 Others on horizon

http://talesfromindonesia.wordpress.com/2012/06/22/of-typhoid-pills-and-crazy-prices-or-the-things-we-do-for-immunity/

SUMMARY Typhoid is a serious illness caused by S. Typhi Typhoid can present many ways and mimic

many other diseases. Diagnosis requires a high index of suspicion

The most common test for Typhoid, the Widal test, is not reliable, is positive after one has a vaccine, and should not be relied on

There is considerable drug resistance in typhoid. FLQs are the DOC except in S, SE Asia. Due to FLQ resistance, better choices there are Azithromax or a 3rd generation cephalosporin

SOURCES/CREDITS 1Brusch JL, Garvey T. Typhoid Fever. Emedicine

medscape.com 2010. http://emedicine.medscape.com/article/231135-print.

Brusch JL. “Typhoid Fever.” Medscape Reference. Accessed 1/22/2014 at http://emedicine.medscape.com/article/231135-overview

Burkholder-Allen K, Rega P. “’Typhoid’” Mary Mallon. Accessed 1/22/2014 at http://www.docstoc.com/docs/161918129/%E2%80%9CTyphoid%E2%80%9D-Mary-Mallon---errata-llc www.errata-llc.com/blog/files/Typhoid_Mary.ppt

Christenson JC. “Salmonella Infections.” Pediatrics in Review accessed online in 11/2014. @ http://pedsinreview.aappublications.org/content/34/9/375

SOURCES/CREDITS Division of Environmental Health and Communicable

Disease Prevention. Missouri Department of Health and Senior services Communicable Disease Investigation Reference Manual . http://www.dhss.mo.gov/CDManual/Typhoidfever.pdf

Ekdahl K, de Song, B, Andersson Y. Travel Associated Typhoid and Paratyphoid Fever. Medscape.com 2005. http://www.medscape.com/viewarticle/511056_print

Harrison’s Practice. Typhoid Fever. http://www.harrisonspractice.com/practice/ub/view/Harrisons%20Practice/141051/0/enteric_fever

Hegazi AM. An update on: Typhoid Fever. http://www.imbabafevers.com/.../An%20update%20on%20typhoid%20fever/Epidemiology%20of%20typhoid%20fever.ppt

7Hohmann EL. Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever. UpToDate 2010. UpToDate reaccessed 1/22/2014 @ http://www.uptodate.com/contents/epidemiology-microbiology-clinical-manifestations-and-diagnosis-of-typhoid-fever?source=search_result&search=typhoid&selectedTitle=1%7E77

Hohmann EL. Microbiology and epidemiology of Salmonellosis. UpToDate 2010. UpToDate reaccessed 1/22/2014 @ www.worldortho.com/dev/index.php?option=com_content&task=view&id=1778&Itemid=420

Hohmann EL. Pathogenesis of typhoid fever. UpToDate 2010. UpToDate reaccessed 1/22/2014 at http://www.uptodate.com/contents/pathogenesis-of-typhoid-fever?source=search_result&search=typhoid&selectedTitle=3%7E77

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Magill AJ, et. Al. Hunter’s Tropical Medicine and Emerging Infectious Diseases. China: Saunders Elsevier, 2013. pp 568-576

Mirza, SH. Multi-drug resistant Typhoid – A Global Review. Infections Disease Journal of Pakistan. Jan – March 2005: pp; 17-20. http://www.idspak.org/journal/2005/Jan-March/page17-20.pdf

Missouri Depart. Of Health and senior Services Communicable Disease Investigation and Reference Manual. Typhoid fever. 7/03.

Zahran RF. Typhoid Fever. http://www.slideworld.org/slideshow.aspx/Typhoid-Fever-ppt-2844722

Rosenberg J. “Typhoid Mary: The sad story of a woman responsible for several typhoid outbreaks. About.com accessed on 1/22/2014 at http://history1900s.about.com/od/1900s/a/typhoidmary.htm

Strickland, GT (ed). Hunter’s Tropical Medicine and Emerging Infectious Diseases, Eight Edition. Philadelphia: W. B. Saunders Company, 2000. p 477