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. 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

Transmission

S 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

Pathophysiology

All 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 ilium 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 ilium. S typhi has specialized fimbriae that adhere to the epithelium
over clusters of lymphoid tissue in the ilium (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

It co-opts the macrophages' cellular machinery for their own reproduction7 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 gallbladder is then infected 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 factors

S 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.

Frequency

United States

Since 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

International

Typhoid 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) - 2.2

Mortality/Morbidity

With 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

Race

Typhoid fever has no racial predilection.

Sex

Fifty-four percent of typhoid fever cases in the United States reported between 1999 and
2006 involved males.17

Age

Most 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. 16,21

Clinical

History

A 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 syndrome

Typhoid 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 103-104°F (39-
40°C). 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 fever

 Incubation Week 1 Week 2 Week 3 Week 4 Post

Systemic Recovery 10%-20%

phase or relapse;
Stepladder fever Very Very common death 3%-4%
pattern or insidious commona (15% of chronic
onset fever untreated carriers;
cases) long-term
neurologic
Acute high fever Very rareb
sequelae
(extremely
Chills Almost allc rare);
gallbladder
Rigors Uncommon cancer
(RR=167;
Anorexia Almost all carriers)

Diaphoresis Very common

Neurologic

Malaise Almost all Almost all Typhoid

state
Insomnia Very (common)
common

Confusion/delirium Commond Very

common

Psychosis Very rare Common

Catatonia Very rare

Frontal headache Very

(usually mild) common

Meningeal signs Raree Rare

Parkinsonism Very rare

Ear, nose, and throat

Coated tongue Very

common
Sore throatf

Pulmonary

Mild cough Common

Bronchitic cough Common

Rales Common

Pneumonia Rare Rare Common

(lobar) (basal)

Cardiovascular

Dicrotic pulse Rare Common

Myocarditis Rare

Pericarditis Extremely
rareg

Thrombophlebitis Very rare

Gastrointestinal

Constipation Very Common

common

Diarrhea Rare Common (pea soup)

Bloating with Very

tympany common
(84%) 30

Diffuse mild Very

abdominal pain common

Sharp right lower Rare

quadrant pain

Gastrointestinal Very rare; Very common

hemorrhage usually
trace
intestinal perforation Rare

Hepatosplenomegaly Common

Jaundice Common

Gallbladder pain Very rare

Urogenital

Urinary retention Common

Hematuria Rare

Renal pain Rare

Musculoskeletal

Myalgias Very rare

Arthralgias Very rare

Rheumatologic

Arthritis (large joint) Extremely rare

Dermatologic

Rose spots Rare

Miscellaneous

Abscess (anywhere) Extremely Extremely Extremely

rare rare rare

Incubation Week 1 Week 2 Week 3 Week 4 Post

Systemic Recovery 10%-20%

phase or relapse;
Stepladder fever Very Very common death 3%-4%
pattern or insidious commona (15% of chronic
onset fever untreated carriers;
cases) long-term
neurologic
Acute high fever Very rareb
Chills Almost allc sequelae
(extremely
Rigors Uncommon rare);
gallbladder
cancer
Anorexia Almost all
(RR=167;
carriers)
Diaphoresis Very common

Neurologic

Malaise Almost all Almost all Typhoid

state
Insomnia Very (common)
common

Confusion/delirium Commond Very

common

Psychosis Very rare Common

Catatonia Very rare

Frontal headache Very

(usually mild) common

Meningeal signs Raree Rare

Parkinsonism Very rare

Ear, nose, and throat

Coated tongue Very

common

Sore throatf

Pulmonary

Mild cough Common

Bronchitic cough Common

Rales Common
Pneumonia Rare Rare Common
(lobar) (basal)

Cardiovascular

Dicrotic pulse Rare Common

Myocarditis Rare

Pericarditis Extremely
rareg

Thrombophlebitis Very rare

Gastrointestinal

Constipation Very Common

common

Diarrhea Rare Common (pea soup)

Bloating with Very

tympany common
(84%) 30

Diffuse mild Very

abdominal pain common

Sharp right lower Rare

quadrant pain

Gastrointestinal Very rare; Very common

hemorrhage usually
trace

intestinal perforation Rare

Hepatosplenomegaly Common

Jaundice Common

Gallbladder pain Very rare

Urogenital
Urinary retention Common

Hematuria Rare

Renal pain Rare

Musculoskeletal

Myalgias Very rare

Arthralgias Very rare

Rheumatologic

Arthritis (large joint) Extremely rare

Dermatologic

Rose spots Rare

Miscellaneous

Abscess (anywhere) Extremely Extremely Extremely

rare rare rare

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 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-Barré 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

Fever2,26,27,28,29,30
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 fever

If 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.

Physical

See History.

Causes

S typhi and Salmonella paratyphi cause typhoid fever.

Differential Diagnoses
Abdominal Abscess Malaria
Amebic Hepatic AbscessesRickettsial diseases
Appendicitis Toxoplasmosis
Brucellosis Tuberculosis
Dengue Fever Tularemia
Influenza Typhus
Leishmaniasis

Other Problems to Be Considered

Endocarditis
Connective-tissue disease
Lymphoproliferative disorders

Workup

Laboratory Studies

The 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
o The criterion standard for diagnosis of typhoid fever has long been culture
isolation of the organism. Cultures are widely considered 100% specific.
o 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
o 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.
o 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
o 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.
o 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 37°C 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 Cultures2,32,33,34

Open table in new window

[ CLOSE WINDOW ]

Table

Incubation Week 1 Week 2 Week 3 Week 4

Bone marrow 90% (may decrease after 5 d of antibiotics)

aspirate (0.5-1 mL)

Blood (10-30 mL), 40%-80% ~20% Variable (20%-60%)

stool, or duodenal
aspirate culture

Urine 25%-30%, timing unpredictable

Incubation Week 1 Week 2 Week 3 Week 4

Bone marrow 90% (may decrease after 5 d of antibiotics)

aspirate (0.5-1 mL)

Blood (10-30 mL), 40%-80% ~20% Variable (20%-60%)

stool, or duodenal
aspirate culture

Urine 25%-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
o Assays that identify Salmonella antibodies or antigens support the
diagnosis of typhoid fever, but these results should be confirmed with
cultures or DNA evidence.
o 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.
o 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
o Most patients with typhoid fever are moderately anemic, have an elevated
erythrocyte sedimentation rate (ESR), thrombocytopenia, and relative
lymphopenia.
o Most also have a slightly elevated prothrombin time (PT) and activated
partial thromboplastin time (aPTT) and decreased fibrinogen levels.
o Circulating fibrin degradation products commonly rise to levels seen in
subclinical disseminated intravascular coagulation (DIC).
o Liver transaminase and serum bilirubin values usually rise to twice the
reference range.
o Mild hyponatremia and hypokalemia are common.
o A serum alanine amino transferase (ALT)–to–lactate 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 Findings

The 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

Staging

The 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

Treatment

Medical Care
If 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 Care

Surgery 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.

Consultations

An 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).

Diet

Fluids 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.

Activity

No 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.

Medication

Antibiotics

Definitive 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
acid–resistant 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 resistance

Chloramphenicol 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 resistance

The 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. However, 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 clinic strains, and it seems highly likely that a gatifloxacin-resistant
strain will be encountered clinically if selective pressure with fluoroquinolones continues
to be exerted.44

Geography of resistance

Among 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 these areas 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.45 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 valid—that uncomplicated disease should be treated empirically with oral
ciprofloxacin and complicated typhoid fever from these regions should be treated with
intravenous ciprofloxacin.39,42,46,19,47

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 new window

[ CLOSE WINDOW ]

Table

Location Severity First-Line Antibiotics Second-Line Antibiotics

South Asia, East Asia 45 Uncomplicated Cefixime PO Azithromycin PO

48, 40

Complicated Ceftriaxone IV or Aztreonam IV or

Cefotaxime IV Imipenem IV

*Note that the combination of azithromycin and fluoroquinolones is not recommended

because it may cause QT prolongation and is relatively contraindicated.

Future directions

Researchers in Cameroon report that a compound derived from the seeds of

Turraeanthus africanus, an African folk remedy for typhoid fever, is active against S typhi
in vitro.51 Perhaps they are on their way to creating an addition to the shrinking arsenal of
effective antimicrobials.

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.

 Dosing
 Interactions
 Contraindications
 Precautions

Adult

500 mg PO/IV q4h until defervescence, then q6h for a total course of 14 d

Pediatric

50-75 mg/kg/d PO/IV divided q6h

 Dosing
 Interactions
 Contraindications
 Precautions

Concurrently with barbiturates, chloramphenicol serum levels may decrease while

barbiturate levels may increase, causing toxicity; manifestations of hypoglycemia may
occur with sulfonylureas; rifampin may reduce serum levels, presumably through hepatic
enzyme induction; may increase effects of anticoagulants; may increase serum
hydantoin levels, possibly resulting in toxicity (chloramphenicol levels may be increased
or decreased)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus

Precautions

Use only for indicated infections or as prophylaxis for bacterial infections; serious and
fatal blood dyscrasias (eg, aplastic anemia, hypoplastic anemia, thrombocytopenia,
granulocytopenia) can occur; evaluate baseline and perform periodic blood studies
approximately every 2 d during therapy; discontinue upon appearance of
reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to
chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term
or during labor because of potential toxic effects on fetus (gray syndrome); higher
relapse rate following use because of the emergence of resistant strains
Amoxicillin (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.

 Dosing
 Interactions
 Contraindications
 Precautions

Adult

1 g PO q8h

Pediatric

20-50 mg/kg/d PO divided q8h for 14 d

 Dosing
 Interactions
 Contraindications
 Precautions

Reduces the efficacy of oral contraceptives

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals

Precautions

Adjust dose in renal impairment; may enhance chance of candidiasis

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.

 Dosing
 Interactions
 Contraindications
  Precautions

Adult

6.5-10 mg/kg/d PO bid/tid; can be given IV if necessary; 160 mg TMP/800 mg SMZ PO

q12h for 10-14 d

Pediatric

<2 months: Do not administer

>2 months: 15-20 mg/kg/d PO, based on TMP, tid/qid for 14 d

 Dosing
 Interactions
 Contraindications
 Precautions

May increase PT when used with warfarin (perform coagulation tests and adjust dose
accordingly); coadministration with dapsone may increase blood levels of both drugs;
coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly
persons; phenytoin levels may increase with coadministration; may potentiate effects of
methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may
increase with coadministration; may increase levels of zidovudine

 Dosing
 Interactions
 Contraindications
 Precautions

Documented hypersensitivity; megaloblastic anemia due to folate deficiency

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus

Precautions

Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC
counts frequently; discontinue therapy if significant hematologic changes occur; goiter,
diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high
doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin);
caution in folate deficiency (eg, patients with long-term alcoholism, elderly persons,
those receiving anticonvulsant therapy, or those with malabsorption syndrome);
hemolysis may occur in patients with G-6-PD deficiency; patients with AIDS may not
tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform
urinalyses and renal function tests during therapy); administer fluids to prevent
crystalluria and stone formation
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.

Adult

20-30 mg/kg/d PO bid for 14 d, but shorter courses may be adequate; 250-500 mg PO
bid for 7-14 d

Pediatric

<18 years: Not recommended

>18 years: Administer as in adults

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h
before or after taking fluoroquinolones; cimetidine may interfere with metabolism of
fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase
serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and
digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal,
hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may
occur with prolonged or repeated antibiotic therapy

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.

Adult

2 g IV q6h

Pediatric

200 mg/kg/d IV in divided doses for 14 d

Infants and children: 50-180 mg/kg/d IV/IM divided q4-6h
>12 years: Administer as in adults

Probenecid may increase levels; coadministration with furosemide and aminoglycosides

may increase nephrotoxicity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals

Precautions

Adjust dose in severe renal impairment; associated with severe colitis

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.

Adult

1 g PO once
Day 1: 500 mg PO
Days 2-5: 250 mg PO qd

Pediatric

<6 months: Not established

>6 months
Day 1: 10 mg/kg PO once; not to exceed 500 mg/d
Days 2-5: 5 mg/kg PO qd; not to exceed 250 mg/d

May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with
coadministration of aluminum and/or magnesium antacids; nephrotoxicity and
neurotoxicity may occur when coadministered with cyclosporine

Documented hypersensitivity; hepatic impairment; administration with pimozide

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals

Precautions

Site reactions can occur with IV route; bacterial or fungal overgrowth may result with
prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice;
caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia;
caution in hospitalized, geriatric, or debilitated patients

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.

Adult

1-2 g IV q12h

Pediatric

>7 days: 25-50 mg/kg/d IV/IM; not to exceed 125 mg/d

Infants and children: 50-75 mg/kg/d IV/IM divided q12h; not to exceed 2 g/d

Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and
aminoglycosides may increase nephrotoxicity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals

Precautions
Adjust dose in renal impairment; caution predelivery and in breastfeeding; pseudobiliary
lithiasis; non– Clostridium difficile diarrhea

Cefoperazone (Cefobid)

Discontinued in the United States. Third-generation cephalosporin with gram-negative

spectrum. Lower efficacy against gram-positive organisms.

 Dosing
 Interactions
 Contraindications
 Precautions

Adult

2-4 g/d IV/IM divided bid; not to exceed 12 g/d

Pediatric

Not established; 100-150 mg/kg/d IV/IM divided q8-12h; not to exceed 12 g/d
(suggested)

 Dosing
 Interactions
 Contraindications
 Precautions

Probenecid may increase levels; coadministration with furosemide and aminoglycosides

may increase nephrotoxicity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in
animals

Precautions

Adjust dose in severe renal impairment; has been associated with severe colitis

Ofloxacin (Floxin)

A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.

 Dosing
 Interactions
  Contraindications
 Precautions

Adult

200-400 mg PO q12h

Pediatric

<18 years: Not recommended

>18 years: Administer as in adults

 Dosing
 Interactions
 Contraindications
 Precautions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h
before or after taking fluoroquinolones; cimetidine may interfere with metabolism of
fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase
serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and
digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal,
hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may
occur with prolonged or repeated antibiotic therapy

Levofloxacin (Levaquin)

For pseudomonal infections and infections due to multidrug-resistant gram-negative

organisms.

 Dosing
 Interactions
 Contraindications
 Precautions

Adult

500 mg PO qd for 7-14 d

Pediatric

<18 years: Not recommended

>18 years: Administer as in adults

 Dosing
 Interactions
 Contraindications
 Precautions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h
before or after taking fluoroquinolones; cimetidine may interfere with metabolism of
fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase
serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and
digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans;
may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal,
hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may
occur with prolonged or repeated antibiotic therapy

Corticosteroids

Dexamethasone 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). 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)53 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. 54

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.

 Dosing
 Interactions
 Contraindications
 Precautions

Adult

3 mg/kg PO/IM/IV initially, followed by 8 doses of 1 mg/kg q6h

Pediatric

Not established

Follow-up

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.
o 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.
o 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.
o 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.

Vaccines

In 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%.
o 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 µg 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).55 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.56
o 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.
o The parenteral heat-phenol–inactivated vaccine (Wyeth-Ayerst) has been
discontinued.
o 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.
o 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.)
o 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.
o 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.
o Stupor, obtundation, or coma indicates severe disease.
o Focal intracranial infections are uncommon, but multiple brain abscesses
have been reported.57
o Other less-common neuropsychiatric manifestations events have included
spastic paraplegia, peripheral or cranial neuritis, Guillain-Barré syndrome,
schizophrenialike illness, mania, and depression.
 Respiratory
o Cough
 o Ulceration of posterior pharynx
o Occasional presentation as acute lobar pneumonia (pneumotyphoid)
 Cardiovascular
o Nonspecific electrocardiographic changes occur in 10%-15% of patients
with typhoid fever.
o 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.
o 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.58
 Hepatobiliary
o Mild elevation of transaminases without symptoms is common in persons
with typhoid fever.
o Jaundice may occur in persons with typhoid fever and may be due to
hepatitis, cholangitis, cholecystitis, or hemolysis.
o Pancreatitis and accompanying acute renal failure and hepatitis with
hepatomegaly have been reported.59
 Intestinal manifestations
o The 2 most common complications of typhoid fever include intestinal
hemorrhage (12% in one British series) and perforation (3%-4.6% of
hospitalized patients).
o 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.
o 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
o Approximately 25% of patients with typhoid fever excrete S typhi in their
urine at some point during their illness.
o Immune complex glomerulitis60 and proteinuria have been reported, and
IgM, C3 antigen, and S typhi antigen can be demonstrated in the
glomerular capillary wall.
o Nephritic syndrome may complicate chronic S typhi bacteremia
associated with urinary schistosomiasis.
o Nephrotic syndrome may occur transiently in patients with glucose-6-
phosphate dehydrogenase deficiency.
o Cystitis: Typhoid cystitis is very rare. Retention of urine in the typhoid
state may facilitate infection with coliforms or other contaminants.
 Hematologic manifestations
o Subclinical disseminated intravascular coagulation is common in persons
with typhoid fever.
o Hemolytic-uremic syndrome is rare.61
o Hemolysis may also be associated with glucose-6-phosphate
dehydrogenase deficiency.
  Musculoskeletal and joint manifestations
o Skeletal muscle characteristically shows Zenker degeneration, particularly
affecting the abdominal wall and thigh muscles.
o Clinically evident polymyositis may occur.62
o 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)
o Neurologic - Polyneuritis, paranoid psychosis, or catatonia63
o Cardiovascular - Thrombophlebitis of lower-extremity veins
o Genitourinary -Orchitis
o 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, visit eMedicine's Public Health Center.
Also, see eMedicine's patient education article Foreign Travel.
 Case study
o 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.
o 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
Organization’s 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 WHO’s
antibiotic guidelines.

Miscellaneous

Special Concerns

Culture-confirmed typhoid fever (enteric fever) should be reported to the state health
department.