BackgroundTyphoid 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. It may
have responsible for the Great Plague of Athens at the end of the
Pelopennesian War.[1] The name S typhi is derived from the ancient
Greek typhos, an ethereal smoke or cloud that was believed to cause
disease and madness. In the advanced stages of typhoid fever, the
patient's level of consciousness is truly clouded. Although
antibiotics have markedly reduced the frequency of typhoid fever in
the developed world, it remains endemic in developing countries.[2]
TransmissionS typhi has no nonhuman vectors. The following are
modes of transmission: Oral transmission via food or beverages
handled by an individual who chronically sheds the bacteria through
stool or, less commonly, urine Hand-to-mouth transmission after
using a contaminated toilet and neglecting hand hygiene Oral
transmission via sewage-contaminated water or shellfish (especially
in the developing world)[3] An inoculum as small as 100,000
organisms causes infection in more than 50% of healthy
volunteers.[4]
PathophysiologyAll 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. Nontyphoidal
salmonellae are phagocytized throughout the distal ileum and colon.
With toll-like receptor (TLR)5 and TLR-4/MD2/CD-14 complex,
macrophages recognize pathogen-associated molecular patterns
(PAMPs) such as flagella and lipopolysaccharides. Macrophages and
intestinal epithelial cells then attract T cells and neutrophils
with interleukin 8 (IL-8), causing inflammation and suppressing the
infection.[5, 6] In contrast to the nontyphoidal salmonellae, S
typhi enters the host's system primarily through the distal ileum.
S typhi has specialized fimbriae that adhere to the epithelium over
clusters of lymphoid tissue in the ileum (Peyer patches), the main
relay point for macrophages traveling from the gut into the
lymphatic system. S typhi has a Vi capsular antigen that masks
PAMPs, avoiding neutrophil-based inflammation. The bacteria then
induce their host macrophages to attract more macrophages.[5] S
typhi co-opts the macrophages' cellular machinery for its own
reproduction[7] 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. Once there, the S typhi bacteria pause and continue to
multiply until some critical density is reached. Afterward, the
bacteria induce macrophage apoptosis, breaking out into the
bloodstream to invade the rest of the body.[6] The bacteria then
infect the gallbladder via either bacteremia or direct extension of
S typhi infected bile. The result is that the organism re-enters
the gastrointestinal tract in the bile and reinfects Peyer patches.
Bacteria that do not reinfect the host are typically shed in the
stool and are then available to infect other hosts.[6, 2] Life
cycle of Salmonella typhi. Risk factorsS typhi are able to survive
a stomach pH as low as 1.5. Antacids, histamine-2 receptor
antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and
achlorhydria decrease stomach acidity and facilitate S typhi
infection.[6] HIV/AIDS is clearly associated with an increased risk
of nontyphoidal Salmonella infection; however, the data and
opinions in the literature as to whether this is true for S typhi
infection are conflicting. If an association exists, it is probably
minor.[8, 9, 10, 11] Other 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. Polymorphisms in their shared
regulatory region are found disproportionately in persons infected
with Mycobacterium leprae and S typhi.[12] On the other hand,
protective host mutations also exist. The fimbriae of S typhi bind
in vitro to cystic fibrosis transmembrane conductance receptor
(CFTR), which is expressed on the gut membrane. Two to 5% of white
persons are heterozygous for the CFTR mutation F508del, which is
associated with a decreased susceptibility to typhoid fever, as
well as to cholera and tuberculosis. The homozygous F508del
mutation in CFTR 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 Africa.[13, 14] Environmental 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 inadequately, sharing food from the same plate, drinking
unpurified water, and living in a household that does not have a
toilet.[15, 12] As the middle class in south Asia 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.[16] American clinicians should keep
this in mind, as members of this cohort often come to the United
States for higher degrees. EpidemiologyFrequencyUnited StatesSince
1900, improved sanitation and successful antibiotic treatment have
steadily decreased the incidence of typhoid fever in the United
States. In 1920, 35,994 cases of typhoid fever were reported. In
2006, there were 314. Between 1999 and 2006, 79% of typhoid fever
cases occurred in patients who had been outside of the country
within the preceding 30 days. Two thirds of these individuals had
just journeyed from the Indian subcontinent. The 3 known outbreaks
of typhoid fever within the United States were traced to imported
food or to a food handler from an endemic region. Remarkably, only
17% of cases acquired domestically were traced to a carrier.[17]
InternationalTyphoid fever occurs worldwide, primarily in
developing nations whose sanitary conditions are poor. Typhoid
fever is endemic in Asia, Africa, Latin America, the Caribbean, and
Oceania, but 80% of cases come from Bangladesh, China, India,
Indonesia, Laos, Nepal, Pakistan, or Vietnam.[18] Within those
countries, typhoid fever is most common in underdeveloped areas.
Typhoid fever infects roughly 21.6 million people (incidence of 3.6
per 1,000 population) and kills an estimated 200,000 people every
year.[19] In the United States, most cases of typhoid fever arise
in international travelers. The average yearly incidence of typhoid
fever per million travelers from 1999-2006 by county or region of
departure was as follows:[17] Canada - 0 Western Hemisphere outside
Canada/United States - 1.3 Africa - 7.6 Asia - 10.5 India - 89 (122
in 2006) Total (for all countries except Canada/United States) -
2.2Mortality/MorbidityWith prompt and appropriate antibiotic
therapy, typhoid fever is typically a short-term febrile illness
requiring a median of 6 days of hospitalization. Treated, it has
few long-term sequelae and a 0.2% risk of mortality.[17] 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 9%-13%.[20] RaceTyphoid fever has no racial
predilection.SexFifty-four percent of typhoid fever cases in the
United States reported between 1999 and 2006 involved males.[17]
AgeMost documented typhoid fever cases involve school-aged children
and young adults. However, 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
unrecognized. 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.
HistoryA severe nonspecific febrile illness in a patient who has
been exposed to S typhi should always raise the diagnostic
possibility of typhoid fever (enteric fever). Classic typhoid fever
syndromeTyphoid fever begins 7-14 days after ingestion of S typhi.
The fever pattern is stepwise, characterized by a rising
temperature over the course of each day that drops by the
subsequent morning. The peaks and troughs rise progressively over
time. Over 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 quadrant pain. Monocytic infiltration
inflames Peyer 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.[2] At approximately the end of the
first week of illness, the fever plateaus at 103-104F (39-40C). The
patient develops rose spots, which are salmon-colored, blanching,
truncal, maculopapules usually 1-4 cm wide and fewer than 5 in
number; these generally resolve within 2-5 days.[2] These are
bacterial emboli to the dermis and occasionally develop in persons
with shigellosis or nontyphoidal salmonellosis.[22] During the
second week of illness, the signs and symptoms listed above
progress. The abdomen becomes distended, and soft splenomegaly is
common. Relative bradycardia and dicrotic pulse (double beat, the
second beat weaker than the first) may develop. In the third week,
the still febrile individual grows more toxic and anorexic with
significant weight loss. The conjunctivae are infected, and the
patient is tachypneic with a thready pulse and crackles over the
lung bases. Abdominal distension is severe. Some patients
experience foul, green-yellow, liquid diarrhea (pea soup diarrhea).
The individual may descend into the typhoid state, which is
characterized by apathy, confusion, and even psychosis. Necrotic
Peyer patches may cause bowel perforation and peritonitis. This
complication is often unheralded and may be masked by
corticosteroids. At this point, overwhelming toxemia, myocarditis,
or intestinal hemorrhage may cause death. If the individual
survives to the fourth week, the fever, mental state, and abdominal
distension slowly improve over a few days. Intestinal and
neurologic complications may still occur in surviving untreated
individuals. Weight loss and debilitating weakness last months.
Some survivors become asymptomatic S typhi carriers and have the
potential to transmit the bacteria indefinitely.[16, 23, 24, 2, 6]
Various presentations of typhoid feverThe 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 12% of
cases. In most contemporary presentations of typhoid fever, the
fever has a steady insidious onset. Young children, individuals
with AIDS, and one third of immunocompetent adults who develop
typhoid fever develop diarrhea rather than constipation. In
addition, in some localities, typhoid fever is generally more apt
to cause diarrhea than constipation. Atypical 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 India and Africa, present primarily with neurologic
manifestations such as delirium or, in extremely rare cases,
parkinsonian symptoms or Guillain-Barr syndrome. Other unusual
complications include pancreatitis,[25] meningitis, orchitis,
osteomyelitis, and abscesses anywhere on the body.[2] Table 1.
Incidence and Timing of Various Manifestations of Untreated Typhoid
Fever[2, 26, 27, 28, 29, 30] (Open Table in a new
window)IncubationWeek 1Week 2Week 3Week 4Post
SystemicRecovery phase or death (15% of untreated cases)10%-20%
relapse; 3%-4% chronic carriers;
long-term neurologic sequelae (extremely rare);
gallbladder cancer (RR=167; carriers)
Stepladder fever pattern or insidious onset feverVery
commonaVery common
Acute high feverVery rareb
ChillsAlmost allc
RigorsUncommon
AnorexiaAlmost all
DiaphoresisVery common
Neurologic
MalaiseAlmost allAlmost allTyphoid state (common)
InsomniaVery common
Confusion/deliriumCommondVery common
PsychosisVery rareCommon
CatatoniaVery rare
Frontal headache
(usually mild)
Very common
Meningeal signsRareeRare
ParkinsonismVery rare
Ear, nose, and throat
Coated tongueVery common
Sore throatf
Pulmonary
Mild coughCommon
Bronchitic coughCommon
RalesCommon
PneumoniaRare (lobar)RareCommon
(basal)
Cardiovascular
Dicrotic pulseRareCommon
MyocarditisRare
PericarditisExtremely rareg
ThrombophlebitisVery rare
Gastrointestinal
ConstipationVery commonCommon
DiarrheaRareCommon (pea soup)
Bloating with tympanyVery common (84%)[30]
Diffuse mild abdominal painVery common
Sharp right lower quadrant painRare
Gastrointestinal hemorrhageVery rare; usually traceVery
common
intestinal perforationRare
HepatosplenomegalyCommon
JaundiceCommon
Gallbladder painVery rare
Urogenital
Urinary retentionCommon
HematuriaRare
Renal painRare
Musculoskeletal
MyalgiasVery rare
ArthralgiasVery rare
Rheumatologic
Arthritis (large joint)Extremely rare
Dermatologic
Rose spotsRare
Miscellaneous
Abscess (anywhere)Extremely rareExtremely rareExtremely rare
a Very common: Symptoms occur in well over half of cases
(approximately 65%-95%).
b Very rare: Symptoms occur in less than 5% of cases.
c Almost all: Symptoms occur in almost all cases.
d Common: Symptoms occur in 35%-65% of cases.
e Rare: Symptoms occur in 5%-35% of cases.
f Blank cells: No mention of the symptom at that phase was found
in the literature.
g Extremely rare: Symptoms have been described in occasional
case reports.
Treated typhoid feverIf appropriate treatment is initiated
within the first few days of full-blown illness, the disease begins
to remit after about 2 days, and the patient's condition markedly
improves within 4-5 days. Any delay in treatment increases the
likelihood of complications and recovery time. CausesS typhi and
Salmonella paratyphi cause typhoid fever.Differential Diagnoses
Abdominal Abscess Amebic Hepatic Abscesses Appendicitis Brucellosis
Dengue Fever Influenza Leishmaniasis Malaria Rickettsial diseases
Toxoplasmosis Tuberculosis Tularemia Typhus
Laboratory StudiesThe diagnosis of typhoid fever (enteric fever)
is primarily clinical. Importantly, the reported sensitivities of
tests for S typhi vary greatly in the literature, even among the
most recent articles and respected journals. Culture The criterion
standard for diagnosis of typhoid fever has long been culture
isolation of the organism. Cultures are widely considered 100%
specific. Culture of bone marrow aspirate is 90% sensitive until at
least 5 days after commencement of antibiotics. However, this
technique is extremely painful, which may outweigh its benefit.[31]
Blood, intestinal secretions (vomitus or duodenal aspirate), and
stool culture results are positive for S typhi in approximately
85%-90% of patients with typhoid fever who present within the first
week of onset. They decline to 20%-30% later in the disease course.
In particular, stool culture may be positive for S typhi several
days after ingestion of the bacteria secondary to inflammation of
the intraluminal dendritic cells. Later in the illness, stool
culture results are positive because of bacteria shed through the
gallbladder. Multiple blood cultures (>3) yield a sensitivity of
73%-97%. Large-volume (10-30 mL) blood culture and clot culture may
increase the likelihood of detection.[32] Stool culture alone
yields a sensitivity of less than 50%, and urine culture alone is
even less sensitive. Cultures of punch-biopsy samples of rose spots
reportedly yield a sensitivity of 63% and may show positive results
even after administration of antibiotics. A single rectal swab
culture upon hospital admission can be expected to detect S typhi
in 30%-40% of patients. S typhi has also been isolated from the
cerebrospinal fluid, peritoneal fluid, mesenteric lymph nodes,
resected intestine, pharynx, tonsils, abscess, and bone, among
others. Bone marrow aspiration and blood are cultured in a
selective medium (eg, 10% aqueous oxgall) or a nutritious medium
(eg, tryptic soy broth) and are incubated at 37C for at least 7
days. Subcultures are made daily to one selective medium (eg,
MacConkey agar) and one inhibitory medium (eg, Salmonella-Shigella
agar). Identification of the organism with these conventional
culture techniques usually takes 48-72 hours from acquisition.
Table 2. Sensitivities of Cultures[2, 32, 33, 34] (Open Table in a
new window)IncubationWeek 1Week 2Week 3Week 4
Bone marrow aspirate (0.5-1 mL)90% (may decrease after 5 d of
antibiotics)
Blood (10-30 mL), stool, or duodenal aspirate
culture40%-80%~20%Variable (20%-60%)
Urine25%-30%, timing unpredictable
Polymerase chain reaction (PCR):[35, 36] PCR has been used for
the diagnosis of typhoid fever with varying success. Nested PCR,
which involves two rounds of PCR using two primers with different
sequences within the H1-d flagellin gene of S typhi, offers the
best sensitivity and specificity. Combining assays of blood and
urine, this technique has achieved a sensitivity of 82.7% and
reported specificity of 100%. However, no type of PCR is widely
available for the clinical diagnosis of typhoid fever. Specific
serologic tests Assays that identify Salmonella antibodies or
antigens support the diagnosis of typhoid fever, but these results
should be confirmed with cultures or DNA evidence. The Widal test
was the mainstay of typhoid fever diagnosis for decades. It is used
to measure agglutinating antibodies against H and O antigens of S
typhi. Neither sensitive nor specific, the Widal test is no longer
an acceptable clinical method. Indirect hemagglutination, indirect
fluorescent Vi antibody, and indirect enzyme-linked immunosorbent
assay (ELISA) for immunoglobulin M (IgM) and IgG antibodies to S
typhi polysaccharide, as well as monoclonal antibodies against S
typhi flagellin,[37] are promising, but the success rates of these
assays vary greatly in the literature. Other nonspecific laboratory
studies Most patients with typhoid fever are moderately anemic,
have an elevated erythrocyte sedimentation rate (ESR),
thrombocytopenia, and relative lymphopenia. Most also have a
slightly elevated prothrombin time (PT) and activated partial
thromboplastin time (aPTT) and decreased fibrinogen levels.
Circulating fibrin degradation products commonly rise to levels
seen in subclinical disseminated intravascular coagulation (DIC).
Liver transaminase and serum bilirubin values usually rise to twice
the reference range. Mild hyponatremia and hypokalemia are common.
A serum alanine amino transferase (ALT)tolactate dehydrogenase
(LDH) ratio of more than 9:1 appears to be helpful in
distinguishing typhoid from viral hepatitis. A ratio of greater
than 9:1 supports a diagnosis of acute viral hepatitis, while ratio
of less than 9:1 supports typhoid hepatitis.[38]
Imaging Studies Radiography: Radiography of the kidneys,
ureters, and bladder (KUB) is useful if bowel perforation
(symptomatic or asymptomatic) is suspected. CT scanning and MRI:
These studies may be warranted to investigate for abscesses in the
liver or bones, among other sites.Procedures Bone marrow
aspiration: The most sensitive method of isolating S typhi is BMA
culture (see Lab Studies).Histologic FindingsThe hallmark
histologic finding in typhoid fever is infiltration of tissues by
macrophages (typhoid cells) that contain bacteria, erythrocytes,
and degenerated lymphocytes. Aggregates 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. In the
intestines, 4 classic pathologic stages occur in the course of
infection: (1) hyperplastic changes, (2) necrosis of the intestinal
mucosa, (3) sloughing of the mucosa, and (4) the development of
ulcers. The ulcers may perforate into the peritoneal cavity. In 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 congested; its serosal surface
may have a fibrinous exudate. Microscopically, the red pulp is
congested and contains typhoid nodules. The gallbladder is
hyperemic and may show evidence of cholecystitis. Liver biopsy
specimens from patients with typhoid fever often show cloudy
swelling, balloon degeneration with vacuolation of hepatocytes,
moderate fatty change, and focal typhoid nodules. Intact typhoid
bacilli can be observed at these sites.[2, 6]
StagingThe proper treatment approach to typhoid fever depends on
whether the illness is complicated or uncomplicated. Complicated
typhoid fever is characterized by melena (3% of all hospitalized
patients with typhoid fever), serious abdominal discomfort,
intestinal perforation, marked neuropsychiatric symptoms, or other
severe manifestations. Depending on the adequacy of diagnosis and
treatment, complicated disease may develop in up to 10% of treated
patients. Delirium, obtundation, stupor, coma, or shock demands a
particularly aggressive approach (see Treatment).[29]
Medical CareIf a patient presents with unexplained symptoms
described in Table 1 within 60 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. Antibiotic therapy should be narrowed once more
information is available. Compliant patients with uncomplicated
disease may be treated on an outpatient basis. They must be advised
to use strict handwashing techniques and to avoid preparing food
for others during the illness course. Hospitalized patients should
be placed in contact isolation during the acute phase of the
infection. Feces and urine must be disposed of safely.
Surgical CareSurgery is usually indicated in cases of intestinal
perforation. Most surgeons prefer simple closure of the perforation
with drainage of the peritoneum. Small-bowel resection is indicated
for patients with multiple perforations. If antibiotic treatment
fails to eradicate the hepatobiliary carriage, the gallbladder
should be resected. Cholecystectomy is not always successful in
eradicating the carrier state because of persisting hepatic
infection.
ConsultationsAn infectious disease specialist should be
consulted. Consultation with a surgeon is indicated upon suspected
gastrointestinal perforation, serious gastrointestinal hemorrhage,
cholecystitis, or extraintestinal complications (arteritis,
endocarditis, organ abscesses). DietFluids and electrolytes should
be monitored and replaced diligently. Oral nutrition with a soft
digestible diet is preferable in the absence of abdominal
distension or ileus.
ActivityNo specific limitations on activity are indicated for
patients with typhoid fever. As 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.
AntibioticsClass SummaryDefinitive treatment of typhoid fever
(enteric fever) is based on susceptibility. As a general principle
of antimicrobial treatment, intermediate susceptibility should be
regarded as equivalent to resistance. Between 1999 and 2006, 13% 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 2003 World Health Organization
(WHO) guidelines to be outdated. These recommend fluoroquinolone
treatment for both complicated and uncomplicated cases of typhoid
fever, but 38% of S typhi isolates taken in the United States in
2006 were fluoroquinolone resistant (nalidixic acidresistant S
typhi [NARST]), and the rate of multidrug resistance was 13%.
(Multidrug-resistant S typhi is, by definition, resistant to the
original first-line agents, ampicillin, chloramphenicol, and
trimethoprim-sulfamethoxazole.) The particular sensitivity pattern
of the organism in its area of acquisition should be the major
basis of empiric antibiotic choice. It may soon become necessary to
treat all cases presumptively for multidrug resistance until
sensitivities are obtained. Note that nalidixic acid is a
nontherapeutic drug that is used outside of the United States as a
stand-in for fluoroquinolones in sensitivity assays. In the United
States, it is still used specifically for S typhi infection.[39,
17] History of antibiotic resistanceChloramphenicol was used
universally to treat typhoid fever from 1948 until the 1970s, when
widespread resistance occurred. Ampicillin and
trimethoprim-sulfamethoxazole (TMP-SMZ) then became treatments of
choice. However, in the late 1980s, some S typhi and S paratyphi
strains (multidrug resistant [MDR] S typhi or S paratyphi)
developed simultaneous plasmid-mediated resistance to all three of
these agents. Fluoroquinolones 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 fluoroquinolones is widespread in many parts of
Asia. In recent years, third-generation cephalosporins have been
used in regions with high fluoroquinolone resistance rates,
particularly in south Asia and Vietnam. Unfortunately, sporadic
resistance has been reported, so it is expected that these will
become less useful over time.[39] Mechanisms of antibiotic
resistanceThe genes for antibiotic resistance in S typhi and S
paratyphi are acquired 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 explains the sudden appearance of MDR strains of
S typhi and S paratyphi, often without intermediate strains that
have less-extensive resistance. The initial strains of
antibiotic-resistant S typhi and S paratyphi carried
chloramphenicol acetyltransferase type I, which encodes an enzyme
that inactivates chloramphenicol via acetylation. MDR strains may
carry dihydrofolate reductase type VII, which confers resistance to
trimethoprim. Interestingly, 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.[40, 41, 42, 30] Resistance to
fluoroquinolones is evolving in an ominous direction.
Fluoroquinolones target DNA gyrase and topoisomerase IV, bacterial
enzymes that are part of a complex that uncoils and recoils
bacterial DNA for transcription.[43] S typhi most commonly develops
fluoroquinolone resistance through specific mutations in gyrA and
parC, which code for the binding region of DNA gyrase and
topoisomerase IV, respectively. A single point mutation gyrA
confers partial resistance. If a second gyrA point mutation is
added, the resistance increases somewhat. However, a mutation in
parC added to a single gyrA mutation confers full in vitro
resistance to first-generation fluoroquinolones. Clinically, these
resistant strains show a 36% failure rate when treated with a
first-generation fluoroquinolone such as ciprofloxacin.[44] The
risk of relapse after bacterial clearance is higher in both
partially and fully resistant strains than in fully susceptible
strains.[18] The third-generation fluoroquinolone gatifloxacin
appears to be highly effective against all known clinical strains
of S typhi both in vitro and in vivo. due to its unique interface
with gyrA. It achieves better results than cephalosporins even
among strains that are considered fluoroquinolone resistant.
However, gatifloxacin is no longer on the market in the United
States, and its use cannot be generalized to any other member of
the class.[45, 46] In any case, as gatifloxacin replaces older
fluoroquinolones in high-prevalence resistance is bound to emerge.
Any two of a number of gyrA mutations, when added to the parC
mutation, confer full in vitro resistance. Although such a
combination has yet to be discovered in vivo, all of these
mutations exist in various clinic strains, and it seems highly
likely that a gatifloxacin-resistant one will be encountered
clinically if selective pressure with fluoroquinolones continues to
be exerted.[44] Geography of resistanceAmong S typhi isolates
obtained in the United States between 1999 and 2006, 43% were
resistant to at least one antibiotic.Nearly half of S typhi
isolates found in the United States now come from travelers to the
Indian subcontinent, where fluoroquinolone resistance is endemic
(see Table 3). The rate of fluoroquinolone resistance in south and
Southeast Asia and, to some extent, in East Asia is generally high
and rising (see Table 3). Susceptibility to chloramphenicol,
TMP-SMZ, and ampicillin in South Asia is rebounding. In Southeast
Asia, MDR strains remain predominant, and some acquired resistance
to fluoroquinolones by the early 2000s. The most recent
professional guideline for the treatment of typhoid fever in south
Asia was issued by the Indian Association of Pediatrics (IAP) in
October 2006. Although 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 IAP recommends cefixime and, as a second-line
agent, azithromycin. For complicated typhoid fever, they recommend
ceftriaxone. Aztreonam and imipenem are second-line agents for
complicated cases.[47] The authors believe that the IAP
recommendations have more validity than the WHO recommendations for
empiric treatments of typhoid fever in both adults and children. In
high-prevalence areas outside the areas discussed above, the rate
of intermediate sensitivity or resistance to fluoroquinolones is
3.7% in the Americas (P =.132), 4.7% (P =.144) in sub-Saharan
Africa, and 10.8% (P =.706) in the Middle East. Therefore, for
strains that originate outside of south or Southeast Asia, the WHO
recommendations may still be validthat uncomplicated disease should
be treated empirically with oral ciprofloxacin and complicated
typhoid fever from these regions should be treated with intravenous
ciprofloxacin.[39, 42, 48, 19, 49] Antibiotic resistance is a
moving target. Reports are quickly outdated, and surveys of
resistance may have limited geographic scope. Therefore, any
recommendation regarding antibiotic treatment must be taken with a
grain of salt. In the authors' opinion, if the origin of the
infection is unknown, the combination of a first-generation
fluoroquinolone and a third-generation cephalosporin should be
used. Table 3. Antibiotic Recommendations by Origin and Severity
(Open Table in a new window)LocationSeverityFirst-Line
AntibioticsSecond-Line Antibiotics
South Asia, East Asia[47]
[50, 40]
UncomplicatedCefixime POAzithromycin PO
ComplicatedCeftriaxone IV or
Cefotaxime IV
Aztreonam IV or
Imipenem IV
Eastern Europe, Middle East, sub-Saharan Africa, South
America[48, 51] UncomplicatedCiprofloxacin PO or
Ofloxacin PO
Cefixime PO or
Amoxicillin PO or
TMP-SMZ PO
or Azithromycin PO
ComplicatedCiprofloxacin IV or
Ofloxacin IV
Ceftriaxone IV or
Cefotaxime IV or
Ampicillin IV
or
TMP-SMZ IV
Unknown geographic origin or Southeast Asia[52, 47]
[50, 40, 48, 51]
UncomplicatedCefixime PO plus
Ciprofloxacin PO or
Ofloxacin PO
Azithromycin PO*
ComplicatedCeftriaxone IV or
Cefotaxime IV, plus
Ciprofloxacin IV or
Ofloxacin IV
Aztreonam IV or
Imipenem IV, plus
Ciprofloxacin IV
or
Ofloxacin IV
*Note that the combination of azithromycin and fluoroquinolones
is not recommended because it may cause QT prolongation and is
relatively contraindicated.
Future directionsA meta-analysis found that azithromycin
appeared to be superior to fluoroquinolones and ceftriaxone with
lower rates of clinical failure and relapse respectively. Although
the data did not permit firm conclusions, if further studies
confirm the trend, azithromycin could become a first-line
treatment.Chloramphenicol (Chloromycetin)Binds to 50S
bacterial-ribosomal subunits and inhibits bacterial growth by
inhibiting protein synthesis. Effective against gram-negative and
gram-positive bacteria. Since its introduction in 1948, has proven
to be remarkably effective for enteric fever worldwide. For
sensitive strains, still most widely used antibiotic to treat
typhoid fever. In the 1960s, S typh i strains with plasmid-mediated
resistance to chloramphenicol began to appear and later became
widespread in many endemic countries of the Americas and Southeast
Asia, highlighting need for alternative agents.Produces rapid
improvement in patient's general condition, followed by
defervescence in 3-5 d. Reduced preantibiotic-era case-fatality
rates from 10%-15% to 1%-4%. Cures approximately 90% of patients.
Administered PO unless patient is nauseous or experiencing
diarrhea; in such cases, IV route should be used initially. IM
route should be avoided because it may result in unsatisfactory
blood levels, delaying defervescence. adultSerious Infections
Caused by Susceptible Strains50 mg/kg/day IV divided q6hr; in
exceptional cases, patients with moderately resistant organisms or
severe infections may require increased dosage up to 100 mg/kg/day;
decrease these high doses as soon as possibleOther Indications
& UsesUse only as alternative for treatment of meningitis,
typhoid, or rickettsial infectionPediatricSystemic
InfectionsInfants and children: As in adults; when adequate
cerebrospinal fluid concentrations desired, may require up to 100
mg/kg/day; however, should reduce dose to 50 mg/kg/day as soon as
possible Infants and children with suspected immature metabolic
functions: 25 mg/kg/day divided q6hr will usually produce
therapeutic concentrations of the drug in the bloodNeonates (2000
g: 50 mg/kg/day IV divided q12hrOther InformationPeaks 10-20 mg/L,
troughs 5-10 mg/LAmoxicillin (Trimox, Amoxil, Biomox)Interferes
with synthesis of cell wall mucopeptides during active
multiplication, resulting in bactericidal activity against
susceptible bacteria. At least as effective as chloramphenicol in
rapidity of defervescence and relapse rate. Convalescence carriage
occurs less commonly than with other agents when organisms are
fully susceptible. Usually given PO with a daily dose of 75-100
mg/kg tid for 14 d. Trimethoprim and sulfamethoxazole (Bactrim DS,
Septra)Inhibits bacterial growth by inhibiting synthesis of
dihydrofolic acid. Antibacterial activity of TMP-SMZ includes
common urinary tract pathogens, except Pseudomonas aeruginosa. As
effective as chloramphenicol in defervescence and relapse rate.
Trimethoprim alone has been effective in small groups of patients.
Ciprofloxacin (Cipro)Fluoroquinolone with activity against
pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and
most gram-negative organisms but no activity against anaerobes.
Inhibits bacterial DNA synthesis and, consequently, growth.
Continue treatment for at least 2 d (7-14 d typical) after signs
and symptoms have disappeared. Proven to be highly effective for
typhoid and paratyphoid fevers. Defervescence occurs in 3-5 d, and
convalescent carriage and relapses are rare. Other quinolones (eg,
ofloxacin, norfloxacin, pefloxacin) usually are effective. If
vomiting or diarrhea is present, should be given IV.
Fluoroquinolones are highly effective against multiresistant
strains and have intracellular antibacterial activity.Not currently
recommended for use in children and pregnant women because of
observed potential for causing cartilage damage in growing animals.
However, arthropathy has not been reported in children following
use of nalidixic acid (an earlier quinolone known to produce
similar joint damage in young animals) or in children with cystic
fibrosis, despite high-dose treatment. Cefotaxime (Claforan)Arrests
bacterial cell wall synthesis, which inhibits bacterial growth.
Third-generation cephalosporin with gram-negative spectrum. Lower
efficacy against gram-positive organisms. Excellent in vitro
activity against S typhi and other salmonellae and has acceptable
efficacy in typhoid fever. Only IV formulations are available.
Recently, emergence of domestically acquired ceftriaxone-resistant
Salmonella infections has been described. Azithromycin
(Zithromax)Treats mild to moderate microbial infections.
Administered PO at 10 mg/kg/d (not exceeding 500 mg), appears to be
effective to treat uncomplicated typhoid fever in children 4-17 y.
Confirmation of these results could provide an alternative for
treatment of typhoid fever in children in developing countries,
where medical resources are scarce. Ceftriaxone
(Rocephin)Third-generation cephalosporin with broad-spectrum
gram-negative activity against gram-positive organisms; Excellent
in vitro activity against S typhi and other salmonellae.
Cefoperazone (Cefobid)Discontinued in the United States.
Third-generation cephalosporin with gram-negative spectrum. Lower
efficacy against gram-positive organisms.
Ofloxacin (Floxin)A pyridine carboxylic acid derivative with
broad-spectrum bactericidal effect.Levofloxacin (Levaquin)For
pseudomonal infections and infections due to multidrug-resistant
gram-negative organisms.CorticosteroidsClass SummaryDexamethasone
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 randomized controlled study in patients aged 3-56
years with severe typhoid fever who were receiving chloramphenicol
therapy. This study compared outcomes in 18 patients given placebo
with outcomes in 20 patients given dexamethasone 3 mg/kg IV over 30
minutes followed by dexamethasone 1 mg/kg every 6 hours for 8
doses. The fatality rate in the dexamethasone arm was 10% versus
55.6% in the placebo arm (P =.003).[54] Nonetheless, this point is
still debated. A 2003 WHO statement endorsed the use of steroids as
described above, but reviews by eminent authors in the New England
Journal of Medicine (2002)[6] and the British Medical Journal
(2006)[55] do not refer to steroids at all. A 1991 trial compared
patients treated with 12 doses of dexamethasone 400 mg or 100 mg to
a retrospective cohort in whom steroids were not administered. This
trial found no difference in outcomes among the groups.[56] The
data are sparse, but the authors of this article agree with the WHO
that dexamethasone should be used in cases of severe typhoid fever.
Dexamethasone (Decadron)Prompt administration of high-dose
dexamethasone reduces mortality in patients with severe typhoid
fever without increasing incidence of complications, carrier
states, or relapse among survivors.
Further Inpatient Care If treated with well-selected
antibiotics, patients with typhoid fever (enteric fever) should
defervesce within 3-5 days. However, patients with complicated
typhoid fever should finish their course intravenously and should
remain in the hospital if unable to manage this at home. Patients
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 Outpatient Care
After discharge, patients should be monitored for relapse or
complications for 3 months after treatment has commenced. Five
percent to 10% of patients treated with antibiotics experience
relapse of typhoid fever after initial recovery. Relapses typically
occur approximately 1 week after therapy is discontinued, but
relapse after 70 days has been reported. In these cases, the blood
culture results are again positive, and high serum levels of H, O,
and Vi antibodies and rose spots may reappear. A relapse of typhoid
fever is generally milder and of shorter duration than the initial
illness. In rare cases, second or even third relapses occur.
Notably, the relapse rate is much lower following treatment with
the new quinolone drugs, which have effective intracellular
penetration. S typhi and S paratyphi rarely develop antibiotic
resistance during treatment. If 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. Previous infection does not confer immunity.
In any suspected relapse, infection with a different strain should
be ruled out. Depending on the antibiotic used, between 0% and 5.9%
of treated patients become chronic carriers. In some cases, the
organism evades antibiotics by sequestering itself within
gallstones or Schistosoma haematobium organisms that are infecting
the bladder. From there, it is shed in stool or urine,
respectively. If 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 3 months. Therefore,
after disease resolution, 3 stool cultures in one-month intervals
should be performed to rule out a carrier state. Concurrent urinary
cultures should be considered. Deterrence/Prevention Travelers to
endemic countries should avoid raw unpeeled fruits or vegetables
since they may have been prepared with contaminated water; in
addition, they should drink only boiled water. In 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
excreta. 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. VaccinesIn endemic areas,
mass immunization with typhoid vaccines at regular intervals
considerably reduces the incidence of infections. Routine typhoid
vaccination is not recommended in the United States but is
indicated for travelers to endemic areas, persons with intimate
exposure to a documented S typhi carrier (eg, household contact),
and microbiology laboratory personnel who frequently work with S
typhi. Vaccines are not approved for use children younger than 2
years. Travelers should be vaccinated at least one week prior to
departing for an endemic area. Because 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. Currently,
the 3 typhoid fever vaccines include injected Vi capsular
polysaccharide (ViCPS; Typhim Vi, Pasteur Merieux) antigen, enteric
Ty21a (Vivotif Berna, Swiss Serum and Vaccine Institute)
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 50%. Vi
capsular polysaccharide antigen vaccine is composed of purified Vi
antigen, the capsular polysaccharide elaborated by S typhi isolated
from blood cultures. Primary vaccination with ViCPS consists of a
single parenteral dose of 0.5 mL (25 g IM) one week before travel.
The vaccine manufacturer does not recommend the vaccine for
children younger than 2 years. Booster doses are needed every 2
years to maintain protection if continued or renewed exposure is
expected. Adverse effects include fever, headache, erythema, and/or
induration of 1 cm or greater. In a study conducted in Nepal, the
ViCPS vaccine produced fewer local and systemic reactions than the
control (the 23-valent pneumococcal vaccine).[57] Among school
children in South Africa, ViCPS produced less erythema and
induration than the control (bivalent vaccine). A systemic review
and meta-analysis of 5 randomized controlled trials on the efficacy
and safety of ViCPS versus placebo or nontyphoid vaccine found a
cumulative efficacy of 55% (95% CI, 30%-70%). The efficacy of
vaccination with ViCPS has not been studied among persons from
areas without endemic disease who travel to endemic regions or
among children younger than 5 years. ViCPS has not been given to
children younger than 1 year. Questions concerning Vi typhoid
vaccine effectiveness in young children (ie, < 5 y) have
inhibited its use in developing countries. Whether the vaccine is
effective under programmatic conditions is also unclear. Sur et al
conducted a phase IV effectiveness trial in slum-dwelling residents
aged 2 years or older in India to determine vaccine protection.
Participants (n=37,673) were randomly assigned to receive a single
dose of either Vi vaccine or inactivated hepatitis A vaccine,
according to geographic clusters. The mean rate of Vi vaccine
coverage was 61% and 60% for the hepatitis A vaccine. Typhoid fever
was diagnosed in 96 subjects in the hepatitis A vaccine group
compared with 34 in the Vi vaccine group (no more than 1 episode
was reported per individual). Protective effect for typhoid with
the Vi vaccine was 61% (P < 0.001) compared with the hepatitis A
vaccine group. Children vaccinated while aged 2-5 years had an 80%
protection level. Unvaccinated members of the Vi vaccine clusters
showed a protection level of 44%. The overall protection level with
all Vi vaccine cluster residents was 57%. The authors concluded
that the Vi vaccine was effective in young children and protected
unvaccinated neighbors of Vi vaccinees.[58] Ty21a is an oral
vaccine that contains live attenuated S typhi Ty21a strains in an
enteric-coated capsule. The vaccine elicits both serum and
intestinal antibodies and cell-mediated immune responses. In the
United States, primary vaccination with Ty21a consists of one
enteric-coated capsule taken on alternate days to a total of 4
capsules. The capsules must be refrigerated (not frozen), and all 4
doses must be taken to achieve maximum efficacy. The optimal
booster schedule has not been determined; however, the longest
reported follow-up study of vaccine trial subjects indicated that
efficacy continued for 5 years after vaccination. The manufacturer
recommends revaccination with the entire 4-dose series every 5
years if continued or renewed exposure to S typhi is expected. This
vaccine may be inactivated if given within 3 days of antibiotics.
Adverse effects are rare. They include abdominal discomfort,
nausea, vomiting, fever, headache, and rash or urticaria. The
vaccine manufacturer of Ty21a recommends against use in children
younger than 6 years. It should not be administered to
immunocompromised persons; the parenteral vaccines present
theoretically safer alternatives for this group. A systemic review
and meta-analysis of 4 randomized controlled trials on the efficacy
and safety of Ty21a versus placebo or nontyphoid vaccine found a
cumulative efficacy of 51% (95% CI, 36%-62%). The efficacy of Ty21a
has not been studied among persons from areas without endemic
disease who travel to disease-endemic regions. Acetone-inactivated
parenteral vaccine is currently available only to members of the US
Armed Forces. Efficacy rates for this vaccine range from 75%-94%.
Booster doses should be administered every 3 years if continued or
renewed exposure is expected. The parenteral heat-phenolinactivated
vaccine (Wyeth-Ayerst) has been discontinued. No information has
been reported concerning the use of one vaccine as a booster after
primary vaccination with a different vaccine. However, using either
the series of 4 doses of Ty21a or 1 dose of ViCPS for persons
previously vaccinated with parenteral vaccine is a reasonable
alternative to administration of a booster dose of parenteral
inactivated vaccine. A more effective vaccine may be on the
horizon. An investigational vaccine using ViCPS conjugated to the
nontoxic recombinant pseudomonas exotoxin A (Vi-rEPA) has been
studied in a randomized controlled trial. The vaccine was given to
children aged 2-5 years and showed an efficacy of 89% (95% CI,
76%-97%) after 3.8 years. Vi-rEPA has not been approved for use in
the United States. Complications Neuropsychiatric manifestations
(In the past 2 decades, reports from disease-endemic areas have
documented a wide spectrum of neuropsychiatric manifestations of
typhoid fever.) A toxic confusional state, characterized by
disorientation, delirium, and restlessness, is characteristic of
late-stage typhoid fever. In some cases, these and other
neuropsychiatric features dominate the clinical picture at an early
stage. Facial twitching or convulsions may be the presenting
feature. Meningismus is not uncommon, but frank meningitis is rare.
Encephalomyelitis may develop, and the underlying pathology may be
that of demyelinating leukoencephalopathy. In rare cases,
transverse myelitis, polyneuropathy, or cranial mononeuropathy
develops. Stupor, obtundation, or coma indicates severe disease.
Focal intracranial infections are uncommon, but multiple brain
abscesses have been reported.[59] Other less-common
neuropsychiatric manifestations events have included spastic
paraplegia, peripheral or cranial neuritis, Guillain-Barr syndrome,
schizophrenialike illness, mania, and depression. Respiratory Cough
Ulceration of posterior pharynx Occasional presentation as acute
lobar pneumonia (pneumotyphoid) Cardiovascular Nonspecific
electrocardiographic changes occur in 10%-15% of patients with
typhoid fever. Toxic myocarditis occurs in 1%-5% of persons with
typhoid fever and is a significant cause of death in endemic
countries. Toxic myocarditis occurs in patients who are severely
ill and toxemic and is characterized by tachycardia, weak pulse and
heart sounds, hypotension, and electrocardiographic abnormalities.
Pericarditis is rare, but peripheral vascular collapse without
other cardiac findings is increasingly described. Pulmonary
manifestations have also been reported in patients with typhoid
fever.[60] Hepatobiliary Mild elevation of transaminases without
symptoms is common in persons with typhoid fever. Jaundice may
occur in persons with typhoid fever and may be due to hepatitis,
cholangitis, cholecystitis, or hemolysis. Pancreatitis and
accompanying acute renal failure and hepatitis with hepatomegaly
have been reported.[61] Intestinal manifestations The 2 most common
complications of typhoid fever include intestinal hemorrhage (12%
in one British series) and perforation (3%-4.6% of hospitalized
patients). From 1884-1909 (ie, preantibiotic era), the mortality
rate in patients with intestinal perforation due to typhoid fever
was 66%-90% but is now significantly lower. Approximately 75% of
patients have guarding, rebound tenderness, and rigidity,
particularly in the right lower quadrant. Diagnosis is particularly
difficult in the approximately 25% of patients with perforation and
peritonitis who do not have the classic physical findings. In many
cases, the discovery of free intra-abdominal fluid is the only sign
of perforation. Genitourinary manifestations Approximately 25% of
patients with typhoid fever excrete S typhi in their urine at some
point during their illness. Immune complex glomerulitis[62] and
proteinuria have been reported, and IgM, C3 antigen, and S typhi
antigen can be demonstrated in the glomerular capillary wall.
Nephritic syndrome may complicate chronic S typhi bacteremia
associated with urinary schistosomiasis. Nephrotic syndrome may
occur transiently in patients with glucose-6-phosphate
dehydrogenase deficiency. Cystitis: Typhoid cystitis is very rare.
Retention of urine in the typhoid state may facilitate infection
with coliforms or other contaminants. Hematologic manifestations
Subclinical disseminated intravascular coagulation is common in
persons with typhoid fever. Hemolytic-uremic syndrome is rare.[63]
Hemolysis may also be associated with glucose-6-phosphate
dehydrogenase deficiency. Musculoskeletal and joint manifestations
Skeletal muscle characteristically shows Zenker degeneration,
particularly affecting the abdominal wall and thigh muscles.
Clinically evident polymyositis may occur.[64] Arthritis is very
rare and most often affects the hip, knee, or ankle. Late sequelae
(rare in untreated patients and exceedingly rare in treated
patients) Neurologic - Polyneuritis, paranoid psychosis, or
catatonia[65] Cardiovascular - Thrombophlebitis of lower-extremity
veins Genitourinary -Orchitis Musculoskeletal Periostitis, often
abscesses of the tibia and ribs Spinal abscess (typhoid spine; very
rare)Prognosis The prognosis among persons with typhoid fever
depends primarily on the speed of diagnosis and initiation of
correct treatment. Generally, untreated typhoid fever carries a
mortality rate of 10%-20%. In properly treated disease, the
mortality rate is less than 1%. An unspecified number of patients
experience long-term or permanent complications, including
neuropsychiatric symptoms and high rates of gastrointestinal
cancers. Patient Education Because 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. Because the protection offered
by vaccination is at best partial, close attention to personal,
food, and water hygiene should be maintained. The US Centers for
Disease Control and Prevention dictum to "boil it, cook it, peel
it, or forget it" is a good rule in any circumstance. If disease
occurs while abroad despite these precautions, one can usually call
the US consulate for a list of recommended doctors. For excellent
patient education resources, see eMedicineHealth's patient
education article Foreign Travel. Case study A 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.
Over the next 2 weeks, he lost a great deal of weight. He had
intermittent but ever-increasing fevers. About 3 weeks after the
onset of symptoms, he developed a few pale, salmon-colored macules
on his trunk. His cough became much more frequent and severe. He
became delirious, listlessly wandering around the house fiddling
with doorknobs. During the fourth week of his illness, he rapidly
declined with increasing somnolence. After nearly 4 weeks of
illness, he died surrounded by his loving family. The patient was
Prince Albert, the Consort to Queen Victoria. He was diagnosed with
typhoid fever. His personal physician, Sir William Jenner, a
leading expert on the disease, diagnosed typhoid fever. Prince
Albert received the best therapy of the day. For the most
up-to-date information, visit the Centers for Disease Control and
Prevention Travelers' Health Typhoid resource (www.cdc.gov/travel)
or call the Travelers' Health automated information line at
877-FYI-TRIP. The World Health Organizations site
(www.who.int/ith), International Society of Travel Medicine site
(www.istm.org), and Travel Doctor
(www.traveldoctor.co.uk/diseases.htm) contain useful information as
well, though the authors disagree with some of the WHOs antibiotic
guidelines.