The Expert Committee endorsed listing of ciprofloxacin, ceftriaxone and
azithromycin as first-choice treatments for typhoid and paratyphoid (enteric)
fever on the core list of the EML and EMLc. Ciprofloxacin is recommended as
first-choice in settings with low prevalence of fluoroquinolone resistance, while
ceftriaxone and azithromycin are recommended first-choice treatments in
settings where there is a high prevalence of fluoroquinolone resistance.
Ciprofloxacin, azithromycin and ceftriaxone are all classified as Watch
group antibiotics (Section 6.2.2).
Following the principle of parsimony, the Expert Committee did not
recommend the addition of ofloxacin for this indication, noting that ofloxacin
and ciprofloxacin have demonstrated similar clinical performance for this
indication in clinical trials.
Enteric fever, a bloodstream infection caused by Salmonella enterica serovars
Typhi and Paratyphi, causes a major public health burden, especially in
children and young adults in resource-limited settings. Recent estimates put
the burden of enteric fever at 16 million cases and an estimated 150000 deaths
per year (1). Resistance to first-line treatments (multidrug resistance (MDR)
defined as resistance against chloramphenicol, ampicillin and trimethoprim/
sulfamethoxazole) and to fluoroquinolone antibiotics is now ubiquitous at the
global level (2). Resistant infections cause high clinical failure rates and prolonged
carriage, increasing the risk of complications (intestinal haemorrhage, gut
perforation and encephalopathy) in the individual patient, and lead to continued
transmission in families and their communities (3). There are now very few
effective treatment options. Worryingly, extensively drug-resistant (XDR) S. Typhi
strains, combining MDR, resistance to fluoroquinolones and third-generation
cephalosporins, have recently been reported in Pakistan (4). The most recent
WHO Guidelines for the diagnosis, treatment and prevention of typhoid were
published in 2003, and are now outdated particularly in an era of widespread
drug resistance (5).
Antibiotic treatment and sanitation have been the only widely used
intervention aimed at reducing the burden of enteric fever. Vaccines have been
underutilized. The recent decision of Gavi, the Vaccine Alliance, to support the
introduction of the new typhoid conjugate vaccine, Typbar-TCV, into the routine
immunization schedules of eligible countries will help, but may take many years
to be fully implemented and effective in endemic countries (6).
In addition to antimicrobial resistance, there are several issues in
the management of enteric fever. The sensitivity of blood culture is low, only
approximately 40% of patients with enteric fever will have a positive blood
culture (5, 7). In low- and middle-income countries, blood culture facilities
are often not available. There are no rapid tests with acceptable sensitivity and
specificity (3, 5). Treatment is usually empirical.
Summary of evidence
The application identified two Cochrane systematic reviews that evaluated
antibiotic treatment of typhoid fever.
A 2011 Cochrane systematic review of 26 trials involving 3033 patients
evaluated fluoroquinolones for treatment of typhoid and paratyphoid fever
(8). The review did not include comparisons with antibiotics that are no
longer recommended for use in enteric fever (e.g. norfloxacin due to its poor
Antibiotic resistance is an important consideration for efficacy; an
earlier version of this SR combined different generations of fluoroquinolones
in one sub-group, stratified according to the prevalence of MDR and nalidixicresistant (NaR) strains (9). However, the updated version grouped studies by each
fluoroquinolone individually. Results are presented as risk ratios (RR; 95%CI)
for categorical data and mean difference (MD; 95%CI) for continuous data.
Ciprofloxacin versus chloramphenicol
Four trials (293 patients) compared ciprofloxacin to chloramphenicol, only one
trial included children above 12 years of age, none of the trials reported the
prevalence of MDR and NaR strains. For clinical failure, the results favoured
ciprofloxacin (RR 0.24, 95%CI 0.07 to 0.82), although confidence intervals were
wide, due to the small sample size (low quality evidence). Fever clearance time
(FCT) (two trials; 147 patients) also favoured ciprofloxacin, the mean difference
(MD) was −62.46 hours (95%CI −75.52 to −49.39) (moderate quality evidence).
Small numbers of events occurred for microbiological failure (two trials,
142 patients; RR 0.05, 95%CI 0.00 to 0.81) (low quality evidence) and relapse
(four trials, RR 0.15, 95%CI 0.02 to 1.15) (low quality evidence). The results for
serious adverse events (two trials) were indeterminate (RR 0.99, 95%CI 0.18
to 5.52) (very low quality evidence) and for non-serious adverse events (four
trials), the results were comparable (RR 1.00, 95%CI 0.61 to 1.64), but with wide
confidence intervals (low quality evidence) (8).
Ofloxacin versus chloramphenicol
Four trials (247 patients) compared ofloxacin to chloramphenicol. The results
for clinical failure were in favour of ofloxacin, but with wide confidence
intervals (RR 0.15, 95%CI 0.03 to 0.64) (low quality evidence). Fever clearance
time (two trials, 140 patients) followed the same trends as clinical failures, the
MD was −75.85 hours (95%CI −88.52 to −63.17) (moderate quality evidence).
Due to the small numbers of events, the results for microbiological failure
(three trials, RR 0.16, 95%CI 0.02 to 1.07) (low quality evidence) and relapse
(RR 0.14, 95%CI 0.01 to 2.65) (low quality evidence) were indeterminate. For
serious adverse events (one trial), the RR was not estimable due to zero events.
For non-serious adverse event (four trials), the results were comparable, with a
RR of 1.06 and wide confidence intervals (95%CI 0.60 to 1.87) (low quality).
The SR included one trial (252 patients) that compared gatifloxacin
(which was not proposed in the application for EML listing), versus
chloramphenicol (RR for clinical failure was 0.79, 95%CI 0.32 to 1.96) (7). Nonserious adverse events favoured gatifloxacin (RR 0.58, 95%CI 0.44 to 0.78).
Ciprofloxacin/ofloxacin versus cotrimoxazole and ampicillin/amoxicillin
The application reported comparisons of ciprofloxacin versus cotrimoxazole
(two trials, 132 patients), ofloxacin versus cotrimoxazole (one trial, 99 patients),
ofloxacin versus ampicillin (one trial, 40 patients), ofloxacin versus amoxicillin
(one trial, 50 patients). However, due to the small sample sizes the results were
indeterminate and the individual outcomes were assessed as low or very low
quality. Therefore, cotrimoxazole and ampicillin/amoxicillin were not proposed
in the application for EML listing.
Ciprofloxacin/ofloxacin versus cefixime
The comparisons of ciprofloxacin versus cefixime and ofloxacin versus cefixime
were each based on one trial. Due to the weakness and low/very low quality of
the evidence, cefixime was not proposed in the application for EML listing.
A randomized controlled trial that compared gatifloxacin versus cefixime
(158 patients), was stopped early by the Independent Data Safety and Monitoring
Board due to the high number of failures (19/70) in the cefixime arm (RR 0.04,
95%CI 0.01 to 0.31) (p<0.001) (10). This trial was included in the SR but was not
part of the comparisons evaluated in the application for inclusion in the EML.
Ciprofloxacin versus ceftriaxone
For this comparison, only one trial (42 adult participants) was available. Due
to the very small number of patients, the result was indeterminate. There is no
estimate for FCT and adverse events were not reported. The overall quality of the
evidence was accessed as very low. More than 50% of strains were MDR.
Ofloxacin versus ceftriaxone
For this comparison, only one trial (47 adult participants) was available. More
than 50% of strains were MDR, no NaR was reported. For clinical failure, a nonsignificant result in favour of ofloxacin was reported, (RR 0.09, 95%CI 0.01 to 1.46), the MD in FCT was −115 hours (95%CI −150.67 to −79.33).
Ciprofloxacin versus azithromycin
For this comparison, only one trial (64 participants) was available. Due to the
small sample size (0 events in both arms), clinical failure, microbiological failure
and relapse were not estimable. The MD for FCT was −12 hours (95%CI −24.39
to 0.39). The quality of the evidence was low/very low.
Ofloxacin versus azithromycin
Two trials were available (213 patients) for this comparison. Clinical failure
favoured azithromycin with a RR of 2.2 (95%CI 1.23 to 3.94) (high quality of
evidence), the MD in FCT of 30.41 hours (95%CI −22.12 to 82.93) (moderate
quality evidence) supported azithromycin. The higher failure rates in the
ofloxacin arm in the more recent of the two trials, reflected the increasing
prevalence of NaR S. typhi isolates in this region.
The systematic review included one azithromycin trial (287 patients),
that compared gatifloxacin to azithromycin (11). Gatifloxacin and azithromycin
had similar high efficacy (RR for clinical failure 0.98, 95%CI 0.32 to 2.96) in this
setting with high proportions of NaR S. typhi strains.
A 2008 Cochrane systematic review of seven trials involving 773 patients
evaluated azithromycin for treatment of uncomplicated typhoid and paratyphoid
The comparison azithromycin versus chloramphenicol (one trial, 77
patients) showed a benefit for azithromycin, but due to the small sample size and
wide confidence intervals no inferences can be made (odds ratio (OR) for clinical
failure 0.16, 95%CI 0.01 to 3.4 (low quality evidence)). Four trials (564 patients)
compared azithromycin to the fluoroquinolones (including gatifloxacin) and
were discussed above.
Two trials (132 patients) compared azithromycin versus ceftriaxone.
Clinical failure (OR 2.58, 95%CI 0.48 to 13.87) and FCT (MD 9.12 h. 95%CI
−1.11 to 19.36) favoured ceftriaxone (moderate quality evidence). No data were
available to assess adverse events.
The application described a systematic search for randomized controlled
trials (RCTs) in enteric fever to supplement evidence obtained from the two SRs.
The majority of identified RCTs had small sample sizes, few events and lacked
sufficient power to detect significant differences. Four trials with sample sizes
greater than 30 patients in each arm were reviewed. Two trials had zero events
for clinical failure. A trial of gatifloxacin versus ofloxacin (218 culture-positive
patients) showed similar numbers of treatment failures in both arms (hazard
ratio, HR 0.81, 95%CI 0.25 to 2.65), however the FCT was significantly shorter
in the gatifloxacin arm (HR 1.59, 95%CI 1.16 to 2.18) in this setting with high
NaR (13). Similar proportions of patients experienced adverse events, most of
which were mild (Grade 1 or Grade 2).
A trial of gatifloxacin versus ceftriaxone (116 culture-positive patients)
showed similar number of failures in the intention-to-treat (ITT) patients, but in
the culture-confirmed patients, the comparison favoured ceftriaxone (HR 0.24,
95%CI 0.08 to 0.73) (14). Treatment failure was associated with the emergence of
high-level fluoroquinolone resistance in S.typhi, requiring the trial to be stopped.
A similar number of non-serious adverse events occurred in each treatment
group, and no serious events were reported.
The 2003 WHO guidelines on the diagnosis, treatment and prevention of typhoid
fever (5) make the following recommendations for treatment of uncomplicated
typhoid fever, based on susceptibility of infection:
– Fully sensitive: a fluoroquinolone (ofloxacin or ciprofloxacin)
as optimal therapy. Chloramphenicol, amoxicillin or
sulfamethoxazole + trimethoprim are alternatives.
– Multidrug resistance: a fluoroquinolone or cefixime as optimal
therapy. Azithromycin or cefixime are alternatives.
– Quinolone resistance: azithromycin or ceftriaxone as optimal
therapy. Cefixime is an alternative.
The 2012 WHO pocket book recommendations for management of
common childhood conditions (15) make the following recommendations for
the treatment of typhoid fever in children:
– Children with typhoid fever should be treated with a
fluoroquinolone (i.e. ciprofloxacin, gatifloxacin, ofloxacin and
perfloxacin) as a first-line treatment for 7–10 days (strong
recommendation, moderate quality evidence).
– If response to treatment is poor, consider drug-resistant
typhoid and treat with a second-line antibiotic such as a third-generation cephalosporin or azithromycin for 5–7 days (strong recommendation, moderate quality evidence).
– Where drug resistance to antibiotics among salmonella isolates is
known, follow national guidelines according to local susceptibility
data (strong recommendations, moderate quality evidence).
Rationale for antibiotic selection
Although recommended in the 2003 WHO guidelines, ampicillin/amoxicillin
and trimethoprim-sulfamethoxazole were not proposed in the application for
inclusion in the EML for typhoid fever due to the lack of data showing any benefit
over comparators based on evidence from the SRs identified.
Chloramphenicol is recommended in the 2003 WHO guidelines but
not in the 2012 WHO pocket book. There has been conflicting evidence from
smaller trials, however, a large trial showed similar efficacy to gatifloxacin, a
fourth-generation fluoroquinolone, but higher numbers of Grade 1 and 2 adverse
events. Due to the need to monitor blood counts, the long treatment duration
and the availability of alternative drugs, chloramphenicol was not proposed in
the application for inclusion on the EML.
The application proposed the inclusion of ofloxacin and ciprofloxacin on
the EML and EMLc, supported by evidence from the SRs and clinical practice
guidelines (CPGs). More clinical trials evaluating ofloxacin have been performed,
however, ofloxacin is not currently included on the EML. As ciprofloxacin is
currently listed and has similar clinical performance, for parsimony, ciprofloxacin
only could be considered.
Although included in the 2003 WHO guidelines, the evidence from the
SRs did not support listing of cefixime. In comparisons with fluoroquinolones,
cefixime, showed higher number of failures and longer FCTs, however, in
comparisons with chloramphenicol, it compared favourably.
The application also proposed listing ceftriaxone and azithromycin on
the EML and EMLc for typhoid fever, supported by evidence from SR and CPGs.
The Expert Committee agreed that knowledge of the local resistance patterns
for S.typhi and S. paratyphi strains was critical for making empiric treatment
choices in the treatment of enteric fever, noting that there are reports of high
rates of fluoroquinolone resistance in some settings. This is the first time
the Expert Committee has considered resistance patterns in making specific
recommendations for empiric treatment.
The Expert Committee considered the various antibiotics proposed in
the application under the guiding principle of parsimony and selected first- and
second-choice antibiotics for this indication for inclusion on the EML and EMLc.
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