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10.1111/j.1469-0691.2011.03552.x
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
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].
960
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,
CMI
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.
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
CMI
961
962
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
CMI
Transparency Declaration
T. Butler has received research grants from Roche, Pfizer,
Chiron, and Abbott.
Role of funding source: not applicable.
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