REVIEW

10.1111/j.1469-0691.2011.03552.x

Treatment of typhoid fever in the 21st century: promises and

shortcomings
T. Butler
Department of Microbiology and Immunology, Ross University School of Medicine, North Brunswick, NJ, USA

Abstract
Emergence of multidrug resistance and decreased ciprofloxacin susceptibility (DCS) in Salmonella enterica serovar Typhi in South Asia
have rendered older drugs, including ampicillin, chloramphenicol, trimethoprimsulphamethoxazole, ciprofloxacin, and ofloxacin, ineffective or suboptimal for typhoid fever. Ideally, treatment should be safe and available for adults and children in shortened courses of
5 days, cause defervescence within 1 week, render blood and stool cultures sterile, and prevent relapse. In this review of 20 prospective clinical trials that enrolled more than 1600 culture-proven patients, azithromycin meets these criteria better than other drugs.
Among fluoroquinolones, which are more effective than cephalosporins, gatifloxacin appears to be more effective than ciprofloxacin and
ofloxacin for patients infected with bacteria showing DCS. Ceftriaxone continues to be useful as a back-up choice, and chloramphenicol,
despite its toxicity for bone marrow and history of plasmid-mediated resistance, is making a comeback in developing countries that
show their bacteria to be susceptible to it.
Keywords: Enteric fever, Salmonella, Salmonella enterica, serovar Paratyphi A, serovar Typhi, Typhi, typhoid fever
Article published online: 25 April 2011
Clin Microbiol Infect 2011; 17: 959963

Corresponding author: T. Butler, Department of Microbiology and

Immunology, Ross University School of Medicine, North Brunswick,
NJ 08902, USA
E-mail: tbutler@rossmed.edu.dm

Introduction
Typhoid fever is an enteric bacterial infection caused by Salmonella enterica serovar Typhi or Paratyphi A. Most cases
are caused by Typhi, which is usually written S. Typhi. It is
transmitted by the faecaloral route, and most of the worlds
estimated more than 2 million cases, which result in over
200 000 deaths every year, occur in southern Asian countries with poor sanitation and unclean water [1]. The majority of infections are in children [1]. In the USA, Europe, and
other industrialized countries with clean water sources,
typhoid fever is rare, but in 1 year, 19961997, in the USA
there were 293 documented cases, of whom about 80%
acquired their infections abroad [2].

Pathogenesis and Transmission

Alone among enteric pathogens, S. Typhi infects only humans,
is ingested, crosses the intestinal epithelium without initially

causing any injury or diarrhoea, and multiplies intracellularly in

phagocytes in Peyers patches, spleen, liver, and bone marrow.
After the onset of fever and bacteraemia, a variable proportion
of patients, 2483% as reported in recent clinical studies [3
6], develop diarrhoea, but this is usually not a chief complaint,
whereas a minority of patients, 727% [310], excrete the
organisms in stools. After recovery from clinical illness, about
14% of patients, predominantly females, become chronic
asymptomatic faecal carriers, owing to underlying gall bladder
stones, which often become the focus of infection lasting for
many years [11]. Enteric infection here is a misnomer, because
S. Typhi merely uses the intestine as a portal of entry for an
inoculum that produces a systemic infection, in which, in a relatively small proportion of patients, organisms are subsequently excreted back into the intestine via the biliary tract.
Hyperplastic Peyers patches in the ileum and proximal colon
in some patients lead to mucosal ulceration with bleeding or
intestinal perforation. Unlike cholera and shigellosis, in which
copious amounts of organisms are shed from intestinal luminal
liquid into the environment, typhoid is spread in more subtle,
varied patterns. The infrequent and transient excretion of

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organisms in stools during acute disease will lead to some

transmission in environments with poor sanitation, whereas
the larger amount of constant and heavy excretion into the
environment comes from the chronic carriers, who are important both in unclean environments, because of water contamination, and in developed countries, where they spread disease
by hand and by touching others food.

Aims of Antimicrobial Treatment

The ideal antimicrobial drug for typhoid fever should be
available for oral and intravenous use in adults and children,
cause defervescence and clinical improvement in 37 days,
render blood and stool cultures negative during and after
treatment, prevent relapses after treatment, and have a low
incidence of side effects and low cost. This treatment will
both benefit the patients by curing them and prevent disease
in nearby exposed persons by curtailing excretion of pathogens in stools. Prevention of death, which would occur in
>10% of untreated patients, owing to complications such as
bleeding from intestinal ulcers, intestinal perforation, and
shock, is an obvious goal of therapy. Fortunately, death or
complication is infrequent when antimicrobial therapy is
given before complications occur, as shown by the reports
of only four deaths, two non-fatal intestinal perforations
requiring surgery and ten cases of intestinal bleeding among
more than 1600 patients entered into 20 trials of this
review.

Trial Methods
Culture-proven patients were febrile children and adults
without complications selected at hospitals by obtaining positive blood cultures in the majority of cases. In a few trials,

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patients were enrolled on the basis of results of bone marrow or stool cultures. Patients were randomly assigned to
drug therapies, and followed for clinical cure on the basis of
defervescence and amelioration of symptoms. Most patients
were followed up at 1 month after the end of therapy for
relapse of symptoms. In most trials, bacteriological cure was
tested by obtaining negative blood cultures after therapy.
Identification of S. Typhi and S. Paratyphi A and determination
of antimicrobial susceptibilities were carried out with the
techniques available at each hospital.

History of Antimicrobial Treatment

Chloramphenicol was the drug of choice for several decades after its introduction in 1948, but has been set aside
in many countries because of the emergence of plasmidmediated resistance and the rare but fatal side effect of
bone marrow aplasia. Trimethoprimsulphamethoxazole
and ampicillin were employed to counter chloramphenicol
resistance in the 1970s, only to be discarded because of
the emergence of plasmid-mediated multidrug resistance
that covered all three drugs. In the 1980s, ceftriaxone and
ciprofloxacin were shown to be effective against multidrugresistant strains of S. Typhi, and became the drugs of
choice. The fluoroquinolones, including ciprofloxacin and
ofloxacin, were preferred to ceftriaxone because they
were available for oral use and were less expensive. However, in the past decade, strains of bacteria have emerged
in Asia that show decreased ciprofloxacin susceptibility
(DCS), and patients infected with them have not
responded to fluoroquinolone therapy as promptly as previously or have failed to clear organisms in stool cultures
[4,5]. Azithromycin was tested in the 1990s, with good
results, and can now be regarded as a promising alternative to fluoroquinolones and cephalosporins [9,10,12].

TABLE 1. Summary of features of antimicrobial drugs in use for typhoid fever; rates and prevalences are given as ranges of
percentages of treated patients or tested bacterial isolates in the cited trials
Drug

Cure ratea

Relapse rateb

Resistance
prevalence

Duration of
therapy (days)

References

Azithromycin
Ceftriaxone
Chloramphenicol
Fluoroquinolone (ciprofloxacin,
ofloxacin, or gatifloxacin)

81100
7297
8396
64100

0
017
014
012

071c
0
088
0d

57
314
714
37

35,710,12
7,8,17,18,20,2529
12,19,21,2527,29
36,9,1721

Trials did not use uniform criteria for cure, but most required defervescence within 7 days of starting therapy without complications or the need for a change of antimicrobial drug and without positive blood culture at the end of treatment.
Relapses were return of symptoms within 1 month of the end of therapy, but follow-up of patients after hospital discharge was incomplete and sometimes not attempted.
c
Not applicable, because an MIC of 8 mg/L was used by some trials, whereas patients with resistant isolates were treated and cured.
d
None was resistant with a fluoroquinolone MIC of 48 mg/L, but the incidence of nalidixic acid resistance and/or decreased ciprofloxacin susceptibility with a ciprofloxacin
MIC of 0.121 mg/L ranged from 0% to 96%.
b

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Randomized Trials with Azithromycin

Randomized Trials with Fluoroquinolones

Nine prospective clinical trials employing azithromycin that

enrolled culture-positive children and adults with typhoid
fever were carried out in Egypt, India, Vietnam, and
Bangladesh [35,710,12,13] (Table 1). The drug was
received by a total of 453 patients, of whom 268 (59%)
were children. Its dosage was 10 or 20 mg/kg/day for children and 500 mg/day or 1 g/day for adults, given orally for
7 days in seven trials and for 5 days in two trials. Two trials
were not comparative [10,13], whereas randomized assignments were made to different comparator drugs in the
remaining trials: chloramphenicol in one [12], ciprofloxacin
in one [9], ofloxacin in two [4,5], gatifloxacin in one [3], and
ceftriaxone in two [7,8]. Clinical responses in non-comparative trials were that 61 of 64 patients (95%) treated with azithromycin were afebrile within 7 days of therapy and were
considered to be cured [10,13]. In comparative trials,
patients treated with azithromycin fared as well as or better
than patients treated with comparator drugs with respect to
cure rate and average time to defervescence. Clinical failures
in these trials were mainly persistence of fever (temperatures above 37.538C) for more than 7 days after the start
of treatment. In trials that included infections caused by bacteria with DCS, patients treated with ofloxacin showed
lower cure rates [4,5] and a greater mean duration of fever
after start of therapy: 174 h vs. 135 h for patients treated
with azithromycin [4]. No relapses were recorded in 267
patients treated with azithromycin followed up for 1 month
after therapy, whereas relapses were recorded in 16 of 276
patients (5.8%) treated with ceftriaxone, ofloxacin, or gatifloxacin [35,7,8]. Bacteriological responses were likewise
very good, with only four of 259 patients (1.5%) whose
blood was recultured after treatment showing growth of
Salmonella [3,7,8,10,12]. Stool cultures performed after treatment and repeated for most patients at 1, 3 and 6 months
later were positive for S. Typhi in only four of 337 patients
(1.2%) [3,5,710,12]. These achievements of the antibiotic
were not predictable from data on in vitro susceptibilities
and blood concentrations, which are traditionally used to
select drugs for human disease. S. Typhi was marginally susceptible, as shown by azithromycin MICs of 416 mg/L,
whereas blood concentrations after dosing rose to only
0.040.4 mg/mL [9]. The explanation of the drugs success
lay in its concentration in intracellular compartments, which
was >50 times that in blood [14]. Additionally, antimicrobial
potency in vivo may be greater than that predicted from
in vitro data, because of the alkaline pH in cells and low
numbers of bacteria [15].

Fluoroquinolones, including ciprofloxacin and ofloxacin, are

currently the drugs of choice for most cases of typhoid
fever. First used in the 1980s, they were recommended after
resistance to most older drugs became widespread. When
clinical and bacteriological responses of published trials of
several antimicrobial drugs were compared in meta-analyses
[16], fluoroquinolones were superior to all others except for
azithromycin. In five trials that compared ciprofloxacin,
ofloxacin or gatifloxacin with ceftriaxone, cefixime or chloramphenicol, the fluoroquinolone was judged to be superior to the comparator with regard to cure rate, fever
clearance time, and relapse [6,1720]. One trial showed ciprofloxacin and chloramphenicol to be equally effective [21].
However, resistance to fluoroquinolones in the form of nalidixic acid resistance, which correlates with DCS, was
reported in the 1990s. DCS is defined as a ciprofloxacin
MIC of 0.121 mg/L, and is not always detected by testing
for nalidixic acid resistance [22]. It became prevalent in Asian
countries, causing short courses of 5 days of fluoroquinolones, as well as a standard 7-day course, to be ineffective
[4,5,22,23]. Gatifloxacin gave good results in two trials that
used 7-day courses [3,6], has lower MICs for bacterial
strains with DCS, and is suggested to be more effective than
older fluoroquinolones, owing to better results of time-kill
experiments [24], but its use was associated with more
relapses than that of azithromycin [3]. Although fluoroquinolones have been used safely in children, physicians in the USA
continue to be advised by the Food and Drug Administration
that these drugs are not approved for use in children and
pregnant or nursing women, because of the potential to
cause musculoskeletal side effects by being incorporated into
cartilage of growing bones. Thus, a shortcoming of fluoroquinolones, in addition to suboptimal performance against infection caused by bacteria with DCS, is that some physicians
are reluctant to use them in children and pregnant or nursing women with typhoid fever because alternative effective
drugs are available.

Randomized Trials with Cephalosporins

Trials of ceftriaxone showed that this antibiotic was a credible alternative to chloramphenicol [2527]. Although more
patients treated with ceftriaxone than with chloramphenicol
showed fever lasting for more than 7 days, and there were
relapses, patients who received ceftriaxone, unlike those
treated with chloramphenicol, did not exhibit bone marrow

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suppression [25,27]. Relapses occurred in patients treated

for 7 days or less, whereas treatment for 814 days resulted
in no relapses [28,29]. In the USA, where chloramphenicol
is virtually obsolete because of its bone marrow toxicity,
most patients with typhoid fever receive ceftriaxone,
often in combination with a fluoroquinolone [22]. Additive
or synergistic effects of these two classes of drug against
S. Typhi have not been evaluated, so combined therapy is not
recommended routinely. Cefixime, on the other hand,
showed much higher rates of failure and relapse than
fluoroquinolones in comparative trials [6,18], and should not
be used.

Tenacity of Chloramphenicol
Although the prevalence of chloramphenicol resistance in
isolated strains of S. Typhi has been reported to be over 80%
in Vietnam [5,18], sampling of S. Typhi in India and Indonesia
has shown no resistance [22]. Surveys of large numbers
of strains from several countries in South Asia between
2002 and 2004 revealed that 23% were resistant to
chloramphenicol as well as to ampicillin and trimethoprim
sulphamethoxozole [1], but different countries showed
prevalences of resistance varying from 0% to 50% [24]. The
fact that most patients with typhoid fever have infections
caused by strains susceptible to chloramphenicol ensures
that this inexpensive, time-honoured drug will remain in use
in the developing countries of Asia. It is the most frequently
used drug for typhoid fever in Turkey [29].

Conclusions
Azithromycin should be used more, both in developing countries with a high prevalence of infection caused by bacteria
with DCS and in returned travellers in industrialized countries. Other than the higher cost, it outperforms other drugs
with regard to cure rates, speed of defervescence against
infections caused by bacteria with DCS, and prevention of
faecal carriage and relapse. Resistance of S. Typhi to azithromycin has not emerged, but cultured strains need to
be tested for susceptibility, because one case of resistant
S. Paratyphi A infection treated with this antibiotic resulted in
clinical failure [30]. Against infections caused by bacteria with
DCS, it is the only effective drug that can be used in short,
5-day courses [4,8]. Ceftriaxone in shortened courses of
5 or 7 days has significant relapse rates [8,28], but, as a
back-up, this antibiotic can achieve clinical cure with good
reliability. Although chloramphenicol continues to be used in

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countries without resistance to it, this old drug allows

relapses [16,31] and exposes patients to serious toxicity.

Transparency Declaration
T. Butler has received research grants from Roche, Pfizer,
Chiron, and Abbott.
Role of funding source: not applicable.

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