74  Typhoid and Paratyphoid (Enteric) Fever

Jason B. Harris, W. Abdullah Brooks

cases/100,000 person-years) and Southeast Asia (≈100 cases/100,000

KEY FEATURES person-years). The incidence of typhoid fever varies in sub-Saharan
Africa, but major epidemics of typhoid fever that occur in some
• Salmonella enterica serotypes Typhi and Paratyphi A, B, parts of sub-Saharan Africa have a high incidence (≈1000
and C are the causative agents of typhoid and cases/100,000 person-years) (Fig. 74.1).
paratyphoid (enteric) fever.
• Enteric fever is a non-specific illness characterized by
prolonged fevers and persistent bacteremia.
Paratyphoid Fever
• Life-threatening complications of enteric fever include S. Paratyphi A is the most common cause of paratyphoid fever
intestinal hemorrhage, perforation, and encephalopathy. and causes up to 5 million cases of enteric fever annually,3 although
this may be an underestimation, as many cases of typhoid fever
• The diagnosis of enteric fever should be considered in in highly endemic areas are assigned clinically to S. Typhi and
any patient with prolonged fever and exposure in an might be S. Paratyphi. The proportion of cases of enteric fever
endemic area. caused by S. Paratyphi A has increased and now ranges from 20%
• Because of the limitations of diagnostic tests, the to 50% in parts of southern Asia.3 This is significant, as current
initiation of antibiotic treatment for enteric fever is typhoid fever vaccines do not protect against S. Paratyphi A.
often based on a presumptive diagnosis. Serotypes Paratyphi B and C are rare causes of enteric fever.
• The choice of empiric antibiotic therapy depends on
local patterns of antibiotic resistance. Drug resistance is Transmission and Patterns of Infection
of increasing concern.
• The World Health Organization (WHO) endorses the Source of Infection
use of typhoid vaccines in control programs, with
S. Typhi and S. Paratyphi A, B, and C are human-restricted
typhoid conjugate vaccine (TCV) being the preferred
pathogens; no known animal reservoirs exist. Enteric fever patients
vaccine. The WHO recommends the introduction of
shed organisms in the stool during acute illness and often for
TCV to be prioritized in countries with the highest
months after convalescence. In the pre-antibiotic era, up to 3%
burden of typhoid fever or a high burden of
of typhoid fever survivors developed chronic asymptomatic bacterial
antimicrobial resistance.
shedding in the stool. Chronic carriage can persist for life, and
gallbladder disease is the major risk factor for carriage. A study
in Nepal found that 5% of individuals undergoing elective cho-
lecystectomy for gallstones grew S. Typhi or S. Paratyphi A from
INTRODUCTION biliary cultures.4 Although chronic carriers are a source of transmis-
sion where disease is sporadic, it is unclear whether carriers are
Typhoid and paratyphoid fever are systemic febrile illnesses caused an important reservoir in endemic areas.
by Salmonella enterica serotype Typhi and serotypes Paratyphi A, B, or
C, respectively. Enteric fever refers to either typhoid or paratyphoid
fever. S. Typhi is the predominant cause of enteric fever and may
Mode of Transmission
be the world’s most common cause of bacteremia (Box 74.1). In endemic areas, most infections are acquired via contaminated
Both typhoid and paratyphoid fever are characterized by food or water, with water playing the greater role in endemic
prolonged fever and sustained bacteremia. The name typhoid, urban settings. The inoculum required to produce disease in 50%
meaning “typhus like,” was coined in 1829 and reflects the difficulty of adult volunteers (ID50) is 107 organisms, though as few as 103
physicians had in differentiating the illness from epidemic typhus. organisms may produce disease. Risk factors include drinking
Among 19th-century American physicians, typho-malaria was a non-boiled water and eating food prepared outside the home.
common diagnosis, indicative of the difficulty differentiating typhoid Although direct contact with a typhoid fever patient is an infection
from other causes of persistent fever. This proved fortuitous in risk factor, more than 80% of cases occur in individuals with no
1948, when two patients were referred for a study of the efficacy known contact.5 In South-central and Southeast Asia, peak transmis-
of chloramphenicol in scrub typhus but were subsequently found sion occurs during monsoon season, although disease is present
to have S. Typhi bacteremia. Both patients improved rapidly after year-round. Large waterborne epidemics may be superimposed
antibiotic therapy, a finding that ushered in the post-antibiotic on endemic seasonality.
era in typhoid fever.1
Antimicrobial Resistance
EPIDEMIOLOGY
Chloramphenicol-resistant S. Typhi was described in 1950, 2
Incidence and Distribution of Enteric Fever years after the antibiotic was first used to treat typhoid fever.
Multi-drug–resistant S. Typhi, carrying plasmid-mediated resistance
Typhoid Fever to chloramphenicol, ampicillin, trimethoprim, and sulfonamides,
became common in the 1980s, and nalidixic acid–resistant S. Typhi
S. Typhi causes approximately 12 to 25 million cases of typhoid and S. Paratyphi A in the 1990s. Nalidixic acid–resistant strains
fever annually with an estimated mortality of 1%.2 The regions are associated with decreased susceptibility to fluoroquinolones,
with the highest incidence are South-central Asia (≈1000 an increased risk of treatment failure, and increased mortality.6 In
608
 CHAPTER 74  Typhoid and Paratyphoid (Enteric) Fever 609

Asia, most S. Typhi and Paratyphi A strains are now nalidixic acid
BOX 74.1  Nomenclature of Salmonella Infections resistant. In the past decade, complete resistance to ciprofloxacin 74
and extended-spectrum cephalosporins has emerged.7 Although
The multiple microbiologic, serologic, and clinical designations
resistance to these newer agents is increasing, susceptibility to
applied to Salmonella infections are confusing.40 Most pathogenic
original first-line agents may be re-emerging, at least in some
Salmonella belong to a single subspecies designated Salmonella
locations. Thus antimicrobial resistance in S. Typhi and Paratyphi
enterica subspecies enterica. In addition to this species
A varies significantly by region and patterns of antibiotic use.
designation, Salmonella are classified serologically. The serogroup
is assigned based on the O antigen alone, whereas the serotype
designation, from which the name is derived, is based on both Severity
the O and H antigens.
The majority of cases are not severe enough to require hospitaliza-
Salmonella enterica subsp. enterica includes over 1400
tion. Case fatality prevalence for typhoid fever patients in the
serotypes. Although the full name of the cause of typhoid fever is
pre-antibiotic era was approximately 15%. Current hospital-based
Salmonella enterica subsp. enterica serotype Typhi, it is normally
mortality rates range by location (0%–15%), with a median
just shortened to S. Typhi. Although serogroup designation is
mortality rate of 2%.8 In the United States, where disease is
performed routinely in many laboratories, the test lacks clinical
sporadic, the fatality rate of reported cases is 0.2%.9
utility. Complete serotype identification is often performed in a
reference laboratory; however, S. Typhi and Paratyphi A can also
be identified by biochemical tests in a routine microbiology Age and Immunity
laboratory. Identification of S. Typhi and Paratyphi A are reviewed
In the most highly endemic communities, the incidence of enteric
in detail in the World Health Organization’s, “The diagnosis,
fever is highest in children between 1 and 5 years. In such areas,
treatment and prevention of typhoid fever.”24
S. Typhi is the leading cause of bacteremia in children and may
Clinically Salmonella are classified as typhoidal or non-
be responsible for over 75% of cases of occult bacteremia.10 In
typhoidal. The typhoidal serotypes are S. Typhi and Paratyphi A,
less endemic areas, the median age of patients with typhoid fever
B, and C. All others are classified as non-typhoidal. However,
increases. Relapse and recurrent infections among patients who
this is also misleading, as many non-typhoidal strains also cause
have recovered from typhoid fever demonstrate that immunity is
invasive infection, which may mimic typhoid fever (see
neither lifelong nor universally acquired after a single illness.
Chapter 49).

Examples of Clinical and Serologic Classification of Pathogenic Sporadic Disease and Travelers
Salmonella In countries where typhoid fever is sporadic (<1/100,000 person-
Clinical Formal years), most cases are imported through travel. In the United
Classification Serotype Designation Serogroup States over 85% of cases are travel related, and most of these
Typhoidal Typhi S. enterica D cases occur in travelers returning from South Asia. Many remaining
subsp. cases can be traced to small foodborne outbreaks and/or a chronic
enterica ser. carrier.9 The risk of travel-related enteric fever is higher among
Typhi travelers visiting friends and relatives.11
Paratyphi A S. enterica A
subsp. NATURAL HISTORY, PATHOGENESIS,
enterica ser. AND PATHOLOGY
Paratyphi A
Paratyphi B S. enterica B Invasion and Latency
(schottmuelleri) subsp.
enterica ser. S. Typhi and S. Paratyphi A, B, and C are rod-shaped, gram-negative
Paratyphi B bacteria that have adapted to survive and replicate in human
Paratyphi C S. enterica C macrophages. S. Typhi and Paratyphi breach the intestinal barrier
(hirschfeldii) subsp. through specialized microfold cells (M cells) that transport the
enterica ser. bacteria across the basolateral membrane where they are phago-
Paratyphi C cytosed by macrophages in the intestinal lymphoid tissue. This
Non-typhoidal Typhimurium S. enterica B invasion phase of infection is usually asymptomatic but may be
subsp. accompanied by transient diarrhea in 10% to 20% of patients.
enterica ser. Latent infection typically lasts 1 to 2 weeks (range 3–60 days),
Typhimurium depending on the number of organisms ingested.
Enteriditis S. enterica D
subsp. Disseminated Infection
enterica ser.
Enteriditis Typhoidal Salmonella deploy an array of virulence factors that
Newport S. enterica C enable them to persist and replicate in an intracellular compart-
subsp. ment.12 Intracellular organisms disseminate throughout the
enterica ser. reticuloendothelial tissues via the blood and lymphatic system.
Newport Infection is established in the intestinal lymphoid tissue, liver,
spleen, gallbladder, and bone marrow.
Patients with typhoid fever generally have low-grade bacteremia.
The median number of culturable bacteria is less than 1 per mL
of whole blood and 10 per mL of bone marrow in patients with
typhoid fever. The proportion of bacteria in the bone marrow
increases over the course of the illness.13 Infection results in the
secretion of inflammatory cytokines, which cause prolonged fever.
610 PART 3  Bacterial Infections

Typhoid incidence
(overall populations)
Study sites
Low (<10 per
100 000 per year)
Middle (10–100 per
100 000 per year)
High (>100 per
100 000 per year)

Fig. 74.1  Global distribution of typhoid fever. (Used with permission from Mogasale V, Maskery B, Ochiai RL, et al. Burden of typhoid fever in
low-income and middle-income countries: a systematic, literature-based update with risk-factor adjustment. Lancet Glob Health 2014;2:e570–80.)

However, unlike prototypical gram-negative bacteremia, overt sepsis TABLE 74.1  Clinical Features of Typhoid and Paratyphoid Fever
with hypotension and neutrophilia is rare.
Clinical Approx.
Feature Frequency*
Pathologic Findings Fever >95%
Intestinal lymphoid tissue is the major site of localized inflammation Flulike symptoms Headache 80%
in enteric fever. Peyer’s patches in the terminal ileum and draining Chills 40%
Cough 30%
mesenteric nodes become enlarged and contain infiltrates consisting Myalgia 20%
predominantly of macrophages and lymphocytes.14 As the disease Arthralgia <5%
progresses, necrosis of the intestinal lymphoid tissue may occur,
with ulceration of the overlying intestinal mucosa. This can lead Abdominal symptoms Anorexia 50%
Abdominal pain 30%
to hemorrhage or intestinal perforation, life-threatening complica- Diarrhea 20%
tions of enteric fever. Other affected organs include the spleen, Constipation 20%
with nodular monocytic infiltrates in the red pulp, and liver, with
Physical findings Coated tongue 50%
small monocytic infiltrates and foci of parenchymal necrosis
Hepatomegaly 10%
(“typhoid nodules”). Monocytic infiltrates also occur in the bone Splenomegaly 10%
marrow and gallbladder. Abdominal 5%
tenderness
<5%
Relapse and Chronic Carriage Rash
Generalized <5%
Untreated, typhoid fever may persist for 3 to 4 weeks. Relapse adenopathy
occurs in 5% to 10% of untreated cases, usually within 2 weeks *The proportion of patients demonstrating these clinical features of
of resolution of the fever. The gallbladder is the primary site of enteric fever varies depending on the time, region, and type of
chronic carriage. The observation that S. enterica forms biofilms clinical population (hospitalized or ambulatory) assessed. Estimates
on cholesterol gallstones may explain the association between are drawn from recent case series in an endemic area presenting for
gallstones and carriage.15 ambulatory or inpatient care.16,38

CLINICAL FEATURES after fever onset, both intestinal perforation and encephalopathy
The clinical features of enteric fever are non-specific. The major may occur within days of initial fever.
clinical findings are listed in Table 74.1. Fever, without localizing Historically, paratyphoid fever was considered less severe than
signs or symptoms, may be the sole manifestation of enteric fever. In typhoid fever. Current evidence suggests that infections caused
highly endemic countries, a typical presentation in young children by S. Typhi and S. Paratyphi A are clinically indistinguishable and
may be nothing more than a fever ≥39°C for 3 or more days. equally severe.17
Most enteric fever cases are diagnosed in the ambulatory setting
and are mild, and up to 90% are treated as outpatients.16 In contrast,
classic descriptions of typhoid fever are based on hospitalized
Mild Illness
patients with more severe disease. Although life-threatening Enteric fever is usually insidious. Fever may increase gradually
complications of enteric fever usually occur more than a week over the first week of illness. Headache, anorexia, malaise, and
 CHAPTER 74  Typhoid and Paratyphoid (Enteric) Fever 611

other non-specific flulike symptoms are common and may precede TABLE 74.2  Complications of Typhoid and Paratyphoid Fever
fever. Abdominal complaints, including diarrhea, constipation, and 74
System Complication Notes
non-localizing abdominal pain, occur in less than a third of cases
but may raise clinical suspicion.17 Gastrointestinal Hemorrhage 10%–15% hospitalized
Physical findings are also non-specific. Relative bradycardia, patients
or pulse-temperature dissociation, is considered a classic sign of Perforation 3% hospitalized patients
enteric fever, but there is no widely accepted definition of relative
Hepatobiliary Jaundice 1%–3% hospitalized
bradycardia, and little evidence that it is a useful predictor.18 Rose patients
spots are small, blanching, pink macular lesions, typically 2 to
4 mm, which usually occur on the chest, abdomen, and/or back Hepatitis Usually subclinical
(↑ ALT/AST)
during the second week of illness but are infrequently observed.
A white, yellow, or brown coating of the tongue that spares the Acute cholecystitis Rare, gallbladder may
tongue’s edges is common. Mild abdominal tenderness may be perforate
present. Hepatomegaly and splenomegaly, if present, are usually Neurologic Mild encephalopathy Confusion or apathy
modest. common
In contrast to other causes of bacteremia, patients with enteric Severe encephalopathy Delirium, stupor, or
fever rarely demonstrate leukocytosis, neutrophilia, or increased coma
immature neutrophils. A typical leukocyte count is 5 to 8 × 106
Seizures Common in children
cells per mL, with 60% to 75% neutrophils,17 and helps with the
≤5 years
differential diagnosis in endemic settings with a high prevalence
of other invasive bacterial diseases. However, neither leukocytosis Meningitis Rare, primarily infants
nor leukopenia excludes enteric fever. Hematocrit and platelet Guillain–Barré syndrome Reported
counts are usually normal or slightly low. Modest elevations, Respiratory Bronchitis Cough is common
typically double the upper end of the normal range, in the aspartate
transaminase and alanine transaminase, are common. Excessive Pneumonia May be other
levels of blood transaminases should prompt concern for other concomitant bacterial
infection
etiologies, including viral hepatitis.
(e.g., S. pneumoniae)
Cardiovascular Myocarditis Usually subclinical
Severe Illness and Complications (ECG changes)
Patients with severe enteric fever are ill or toxic appearing and Shock Uncommon
generally have been febrile for longer than 1 week. They are likely Hematologic Anemia Usually subclinical
to have moderate abdominal pain or tenderness and either constipa-
DIC Usually subclinical
tion or diarrhea. Moderate hepatomegaly and splenomegaly are
(↑ PT/PTT)
also common.
The major complications of typhoid fever are listed in Table Other Pyogenic infections Uncommon
74.2. Complications associated with increased mortality include Hemolytic uremic Reported
intestinal hemorrhage and perforation, severe encephalopathy, syndrome
seizures, and pneumonia,19 although pneumonia has also been Miscarriage Reported
noted frequently in children without other complications.10
ALT, Alanine aminotransferase; AST, aspartate aminotransferase;
DIC, disseminated intravascular coagulation; ECG, echocardiogram;
Gastrointestinal Complications PT, prothrombin time; PTT, partial thromboplastin time.
Some degree of intestinal hemorrhage occurs in up to 10% of
hospitalized patients; this is usually self-limited. Intestinal perfora-
tion (Fig. 74.2) occurs in up to 3% of hospitalized patients and
is associated with substantial mortality. A recent series of 27 cases
of intestinal perforation demonstrated that the median length of
illness preceding perforation was 9 days (range 1–22 days) from
the onset of fever.20 Perforation is suggested by clinical signs of
sepsis and peritonitis, including tachycardia, leukocytosis with
predominant neutrophilia, and abdominal pain with guarding and
rebound tenderness. Radiographic evidence of pneumoperitoneum
may be present in only 50% of cases. Perforation may be difficult
to recognize, as patients may be toxic appearing with accompanying
abdominal tenderness even before perforation.

Neurologic Complications
Severe enteric fever may present with encephalopathy. A history
of confusion is common, and patients often demonstrate an apathetic
affect. Severe encephalopathy manifested by delirium, stupor, and
coma occurs in a smaller number of hospitalized patients and is
associated with a high risk of mortality.19,21,22 Seizures are most
common in young children and are associated with increased Fig. 74.2  Intraoperative photograph of intestinal perforation caused by
mortality risk.19 Even in severe encephalopathy or seizure cases, S. Typhi. A single perforation is seen on the anti-mesenteric border of the
cerebrospinal fluid cultures are usually negative, and pleocytosis, inflamed small bowel along with patchy exudates on the serosal surface.
if present, reveals fewer than 35 cells per µL.21,22 Meningitis is (Photo courtesy Dr. Pukar Maskey, Patan Hospital, Katmandu, Nepal.)
612 PART 3  Bacterial Infections

uncommon and is seen primarily in infants. Focal neurologic or another normally sterile clinical specimen. The isolation of a
findings have been reported but should prompt consideration of causative organism also provides the opportunity to optimize
an alternative diagnosis. antimicrobial therapy.
Isolation of S. Typhi or Paratyphi A is most commonly achieved
by blood culture. Factors that affect the sensitivity of blood isolation
Other Complications include the culture medium, prior antibiotic exposure, blood
Pneumonia is a serious co-morbidity associated with severe enteric volume, and the duration of illness before sample collection. A
fever.19 Although enteric fever is a disseminated bacterial infection, recent meta-analysis suggests that blood culture has an overall
distal pyogenic complications are not common. This contrasts sensitivity of 60% for diagnosing typhoid fever,23 reflecting the
with invasive non-typhoidal Salmonella, in which osteomyelitis low number of organisms present in the blood and prior antibiotic
and endovascular infection occur more frequently. Numerous other use. High blood volumes optimize the yield of blood culture; the
enteric fever complications have been reported, affecting all major WHO recommends that 10 to 15 mL of blood be obtained from
organ systems.16 school-aged children and 2 to 4 mL of blood be used for culture
in toddlers and preschool-aged children.24 Although alternatives
PATIENT EVALUATION, DIAGNOSIS, to standard blood culture (e.g., direct plating of the buffy coats
or the use of selective ox bile media) have been recommended,
AND DIFFERENTIAL DIAGNOSIS the use of routine blood cultures with standard broth media is
Enteric fever can be a life-threatening infection if not treated with preferable because such methods may detect other potential
appropriate antimicrobial therapy and should be suspected in any bacterial pathogens as well.
patient with prolonged fever and exposure to an endemic area. Bone marrow cultures have an 80% to 95% sensitivity for
There are no reliable clinical criteria to establish the diagnosis of isolating S. Typhi. Bone marrow cultures may remain positive for
enteric fever and no sensitive and specific diagnostic laboratory several days after initiating antibiotics. However, the invasiveness
tests. Therefore the diagnosis of enteric fever is usually presumptive. of bone marrow culture limits its practical utility in uncomplicated
cases. Under optimal conditions, a single high-volume (>15 mL)
blood culture in an adult has a sensitivity nearly equivalent to a
Clinical Evaluation 1-mL bone marrow culture.13,24
The first requirement for diagnosis is clinical suspicion. In a highly Stool cultures are positive in over 50% and 30% of infected
endemic area, 3 or more days of non-focal fever should prompt children and adults, respectively. Rectal swabs are not recommended,
consideration of enteric fever. Patients should undergo a routine and the yield of stool cultures is optimized by the use of >1 gram
clinical history and physical examination. Although most of the of stool and a selective enrichment broth.24 Cultures obtained from
findings associated with enteric fever are non-specific, many other intestinal biopsies of patients with perforation are rarely positive.20
causes of febrile illness will become apparent after a careful history
and examination. Routine laboratory studies are also of limited
value in establishing a diagnosis of enteric fever but may be more
Serologic and Molecular Diagnosis
useful in eliminating other potential causes of non-focal fever. The most commonly utilized diagnostic test for enteric fever is
In a highly endemic area, factors that should increase the clinical Widal’s test, which was developed in 1896 and detects agglutinating
suspicion for enteric fever early in the course of the illness include antibodies against the O and H antigens of S. Typhi. Widal’s test
young age, temperature above 39°C, ill appearance, and any is not sufficiently sensitive, specific, or reliable enough to be an
abdominal complaints, including diarrhea, constipation, or optimal diagnostic assay for typhoid fever, and it does not aid in
abdominal pain.10 In the most highly endemic settings, 3 or more the diagnosis of paratyphoid fever, because these antibodies are
days of fever without localizing signs and a combination of any not cross-reactive against S. Paratyphi A, B, and C antigens. A
of these features in the absence of another obvious cause may be false-negative Widal’s test may result from the assay being per-
sufficient to prompt a diagnostic evaluation for enteric fever along formed early in the course of illness, and a false-positive Widal’s
with the initiation of empiric therapy. test is more likely in an area of high endemicity, where antibodies
As fever duration increases, the likelihood of enteric fever may represent past infection.
increases. Any patient with 7 or more days of unexplained fever Rapid serologic tests, including the IDL Tubex and Typhidot
from an area where enteric fever is endemic should undergo a assays, are available. In principle, tests such as Tubex, which detects
diagnostic evaluation and empiric treatment should be considered, immunoglobulin M (IgM) antibodies to the O9 antigen—a
given the potential complications of untreated enteric fever.16 T-cell–independent response to Salmonella infection, which is
therefore rapid—and Typhidot, which detects both IgM and IgG
to the 50 kD antigen of S. Typhi, should be useful in identifying
Differential Diagnosis early acute infection.24 However, in practice, these tests have met
The differential diagnosis should reflect local febrile disease with mixed success in highly endemic settings because they have
prevalence. Malaria, dengue fever, influenza, leptospirosis, rickettsial not consistently demonstrated an ability to distinguish between
infections, urinary tract infection, and other causes of childhood current and past infection, and in some cases, have not consistently
occult bacteremia (e.g., Streptococcus pnuemoniae, Haemophilus been as sensitive as the Widal’s test.25,26 Although diagnostic
influenzae, and Neisseria meningitiditis) should all be considered in approaches based on the detection of anti-Salmonella IgA in
the differential diagnosis of fever without localizing signs. In secretions of peripheral blood lymphocytes are promising, these
patients with prolonged fever (>7 days) with or without localizing tests are not yet commercially available.27
signs, the infectious differential diagnosis includes malaria,
Epstein–Barr virus infection, tuberculosis, brucellosis, tularemia,
plague, occult abscesses (including amebic liver abscess), and typhus.
TREATMENT AND PREVENTION OF ENTERIC FEVER
Appropriate antibiotics and supportive care reduce the mortality
of enteric fever from 10% to 15% to less than 1%. Fevers resolve
Microbiologic Diagnosis after an average of 3 to 5 days of appropriate antibiotics, compared
Although presumptive diagnosis of enteric fever is sufficient with 3 to 4 weeks in untreated infections. The widespread emer-
justification to initiate treatment in an ill-appearing patient, a gence of antibiotic-resistant S. Typhi and Paratyphi A complicates
definitive diagnosis of enteric fever can only be made by isolation the choice of antibiotics. Most patients can be managed in an
of S. Typhi or S. Paratyphi A, B, or C from blood, bone marrow, ambulatory setting.
 CHAPTER 74  Typhoid and Paratyphoid (Enteric) Fever 613

Antibiotics for Enteric Fever Chloramphenicol, Ampicillin, and 74

Uncomplicated enteric fever is usually treated with a single anti- Trimethoprim–Sulfamethoxazole
bacterial drug. Antimicrobial choice depends on patient age, their The original “first-line” therapies for enteric fever include chlor-
ability to take oral medications, and drug availability and cost. amphenicol, ampicillin, and trimethoprim–sulfamethoxazole.28
Knowledge of antibiotic resistance patterns is essential because in After decades of increasing resistance among S. Typhi and Paratyphi
most cases, empiric antibiotics are initiated before an isolate is A to these antibiotics, the trend may be reversing. Chloramphenicol
obtained. Table 74.3 summarizes antibiotic therapy for enteric fever. results in a marked decrease in mortality and clearance of fevers

TABLE 74.3  Antibiotics Commonly Used in Enteric Fever

Typical Pediatric Typical
Antibiotic Route Dosage* Adult Dosage Duration Comments
Original first-line Chloramphenicol PO/IV 12.5–25 mg/kg qid 2–3 grams/day 14–21 days These agents are effective for
agents (divided qid) susceptible strains; however,
multi-drug resistance to all of
Amoxicillin PO Severe infections: 875 mg PO 14 days
these agents is common in
<3 mo: ≤30 mg/kg/ Q12hr or
many areas.
day PO divided 500 mg PO
Q12hour × 10–14 Q8hr ×
days 10–14 days
>3mo and <40kg:
45 mg/kg/day PO
divided Q12hr ×
10–14 days
>40kg: 875 mg PO
Q12hr or 500 mg
PO Q8hr × 10–14
days
Ampicillin IV Severe infection: 2 gram q6 14 days
200–400 mg/kg/
day IV/IM divided
Q6hr × 10–14 days
TMP/SMX PO/IV >2mo: 8-12 mg/kg/ 160 mg/800 mg 14 days
day IV (TMP) qid
divided Q6-12hr;
40-60 mg/kg/day IV
(SMX) divided
Q6-12hr
or
15-20 mg/kg/day PO
(TMP); 75-100 mg/
kg/day (SMX)
divided Q6hr
Fluoroquinolones27 Ofloxacin PO/IV 15 mg/kg bid 400 mg bid 5–14 days Fluoroquinolones are effective for
susceptible strains only. NaR
Ciprofloxacin PO/IV 15 mg/kg bid 500 mg bid 5–14 days
is a marker of decreased
Gatifloxacin PO 10 mg/kg qday 10 mg/kg/day 7 days susceptibility in laboratories
qday that are not equipped to
evaluate current CLSI
breakpoints. Short courses of
5–7 days are acceptable in
uncomplicated cases.
Courses of 10–14 days are
recommended in patients
requiring hospitalization or
parenteral therapy.
Third-generation Ceftriaxone IV 50–100 mg/kg q24 2 gm IV q24 10–14 days** These are an alternative to
cephalosporins fluoroquinolones for NaR
Cefixime PO 10 mg/kg bid 200 mg PO bid 7–14 days
strains and for empiric therapy
Off label: 15–20 mg/ Off label:
in areas where NaR is
kg/day PO divided 15–20 mg/
common.
Q12hr × 7–14 kg/day PO
days; not to divided Q12h
exceed 400 mg/ × 7–14 days;
day not to exceed
400 mg/day
Macrolides31 Azithromycin PO 20 mg/kg qday 1 gm PO qday 7 days An alternative for uncomplicated
infections, caused by NaR
strains and for empiric therapy
where multi-drug resistance
and NaR are common.

Continued
614 PART 3  Bacterial Infections

TABLE 74.3  Antibiotics Commonly Used in Enteric Fever—cont’d

Typical Pediatric Typical
Antibiotic Route Dosage* Adult Dosage Duration Comments
Eradication of Ciprofloxacin PO — 500–750 mg 28 days If eradication is indicated for
carriage bid public health reasons, a trial
of medical therapy is justified
even in patients with evidence
of cholelithiasis.35
*Weight-based pediatric dosage should not exceed adult maximum.
**Recommended that treatment continue for at least 7 days post-defervescence to minimize relapse.
Hr, Hour; IV, intravenously; Mo, months old; NaR, nalidixic acid resistance; PO, orally; SMX, sulfamethoxazole; TMP, trimethoprim.

in 3 to 5 days. It is inexpensive, has excellent oral bioavailability, At present, due to widespread resistance, fluoroquinolones
is available even in the poorest parts of the world, and has broad- should only be used to treat patients with typhoid fever when the
spectrum activity against other occult childhood bacterial infections isolate is confirmed to be fluoroquinolone susceptible.
(including bacteremia and meningitis caused by H. influenzae,
S. pneumoniae, and N. meningitides). However, up to 1:20,000 patients
develop fatal irreversible aplastic anemia. Also, chloramphenicol
Third-Generation Cephalosporins
does not substantially reduce the risk of relapse and chronic carriage. The emergence of NaR strains with decreased fluoroquinolone
Ampicillin and its oral formulation amoxicillin and trimethoprim– susceptibility (and associated treatment failures) has caused a shift
sulfamethoxazole are also inexpensive, broad-spectrum antibiotics toward third-generation cephalosporins as first-line therapy in
that are effective against susceptible strains of S. Typhi and more severe cases, although this approach may take longer for
Paratyphi A, and are generally available in highly endemic settings. defervescence and has a higher relapse rate.29 Ceftriaxone is an
In populations with a known prevalence of G6PD deficiency, effective antibiotic for treating enteric fever, including cases caused
sulfonamides should generally be avoided. by NaR isolates. However, ceftriaxone must be given parenterally,
and short courses of ceftriaxone (≤7 days) are associated with high
Fluoroquinolones and Nalidixic Acid–Resistant S. Typhi rates of relapse.32 Furthermore, clinical defervescence is often
delayed, and longer courses of ceftriaxone may be required,
and S. Paratyphi A depending on the clinical response.33 In such cases, treatment for
Widespread acquisition of resistance to chloramphenicol, ampicillin, at least 7 days post-defervescence can be considered. Cefixime is
and trimethoprim–sulfamethoxazole led to the use of fluoroqui- an oral third-generation cephalosporin that may be used to treat
nolones as the first-line therapy. However, this approach is now enteric fever, although short courses also result in high rates of
outdated in areas where strains with reduced susceptibility to relapse. Resistance to ceftriaxone and other extended-spectrum
fluoroquinolones predominate. This includes South and Southeast beta-lactam antibiotics is rare but increasing.7 Indeed, a recent
Asia, where increasing resistance has led to poor clinical responses outbreak of typhoid caused by an XDR strain of S. Typhi resistant
to fluoroquinolones. to a number of antimicrobials including ceftriaxone and fluoro-
Recognizing the role of increasing quinolone resistance in quinolones in Pakistan is particularly disconcerting.34
poor treatment outcomes, the Clinical Laboratory and Standards
Institute amended the criteria for susceptibility to quinolone
antibiotics for S. Typhi and S. Paratyphi A, B, and C in 2012
Azithromycin
and 2013. Before this time, nalidixic acid resistance (NaR) served Azithromycin is an effective oral treatment for uncomplicated
as a marker for the potential for decreased clinical effectiveness of enteric fever, including enteric fever caused by NaR and multi-
quinolone antibiotics. However, a complicating factor is that many drug–resistant isolates.35 A 7-day course of azithromycin appears
laboratories are unable to test for these updated breakpoints in to be as effective as gatifloxacin in the treatment of enteric fever
S. Typhi and Paratyphi isolates. For such strains, NaR may still serve caused by NaR isolates and results in lower rates of clinical failure
as a useful marker of decreased susceptibility to fluoroquinolone and relapse compared with cefixime or ceftriaxone. Azithromycin
antibiotics. is safe in children, has excellent bioavailability and pharmacokinetics
In the absence of resistance, ciprofloxacin and ofloxacin are with once-daily dosing, and reaches high intracellular concentra-
highly efficacious in the treatment of enteric fever. Both have tions, which may contribute to the high rates of cure seen after
excellent oral bioavailability and result in rapid defervescence (an 7 days of therapy.
average of ≈3–4 days) and decreased rates of relapse and carriage
compared with chloramphenicol and beta-lactam antibiotics.
Concern about fluoroquinolone-induced cartilage toxicity in
Supportive and Adjunctive Therapy
children is based on animal models; however, several studies support Adjunctive therapy is aimed at managing the inflammatory com-
its safety in children.29 Gatifloxacin is a newer-generation fluoro- plications of infection. In a double-blind trial in Indonesia in the
quinolone that is available in many countries where enteric fever 1980s, a short course of high-dose intravenous dexamethasone
is endemic and has better efficacy in the treatment of uncomplicated initiated concurrently with the first dose of antibiotics significantly
enteric fever caused by NaR Salmonella relative to ofloxacin.30 reduced mortality in critically ill patients with typhoid fever with
However, results from a recent trial comparing gatifloxacin with shock and/or profound encephalopathy manifested as delirium
ceftriaxone suggest that for quinolone-resistant strains, it is better or obtundation.36 In suspected cases of severe typhoid fever,
to avoid gatifloxacin and use an alternative agent.31 A disadvantage dexamethasone should be administered along with intravenous
is that gatifloxacin is associated with increased frequency of antibiotics as soon as possible, usually before the results of blood
hypoglycemia and hyperglycemia compared with other fluoro- cultures are obtained, and may be administered at an initial dose
quinolones, and for this reason was withdrawn from the U.S. of 3 mg/kg IV, followed by 1 mg/kg IV every 6 hours for seven
market. additional doses. Recent evidence continues to support the initial
 CHAPTER 74  Typhoid and Paratyphoid (Enteric) Fever 615

administration of high-dose dexamethasone along with antibiotics Typhoid conjugate vaccines have been shown to induce long-term
in severe cases of enteric fever with shock or encephalopathy in immune responses even in young children and are now WHO 74
adults and children. pre-qualified. In 2018 the WHO updated its position statement
Supportive care, including rehydration and nutritional manage- to endorse the use of typhoid vaccines in control programs, with
ment, is important in patients with enteric fever. Rehydration TCV being the preferred vaccine. The WHO recommends the
and nutritional supplementation can be managed according to introduction of TCV to be prioritized in countries with the highest
WHO standards. Despite historical concerns regarding their burden of typhoid fever or a high burden of antimicrobial
use, debilitating fevers and malaise can be managed safely with resistance.39
antipyretics.37 Other strategies to prevent S. Typhi and Paratyphi A include
interventions to reduce exposure to food- and water-borne bacteria.
On a household level, these include boiling and storing water in
Management of Intestinal Complications narrow-mouthed, covered containers. Food safety involves hand-
Prompt surgical intervention in suspected cases of perforation is washing with soap before preparing or consuming foods and
the mainstay of therapy. The majority of cases involve a single avoiding certain food types in endemic areas, such as raw foods
perforation along the anti-mesenteric border of the terminal and shellfish, and consuming only foods that are thoroughly cooked
ileum. However, careful inspection of the bowel is required, and hot at the time of consumption.24
as multiple perforations are present in approximately 25% of
patients and perforation can occur along the proximal or distal
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