File - International Nursing Symposium

Seventh International Symposium in
Continuing Nursing Education/March 2014
Donald W. McLaren, MD
 To
discuss epidemiology of typhoid
 To discuss myriad of ways Typhoid can
 To discuss challenges in diagnosis and give
some guidelines for diagnosis
 To discuss antibiotic resistance patterns and
treatment recommendations for Typhoid
 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
 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. .
 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
Suspected Ms. Mallon but getting stool and
blood specimen proved to be a real challenge
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 carrier
 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)
 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 All Rights Reserved.
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
 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
 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)
Remain in mononuclear cells in the liver, spleen,
LNs, bone marrow (Source of relapse, late
 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
 “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.”
 “Typhoid
fever usually presents
nonspecifically with abdominal pain, fever,
chills and constitutional symptoms; as a
result many other diagnoses may be
Hohmann EL. Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid
fever. UpToDate 2010.
 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
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 weeksmonths, but can still get neuro, GI complications.
Weight loss and debilitation can last for months.
 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
Strickland, GT (ed). Hunter’s Tropical Medicine and Emerging Infectious
Diseases, Eight Edition. Philadelphia: W. B. Saunders Company, 2000. p 477
 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
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
 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
Figure 1
Bal, S. K. et al. CMAJ 2004;170:1095
Copyright ©2004 Canadian Medical Association or its licensors - Copyright 1995-2014 Henriette Kress.
 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
 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
 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
 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.
 Not
real helpful but
 Anemia (normocytic) common
 WBC normal or decreased (15-30%) but
 Tends to be increased in children, or if
 Increased ESR
 Thrombocytopenia common
 LFTs (ALT, AST, bili) about double in 90+%
 LDH, CPK often elevated; Na, K can be low
 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% 2nd 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 culture
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
 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
Gross intestinal hemorrhage
Intestinal perforation
Toxic myocarditis
Transient deafness
Toxic hepatitis
Transient paralysis – LE
Hegazi AM. An update on: Typhoid Fever. http://www.
Magill AJ, et. Al. Hunter’s Tropical Medicine and Emerging Infectious Diseases. China: Saunders Elsevier, 2013.
pp 568-576
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
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
 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
 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
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
Late perforation
Intestinal hemorrhage
Other (myocarditis 4.4%)
Hegazi AM. An update on: Typhoid Fever. http://www.
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)
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
 Resistance
has lead to favoring FLQs,
ceftriaxone, over 1st line drugs for initial
 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
 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
 Alternatives being investigated – include
imipenen, newer or higher doses of old
fluoroquinolones, combinations.
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 intracellular levels (IC levels 50-100X > blood levels)
 Azithromax as effective as FLQ and have lower
failure rate and relapse rate than 3rd generation
 3rd
generation cephalosporins (i.e.
Ceftriaxone or cefixime) compared to FLQs
- longer to defervescence and higher
relapse rate
 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.
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)
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.
 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.
 Outside
U.S. Fluoroquinolones 1st line in
children and studies support they are ok if
 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
– 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
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.
 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.
 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
 In
past Ampicillin for 6-12 weeks +
 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
Ciprofloxacin 500-750 mg BID for 4 weeks
Ofloxacin 400 mg BID for 4 weeks
 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. © Docstoc® 2013. All rights
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
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
 1Brusch
JL, Garvey T. Typhoid Fever. Emedicine 2010.
Brusch JL. “Typhoid Fever.” Medscape Reference.
Accessed 1/22/2014 at
Burkholder-Allen K, Rega P. “’Typhoid’” Mary Mallon.
Accessed 1/22/2014 at
Christenson JC. “Salmonella Infections.” Pediatrics in
Review accessed online in 11/2014. @
Division of Environmental Health and Communicable
Disease Prevention. Missouri Department of Health
and Senior services Communicable Disease
Investigation Reference Manual .
Ekdahl K, de Song, B, Andersson Y. Travel Associated
Typhoid and Paratyphoid Fever. 2005.
Harrison’s Practice. Typhoid Fever.
Hegazi AM. An update on: Typhoid Fever.
 7Hohmann
EL. Epidemiology, microbiology, clinical
manifestations, and diagnosis of typhoid fever. UpToDate 2010.
UpToDate reaccessed 1/22/2014 @
Hohmann EL. Microbiology and epidemiology of Salmonellosis.
UpToDate 2010. UpToDate reaccessed 1/22/2014 @
Hohmann EL. Pathogenesis of typhoid fever. UpToDate 2010.
UpToDate reaccessed 1/22/2014 at
Hohmann EL. Treatment and prevention of typhoid fever.
UpToDate 2010. UpToDate reaccessed 1/22/2014 @
Kadhiravan, T. Drug-resistant Typhoid Fever – Implications
for Clinical practice. Medicine Update 2007; pp. 584-586.
Kalra SP, Naithani N, Mehta SR, Swamy AJ. Current trends
in the Management of Typhoid Fever. MJAFI 2003; 59:130135.
Kumar R. Typhoid Fever. Power Point referencing World
Health Organization 2003. N Engl. J Med, Vol 347,No.22.
Magill AJ, et. Al. Hunter’s Tropical Medicine and Emerging
Infectious Diseases. China: Saunders Elsevier, 2013. pp 568576
Mirza, SH. Multi-drug resistant Typhoid – A Global Review.
Infections Disease Journal of Pakistan. Jan – March 2005:
pp; 17-20.
Missouri Depart. Of Health and senior Services
Communicable Disease Investigation and
Reference Manual. Typhoid fever. 7/03.
 Zahran RF. Typhoid Fever.
 Rosenberg J. “Typhoid Mary: The sad story of a
woman responsible for several typhoid
outbreaks. accessed on 1/22/2014 at
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and Emerging Infectious Diseases, Eight Edition.
Philadelphia: W. B. Saunders Company, 2000. p

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