Seventh International Symposium in Continuing Nursing EducationMarch 2014 Donald W McLaren MD Purpose of talk To discuss epidemiology of typhoid To discuss myriad of ways Typhoid can present ID: 380439
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Slide1
Typhoid Fever
Seventh International Symposium in Continuing Nursing Education/March 2014
Donald W. McLaren, MD
Slide2
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 TyphoidSlide3Slide4Slide5
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 madnessSlide6
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) 1984-1989Slide7
©
Homeschool
Freebie of the Day. .Slide8
http://quigleyscabinet.blogspot.com/2010/07/typhoid-mary.htmlSlide9
“Typhoid Mary”
Mary Mallon (born 1869)
Emigrated from Ireland at about age 15
First healthy carrier identified in the U.S.
Unfortunately worked as a cook
Hired by Charles Warren, investment banker
6 of 11 in his household became infected
Hired civil engineer George Soper to investigate
Suspected Ms. Mallon but getting stool and blood specimen proved to be a real challengeSlide10
“typhoid Mary” continued
She with knife in hand put up resistance
After unsuccessful attempts, 5 police officers took 5 hours to find her hiding in a closet
Known infected 47 – maybe many more – 3 died
Initially quarantined 3 years but released upon promise never to cook again for others
Released once but started cooking again
Lived in enforced quarantine for 23 more years
Was demonized and butt of jokes
Became term for disease carrierSlide11
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)Slide12
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, relativesSlide13
© 2014 Top-10-List.com. All Rights Reserved.
http://top-10-list.org/2010/02/27/top-10-epidemics-list/2/Slide14
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 severeSlide15
© Society for Science & the Public 2000 - 2013. All rights reserved.
https://www.sciencenews.org/article/cheap-shots-%E2%80%94-typhoid-vaccine-shows-broad-coverageSlide16Slide17
Pathophysiology
Greater dose - higher attack rate, shorter incubation. About 30% of volunteers given 10
5
CFU, 10-20% with 10
3
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 ileumSlide18
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)Slide19
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 worseSlide20
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.”Slide21
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.comSlide22
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 unreliableSlide23
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.Slide24
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 Slide25
Clinical history
Strickland, GT (ed). Hunter’s Tropical Medicine and Emerging Infectious Diseases, Eight Edition. Philadelphia: W. B. Saunders Company, 2000. p 477Slide26
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 Slide27
17
Strickland, GT (ed). Hunter’s Tropical Medicine and Emerging Infectious Diseases, Eight Edition. Philadelphia: W. B. Saunders Company, 2000. p 477Slide28
Magill AJ, et. Al. Hunter’s Tropical Medicine and Emerging Infectious Diseases. China: Saunders Elsevier, 2013. pp 568-576Slide29
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 temperatureSlide30
Rose spots
(http://en.wikipedia.org/wiki/File:Salmonella_typhi_typhoid_fever_PHIL_2215_lores.jpgSlide31
http://www.zipheal.com/typhoid/typhoid-fever-symptoms/3761Slide32
Copyright ©2004 Canadian Medical Association or its licensors
Bal, S. K. et al. CMAJ 2004;170:1095
Figure 1Slide33
Clinical – classic fever curve
http://www.worldortho.com/dev/index.php?option=com_content&task=view&id=1786&Itemid=420Slide34
http://www.henriettes-herb.com
- Copyright 1995-2014 Henriette Kress.Slide35
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.
Slide36
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 > 39
o
C, 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 568-576Slide37
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 pneumoniaSlide38
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.Slide39
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 lowSlide40
Diagnosis
Definitive diagnosis a + culture
Positive from different places at different times
Bone marrow most consistently + throughout disease
– 90% sensitive up to 5 days after antibiotics started
Stool + 30-50% early
; 20% 2
nd
week; higher with later increased shedding from GB. Urine less.
Blood 90% week 1, but less after first week
Blood overall 40-80%. Can increase with high volume culture (10-15 cc) and multiple cultures
Rose spots – about 60% positive cultureSlide41
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 endemicSlide42
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 PCRSlide43
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. i
mbabafevers.com/.../An%20update%20on%20
typhoid
%20fever/Epidemiology%20of%20
typhoid
%20fever.pptSlide44
Magill AJ, et. Al. Hunter’s Tropical Medicine and Emerging Infectious Diseases. China: Saunders Elsevier, 2013. pp 568-576Slide45
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 cholecystitisSlide46
Intestinal perforation
Rare in children but as high as 25% in adults
Classically in 3
rd
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 3
rd
week
80% single perforation
May be masked by steroids
Tx: Surgery and broaden antibiotic coverage
High mortalitySlide47
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 childrenSlide48
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, leishmaniasisSlide49
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. i
mbabafevers.com/.../An%20update%20on%20
typhoid
%20fever/Epidemiology%20of%20
typhoid
%20fever.pptSlide50
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)Slide51
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 CMPSlide52
Treatment - resistance
Resistance has lead to favoring FLQs, ceftriaxone, over 1
st
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 IndiaSlide53
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, 3
rd
generation cephalosporins
Alternatives being investigated – include imipenen, newer or higher doses of old fluoroquinolones, combinations. Slide54
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 childrenSlide55
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 3
rd
generation cephalosporins
3
rd
generation cephalosporins (i.e. Ceftriaxone or cefixime) compared to FLQs - longer to defervescence and higher relapse rate Slide56
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 FQs
Azithromycin
1 gm orally then 500 daily for 5-7 days OR 1 gm po daily X 5 days
CMP
2-3 gm/day divided q6hr for 14 days
Hohmann EL. Treatment and prevention of typhoid fever. UpToDate 2010. UpToDate.comSlide57
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.comSlide58
Treatment (children) cont
10
Azithromycin
10-20 mg/kg to 1 g maximum once daily for 5-7 days
If fully susceptible
Amox
100 mg/kg/d q8hr max 4 g/day for 14 days
TMP-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.comSlide59
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 1
st
choice– use Azithromax or 3
rd
generation cephalosporin
CMP, Amp, TMP-SMX ok if not resistantSlide60
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 daysSlide61
http://thedhakaproject.blogspot.com/2011/02/treatment-of-typhoid-fever.htmlSlide62
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.Slide63
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.Slide64
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 preparersSlide65
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 weeks
Ofloxacin
400 mg BID for 4 weeksSlide66
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. Slide67
http://www.docstoc.com/docs/11383809/Spots-Typhoid-Fever
©
Docstoc
® 2013. All rights reserved. Slide68
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 horizonSlide69
http://talesfromindonesia.wordpress.com/2012/06/22/of-typhoid-pills-and-crazy-prices-or-the-things-we-do-for-immunity/Slide70
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 3
rd
generation cephalosporin Slide71
Sources/credits
1
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http://emedicine.medscape.com/article/231135-print
.
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http://www.i
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typhoid
%20fever/Epidemiology%20of%20
typhoid
%20fever.pptSlide73
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http://www.uptodate.com/contents/pathogenesis-of-typhoid-fever?source=search_result&search=typhoid&selectedTitle=3%7E77
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UpToDate
reaccessed 1/22/2014 @
http://www.uptodate.com/contents/treatment-and-prevention-of-typhoid-fever?source=search_result&search=typhoid&selectedTitle=2%7E77Slide74
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http://www.apiindia.org/medicine_update_2007/98.pdf
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