Thyfoid Fever

Introduction
Background
Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness
caused primarily by Salmonella typhi. The protean manifestations of typhoid fever make
this disease a true diagnostic challenge. The classic presentation includes fever,
malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling
illness that may progress to delirium, obtundation, intestinal hemorrhage, bowel
perforation, and death within one month of onset. Survivors may be left with long-term or
permanent neuropsychiatric complications.
S typhi has been a major human pathogen for thousands of years, thriving in conditions
of poor sanitation, crowding, and social chaos. t may have responsible for the !reat
"lague of #thens at the end of the "elopennesian $ar.
%
The name S typhi is derived
from the ancient !reek typhos, an ethereal smoke or cloud that was believed to cause
disease and madness. n the advanced stages of typhoid fever, the patient&s level of
consciousness is truly clouded. #lthough antibiotics have markedly reduced the
fre'uency of typhoid fever in the developed world, it remains endemic in developing
countries.
(
Transmission
S typhi has no nonhuman vectors. The following are modes of transmission)
*ral transmission via food or beverages handled by an individual who chronically
sheds the bacteria through stool or, less commonly, urine
+and-to-mouth transmission after using a contaminated toilet and neglecting
hand hygiene
*ral transmission via sewage-contaminated water or shellfish ,especially in the
developing world-
.
#n inoculum as small as %//,/// organisms causes infection in more than 0/1 of
healthy volunteers.
2
Pathophysiology
#ll pathogenic Salmonella species are engulfed by phagocytic cells, which then pass
them through the mucosa and present them to the macrophages in the lamina propria.
3ontyphoidal salmonellae are phagocyti4ed throughout the distal ilium and colon. $ith
toll-like receptor ,T56-70 and T56-289:(8;:-%2 comple<, macrophages recogni4e
pathogen-associated molecular patterns ,"#9"s- such as flagella and
lipopolysaccharides. 9acrophages and intestinal epithelial cells then attract T cells and
neutrophils with interleukin = ,5-=-, causing inflammation and suppressing the
infection.
0,>
n contrast to the nontyphoidal salmonellae, S typhi enters the host&s system primarily
through the distal ilium. S typhi has speciali4ed fimbriae that adhere to the epithelium
over clusters of lymphoid tissue in the ilium ,"eyer patches-, the main relay point for
macrophages traveling from the gut into the lymphatic system. S typhi has a ?i capsular
antigen that masks "#9"s, avoiding neutrophil-based inflammation. The bacteria then
induce their host macrophages to attract more macrophages.
0
t co-opts the macrophages& cellular machinery for their own reproduction
@
as it is carried
through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then
through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph
nodes. *nce there, the S typhi bacteria pause and continue to multiply until some critical
density is reached. #fterward, the bacteria induce macrophage apoptosis, breaking out
into the bloodstream to invade the rest of the body.
>
The gallbladder is then infected via either bacteremia or direct e<tension of S typhi 7
infected bile. The result is that the organism re-enters the gastrointestinal tract in the bile
and reinfects "eyer patches. Aacteria that do not reinfect the host are typically shed in
the stool and are then available to infect other hosts.
>,(
Life cycle of Salmonella typhi.
Risk factors
S typhi are able to survive a stomach p+ as low as %.0. #ntacids, histamine-( receptor
antagonists ,+( blockers-, proton pump inhibitors, gastrectomy, and achlorhydria
decrease stomach acidity and facilitate S typhi infection.
>
+?8#:S is clearly associated with an increased risk of nontyphoidal Salmonella
infectionB however, the data and opinions in the literature as to whether this is true for S
typhi infection are conflicting. f an association e<ists, it is probably minor.
=,C,%/,%%
*ther risk factors for clinical S typhi infection include various genetic polymorphisms.
These risk factors often also predispose to other intracellular pathogens. For instance,
PARK2 and PACGR code for a protein aggregate that is essential for breaking down the
bacterial signaling molecules that dampen the macrophage response. "olymorphisms in
their shared regulatory region are found disproportionately in persons infected with
Mycobacterium leprae and S typhi.
%(
*n the other hand, protective host mutations also e<ist. The fimbriae of S typhi bind in
vitro to cystic fibrosis transmembrane conductance receptor ,;FT6-, which is e<pressed
on the gut membrane. Two to 01 of white persons are hetero4ygous for the ;FT6
mutation F0/=del, which is associated with a decreased susceptibility to typhoid fever,
as well as to cholera and tuberculosis. The homo4ygous F0/=del mutation in ;FT6 is
associated with cystic fibrosis. Thus, typhoid fever may contribute to evolutionary
pressure that maintains a steady occurrence of cystic fibrosis, just as malaria maintains
sickle cell disease in #frica.
%.,%2
Dnvironmental and behavioral risk factors that are independently associated with typhoid
fever include eating food from street vendors, living in the same household with
someone who has new case of typhoid fever, washing the hands inade'uately, sharing
food from the same plate, drinking unpurified water, and living in a household that does
not have a toilet.
%0,%(
#s the middle class in south #sia grows, some hospitals there are
seeing a large number of typhoid fever cases among relatively well-off university
students who live in group households with poor hygeine.
%>
#merican clinicians should
keep this in mind, as members of this cohort often come to the United States for higher
degrees.
Frequency
United States
Since %C//, improved sanitation and successful antibiotic treatment have steadily
decreased the incidence of typhoid fever in the United States. n %C(/, .0,CC2 cases of
typhoid fever were reported. n (//>, there were .%2.
Aetween %CCC and (//>, @C1 of typhoid fever cases occurred in patients who had been
outside of the country within the preceding ./ days. Two thirds of these individuals had
just journeyed from the ndian subcontinent. The . known outbreaks of typhoid fever
within the United States were traced to imported food or to a food handler from an
endemic region. 6emarkably, only %@1 of cases ac'uired domestically were traced to a
carrier.
%@
International
Typhoid fever occurs worldwide, primarily in developing nations whose sanitary
conditions are poor. Typhoid fever is endemic in #sia, #frica, 5atin #merica, the
;aribbean, and *ceania, but =/1 of cases come from Aangladesh, ;hina, ndia,
ndonesia, 5aos, 3epal, "akistan, or ?ietnam.
%=
$ithin those countries, typhoid fever is
most common in underdeveloped areas. Typhoid fever infects roughly (%.> million
people ,incidence of ..> per %,/// population- and kills an estimated (//,/// people
every year.
%C
n the United States, most cases of typhoid fever arise in international travelers. The
average yearly incidence of typhoid fever per million travelers from %CCC-(//> by county
or region of departure was as follows)
%@
;anada - /
$estern +emisphere outside ;anada8United States - %..
#frica - @.>
#sia - %/.0
ndia - =C ,%(( in (//>-
Total ,for all countries e<cept ;anada8United States- - (.(
ortality!or"idity
$ith prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term
febrile illness re'uiring a median of > days of hospitali4ation. Treated, it has few long-
term se'uelae and a /.(1 risk of mortality.
%@
Untreated typhoid fever is a life-threatening
illness of several weeks& duration with long-term morbidity often involving the central
nervous system. The case fatality rate in the United States in the pre-antibiotic era was
C1-%.1.
(/
Race
Typhoid fever has no racial predilection.
Se#
Fifty-four percent of typhoid fever cases in the United States reported between %CCC and
(//> involved males.
%@
$ge
9ost documented typhoid fever cases involve school-aged children and young adults.
+owever, the true incidence among very young children and infants is thought to be
higher. The presentations in these age groups may be atypical, ranging from a mild
febrile illness to severe convulsions, and the S typhi infection may go unrecogni4ed. This
may account for conflicting reports in the literature that this group has either a very high
or a very low rate of morbidity and mortality.
%>,(%
%linical
&istory
# severe nonspecific febrile illness in a patient who has been e<posed to S typhi should
always raise the diagnostic possibility of typhoid fever ,enteric fever-.
%lassic typhoid fe'er syndrome
Typhoid fever begins @-%2 days after ingestion of S typhi. The fever pattern is stepwise,
characteri4ed by a rising temperature over the course of each day that drops by the
subse'uent morning. The peaks and troughs rise progressively over time.
*ver the course of the first week of illness, the notorious gastrointestinal manifestations
of the disease develop. These include diffuse abdominal pain and tenderness and, in
some cases, fierce colicky right upper 'uadrant pain. 9onocytic infiltration inflames
"eyer patches and narrows the bowel lumen, causing constipation that lasts the duration
of the illness. The individual then develops a dry cough, dull frontal headache, delirium,
and an increasingly stuporous malaise.
(
#t appro<imately the end of the first week of illness, the fever plateaus at %/.-%/2EF ,.C-
2/E;-. The patient develops rose spots, which are salmon-colored, blanching, truncal,
maculopapules usually %-2 cm wide and fewer than 0 in numberB these generally resolve
within (-0 days.
(
These are bacterial emboli to the dermis and occasionally develop in
persons with shigellosis or nontyphoidal salmonellosis.
((
:uring the second week of illness, the signs and symptoms listed above progress. The
abdomen becomes distended, and soft splenomegaly is common. 6elative bradycardia
and dicrotic pulse ,double beat, the second beat weaker than the first- may develop.
n the third week, the still febrile individual grows more to<ic and anore<ic with significant
weight loss. The conjunctivae are infected, and the patient is tachypneic with a thready
pulse and crackles over the lung bases. #bdominal distension is severe. Some patients
e<perience foul, green-yellow, li'uid diarrhea ,pea soup diarrhea-. The individual may
descend into the typhoid state, which is characteri4ed by apathy, confusion, and even
psychosis. 3ecrotic "eyer patches may cause bowel perforation and peritonitis. This
complication is often unheralded and may be masked by corticosteroids. #t this point,
overwhelming to<emia, myocarditis, or intestinal hemorrhage may cause death.
f the individual survives to the fourth week, the fever, mental state, and abdominal
distension slowly improve over a few days. ntestinal and neurologic complications may
still occur in surviving untreated individuals. $eight loss and debilitating weakness last
months. Some survivors become asymptomatic S typhi carriers and have the potential to
transmit the bacteria indefinitely.
%>,(.,(2,(,>
(arious presentations of typhoid fe'er
Incu"ation )eek * )eek + )eek , )eek - Post
Systemic 6ecovery
phase or
death
,%01 of
untreated
cases-
%/1-(/1
relapseB
.1-21
chronic
carriersB
long-term
neurologic
se'uelae
,e<tremely
rare-B
gallbladder
cancer
,66F%>@B
carriers-
Stepladder fever
pattern or insidious
onset fever
?ery
common
a

?ery common
#cute high fever ?ery rare
b
;hills #lmost all
c

6igors Uncommon
#nore<ia #lmost all
:iaphoresis ?ery common
.eurologic
9alaise #lmost all #lmost all Typhoid
state
,common-
nsomnia ?ery
common
;onfusion8delirium ;ommon
d
?ery
common
"sychosis ?ery rare ;ommon
;atatonia ?ery rare
Frontal headache
,usually mild-
?ery
common
9eningeal signs 6are
e
6are
"arkinsonism ?ery rare
/ar0 nose0 and throat
;oated tongue ?ery
common
Sore throat
f

Pulmonary
9ild cough ;ommon
Aronchitic cough ;ommon
6ales ;ommon
"neumonia 6are
,lobar-
6are ;ommon
,basal-
The clinical course of a given individual with typhoid fever may deviate from the above
description of classic disease. The timing of the symptoms and host response may vary
based on geographic region, race factors, and the infecting bacterial strain. The
stepladder fever pattern that was once the hallmark of typhoid fever now occurs in as
few as %(1 of cases. n most contemporary presentations of typhoid fever, the fever has
a steady insidious onset.
Goung children, individuals with #:S, and one third of immunocompetent adults who
develop typhoid fever develop diarrhea rather than constipation. n addition, in some
localities, typhoid fever is generally more apt to cause diarrhea than constipation.
#typical manifestations of typhoid fever include isolated severe headaches that may
mimic meningitis, acute lobar pneumonia, isolated arthralgias, urinary symptoms, severe
jaundice, or fever alone. Some patients, especially in ndia and #frica, present primarily
with neurologic manifestations such as delirium or, in e<tremely rare cases, parkinsonian
symptoms or !uillain-AarrH syndrome. *ther unusual complications include
pancreatitis,
(0
meningitis, orchitis, osteomyelitis, and abscesses anywhere on the body.
(
Table %. ncidence and Timing of ?arious 9anifestations of Untreated Typhoid
Fever
(,(>,(@,(=,(C,./
a
?ery common) Symptoms occur in well over half of cases ,appro<imately >01-C01-.
b
?ery rare) Symptoms occur in less than 01 of cases.
c
#lmost all) Symptoms occur in almost all cases.
d
;ommon) Symptoms occur in .01->01 of cases.
e
6are) Symptoms occur in 01-.01 of cases.
f
Alank cells) 3o mention of the symptom at that phase was found in the literature.
g
D<tremely rare) Symptoms have been described in occasional case reports.
Treated typhoid fe'er
f appropriate treatment is initiated within the first few days of full-blown illness, the
disease begins to remit after about ( days, and the patient&s condition markedly
improves within 2-0 days. #ny delay in treatment increases the likelihood of
complications and recovery time.
Physical
See +istory.
%auses
S typhi and Salmonella paratyphi cause typhoid fever.
1ifferential 1iagnoses
#bdominal #bscess 9alaria
#mebic +epatic #bscesses6ickettsial diseases
#ppendicitis To<oplasmosis
Arucellosis Tuberculosis
:engue Fever Tularemia
nfluen4a Typhus
5eishmaniasis
2ther Pro"lems to Be %onsidered
Dndocarditis
;onnective-tissue disease
5ymphoproliferative disorders
)orkup
La"oratory Studies
The diagnosis of typhoid fever ,enteric fever- is primarily clinical.
mportantly, the reported sensitivities of tests for S typhi vary greatly in the literature,
even among the most recent articles and respected journals.
;ulture
o The criterion standard for diagnosis of typhoid fever has long been culture
isolation of the organism. ;ultures are widely considered %//1 specific.
o ;ulture of bone marrow aspirate is C/1 sensitive until at least 0 days
after commencement of antibiotics. +owever, this techni'ue is e<tremely
painful, which may outweigh its benefit.
.%
o Alood, intestinal secretions ,vomitus or duodenal aspirate-, and stool
culture results are positive for S typhi in appro<imately =01-C/1 of
patients with typhoid fever who present within the first week of onset.
They decline to (/1-./1 later in the disease course. n particular, stool
culture may be positive for S typhi several days after ingestion of the
bacteria secondary to inflammation of the intraluminal dendritic cells.
5ater in the illness, stool culture results are positive because of bacteria
shed through the gallbladder.
o 9ultiple blood cultures ,I.- yield a sensitivity of @.1-C@1. 5arge-volume
,%/-./ m5- blood culture and clot culture may increase the likelihood of
detection.
.(
o Stool culture alone yields a sensitivity of less than 0/1, and urine culture
alone is even less sensitive. ;ultures of punch-biopsy samples of rose
spots reportedly yield a sensitivity of >.1 and may show positive results
even after administration of antibiotics. # single rectal swab culture upon
hospital admission can be e<pected to detect S typhi in ./1-2/1 of
patients. S typhi has also been isolated from the cerebrospinal fluid,
peritoneal fluid, mesenteric lymph nodes, resected intestine, pharyn<,
tonsils, abscess, and bone, among others.
o Aone marrow aspiration and blood are cultured in a selective medium ,eg,
%/1 a'ueous o<gall- or a nutritious medium ,eg, tryptic soy broth- and
are incubated at .@E; for at least @ days. Subcultures are made daily to
one selective medium ,eg, 9ac;onkey agar- and one inhibitory medium
,eg, Salmonella-Shigella agar-. dentification of the organism with these
conventional culture techni'ues usually takes 2=-@( hours from
ac'uisition.
Table (. Sensitivities of ;ultures
(,.(,..,.2
*pen table in new window
J ;5*SD $3:*$ K
Table
Incu"ation )eek * )eek + )eek , )eek -
Aone marrow
aspirate ,/.0-% m5-
C/1 ,may decrease after 0 d of antibiotics-
Alood ,%/-./ m5-,
stool, or duodenal
aspirate culture
2/1-=/1 L(/1 ?ariable ,(/1->/1-
Urine (01-./1, timing unpredictable
Incu"ation )eek * )eek + )eek , )eek -
Aone marrow
aspirate ,/.0-% m5-
C/1 ,may decrease after 0 d of antibiotics-
Alood ,%/-./ m5-,
stool, or duodenal
aspirate culture
2/1-=/1 L(/1 ?ariable ,(/1->/1-
Urine (01-./1, timing unpredictable
"olymerase chain reaction ,";6-)
.0,.>
";6 has been used for the diagnosis of
typhoid fever with varying success. 3ested ";6, which involves two rounds of
";6 using two primers with different se'uences within the +%-d flagellin gene of
S typhi, offers the best sensitivity and specificity. ;ombining assays of blood and
urine, this techni'ue has achieved a sensitivity of =(.@1 and reported specificity
of %//1. +owever, no type of ";6 is widely available for the clinical diagnosis of
typhoid fever.
Specific serologic tests
o #ssays that identify Salmonella antibodies or antigens support the
diagnosis of typhoid fever, but these results should be confirmed with
cultures or :3# evidence.
o The $idal test was the mainstay of typhoid fever diagnosis for decades. t
is used to measure agglutinating antibodies against + and * antigens of
S typhi. 3either sensitive nor specific, the $idal test is no longer an
acceptable clinical method.
o ndirect hemagglutination, indirect fluorescent ?i antibody, and indirect
en4yme-linked immunosorbent assay ,D5S#- for immunoglobulin 9
,g9- and g! antibodies to S typhi polysaccharide, as well as
monoclonal antibodies against S typhi flagellin,
.@
are promising, but the
success rates of these assays vary greatly in the literature.
*ther nonspecific laboratory studies
o 9ost patients with typhoid fever are moderately anemic, have an elevated
erythrocyte sedimentation rate ,DS6-, thrombocytopenia, and relative
lymphopenia.
o 9ost also have a slightly elevated prothrombin time ,"T- and activated
partial thromboplastin time ,a"TT- and decreased fibrinogen levels.
o ;irculating fibrin degradation products commonly rise to levels seen in
subclinical disseminated intravascular coagulation ,:;-.
o 5iver transaminase and serum bilirubin values usually rise to twice the
reference range.
o 9ild hyponatremia and hypokalemia are common.
o # serum alanine amino transferase ,#5T-7to7lactate dehydrogenase
,5:+- ratio of more than C)% appears to be helpful in distinguishing
typhoid from viral hepatitis. # ratio of greater than C)% supports a
diagnosis of acute viral hepatitis, while ratio of less than C)% supports
typhoid hepatitis.
.=
Imaging Studies
6adiography) 6adiography of the kidneys, ureters, and bladder ,MUA- is useful if
bowel perforation ,symptomatic or asymptomatic- is suspected.
;T scanning and 96) These studies may be warranted to investigate for
abscesses in the liver or bones, among other sites.
Procedures
Aone marrow aspiration) The most sensitive method of isolating S typhi is A9#
culture ,see 5ab Studies-.
&istologic Findings
The hallmark histologic finding in typhoid fever is infiltration of tissues by macrophages
,typhoid cells- that contain bacteria, erythrocytes, and degenerated lymphocytes.
#ggregates of these macrophages are called typhoid nodules, which are found most
commonly in the intestine, mesenteric lymph nodes, spleen, liver, and bone marrow but
may be found in the kidneys, testes, and parotid glands. n the intestines, 2 classic
pathologic stages occur in the course of infection) ,%- hyperplastic changes, ,(- necrosis
of the intestinal mucosa, ,.- sloughing of the mucosa, and ,2- the development of ulcers.
The ulcers may perforate into the peritoneal cavity.
n the mesenteric lymph nodes, the sinusoids are enlarged and distended by large
collections of macrophages and reticuloendothelial cells. The spleen is enlarged, red,
soft, and congestedB its serosal surface may have a fibrinous e<udate. 9icroscopically,
the red pulp is congested and contains typhoid nodules. The gallbladder is hyperemic
and may show evidence of cholecystitis. 5iver biopsy specimens from patients with
typhoid fever often show cloudy swelling, balloon degeneration with vacuolation of
hepatocytes, moderate fatty change, and focal typhoid nodules. ntact typhoid bacilli can
be observed at these sites.
(,>
Staging
The proper treatment approach to typhoid fever depends on whether the illness is
complicated or uncomplicated. ;omplicated typhoid fever is characteri4ed by melena
,.1 of all hospitali4ed patients with typhoid fever-, serious abdominal discomfort,
intestinal perforation, marked neuropsychiatric symptoms, or other severe
manifestations. :epending on the ade'uacy of diagnosis and treatment, complicated
disease may develop in up to %/1 of treated patients. :elirium, obtundation, stupor,
coma, or shock demands a particularly aggressive approach
Treatment
edical %are
f a patient presents with une<plained symptoms described in Table % within >/ days of
returning from an typhoid fever ,enteric fever- endemic area or following consumption of
food prepared by an individual who is known to carry typhoid, broad-spectrum empiric
antibiotics should be started immediately. Treatment should not be delayed for
confirmatory tests since prompt treatment drastically reduces the risk of complications
and fatalities. #ntibiotic therapy should be narrowed once more information is available.
;ompliant patients with uncomplicated disease may be treated on an outpatient basis.
They must be advised to use strict handwashing techni'ues and to avoid preparing food
for others during the illness course. +ospitali4ed patients should be placed in contact
isolation during the acute phase of the infection. Feces and urine must be disposed of
safely.
Surgical %are
Surgery is usually indicated in cases of intestinal perforation. 9ost surgeons prefer
simple closure of the perforation with drainage of the peritoneum. Small-bowel resection
is indicated for patients with multiple perforations.
f antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should
be resected. ;holecystectomy is not always successful in eradicating the carrier state
because of persisting hepatic infection.
%onsultations
#n infectious disease specialist should be consulted. ;onsultation with a surgeon is
indicated upon suspected gastrointestinal perforation, serious gastrointestinal
hemorrhage, cholecystitis, or e<traintestinal complications ,arteritis, endocarditis, organ
abscesses-.
1iet
Fluids and electrolytes should be monitored and replaced diligently. *ral nutrition with a
soft digestible diet is preferable in the absence of abdominal distension or ileus.
$cti'ity
3o specific limitations on activity are indicated for patients with typhoid fever. #s with
most systemic diseases, rest is helpful, but mobility should be maintained if tolerable.
The patient should be encouraged to stay home from work until recovery.
edication
$nti"iotics
:efinitive treatment of typhoid fever ,enteric fever- is based on susceptibility. #s a
general principle of antimicrobial treatment, intermediate susceptibility should be
regarded as e'uivalent to resistance. Aetween %CCC and (//>, %.1 of S typhi isolates
collected in the United States were multidrug resistant.
Until susceptibilities are determined, antibiotics should be empiric, for which there are
various recommendations. The authors of this article consider the (//. $orld +ealth
*rgani4ation ,$+*- guidelines to be outdated. These recommend fluoro'uinolone
treatment for both complicated and uncomplicated cases of typhoid fever, but .=1 of S
typhi isolates taken in the United States in (//> were fluoro'uinolone resistant ,nalidi<ic
acid7resistant S typhi J3#6STK-, and the rate of multidrug resistance was %.1.
,9ultidrug-resistant S typhi is, by definition, resistant to the original first-line agents,
ampicillin, chloramphenicol, and trimethoprim-sulfametho<a4ole.-
The particular sensitivity pattern of the organism in its area of ac'uisition should be the
major basis of empiric antibiotic choice. t may soon become necessary to treat all cases
presumptively for multidrug resistance until sensitivities are obtained.
3ote that nalidi<ic acid is a nontherapeutic drug that is used outside of the United States
as a stand-in for fluoro'uinolones in sensitivity assays. n the United States, it is still
used specifically for S typhi infection.
.C,%@
&istory of anti"iotic resistance
;hloramphenicol was used universally to treat typhoid fever from %C2= until the %C@/s,
when widespread resistance occurred. #mpicillin and trimethoprim-sulfametho<a4ole
,T9"-S9N- then became treatments of choice. +owever, in the late %C=/s, some S
typhi and S paratyphi strains ,multidrug resistant J9:6K S typhi or S paratyphi-
developed simultaneous plasmid-mediated resistance to all three of these agents.
Fluoro'uinolones are now recommended by most authorities for the treatment of typhoid
fever. They are highly effective against susceptible organisms, yielding a better cure rate
than cephalosporins. Unfortunately, resistance to first-generation fluoro'uinolones is
widespread in many parts of #sia.
n recent years, third-generation cephalosporins have been used in regions with high
fluoro'uinolone resistance rates, particularly in south #sia and ?ietnam. Unfortunately,
sporadic resistance has been reported, so it is e<pected that these will become less
useful over time.
.C
echanisms of anti"iotic resistance
The genes for antibiotic resistance in S typhi and S paratyphi are ac'uired from
Escherichia coli and other gram-negative bacteria via plasmids. The plasmids contain
cassettes of resistance genes that are incorporated into a region of the Salmonella
genome called an integron. Some plasmids carry multiple cassettes and immediately
confer resistance to multiple classes of antibiotics. This e<plains the sudden appearance
of 9:6 strains of S typhi and S paratyphi, often without intermediate strains that have
less-e<tensive resistance.
The initial strains of antibiotic-resistant S typhi and S paratyphi carried chloramphenicol
acetyltransferase type , which encodes an en4yme that inactivates chloramphenicol via
acetylation. 9:6 strains may carry dihydrofolate reductase type ?, which confers
resistance to trimethoprim. nterestingly, in areas where these drugs have fallen out of
use, S typhi has reverted to wild type, and they are often more effective than newer
agents.
2/,2%,2(,./
6esistance to fluoro'uinolones is evolving in an ominous direction. Fluoro'uinolones
target :3# gyrase and topoisomerase ?, bacterial en4ymes that are part of a comple<
that uncoils and recoils bacterial :3# for transcription.
2.
S typhi most commonly
develops fluoro'uinolone resistance through specific mutations in gyrA and parC, which
code for the binding region of :3# gyrase and topoisomerase ?, respectively.
# single point mutation gyrA confers partial resistance. f a second gyrA point mutation is
added, the resistance increases somewhat. +owever, a mutation in parC added to a
single gyrA mutation confers full in vitro resistance to first-generation fluoro'uinolones.
;linically, these resistant strains show a .>1 failure rate when treated with a first-
generation fluoro'uinolone such as ciproflo<acin.
22
The risk of relapse after bacterial
clearance is higher in both partially and fully resistant strains than in fully susceptible
strains.
%=
The third-generation fluoro'uinolone gatiflo<acin appears to be highly effective against
all known clinical strains of S typhi both in vitro and in vivo. +owever, any two of a
number of gyrA mutations, when added to the parC mutation, confer full in vitro
resistance. #lthough such a combination has yet to be discovered in vivo, all of these
mutations e<ist in clinic strains, and it seems highly likely that a gatiflo<acin-resistant
strain will be encountered clinically if selective pressure with fluoro'uinolones continues
to be e<erted.
22
3eography of resistance
#mong S typhi isolates obtained in the United States between %CCC and (//>, 2.1
were resistant to at least one antibiotic.
3early half of S typhi isolates found in the United States now come from travelers to the
ndian subcontinent, where fluoro'uinolone resistance is endemic ,see Table .-. The
rate of fluoro'uinolone resistance in south and Southeast #sia and, to some e<tent, in
Dast #sia is generally high and rising ,see Table .-. Susceptibility to chloramphenicol,
T9"-S9N, and ampicillin in these areas is rebounding. n Southeast #sia, 9:6 strains
remain predominant, and some ac'uired resistance to fluoro'uinolones by the early
(///s.
The most recent professional guideline for the treatment of typhoid fever in south #sia
was issued by the ndian #ssociation of "ediatrics ,#"- in *ctober (//>. #lthough
these guidelines were published for pediatric typhoid fever, the authors feel that they are
also applicable to adult cases. For empiric treatment of uncomplicated typhoid fever, the
#" recommends cefi<ime and, as a second-line agent, a4ithromycin. For complicated
typhoid fever, they recommend ceftria<one. #4treonam and imipenem are second-line
agents for complicated cases.
20
The authors believe that the #" recommendations have
more validity than the $+* recommendations for empiric treatments of typhoid fever in
both adults and children.
n high-prevalence areas outside the areas discussed above, the rate of intermediate
sensitivity or resistance to fluoro'uinolones is ..@1 in the #mericas ,P F.%.(-, 2.@1 ,P
F.%22- in sub-Saharan #frica, and %/.=1 ,P F.@/>- in the 9iddle Dast. Therefore, for
strains that originate outside of south or Southeast #sia, the $+* recommendations
may still be validOthat uncomplicated disease should be treated empirically with oral
ciproflo<acin and complicated typhoid fever from these regions should be treated with
intravenous ciproflo<acin.
.C,2(,2>,%C,2@
#ntibiotic resistance is a moving target. 6eports are 'uickly outdated, and surveys of
resistance may have limited geographic scope. Therefore, any recommendation
regarding antibiotic treatment must be taken with a grain of salt. n the authors& opinion,
if the origin of the infection is unknown, the combination of a first-generation
fluoro'uinolone and a third-generation cephalosporin should be used.
Table .. #ntibiotic 6ecommendations by *rigin and Severity
*pen table in new window
J ;5*SD $3:*$ K
Ta"le
Location Se'erity First4Line $nti"iotics Second4Line $nti"iotics
South #sia, Dast #sia
20
2=, 2/
Uncomplicated ;efi<ime "* #4ithromycin "*
;omplicated ;eftria<one ? or
;efota<ime ?
#4treonam ? or
mipenem ?
P3ote that the combination of a4ithromycin and fluoro'uinolones is not recommended
because it may cause QT prolongation and is relatively contraindicated.
Future directions
6esearchers in ;ameroon report that a compound derived from the seeds of
urraeanthus a!ricanus, an #frican folk remedy for typhoid fever, is active against S
typhi in vitro.
0%
"erhaps they are on their way to creating an addition to the shrinking
arsenal of effective antimicrobials.
%hloramphenicol 5%hloromycetin6
Ainds to 0/S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting
protein synthesis. Dffective against gram-negative and gram-positive bacteria. Since its
introduction in %C2=, has proven to be remarkably effective for enteric fever worldwide.
For sensitive strains, still most widely used antibiotic to treat typhoid fever. n the %C>/s,
S typh i strains with plasmid-mediated resistance to chloramphenicol began to appear
and later became widespread in many endemic countries of the #mericas and Southeast
#sia, highlighting need for alternative agents.
"roduces rapid improvement in patient&s general condition, followed by defervescence in
.-0 d. 6educed preantibiotic-era case-fatality rates from %/1-%01 to %1-21. ;ures
appro<imately C/1 of patients. #dministered "* unless patient is nauseous or
e<periencing diarrheaB in such cases, ? route should be used initially. 9 route should
be avoided because it may result in unsatisfactory blood levels, delaying defervescence.
:osing
nteractions
;ontraindications
"recautions
$dult
0// mg "*8? '2h until defervescence, then '>h for a total course of %2 d
Pediatric
0/-@0 mg8kg8d "*8? divided '>h
:osing
nteractions
;ontraindications
"recautions
;oncurrently with barbiturates, chloramphenicol serum levels may decrease while
barbiturate levels may increase, causing to<icityB manifestations of hypoglycemia may
occur with sulfonylureasB rifampin may reduce serum levels, presumably through hepatic
en4yme inductionB may increase effects of anticoagulantsB may increase serum
hydantoin levels, possibly resulting in to<icity ,chloramphenicol levels may be increased
or decreased-
Pregnancy
; - Fetal risk revealed in studies in animals but not established or not studied in humansB
may use if benefits outweigh risk to fetus
Precautions
Use only for indicated infections or as prophyla<is for bacterial infectionsB serious and
fatal blood dyscrasias ,eg, aplastic anemia, hypoplastic anemia, thrombocytopenia,
granulocytopenia- can occurB evaluate baseline and perform periodic blood studies
appro<imately every ( d during therapyB discontinue upon appearance of
reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to
chloramphenicolB adjust dose in liver or kidney dysfunctionB caution in pregnancy at term
or during labor because of potential to<ic effects on fetus ,gray syndrome-B higher
relapse rate following use because of the emergence of resistant strains
$mo#icillin 5Trimo#0 $mo#il0 Biomo#6
nterferes with synthesis of cell wall mucopeptides during active multiplication, resulting
in bactericidal activity against susceptible bacteria. #t least as effective as
chloramphenicol in rapidity of defervescence and relapse rate. ;onvalescence carriage
occurs less commonly than with other agents when organisms are fully susceptible.
Usually given "* with a daily dose of @0-%// mg8kg tid for %2 d.
:osing
nteractions
;ontraindications
"recautions
$dult
% g "* '=h
Pediatric
(/-0/ mg8kg8d "* divided '=h for %2 d
:osing
nteractions
;ontraindications
"recautions
Reduces the efficacy of oral contraceptives
Pregnancy
A - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals
Precautions
#djust dose in renal impairmentB may enhance chance of candidiasis
Trimethoprim and sulfametho#a7ole 5Bactrim 1S0 Septra6
nhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. #ntibacterial activity
of T9"-S9N includes common urinary tract pathogens, e<cept Pseu"omonas
aeruginosa. #s effective as chloramphenicol in defervescence and relapse rate.
Trimethoprim alone has been effective in small groups of patients.
:osing
nteractions
;ontraindications
"recautions
$dult
>.0-%/ mg8kg8d "* bid8tidB can be given ? if necessaryB %>/ mg T9"8=// mg S9N "*
'%(h for %/-%2 d
Pediatric
R( months) :o not administer
I( months) %0-(/ mg8kg8d "*, based on T9", tid8'id for %2 d
:osing
nteractions
;ontraindications
"recautions
9ay increase "T when used with warfarin ,perform coagulation tests and adjust dose
accordingly-B coadministration with dapsone may increase blood levels of both drugsB
coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly
personsB phenytoin levels may increase with coadministrationB may potentiate effects of
methotre<ate in bone marrow depressionB hypoglycemic response to sulfonylureas may
increase with coadministrationB may increase levels of 4idovudine
:osing
nteractions
;ontraindications
"recautions
Documented hypersensitivity; megaloblastic anemia due to folate deficiency
Pregnancy
; - Fetal risk revealed in studies in animals but not established or not studied in humansB
may use if benefits outweigh risk to fetus
Precautions
:iscontinue at first appearance of skin rash or sign of adverse reactionB obtain ;A;
counts fre'uentlyB discontinue therapy if significant hematologic changes occurB goiter,
diuresis, and hypoglycemia may occur with sulfonamidesB prolonged ? infusions or high
doses may cause bone marrow depression ,if signs occur, give 0-%0 mg8d leucovorin-B
caution in folate deficiency ,eg, patients with long-term alcoholism, elderly persons,
those receiving anticonvulsant therapy, or those with malabsorption syndrome-B
hemolysis may occur in patients with !->-": deficiencyB patients with #:S may not
tolerate or respond to T9"-S9NB caution in renal or hepatic impairment ,perform
urinalyses and renal function tests during therapy-B administer fluids to prevent
crystalluria and stone formation
%iproflo#acin 5%ipro6
Fluoro'uinolone with activity against pseudomonads, streptococci, 96S#,
Staphylococcus epi"ermi"is, and most gram-negative organisms but no activity against
anaerobes. nhibits bacterial :3# synthesis and, conse'uently, growth. ;ontinue
treatment for at least ( d ,@-%2 d typical- after signs and symptoms have disappeared.
"roven to be highly effective for typhoid and paratyphoid fevers. :efervescence occurs
in .-0 d, and convalescent carriage and relapses are rare. *ther 'uinolones ,eg,
oflo<acin, norflo<acin, peflo<acin- usually are effective. f vomiting or diarrhea is present,
should be given ?. Fluoro'uinolones are highly effective against multiresistant strains
and have intracellular antibacterial activity.
3ot currently recommended for use in children and pregnant women because of
observed potential for causing cartilage damage in growing animals. +owever,
arthropathy has not been reported in children following use of nalidi<ic acid ,an earlier
'uinolone known to produce similar joint damage in young animals- or in children with
cystic fibrosis, despite high-dose treatment.
$dult
(/-./ mg8kg8d "* bid for %2 d, but shorter courses may be ade'uateB (0/-0// mg "*
bid for @-%2 d
Pediatric
R%= years) 3ot recommended
I%= years) #dminister as in adults
Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h
before or after taking fluorouinolones; cimetidine may interfere !ith metabolism of
fluorouinolones; reduces therapeutic effects of phenytoin; probenecid may increase
serum concentrations; may increase to"icity of theophylline, caffeine, cyclosporine, and
digo"in #monitor digo"in levels$; may increase effects of anticoagulants #monitor %&$
Pregnancy
; - Fetal risk revealed in studies in animals but not established or not studied in humansB
may use if benefits outweigh risk to fetus
Precautions
n prolonged therapy, perform periodic evaluations of organ system functions ,eg, renal,
hepatic, hematopoietic-B adjust dose in renal function impairmentB superinfections may
occur with prolonged or repeated antibiotic therapy
%efota#ime 5%laforan6
#rrests bacterial cell wall synthesis, which inhibits bacterial growth. Third-generation
cephalosporin with gram-negative spectrum. 5ower efficacy against gram-positive
organisms. D<cellent in vitro activity against S typhi and other salmonellae and has
acceptable efficacy in typhoid fever. *nly ? formulations are available. 6ecently,
emergence of domestically ac'uired ceftria<one-resistant Salmonella infections has
been described.
$dult
( g ? '>h
Pediatric
(// mg8kg8d ? in divided doses for %2 d
nfants and children) 0/-%=/ mg8kg8d ?89 divided '2->h
I%( years) #dminister as in adults
"robenecid may increase levelsB coadministration with furosemide and aminoglycosides
may increase nephroto<icity
Pregnancy
A - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals
Precautions
#djust dose in severe renal impairmentB associated with severe colitis
$7ithromycin 58ithroma#6
Treats mild to moderate microbial infections. #dministered "* at %/ mg8kg8d ,not
e<ceeding 0// mg-, appears to be effective to treat uncomplicated typhoid fever in
children 2-%@ y. ;onfirmation of these results could provide an alternative for treatment
of typhoid fever in children in developing countries, where medical resources are scarce.
$dult
% g "* once
:ay %) 0// mg "*
:ays (-0) (0/ mg "* 'd
Pediatric
R> months) 3ot established
I> months
:ay %) %/ mg8kg "* onceB not to e<ceed 0// mg8d
:ays (-0) 0 mg8kg "* 'dB not to e<ceed (0/ mg8d
9ay increase to<icity of theophylline, warfarin, and digo<inB effects are reduced with
coadministration of aluminum and8or magnesium antacidsB nephroto<icity and
neuroto<icity may occur when coadministered with cyclosporine
:ocumented hypersensitivityB hepatic impairmentB administration with pimo4ide
Pregnancy
A - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals
Precautions
Site reactions can occur with ? routeB bacterial or fungal overgrowth may result with
prolonged antibiotic useB may increase hepatic en4ymes and cholestatic jaundiceB
caution in patients with impaired hepatic function, prolonged QT intervals, or pneumoniaB
caution in hospitali4ed, geriatric, or debilitated patients
%eftria#one 5Rocephin6
Third-generation cephalosporin with broad-spectrum gram-negative activity against
gram-positive organismsB D<cellent in vitro activity against S typhi and other
salmonellae.
$dult
%-( g ? '%(h
Pediatric
I@ days) (0-0/ mg8kg8d ?89B not to e<ceed %(0 mg8d
nfants and children) 0/-@0 mg8kg8d ?89 divided '%(hB not to e<ceed ( g8d
"robenecid may increase levelsB coadministration with ethacrynic acid, furosemide, and
aminoglycosides may increase nephroto<icity
Pregnancy
A - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals
Precautions
#djust dose in renal impairmentB caution predelivery and in breastfeedingB pseudobiliary
lithiasisB non7 Clostri"ium "i!!icile diarrhea
%efopera7one 5%efo"id6
:iscontinued in the United States. Third-generation cephalosporin with gram-negative
spectrum. 5ower efficacy against gram-positive organisms.
:osing
nteractions
;ontraindications
"recautions
$dult
(-2 g8d ?89 divided bidB not to e<ceed %( g8d
Pediatric
3ot establishedB %//-%0/ mg8kg8d ?89 divided '=-%(hB not to e<ceed %( g8d
,suggested-
:osing
nteractions
;ontraindications
"recautions
"robenecid may increase levelsB coadministration with furosemide and aminoglycosides
may increase nephroto<icity
Pregnancy
A - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals
Precautions
#djust dose in severe renal impairmentB has been associated with severe colitis
2flo#acin 5Flo#in6
# pyridine carbo<ylic acid derivative with broad-spectrum bactericidal effect.
:osing
nteractions
;ontraindications
"recautions
$dult
(//-2// mg "* '%(h
Pediatric
R%= years) 3ot recommended
I%= years) #dminister as in adults
:osing
nteractions
;ontraindications
"recautions
#ntacids, iron salts, and 4inc salts may reduce serum levelsB administer antacids (-2 h
before or after taking fluoro'uinolonesB cimetidine may interfere with metabolism of
fluoro'uinolonesB reduces therapeutic effects of phenytoinB probenecid may increase
serum concentrationsB may increase to<icity of theophylline, caffeine, cyclosporine, and
digo<in ,monitor digo<in levels-B may increase effects of anticoagulants ,monitor "T-
Pregnancy
; - Fetal risk revealed in studies in animals but not established or not studied in humansB
may use if benefits outweigh risk to fetus
Precautions
n prolonged therapy, perform periodic evaluations of organ system functions ,eg, renal,
hepatic, hematopoietic-B adjust dose in renal function impairmentB superinfections may
occur with prolonged or repeated antibiotic therapy
Le'oflo#acin 5Le'aquin6
For pseudomonal infections and infections due to multidrug-resistant gram-negative
organisms.
:osing
nteractions
;ontraindications
"recautions
$dult
0// mg "* 'd for @-%2 d
Pediatric
R%= years) 3ot recommended
I%= years) #dminister as in adults
:osing
nteractions
;ontraindications
"recautions
#ntacids, iron salts, and 4inc salts may reduce serum levelsB administer antacids (-2 h
before or after taking fluoro'uinolonesB cimetidine may interfere with metabolism of
fluoro'uinolonesB reduces therapeutic effects of phenytoinB probenecid may increase
serum concentrationsB may increase to<icity of theophylline, caffeine, cyclosporine, and
digo<in ,monitor digo<in levels-B may increase effects of anticoagulants ,monitor "T-
Pregnancy
; - Fetal risk revealed in studies in animals but not established or not studied in humansB
may use if benefits outweigh risk to fetus
Precautions
n prolonged therapy, perform periodic evaluations of organ system functions ,eg, renal,
hepatic, hematopoietic-B adjust dose in renal function impairmentB superinfections may
occur with prolonged or repeated antibiotic therapy
%orticosteroids
:e<amethasone may decrease the likelihood of mortality in severe typhoid fever cases
complicated by delirium, obtundation, stupor, coma, or shock if bacterial meningitis has
been definitively ruled out by cerebrospinal fluid studies. To date, the most systematic
trial of this has been a randomi4ed controlled study in patients aged .-0> years with
severe typhoid fever who were receiving chloramphenicol therapy. This study compared
outcomes in %= patients given placebo with outcomes in (/ patients given
de<amethasone . mg8kg ? over ./ minutes followed by de<amethasone % mg8kg every
> hours for = doses. The fatality rate in the de<amethasone arm was %/1 versus 00.>1
in the placebo arm ,P F.//.-.

3onetheless, this point is still debated. # (//. $+*
statement endorsed the use of steroids as described above, but reviews by eminent
authors in the #e$ Englan" %ournal o! Me"icine ,(//(-
>
and the &ritish Me"ical %ournal
,(//>-
0.
do not refer to steroids at all. # %CC% trial compared patients treated with %(
doses of de<amethasone 2// mg or %// mg to a retrospective cohort in whom steroids
were not administered. This trial found no difference in outcomes among the groups.
02
The data are sparse, but the authors of this article agree with the $+* that
de<amethasone should be used in cases of severe typhoid fever.
1e#amethasone 51ecadron6
"rompt administration of high-dose de<amethasone reduces mortality in patients with
severe typhoid fever without increasing incidence of complications, carrier states, or
relapse among survivors.
:osing
nteractions
;ontraindications
"recautions
$dult
. mg8kg "*898? initially, followed by = doses of % mg8kg '>h
Pediatric
3ot established
Follo94up
Further Inpatient %are
f treated with well-selected antibiotics, patients with typhoid fever ,enteric fever-
should defervesce within .-0 days. +owever, patients with complicated typhoid
fever should finish their course intravenously and should remain in the hospital if
unable to manage this at home.
"atients with complicated typhoid fever should be admitted through the acute
phase of the illness. Uncomplicated cases are generally treated on an outpatient
basis unless the patient is a public health risk or cannot be fully monitored
outside the home.
Further 2utpatient %are
#fter discharge, patients should be monitored for relapse or complications for .
months after treatment has commenced.
Five percent to %/1 of patients treated with antibiotics e<perience relapse of
typhoid fever after initial recovery. 6elapses typically occur appro<imately % week
after therapy is discontinued, but relapse after @/ days has been reported. n
these cases, the blood culture results are again positive, and high serum levels
of +, *, and ?i antibodies and rose spots may reappear.
o # relapse of typhoid fever is generally milder and of shorter duration than
the initial illness. n rare cases, second or even third relapses occur.
3otably, the relapse rate is much lower following treatment with the new
'uinolone drugs, which have effective intracellular penetration.
o S typhi and S paratyphi rarely develop antibiotic resistance during
treatment. f an antibiotic has been chosen according to sensitivities,
relapse should dictate a search for anatomic, pathologic, or genetic
predispositions rather than for an alternate antibiotic.
o "revious infection does not confer immunity. n any suspected relapse,
infection with a different strain should be ruled out.
:epending on the antibiotic used, between /1 and 0.C1 of treated patients
become chronic carriers. n some cases, the organism evades antibiotics by
se'uestering itself within gallstones or Schistosoma haematobium organisms
that are infecting the bladder. From there, it is shed in stool or urine, respectively.
f present, these diseases must be cured before the bacterium can be eliminated.
Untreated survivors of typhoid fever may shed the bacterium in the feces for up
to . months. Therefore, after disease resolution, . stool cultures in one-month
intervals should be performed to rule out a carrier state. ;oncurrent urinary
cultures should be considered.
1eterrence!Pre'ention
Travelers to endemic countries should avoid raw unpeeled fruits or vegetables
since they may have been prepared with contaminated waterB in addition, they
should drink only boiled water.
n endemic countries, the most cost-effective strategy for reducing the incidence
of typhoid fever is the institution of public health measures to ensure safe
drinking water and sanitary disposal of e<creta. The effects of these measures
are long-term and reduce the incidence of other enteric infections, which are a
major cause of morbidity and mortality in those areas.
(accines
n endemic areas, mass immuni4ation with typhoid vaccines at regular intervals
considerably reduces the incidence of infections. 6outine typhoid vaccination is not
recommended in the United States but is indicated for travelers to endemic areas,
persons with intimate e<posure to a documented S typhi carrier ,eg, household contact-,
and microbiology laboratory personnel who fre'uently work with S typhi. ?accines are
not approved for use children younger than ( years.
Travelers should be vaccinated at least one week prior to departing for an
endemic area. Aecause typhoid vaccines lose effectiveness after several years,
consultation with a specialist in travel medicine is advised if the individual is
traveling several years after vaccination.
The only absolute contraindication to vaccination is a history of severe local or
systemic reactions following a previous dose. The typhoid vaccines available in
the United States have not been studied in pregnant women.
;urrently, the . typhoid fever vaccines include injected ?i capsular
polysaccharide ,?i;"SB Typhim ?i, "asteur 9erieu<- antigen, enteric Ty(%a
,?ivotif Aerna, Swiss Serum and ?accine nstitute- live-attenuated vaccine, and
an acetone-inactivated parenteral vaccine ,used only in members of the armed
forces-. The efficacy of both vaccines available to the general public approaches
0/1.
o ?i capsular polysaccharide antigen vaccine is composed of purified ?i
antigen, the capsular polysaccharide elaborated by S typhi isolated from
blood cultures.
"rimary vaccination with ?i;"S consists of a single parenteral
dose of /.0 m5 ,(0 Sg 9- one week before travel. The vaccine
manufacturer does not recommend the vaccine for children
younger than ( years. Aooster doses are needed every ( years to
maintain protection if continued or renewed e<posure is e<pected.
#dverse effects include fever, headache, erythema, and8or
induration of % cm or greater. n a study conducted in 3epal, the
?i;"S vaccine produced fewer local and systemic reactions than
the control ,the (.-valent pneumococcal vaccine-.
00
#mong school
children in South #frica, ?i;"S produced less erythema and
induration than the control ,bivalent vaccine-.
# systemic review and meta-analysis of 0 randomi4ed controlled
trials on the efficacy and safety of ?i;"S versus placebo or
nontyphoid vaccine found a cumulative efficacy of 001 ,C01 ;,
./1-@/1-.
The efficacy of vaccination with ?i;"S has not been studied
among persons from areas without endemic disease who travel to
endemic regions or among children younger than 0 years. ?i;"S
has not been given to children younger than % year.
Questions concerning ?i typhoid vaccine effectiveness in young
children ,ie, R0 y- have inhibited its use in developing countries.
$hether the vaccine is effective under programmatic conditions is
also unclear.
Sur et al conducted a phase ? effectiveness trial in slum-dwelling
residents aged ( years or older in ndia to determine vaccine
protection. "articipants ,nF.@,>@.- were randomly assigned to
receive a single dose of either ?i vaccine or inactivated hepatitis #
vaccine, according to geographic clusters. The mean rate of ?i
vaccine coverage was >%1 and >/1 for the hepatitis # vaccine.
Typhoid fever was diagnosed in C> subjects in the hepatitis #
vaccine group compared with .2 in the ?i vaccine group ,no more
than % episode was reported per individual-. "rotective effect for
typhoid with the ?i vaccine was >%1 ,P R/.//%- compared with
the hepatitis # vaccine group. ;hildren vaccinated while aged (-0
years had an =/1 protection level. Unvaccinated members of the
?i vaccine clusters showed a protection level of 221. The overall
protection level with all ?i vaccine cluster residents was 0@1. The
authors concluded that the ?i vaccine was effective in young
children and protected unvaccinated neighbors of ?i vaccinees.
0>
o Ty(%a is an oral vaccine that contains live attenuated S typhi Ty(%a
strains in an enteric-coated capsule. The vaccine elicits both serum and
intestinal antibodies and cell-mediated immune responses.
n the United States, primary vaccination with Ty(%a consists of one
enteric-coated capsule taken on alternate days to a total of 2
capsules. The capsules must be refrigerated ,not fro4en-, and all 2
doses must be taken to achieve ma<imum efficacy.
The optimal booster schedule has not been determinedB however, the
longest reported follow-up study of vaccine trial subjects indicated that
efficacy continued for 0 years after vaccination. The manufacturer
recommends revaccination with the entire 2-dose series every 0 years
if continued or renewed e<posure to S typhi is e<pected. This vaccine
may be inactivated if given within . days of antibiotics.
#dverse effects are rare. They include abdominal discomfort, nausea,
vomiting, fever, headache, and rash or urticaria.
The vaccine manufacturer of Ty(%a recommends against use in
children younger than > years. t should not be administered to
immunocompromised personsB the parenteral vaccines present
theoretically safer alternatives for this group.
# systemic review and meta-analysis of 2 randomi4ed controlled trials
on the efficacy and safety of Ty(%a versus placebo or nontyphoid
vaccine found a cumulative efficacy of 0%1 ,C01 ;, .>1->(1-.
The efficacy of Ty(%a has not been studied among persons from
areas without endemic disease who travel to disease-endemic
regions.
#cetone-inactivated parenteral vaccine is currently available only to members of
the US #rmed Forces. Dfficacy rates for this vaccine range from @01-C21.
Aooster doses should be administered every . years if continued or renewed
e<posure is e<pected.
o The parenteral heat-phenol7inactivated vaccine ,$yeth-#yerst- has been
discontinued.
o 3o information has been reported concerning the use of one vaccine as a
booster after primary vaccination with a different vaccine. +owever, using
either the series of 2 doses of Ty(%a or % dose of ?i;"S for persons
previously vaccinated with parenteral vaccine is a reasonable alternative
to administration of a booster dose of parenteral inactivated vaccine.
o # more effective vaccine may be on the hori4on. #n investigational
vaccine using ?i;"S conjugated to the nonto<ic recombinant
pseudomonas e<oto<in # ,?i-rD"#- has been studied in a randomi4ed
controlled trial. The vaccine was given to children aged (-0 years and
showed an efficacy of =C1 ,C01 ;, @>1-C@1- after ..= years. ?i-rD"#
has not been approved for use in the United States.
%omplications
3europsychiatric manifestations ,n the past ( decades, reports from disease-
endemic areas have documented a wide spectrum of neuropsychiatric
manifestations of typhoid fever.-
o # to<ic confusional state, characteri4ed by disorientation, delirium, and
restlessness, is characteristic of late-stage typhoid fever. n some cases,
these and other neuropsychiatric features dominate the clinical picture at an
early stage.
o Facial twitching or convulsions may be the presenting feature. 9eningismus
is not uncommon, but frank meningitis is rare. Dncephalomyelitis may
develop, and the underlying pathology may be that of demyelinating
leukoencephalopathy. n rare cases, transverse myelitis, polyneuropathy, or
cranial mononeuropathy develops.
o Stupor, obtundation, or coma indicates severe disease.
o Focal intracranial infections are uncommon, but multiple brain abscesses
have been reported.
0@
o *ther less-common neuropsychiatric manifestations events have included
spastic paraplegia, peripheral or cranial neuritis, !uillain-AarrH syndrome,
schi4ophrenialike illness, mania, and depression.
6espiratory
o ;ough
o Ulceration of posterior pharyn<
o *ccasional presentation as acute lobar pneumonia ,pneumotyphoid-
;ardiovascular
o 3onspecific electrocardiographic changes occur in %/1-%01 of patients
with typhoid fever.
o To<ic myocarditis occurs in %1-01 of persons with typhoid fever and is a
significant cause of death in endemic countries. To<ic myocarditis occurs
in patients who are severely ill and to<emic and is characteri4ed by
tachycardia, weak pulse and heart sounds, hypotension, and
electrocardiographic abnormalities.
o "ericarditis is rare, but peripheral vascular collapse without other cardiac
findings is increasingly described. "ulmonary manifestations have also
been reported in patients with typhoid fever.
0=
+epatobiliary
o 9ild elevation of transaminases without symptoms is common in persons
with typhoid fever.
o Taundice may occur in persons with typhoid fever and may be due to
hepatitis, cholangitis, cholecystitis, or hemolysis.
o "ancreatitis and accompanying acute renal failure and hepatitis with
hepatomegaly have been reported.
0C
ntestinal manifestations
o The ( most common complications of typhoid fever include intestinal
hemorrhage ,%(1 in one Aritish series- and perforation ,.1-2.>1 of
hospitali4ed patients-.
o From %==2-%C/C ,ie, preantibiotic era-, the mortality rate in patients with
intestinal perforation due to typhoid fever was >>1-C/1 but is now
significantly lower. #ppro<imately @01 of patients have guarding,
rebound tenderness, and rigidity, particularly in the right lower 'uadrant.
o :iagnosis is particularly difficult in the appro<imately (01 of patients with
perforation and peritonitis who do not have the classic physical findings.
n many cases, the discovery of free intra-abdominal fluid is the only sign
of perforation.
!enitourinary manifestations
o #ppro<imately (01 of patients with typhoid fever e<crete S typhi in their
urine at some point during their illness.
o mmune comple< glomerulitis
>/
and proteinuria have been reported, and
g9, ;. antigen, and S typhi antigen can be demonstrated in the
glomerular capillary wall.
o 3ephritic syndrome may complicate chronic S typhi bacteremia
associated with urinary schistosomiasis.
o 3ephrotic syndrome may occur transiently in patients with glucose->-
phosphate dehydrogenase deficiency.
o ;ystitis) Typhoid cystitis is very rare. 6etention of urine in the typhoid
state may facilitate infection with coliforms or other contaminants.
+ematologic manifestations
o Subclinical disseminated intravascular coagulation is common in persons
with typhoid fever.
o +emolytic-uremic syndrome is rare.
>%
o +emolysis may also be associated with glucose->-phosphate
dehydrogenase deficiency.
9usculoskeletal and joint manifestations
o Skeletal muscle characteristically shows Nenker degeneration, particularly
affecting the abdominal wall and thigh muscles.
o ;linically evident polymyositis may occur.
>(
o #rthritis is very rare and most often affects the hip, knee, or ankle.
5ate se'uelae ,rare in untreated patients and e<ceedingly rare in treated
patients-
o 3eurologic - "olyneuritis, paranoid psychosis, or catatonia
>.


o ;ardiovascular - Thrombophlebitis of lower-e<tremity veins
o !enitourinary -*rchitis
o 9usculoskeletal
"eriostitis, often abscesses of the tibia and ribs
Spinal abscess ,typhoid spineB very rare-
Prognosis
The prognosis among persons with typhoid fever depends primarily on the speed
of diagnosis and initiation of correct treatment. !enerally, untreated typhoid fever
carries a mortality rate of %/1-(/1. n properly treated disease, the mortality
rate is less than %1.
#n unspecified number of patients e<perience long-term or permanent
complications, including neuropsychiatric symptoms and high rates of
gastrointestinal cancers.
Patient /ducation
Aecause vigilant hand hygiene, vaccination, and the avoidance of risky foods and
beverages are mainstays of prevention, educating travelers before they enter a
disease-endemic region is important.
Aecause the protection offered by vaccination is at best partial, close attention to
personal, food, and water hygiene should be maintained. The US ;enters for
:isease ;ontrol and "revention dictum to Uboil it, cook it, peel it, or forget itU is a
good rule in any circumstance. f disease occurs while abroad despite these
precautions, one can usually call the US consulate for a list of recommended
doctors.
For e<cellent patient education resources, visit e9edicine&s "ublic +ealth ;enter.
#lso, see e9edicine&s patient education article Foreign Travel.
;ase study
o # wealthy middle-aged man presented to his physician a few days after
the onset of flulike symptoms, including fever, myalgias, chills, severe
abdominal pain, and a cough, in addition to severe abdominal pain. *ver
the ne<t ( weeks, he lost a great deal of weight. +e had intermittent but
ever-increasing fevers. #bout . weeks after the onset of symptoms, he
developed a few pale, salmon-colored macules on his trunk. +is cough
became much more fre'uent and severe. +e became delirious, listlessly
wandering around the house fiddling with doorknobs. :uring the fourth
week of his illness, he rapidly declined with increasing somnolence. #fter
nearly 2 weeks of illness, he died surrounded by his loving family.
o The patient was "rince #lbert, the ;onsort to Queen ?ictoria. +e was
diagnosed with typhoid fever. +is personal physician, Sir $illiam Tenner,
a leading e<pert on the disease, diagnosed typhoid fever. "rince #lbert
received the best therapy of the day.
For the most up-to-date information, visit the ;enters for :isease ;ontrol and
"revention Travelers& +ealth Typhoid resource ,www.cdc.gov8travel- or call the
Travelers& +ealth automated information line at =@@-FG-T6". The $orld +ealth
*rgani4ationVs site ,www.who.int8ith-, nternational Society of Travel 9edicine
site ,www.istm.org-, and Travel :octor ,www.traveldoctor.co.uk8diseases.htm-
contain useful information as well, though the authors disagree with some of the
$+*Vs antibiotic guidelines.
iscellaneous
Special %oncerns
;ulture-confirmed typhoid fever ,enteric fever- should be reported to the state health
department.