Review of Antibacterial Medicines For The Treatment of Enteric Fever For The WHO Model List of Essential Medicines 2019 Update

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Review of Antibacterial Medicines for the Treatment of Enteric Fever for the
WHO Model List of Essential Medicines 2019 update
Article · February 2019
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Review of Antibacterial Medicines for the Treatment of Enteric Fever for the WHO Model List of Essential
Medicines 2019 Update
Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom
Table of Contents
Essential Medicine List Application for Special Indication..................................2
Typhoid and Paratyphoid Fever .................................................................................2
Scope of work .....................................................................................................................3
Introduction..................................................................................................................................3
Background to this application ............................................................................................... 3
General considerations regarding enteric fever trials ................................................... 4
Synopsis of evidence from Systematic Reviews................................................................. 5
Methods ........................................................................................................................................ 5
Results........................................................................................................................................... 6
Synopsis of evidence from Randomised Controlled Trials ............................................ 9
Methods ........................................................................................................................................ 9
Results.........................................................................................................................................10
Synopsis of guidelines ...............................................................................................................11
Methods ......................................................................................................................................11
Results.........................................................................................................................................11
Selection of antibiotics .............................................................................................................11
FDA warning .............................................................................................................................14
References..................................................................................................................................... 15
1
Essential Medicine List Application for Special Indication:
Typhoid and Paratyphoid Fever

1,2 1 1,3 1
Authors: Christiane Dolecek , Sunil Pokharel , Buddha Basnyat , Piero Olliaro
1Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford,
UK.
2Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University,
Bangkok, Thailand.
3Oxford University Clinical Research Unit Nepal, Patan Academy of Health Sciences, Kathmandu, Nepal.
*Email: christiane.dolecek@ndm.ox.ac.uk
Acknowledgements:
We would like to acknowledge the expert help of Miss Eli Harriss, Knowledge Centre Manager and
Outreach Librarian at Bodleian Health Care Libraries, University of Oxford, UK.
2
Scope of work
The objective of this application is to review the available evidence on the efficacy and safety of antibiotic
treatments for enteric fever (typhoid fever and paratyphoid fever) and add enteric fever as new indication
for selected antibiotics listed in the current Essential Medicine List [1].
Introduction
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 150 000 deaths per year,
causing 10 Mio DALYs [2].. 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 [3]. 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 [4]. There are now very few effective treatment options. Worryingly, Extensively Drug
Resistant (XDR) S. Typhi strains, combining MDR, resistance to fluoroquinolones and third-generation
cephalosporines, have recently been reported in Pakistan [5]. The, current WHO Guidelines 'Background
document: The diagnosis, treatment and prevention of typhoid fever' were last published in 2003, are
clearly now outdated particularly in an era of widespread drug resistance [6].
Antibiotic treatment and sanitation have been the only widely used intervention aimed at reducing the
burden of enteric fever. Vaccines have been underutilised. The recent decision of Gavi, the Vaccine
Alliance, to support the introduction of the new typhoid conjugate vaccine, Typbar-TCV into the routine
immunisation schedules of eligible countries will help, but may take many years to be fully implemented
and effective in endemic countries [7].
Background to this application
The WHO Essential Medicine List (EML) lists the most efficacious and safe medicines, including antibiotics
to treat illnesses that are considered high priority. The 20th EML, published in 2017, provided new guidance
to optimise antibiotic use for many common infections and categorised antibiotics into three groups:
3
ACCESS, WATCH, RESERVE. The choice of an effective antibiotics to treat patients is an important tool in
the fight against antimicrobial drug resistance (AMR) and is part of the WHO Global Action [8].
The aim of this proposal is to add enteric fever as new indication for selected antibiotics included in the
Essential Medicines List. We performed systematic reviews to evaluate the safety and efficacy of antibiotics
that are recommended in national and international enteric fever treatment guidelines following the
process outlined in the Guideline Development Handbook [9]. We believe that special attention
should be paid to the impact of drug resistance on treatment, and the impact of sub-optimal treatment on
individuals and on secondary transmission in the community.
This review was based on the syndrome-based approach that McMaster University performed for the 2017
EML update. It needs to be noted that the patterns of antimicrobial susceptibilities can differ from place to
place and over time, and that knowledge about local resistance patterns is necessary to inform empiric
treatment. Surveillance and sharing of antimicrobial resistance data is critical in order to combat resistance
and to inform the correct choice of antibiotic treatment [8].
General considerations regarding enteric fever trials
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 [6, 10]. In low and middle income countries (LMICs), blood culture facilities are often not
available. There are no rapid tests with acceptable sensitivity and specificity [4, 6]. Treatment is usually
empirical.
The Cochrane Collaboration performed several systematic reviews evaluating the efficacy and safety of
fluoroquinolnes and azithromycin for the treatment of enteric fever [11, 12]. An issue that was
consistently highlighted were the small sample sizes of randomised controlled trials (RCTs) and the lack of
standardised outcome definitions, which made pooling of data in a meta-analysis difficult [13]. Earlier trails
did not perform intention-to-treat analysis (ITT), but only reported the results for blood culture positive
patients. All RCTs of antibiotics were conducted in patients with uncomplicated enteric fever. The majority
of trials include typhoid fever patients only, since the proportion of S. Paratyphi A strains in Asia has
increased only relatively recently. Typhoid and paratyphoid fever are clinically indistinguishable [14], there
is no evidence of a different impact of treatment between the serovars and treatment recommendations
4
apply to both. We will use enteric fever as the more comprehensive term.
Synopsis of evidence from Systematic Reviews
Methods
Data searches for systematic reviews and meta-analyses of randomised controlled trials in
enteric fever
We developed a comprehensive search syntax, combining systematic reviews, meta-analysis with
randomised controlled trials AND enteric fever/typhoid fever/paratyphoid fever. We performed a
systematic search in MEDLINE, Embase and the Cochrane Database of Systematic Reviews (Appendix Table
1 and Figure 1) from January 1990 to January 2018. We identified 218 articles. Two researchers (CD, SK)
independently screened titles, abstracts and full texts. Screening at title and abstract level excluded 193
references, 25 full text articles were accessed for eligibility. We excluded 13 articles and reviewed 12
systematic reviews (SR). One SR was a duplication [15], two full texts could not be retrieved [16, 17], one
article was a published protocol [18], one was an older review on chloramphenicol in infectious diseases
[19], two references pertained to a Cochrane SR, that had been withdrawn [20, 21] and three were SR on
fluoroquinolones for the treatment of enteric fever by the Cochrane Collaboration or their authors [13, 22,
23], which were superseded by the most recent version [11]. We retained two Cochrane SR for final
assessment, one on FQ for the treatment of enteric fever [11] and one on azithromycin [24].
Quality assessment of outcomes reported in Systematic Reviews and Meta-analyses
We evaluated the quality of evidence for the following outcomes: clinical failure, fever clearance time
(FCT), microbiological failure, relapse, serious adverse events and non-serious adverse events according to
the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) criteria, as outlined
in the WHO Handbook for Guideline Development [9]. We adopted the approach used for the
Recommendations for Management of Common Childhood Conditions [25] in our assessment. Two
researchers independently evaluated limitations of the study (in terms of study design, allocation,
concealment, blinding and loss to follow-up), precision of results, consistency, generalizability and
5
reporting bias. Appendix Table 2 shows a detailed description of the GRADE assessment.
Results
Effa 2011
The Cochrane SR on fluoroquinolones for treating typhoid and paratyphoid fever included 26 trails,
involving 3033 patients [11]. The 2011 update does not include comparisons with antibiotics that are no
longer recommended for use in enteric fever (e.g. norfloxacin due to its poor bioavailability).
An important consideration for efficacy is antibiotic resistance; an earlier version of this Cochrane SR
combined different generations of fluoroquinolones in one subgroup, stratified according to the prevalence
of MDR and nalidixic resistant (NaR) strains [13]. However, the most recent SR 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.
Outcomes: Fluoroquinolones versus first-line drugs
Ciprofloxacin versus chloramphenicol
Four trials (Gottuzzo 1992, Morelli 1992, Gasem 2003, Rizvi 2009*; 293 patients) compared ciprofloxacin to
chloramphenicol, only one trial included children above 12 years (Rizvi, 2009), none of the trials reported
the prevalence of MDR and NaR strains.
For clinical failure (4 trials, 293 patients) the results favoured ciprofloxacin (RR 0.24; 95% CI 0.07 to 0.82),
confidence intervals were wide, due to the small sample size (low quality evidence). Appendix Table 3
shows the GRADE outcome assessment.
Fever clearance time (FCT) (2 trials; 147 patients) also favoured ciprofloxacin, the mean difference (MD)
was -62.46 hours (95% CI, -75.52 to -49.39) (moderate quality).
Small numbers of events occurred for microbiological failure (two trials, 142 patients; RR 0.05; 0.00 to 0.81)
(low quality evidence) and relapse (4 trials, RR 0.15; 0.02 to 1.15) (low quality evidence).
The results for serious adverse events (2 trials) were indeterminate (RR 0.99; 0.18 to 5.52) (very low quality
6
evidence) and for non-serious adverse events (4 trials), the results were comparable (RR 1.00; 0.61-1.64),
but with wide confidence intervals (low quality evidence).
Ofloxacin versus chloramphenicol
Four trials (Morelli 1992, Yousaf 1992, Phongmany 2005, Rizvi 2007*; 247 patients) compared ofloxacin to
chloramphenicol.
The results for clinical failure (4 trials) were in favour of ofloxacin, but with wide confidence intervals (RR
0.15; 0.03 to 0.64) (low quality evidence). Fever clearance time (2 trials, 140 patients) followed the same
trends as clinical failures, the MD was -75.85 hours (-88.52 to -63.17) (moderate quality evidence).
Due to the small numbers of events, the results for microbiological failure (3 trials, RR 0.16; 0.02 to 1.07)
(low quality evidence) and relapse (RR 0.14; 0.01 to 2.65) (low quality evidence) were indeterminate.
For serious adverse events (1 trial), the RR was not estimable due to zero events. For non-serious adverse
event (4 trials), the results were comparable with a RR of 1.06, with wide confidence intervals (0.60 to
1.87) (low quality).
*Rizvi performed a multi-arm study and compared ofloxacin, ciprofloxacin, chloramphenicol, cefixime and
cotrimoxazole. None of the studies reported resistance.
The SR includes one trial (252 patients), that compared gatifloxacin, which is not part of this application,
versus chloramphenicol (RR for clinical failure was 0.79; 0.32 to 1.96) [10]. Non-serious adverse events
favoured gatifloxacin (0.58; 0.44 to 0.78).
Ciprofloxacin/ofloxacin versus cotrimoxazole and ampicillin/amoxicillin
We also tabulated the results (Appendix Table 3. GRADE outcome assessment) for the comparisons of
ciprofloxacin versus cotrimoxazole (2 trials, 132 patients), ofloxacin versus cotrimoxazole (1 trial, 99
patients), ofloxacin versus ampicillin (1 trial, 40 patients), ofloxacin versus amoxicillin (1 trial, 50 patients),
however, due to the small sample sizes the results were indeterminate and the individual outcomes were
accessed as low or very low quality. We therefore did not add cotrimoxazole and ampicillin/amoxicillin to
the list.
7
Ciprofloxacin/ofloxacin versus third-generation cephalosporines
Ciprofloxacin/ofloxacin versus cefixime
The comparisons of ciprofloxacin versus cefixime and ofloxacin versus cefixime were each based on one
trial (Rizvi, 2007, Phuong, 1999). Due to the weakness and low/very low quality of the evidence, cefixime
was not included here (Appendix Table 3. GRADE outcome assessment).
A RCT that compared the fourth generation fluoroquinolone gatifloxacin, which is not part of the EML,
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; 0.01 to 0.31) (p<0.001) [26]. This
trial is included in the SR [11], but does not constitute part of the comparisons evaluated for inclusion in
the EML list, due to the gatifloxacin arm.
Ciprofloxacin versus ceftriaxone
For this comparison, there was only one trial available (Wallace 1993; 42 participants, adults only). 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
One trial was available (Smith, 1994; 47 participants, adults only), More than 50% of strains were MDR, no
NaR was reported. For clinical failure, they reported a non-significant result in favour of ofloxacin, (RR was
0.09, 0.01 to 1.46), the mean difference in FCT was -115 hours (-150.67 to -79.33).
Ciprofloxacin/ofloxacin versus azithromycin
Ciprofloxacin versus azithromycin
Only one trial (Girgis 1999, Egypt, 64 participants) was available for this comparison. 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 (-24.39 to 0.39). The quality of the evidence was low/very low.
8
Ofloxacin versus azithromycin
Two trials were available (Chinh 2000; Parry 2007; 213 patients). Clinical failure favoured azithromycin with
a RR of 2.2 (1.23 to 3.94) (high quality of evidence), the MD in FCT of 30.41 hours (-22.12 to 82.93)
(moderate quality) supports azithromycin (Appendix Table 3. GRADE outcome assessment).
The higher failure rates in the ofloxacin arm in the more recent trial (Parry, 2007), reflected the increasing
prevalence of NaR S. Typhi isolates in this region.
The SR includes one azithromycin trial (287 patients), that compared gatifloxacin to azithromycin [27].
Whilst gatifloxacin is not part of this application, gatifloxacin and azithromycin had similar high efficacy (RR
for clinical failure 0.98 (0.32 to 2.96)) in this setting with high proportions of NaR S. Typhi strains.
Effa 2008
The Cochrane SR on azithromycin for treating uncomplicated typhoid and paratyphoid fever included 7
trials and 773 patients [12].
The comparison azithromycin versus chloramphenicol (Butler 1999; 77 patients) showed a benefit for
azithromycin, but due to the small sample size and wide confidence intervals no inferences can be made
(OR for clinical failure, 0.16 (0.01 to 3.4) (low quality evidence). Four trials (564 patients) compared
azithromycin to the fluoroquinolones (this included gatifloxacin) and were discussed above.
Two trials (Frenck 2000, Frenck 2004; 132 patients) compared azithromycin versus ceftriaxone. Clinical
failure (OR 2.58; 0.48 to 13.87) and FCT (MD 9.12 h; -1.11 to 19.36) favoured ceftriaxone (moderate quality
evidence). No data were available to assess adverse events.
Synopsis of evidence from Randomised Controlled Trials
Methods
Search strategy for randomised controlled enteric fever trials
We performed systematic searches for enteric fever RCTs to supplement the evidence obtained from the
SR. We searched PubMed from 1990 to October 2018 for all randomised controlled trials for the treatment
9
of enteric fever, including the two MeSH terms “Typhoid Fever” or “Paratyphoid Fever”, with typhoid,
paratyphoid, “enteric fever” or “enteric fevers” as text words.
Two investigators independently screened the identified 341 articles, and retained 44 enteric fever
treatment trials (Appendix Figure 2. Flowchart of additional randomised controlled trials). We removed
duplicate articles that were included in the SR and reports of antibiotics that were no longer in clinical use,
ultimately retaining 12 RCTs for review. Two researchers independently abstracted the trial data (Appendix
Table 7. Characteristics and outcomes of additional randomised controlled trials).
Quality assessment of randomised controlled trials
We used the Cochrane risk of bias assessment tool to assess the quality of the 12 RCTs. Appendix Table 6.
Quality assessment of randomised controlled trials.
Results
In keeping with previous SR results, the majority of RCTs had small sample sizes, few events and had a lack
of power to detect significant differences (Appendix Table 7. Characteristics and outcomes of additional
randomised controlled trials). We selected four trials with a sample size of more than 30 patients in each
arm for further review. Two of those had zero events for clinical failure (Tatli 2003, 72 patients and Girgis
1995, 93 patients). A larger 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 [28]. Similar proportions of patients experienced adverse events, most of which were mild (grade
1 or grade 2).
One larger, more recent trial (116 culture positive patients) compared gatifloxacon versus ceftriaxone;
there were similar number of failures in the ITT patients, but in the culture confirmed patients, the
comparison favoured ceftriaxone (HR 0·24; 95% CI 0·08 to 0·73) [29]. 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.
10
Synopsis of guidelines
Methods
Search strategy for Clinical Practice Guidelines
We performed a systematic review of Clinical Practice Guidelines (CPGs). The search strategy is listed in
Appendix Table 8, publication dates were restricted from January 1990 to January 2019. Two investigators
independently screened 321 articles. The Flow Chart is shown in Appendix Figure 3. We retained nine
articles for full-text review and of those four for evaluation.
Quality assessment of Clinical Practice Guidelines
We used the AGREE (Appraisal of Guidelines, Research and Evaluation) II instrument to appraise the quality
of CPGs [30]. Amongst other items, the CPG needed to contain an explicit methods section, which included
the search strategy, state how decisions were made and potential conflicts of interest. Two researchers
independently assessed the quality of the selected guidelines using the AGREE II score sheet. We evaluated
the following five domains: scope and purpose, stakeholder involvement, rigor of development, clarity of
presentation, editorial independence. Individual quality scores of the domain were added up and scaled as
percentage of the maximum attainable score of the domain. We calculated mean percentages for each
domain and these were used to arrive at an overall percentage score for the guideline.
Results
We evaluated four CPGs, but removed two due to low scores [31, 32]. The highest scoring CPG (88%) was
the WHO Recommendations for Management of Common Childhood Conditions: Pocket Book
Recommendations [25]. The WHO Background document: The diagnosis, treatment and prevention of
typhoid fever, was published in 2003 and did not conform to the more formalised structure of
contemporary guideline development (56%).
The recommendations of both guidelines are shown in Appendix Table 10.
11
Selection of antibiotics
Please note that knowing the local resistance pattern for S. Typhi and S. Paratyphi strains is critical for
making empiric choices.
Although listed in an earlier CPG (WHO Guidelines), ampicillin/amoxicillin and trimethoprim-
sulfamethoxazole were not included due to the lack of data showing any benefit over comparators
(evidence from SR).
Chloramphenicol is recommended in the WHO treatment guidelines [6], but not in the pocket handbook
[25]. 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 adverse events (grade 1 and 2).
Due to the necessity to monitor blood counts, the long treatment duration, and the availability of
alternative drugs, chloramphenicol is not listed for inclusion in the EML.
We are listing ofloxacin and ciprofloxacin supported by evidence from SR and CPG. More clinical trials
evaluating ofloxacin have been performed, however, ofloxacin is not included in the EML. We therefore list
ciprofloxacin, which has similar clinical performance.
Although included in the WHO guidelines [6], the evidence from the SR does not support listing cefixime. In
comparisons with fluoroquinolones, cefixime, showed higher number of failures and longer FCTs, however,
in comparisons with chloramphenicol, it compared favourably.
We are listing ceftriaxone and azithromycin supported from evidence from SR and CPG.
12
Review of Antibacterial Medicines for the Treatment of Enteric Fever for the WHO Model List of Essential Medicines 2019 Update
EVIDENCE FROM
CPG-
CPG-WHO WHO
Treatment Pocket
Antibiotic Adults Children additional Guideines book EML Comments
SR RCTs 2003 2012
Ampicillin/ not selected for
^ 
Amoxycillin  EML
Trimethoprim not selected for
^ 
/sulfamethoxazole EML
not selected for
Chloramphenicol   see comments in the text
 EML
oral, divided into two daily
Ciprofloxacin 20 mg/kg/day     doses primary indication

20-30 mg/kg/day 
oral, divided into two daily
doses
Ofloxacin 20 mg/kg/day 20 mg/kg/day      NOT IN EML, CIPROFLOXACIN HAS primary indication
SIMILAR CLINICAL PERFORMANCE
WITHIN THE PHARMACOLOGICAL
CLASS.
not selected for
Cefixime ^ 
 EML
Azithromycin 20 mg/kg/day 20 mg/kg/day     oral, once daily dose primary indication
Ceftriaxone 2g 65-80 mg/kg/day      intravenous, once daily dose
Treatment duration is 7 days
^Limited evidence in favour of antibiotics.
13
FDA warning
Both fluoroquinolones and azithromycin have black box warnings by the FDA. In 2016, the FDA enhanced
warnings about the association of fluoroquinolones with disabling and potentially permanent side effects
involving tendons, muscles, joints, nerves and the central nervous system. Because the risk of these serious
side effects generally outweighs the benefits for patients with acute bacterial sinusitis, acute bacterial
exacerbation of chronic bronchitis and uncomplicated urinary tract infections, the FDA determined that
fluoroquinolones should be reserved for use in patients with these conditions who have no alternative
treatment options. The U.S. Food and Drug Administration (FDA) is warning the public that azithromycin
(Zithromax or Zmax) can cause abnormal changes in the electrical activity of the heart that may lead to a
potentially fatal irregular heart rhythm. Patients at particular risk for developing this condition include
those with known risk factors such as existing QT interval prolongation, low blood levels of potassium or
magnesium, a slower than normal heart rate, or use of certain drugs used to treat abnormal heart rhythms,
or arrhythmias. This communication is a result of our review of a study by medical researchers as well as
another study by a manufacturer of the drug that assessed the potential for azithromycin to cause
abnormal changes in the electrical activity of the heart.
14
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Article · February 2019

Christiane Dolecek Sunil Pokharel

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Medicines 2019 Update

Essential Medicine List Application for Special Indication..................................2

Typhoid and Paratyphoid Fever .................................................................................2

Scope of work .....................................................................................................................3

Background to this application ............................................................................................... 3

General considerations regarding enteric fever trials ................................................... 4

Synopsis of evidence from Systematic Reviews................................................................. 5

Synopsis of evidence from Randomised Controlled Trials ............................................ 9

Synopsis of guidelines ...............................................................................................................11

Selection of antibiotics .............................................................................................................11

FDA warning .............................................................................................................................14

Medicines 2019 Update

Essential Medicine List Application for Special Indication:

Typhoid and Paratyphoid Fever

Outreach Librarian at Bodleian Health Care Libraries, University of Oxford, UK.

Medicines 2019 Update

resistance against chloramphenicol, ampicillin and trimethoprim/sulfamethoxazole) and to fluoroquinolone

clearly now outdated particularly in an era of widespread drug resistance [6].

and effective in endemic countries [7].

Background to this application

Medicines 2019 Update

individuals and on secondary transmission in the community.

and to inform the correct choice of antibiotic treatment [8].

General considerations regarding enteric fever trials

Medicines 2019 Update

Synopsis of evidence from Systematic Reviews

We developed a comprehensive search syntax, combining systematic reviews, meta-analysis with

randomised controlled trials AND enteric fever/typhoid fever/paratyphoid fever. We performed a

Quality assessment of outcomes reported in Systematic Reviews and Meta-analyses

Medicines 2019 Update

mean difference (MD; 95% CI) for continuous data.

Outcomes: Fluoroquinolones versus first-line drugs

Ciprofloxacin versus chloramphenicol

the prevalence of MDR and NaR strains.

shows the GRADE outcome assessment.

was -62.46 hours (95% CI, -75.52 to -49.39) (moderate quality).

Medicines 2019 Update

but with wide confidence intervals (low quality evidence).

Ofloxacin versus chloramphenicol

1.87) (low quality).

cotrimoxazole. None of the studies reported resistance.

favoured gatifloxacin (0.58; 0.44 to 0.78).

Ciprofloxacin/ofloxacin versus cotrimoxazole and ampicillin/amoxicillin

Medicines 2019 Update

Ciprofloxacin/ofloxacin versus third-generation cephalosporines

Ciprofloxacin/ofloxacin versus cefixime

was not included here (Appendix Table 3. GRADE outcome assessment).

the EML list, due to the gatifloxacin arm.

Ciprofloxacin versus ceftriaxone

strains were MDR.

Ofloxacin versus ceftriaxone

Ciprofloxacin/ofloxacin versus azithromycin

Ciprofloxacin versus azithromycin

Medicines 2019 Update

Ofloxacin versus azithromycin

(moderate quality) supports azithromycin (Appendix Table 3. GRADE outcome assessment).

prevalence of NaR S. Typhi isolates in this region.