Bope: Conn's Current Therapy 2011, 

1st ed.
Copyright © 2010 Saunders, An Imprint of Elsevier
Typhoid Fever

Method of: Tamilarasu Kadhiravan, MD

Typhoid fever is a bacteremic infection caused by the gram-negative bacillus Salmonella

enterica serotype Typhi.S. Paratyphi also causes an illness clinically indistinguishable
from typhoid fever. Humans are the only known host of S. Typhi, and it is transmitted by
ingestion of contaminated food or water. Improvement in sanitation and hygiene led to the
elimination of typhoid fever from the developed world long before the advent of
antibiotics. On the other hand, in parts of the world lacking sanitation, it continues to be an
important cause of febrile illness despite the availability of effective antibiotics.

Epidemiology

Typhoid fever is endemic in the developing world, especially the South and South East
Asian countries of India, Nepal, Pakistan, Bangladesh, Vietnam, and Indonesia. Annual
incidence in endemic settings is typically more than 100 cases per 100,000 population,
and it predominantly affects children and young adults. Apart from sick persons
with typhoid fever, convalescent carriers and asymptomatically infected food handlers
(long-term carriers) are the sources of infection. Potential vehicles of infection include food
or water consumed from roadside eateries, ice cubes and ice cream made from
contaminated water, and raw vegetables and fruits. In contrast, most cases of typhoid
fever in developed countries are imported by travel, especially to the Indian subcontinent.

Pathogenesis and Clinical Features

Following ingestion, the bacilli invade and multiply in the small intestinal lymphoid tissue
before entering the bloodstream. This primary bacteremia leads to widespread seeding of
the reticuloendothelial system and intestinal lymphoid tissue, where the infection is
amplified and spills over into the circulation. Onset of symptoms usually coincides with this
secondary bacteremia. Interestingly, unlike other Gram-negative bacteremic infections,
septic shock develops relatively late in the course of illness, and the infection can be
eminently cured by oral antibiotic therapy. Nonetheless, it should be emphasized that any
delay in initiating antibiotic therapy increases the risk of complications (Box 1).

BOX 1 
Complications of typhoid fever
Abdominal
   Paralytic ileus
   Intestinal hemorrhage
   Intestinal perforation
   Secondary peritonitis
   Symptomatic liver dysfunction
   Acalculous cholecystitis
Long-term
   Gallbladder cancer
Extra-abdominal
   Encephalopathy
    Cerebellar dysfunction
   Myocarditis
   Osteomyelitis and soft tissue abscesses
   Multiorgan dysfunction syndrome
   Hemophagocytic syndrome
   Hemolysis
   Glomerulonephritis

During the first week, temperature gradually increases in a stepladder fashion. Localizing
symptoms are usually minimal. Anorexia, lassitude, and malaise are often marked.
Headache and vomiting are common; however, a supple neck helps rule out meningitis.
Abdominal symptoms such as constipation, loose stools, and abdominal pain are not
infrequent, but they are nonspecific and often overlooked. Soft, tender enlargement of liver
or spleen is seen in about half the patients. Rose spots and relative bradycardia, though
classic, are rare. When the infection goes untreated, hypertrophied lymphoid tissue of the
Peyer's patches can ulcerate toward the end of the second week, resulting in torrential
gastrointestinal bleeding, small intestinal perforation, and secondary bacterial peritonitis.
Patients with severe illness can present with a muttering delirium described as coma
vigil. Untreated typhoid fever often resolves spontaneously in about 4 to 6 weeks.
However, the risk of death is high (>10%), and relapses are frequent. Many patients
excrete S. Typhi in feces and urine during convalescence (convalescent carriers), and
some of them continue to excrete beyond 1 year (long-term carriers).

Current Pattern of Antimicrobial Susceptibility

Since 1990, a sea change has occurred in the antimicrobial susceptibility of S. Typhi in
endemic countries and elsewhere. Unregulated use of fluoroquinolones has resulted in
emergence of S. Typhi strains with decreased susceptibility. These strains have a
subthreshold increase in minimal inhibitory concentration that is not detected by
conventional disk-diffusion testing. Resistance to nalidixic acid (NegGram) (a quinolone) is
a surrogate marker for such strains. In fact, most infections in the community are now
caused by nalidixic acid-resistant S. Typhi (NARST). Not surprisingly, this change is
reflected in far-away geographic locales such as the United States and the United
Kingdom.

Diagnosis

Clinical features are nonspecific, and laboratory testing is essential to confirm a diagnosis
of typhoid fever. A soft splenomegaly, absence of leukocytosis, mild leukopenia, and
modest elevation of transaminases are subtle pointers to a diagnosis of typhoid fever.
Blood culture drawn early in the illness before initiation of antibiotics is often fruitful and is
the gold standard for the diagnosis of typhoid fever. The time-honored Widal test, which
detects agglutinating antibodies to somatic and flagellar antigens of S. Typhi, adds little to
decision making. Initial enthusiasm about rapid serologic tests such as Typhidot and
Tubex TF has not been confirmed in community-based studies. None of these tests are
sensitive enough to rule out typhoid. In a patient who has nonlocalizing acute febrile illness
lasting more than 5 to 7 days in a suggestive epidemiologic setting (residence in or travel
to endemic area; outbreaks), it is prudent to treat presumptively for typhoid fever, after
reasonably ruling out competing diagnoses such as malaria, dengue, leptospirosis, and
rickettsial infection.
    Current Diagnosis
▪    Typhoid fever typically manifests as an undifferentiated acute febrile
illness.
  
Soft splenomegaly, normal or low white cell count, and elevated liver
enzymes are subtle diagnostic pointers.
▪    Blood culture, drawn before antibiotic administration, is the most useful
  
investigation.
   ▪    Consider presumptive treatment in appropriate epidemiologic settings.
Treatment

Fluoroquinolones (ciprofloxacin [Cipro] or ofloxacin [Floxin] [1] 7.5mg/kg twice a day for 5 to

7 days) are unparalleled in efficacy for treating fully susceptible S. Typhi strains. However,
their use is associated with frequent treatment failures, prolonged defervescence, and
higher rates of complications in NARST infections. Given the widespread emergence of
NARST, fluoroquinolones are no longer to be considered the drug of choice. Several
alternatives have been evaluated in randomized, controlled trials for treating
uncomplicated typhoid fever caused by NARST (Table 1). Ease of oral administration,
proven efficacy, and safety make azithromycin (Zithromax) [1] a reasonable first choice for
uncomplicated typhoid fever. In hospitalized seriously ill patients and treatment failures,
parenteral ceftriaxone (Rocephin)[1] is preferred. Usually, it takes about 4 to 7 days for
defervescence after the initiation of antibiotics. Antipyretics should be used for symptom
relief; ibuprofen (Motrin; 10mg/kg every 6 hours) is superior to acetaminophen (Tylenol;
12mg/kg every 6 hours). However, ibuprofen should be avoided when dengue fever is a
possibility. A soft, low-residue diet is traditionally advised to prevent intestinal perforation.
Such a practice, however, is not founded on scientific evidence. Treatment of S. Paratyphi
infection is identical to that of S. Typhi infection.

   Current Therapy
▪    Decreased susceptibility to fluoroquinolones is widespread
  
among Salmonella enterica serotype Typhi.
   ▪    High-dose fluoroquinolones are suboptimal for treating such infections.
▪    Azithromycin (Zithromax)[1] is the preferred drug for
  
uncomplicated typhoid fever.
▪    Ceftriaxone (Rocephin)[1] is preferred for treating hospitalized and seriously
  
ill patients.
1 Not FDA approved for this indication

TABLE 1   -- Outcomes of Alternative Treatments for Nalidixic Acid–Resistant S. Typhi

(NARST) Infection Evaluated in Randomized, Controlled Trials
Fever
Clearanc Rate of
e Time Treatme Relapse
Drug Dosage Comments
(Median nt Rate
or Failure
Mean)
High-dose ofloxacin 10mg/kg[3]bi 8.2 d 36% < 1%; Not
 Fever
Clearanc Rate of
e Time Treatme Relapse
Drug Dosage Comments
(Median nt Rate
or Failure
Mean)
insufficie
(Floxin)[1] d?7d recommended
nt data
Serious concerns
Gatifloxacin (Tequin) 10mg/kg qd
[2] 4.4 d 9% 3% about
?7d
dysglycemia
10- < 1%; Unproven in
Azithromycin
20[3]mg/kg 4.4 d 9% insufficie complicatedtyph
(Zithromax)[1]
qd ? 7 d nt data oid fever
10mg/kg[3]bi High cost; not
Cefixime (Suprax)[1] 5.8 d 27% 9%
d?7d recommended
60-75mg/kg High relapse rate
Ceftriaxone*(Rocephi
qd ? 10-14 6.1 d 9% 5% (14%) with 7-day
n)[1]
d regimen
Data from Dolecek C, Tran TP, Nguyen NR, et al: A multi-center randomised controlled trial of
gatifloxacin versus azithromycin for the treatment of uncomplicated  typhoid fever in children
and adults in Vietnam. PLoS One 2008;3:e2188; Pandit A, Arjyal A, Day JN, et al: An open
randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated
enteric fever. PLoS One 2007;2:e542; and Parry CM, Ho VA, Phuong le T, et al: Randomized
controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for
treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents
Chemother 2007;51:819.
1 Not FDA approved for this indication.

2 Not available in the United States.

3 Exceeds dosage recommended by the manufacturer.

* No trials on treatment of NARST infection; extrapolated data from Parry CM, Hien TT, Dougan G, White NJ, Farrar
JJ: Typhoid fever. N Engl J Med 2002;347(22):1770-1782.

Prevention

Sustained improvement in sanitation and access to safe drinking water are essential to
control typhoid fever in endemic areas. Avoiding potentially contaminated food and
beverages and pretravel vaccination decrease the risk oftyphoid fever among travelers
(see the article on travel medicine). Recently, mass administration of the Vi polysaccharide
vaccine (Typhim Vi, Typherix [outside United States]) has been found to confer herd
immunity and is a potential tool for the control of typhoid fever in endemic settings.

References
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