Background

Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused
primarily by Salmonella enterica serotype typhi and, to a lesser extent, S
enterica serotypes paratyphi A, B, and C. The terms typhoid and enteric fever are commonly used
to describe both major serotypes.
Typhoid fever has a wide variety of presentations that range from an overwhelming multisystemic
illness to relatively minor cases of diarrhea with low-grade fever. The classic presentation is fever,
malaise, diffuse abdominal pain, and constipation. Untreated typhoid fever may progress
to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within 1 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] Infections with S paratyphi may be surpassing those
caused by S typhi, in part because of immunological naivete among the population and incomplete
coverage by vaccines that target typhi.
Note that some writers refer to the typhoid and paratyphoid fever as distinct syndromes caused
by the typhi versus paratyphi serovars, while others use the term typhoid fever for a disease
caused by either one. We use the latter terminology. We refer to these serovars collectively as
typhoidal salmonella.

Pathophysiology
All pathogenic Salmonella species, when present in the gut 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. [3, 4]
In contrast to the nontyphoidal salmonellae, S typhi and paratyphi enter the host's system
primarily through the distal ileum. They have 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. The bacteria then induce their host macrophages
to attract more macrophages. [3]
S typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation, while
the most common paratyphi serovar, paratyphi A, does not. This may explain the greater
infectivity of typhi compared with most of its cousins. [5]
Typhoidal salmonella co-opt the macrophages' cellular machinery for their own reproduction [6] as
they are 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, they 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. [4]
The bacteria then infect the gallbladder via either bacteremia or direct extension of 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. [2, 4] See the image below.

Life cycle of Salmonella typhi.

Chronic carriers are responsible for much of the transmission of the organism. While
asymptomatic, they may continue to shed bacteria in their stool for decades. The organisms
sequester themselves either as a biofilm on gallstones or gallbladder epithelium or, perhaps,
intracellularly, within the epithelium itself. [7] The bacteria excreted by a single carrier may have
multiple genotypes, making it difficult to trace an outbreak to its origin. [8]
Risk factors
Typhoidal salmonella have no nonhuman vectors. An inoculum as small as 100,000 organisms
of typhi causes infection in more than 50% of healthy volunteers. [9] Paratyphi requires a much
higher inoculum to infect, and it is less endemic in rural areas. Hence, the patterns of transmission
are slightly different.
The following are modes of transmission of typhoidal salmonella:
 Oral transmission via food or beverages handled by an often asymptomatic individual—a
carrier—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). [10, 11, 12]
Paratyphi is more commonly transmitted in food from street vendors. It is believed that some such
foods provide a friendly environment for the microbe.
Paratyphi is more common among newcomers to urban areas, probably because they tend to be
immunologically naïve to it. Also, travellers get little or no protection against paratyphi from the
current typhoid vaccines, all of which target typhi. [13, 14]
Typhoidal salmonella 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. [4]
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 or paratyphi
infection are conflicting. If an association exists, it is probably minor. [15, 16, 17, 18]
Other risk factors for typhoid fever 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. [11]
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. [19, 20]
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
hygiene. [21] American clinicians should keep this in mind, as students from these areas often come
to the United States for further education. [22]

Epidemiology
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. [23]
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. [24] 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. [25]
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: [23]
 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. [23] 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%. [26]
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. [23]
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.

History
A severe nonspecific febrile illness in a patient who has been exposed to typhoidal salmonella
should always raise the diagnostic possibility of typhoid fever (enteric fever).
Classic typhoid fever syndrome
The clinical syndromes associated with S typhi and paratyphi are indistinguishable. Typhoid fever
begins 7-14 days after ingestion of the organism . 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. [28]
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. [21, 29, 30, 2, 4]
Various presentations of typhoid fever
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, [31] meningitis, orchitis,
osteomyelitis, and abscesses anywhere on the body. [2]
Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid
Fever [2, 32, 33, 34, 35, 36] (Open Table in a new window)

Incubat Week Week Week

Week 3 Post
ion 1 2 4

Systemic

Stepladder
Very
fever pattern 10%-
comm Very common
or insidious 20%
ona
onset fever relapse;
3%-4%
chronic
Acute high Very
carriers
fever rareb
;
Recov
long-
Chills Almost allc ery
term
phase
neurolo
or
Rigors Uncommon gic
death
sequela
(15%
e
Anorexia Almost all of
(extrem
untrea
ely
ted
Diaphoresis Very common rare);
cases)
gallblad
der
Neurologic
cancer
(RR=16
Almost Almost 7;
Malaise
all all Typhoi carriers
d state )
Very (comm
Insomnia comm on)
on
 Very
Confusion/deli Comm
comm
rium ond
on

Very Comm
Psychosis
rare on

Very
Catatonia
rare

Frontal Very
headache comm
(usually mild) on

Meningeal
Raree Rare
signs

Very
Parkinsonism
rare

Ear, nose, and throat

Very
Coated tongue comm
on

Sore throatf

Pulmonary

Comm
Mild cough
on

Bronchitic Comm
cough on
 Comm
Rales
on

Comm
Rare
Pneumonia Rare on
(lobar)
(basal)

Cardiovascular

Dicrotic pulse Rare Common

Myocarditis Rare

Extrem
Pericarditis ely
rareg

Thrombophleb Very
itis rare

Gastrointestinal

Very
Constipation comm Common
on

Diarrhea Rare Common (pea soup)

Very
comm
Bloating with
on
tympany
(84%) [
36]

Diffuse mild Very

abdominal comm
pain on
Sharp right
lower Rare
quadrant pain

Very
Gastrointestin rare;
Very common
al hemorrhage usually
trace

intestinal
Rare
perforation

Hepatospleno
Common
megaly

Jaundice Common

Gallbladder
Very rare
pain

Urogenital

Urinary
Common
retention

Hematuria Rare

Renal pain Rare

Musculoskeletal

Myalgias Very rare

Arthralgias Very rare

Rheumatologic
Arthritis (large
Extremely rare
joint)

Dermatologic

Rose spots Rare

Miscellaneous

Extrem Extrem
Abscess Extrem
ely ely
(anywhere) ely rare
rare 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 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.

Causes
S typhi and Salmonella paratyphi cause typhoid/enteric fever.

Differential Diagnoses
 Abdominal Abscess
 Amebic Liver/Hepatic Abscesses
 Appendicitis
 Brucellosis
 Dengue
 Influenza
 Leishmaniasis
 Malaria
 Rickettsial diseases
  Toxoplasmosis
 Tuberculosis (TB)
 Tularemia
 Typhus

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
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. [37]
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. [38]
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 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 Cultures [2, 38, 39, 40] (Open Table in a new window)

Week Week Week Week

Incubation
1 2 3 4
Bone marrow aspirate (0.5-1
90% (may decrease after 5 d of antibiotics)
mL)

Blood (10-30 mL), stool, or Variable (20%-

40%-80% ~20%
duodenal aspirate culture 60%)

Urine 25%-30%, timing unpredictable

Polymerase chain reaction

Polymerase chain reaction (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. [41, 42]
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, [43] are promising,
but the success rates of these assays vary greatly in the literature.
Other nonspecific laboratory studies
Since the sensitivity of cultures of blood, bone marrow, urine and stool vary with the duration of
disease, various nonspecific tests have been studied regarding usefulness in diagnosing typhoid
fever.
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 combination of absolute eosinopenia, elevated aspartate aminotransferase levels, and elevated
C-reactive protein levels (>40 mg/L) have been shown to be a positive predictor of S typhi and S
paratyphi bacteremia. [44]
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. [45]

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.

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 (see
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.

Antibiotics
Class Summary
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 recommend combination treatment with
ceftriaxone and ciprofloxacin when neither the sensitivities nor the geographical origin of the
bacteria is known.
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.
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 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.
H58 type S typhi has become the predominant multidrug-resistant (MDR) isolate throughout Asia
and Africa, 75% of all resistant strains. [47] However, MDR isolates can be very localized. Most
isolates of S typhi and S paratyphi from Pakistan exhibited a high degree of multidrug resistance,
while isolates from Bangladesh, India, and Nepal showed a low rate. [48]
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. [49]
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. [50, 51, 52, 36]
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. [53] 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. [54] The risk of relapse after bacterial clearance is higher in both partially and fully
resistant strains than in fully susceptible strains. [24]
The third-generation fluoroquinolone gatifloxacin appears to be highly effective against all known
clinical strains of S typhi both in vitro and in vivo owing 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. [55, 56]
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. [54]
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 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. [57] The authors believe
that the IAP recommendations apply to 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. [49, 52, 58, 25, 59]
Resistance in the United States
In the United States in 2012, 68% of S typhi isolates and 95% of S paratyphi isolates were fully
resistant to nalidixic acid. While full resistance to ciprofloxacin was considerably less, intermediate
susceptibilities to ciprofloxacin in both organisms closely matched resistance to nalidixic acid. 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. [49, 23]
The rate of multidrug resistance in 2012 was 9% in S typhi and 0% in S paratyphi. (Multidrug-
resistant S typhi is, by definition, resistant to the original first-line agents, ampicillin,
chloramphenicol, and trimethoprim-sulfamethoxazole.)
There have been no cases of ceftriaxone-resistant S typhi or S paratyphi documented in the United
States, at least since 2003. [60]
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. However, 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. This allows for most effective clearance if the organism
is fluoroquinolone-susceptible but still covers strains that are not.
Ceftriaxone and azithromycin continue to be effective against most isolates of S typhi and S
paratyphi, although resistance to ceftriaxone appears to be increasing, especially in extensively
drug-resistant (XDR) strain of S typhi identified in Pakistan in 2016. [61] This variant continues to
remain sensitive to azithromycin and to the carbapenems.
Antibiotic treatment of typhoid fever
Severe or complicated infections
For infections that are not acquired in Pakistan, ceftriaxone should be started empirically. In this
setting, resistance to ceftriaxone is unusual. In cases that do not originate in southern Asia, a
fluoroquinolone should be considered because of its potential advantage of hastening defervesce
then is achievable by cephalosporins.
For infections that are acquired in Pakistan, a carbapenem should be administered because of the
risk of XDR strains.
Mild or uncomplicated infections
In less-severe uncomplicated infections, it is appropriate to begin oral therapy. Unless the risk of
fluoroquinolone resistance is significant, ciprofloxacin or ofloxacin is preferred. Azithromycin
offers dual advantages of low risk of resistance and excellent oral absorption.
Because of the risk of developing antibiotic resistance, the concept of using dual antibiotic therapy
has been revived. In addition, some evidence shows that the clinical course is improved with such
combinations. Specifically, the combination of cefixime-ofloxacin has been approved by the Indian
Regulatory Authority for the treatment of typhoid fever. [62]
Table 3. Antibiotic Recommendations by Origin and Severity
Location
Severity
First-Line Antibiotics
Second-Line Antibiotics
South Asia, East Asia [57]
[63, 50]

Uncomplicated
Cefixime PO
Azithromycin PO
Complicated
Ceftriaxone IV or
Cefotaxime IV
Aztreonam IV or
Imipenem IV
Eastern Europe, Middle East, sub-Saharan Africa, South America [58, 64]
Uncomplicated
Ciprofloxacin PO or
Ofloxacin PO
Cefixime PO or
Amoxicillin PO or
TMP-SMZ PO
or Azithromycin PO
Complicated
Ciprofloxacin IV or
Ofloxacin IV
Ceftriaxone IV or
Cefotaxime IV or
Ampicillin IV
or
TMP-SMZ IV
Unknown geographic origin or Southeast Asia [65, 57]
[63, 50, 58, 64]

Uncomplicated
Cefixime PO plus
Ciprofloxacin PO or
Ofloxacin PO
Azithromycin PO*
Complicated
Ceftriaxone 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 directions
A 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. [66]

Chloramphenicol (Chloromycetin)

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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.

Amoxicillin (Trimox, Amoxil, Biomox)

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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)

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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)

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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)

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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)

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Third-generation cephalosporin with broad-spectrum gram-negative activity against gram-positive
organisms; Excellent in vitro activity against S typhi and other salmonellae.

Levofloxacin (Levaquin)

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

Corticosteroids
Class Summary
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). [67]
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) [4] and the British Medical Journal (2006) [68] 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. [69]
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)

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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 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

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.