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Meta-Analysis
. 2014 Jun 19;2014(6):CD008625.
doi: 10.1002/14651858.CD008625.pub2.

Antimicrobial drugs for treating cholera

Affiliations
Meta-Analysis

Antimicrobial drugs for treating cholera

Ya'ara Leibovici-Weissman et al. Cochrane Database Syst Rev. .

Abstract

Background: Cholera is an acute watery diarrhoea caused by infection with the bacterium Vibrio cholerae, which if severe can cause rapid dehydration and death. Effective management requires early diagnosis and rehydration using oral rehydration salts or intravenous fluids. In this review, we evaluate the additional benefits of treating cholera with antimicrobial drugs.

Objectives: To quantify the benefit of antimicrobial treatment for patients with cholera, and determine whether there are differences between classes of antimicrobials or dosing schedules.

Search methods: We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; African Index Medicus; LILACS; Science Citation Index; metaRegister of Controlled Trials; WHO International Clinical Trials Registry Platform; conference proceedings; and reference lists to March 2014.

Selection criteria: Randomized and quasi-randomized controlled clinical trials in adults and children with cholera that compared: 1) any antimicrobial treatment with placebo or no treatment; 2) different antimicrobials head-to-head; or 3) different dosing schedules or different durations of treatment with the same antimicrobial.

Data collection and analysis: Two reviewers independently applied inclusion and exclusion criteria, and extracted data from included trials. Diarrhoea duration and stool volume were defined as primary outcomes. We calculated mean difference (MD) or ratio of means (ROM) for continuous outcomes, with 95% confidence intervals (CI), and pooled data using a random-effects meta-analysis. The quality of evidence was assessed using the GRADE approach.

Main results: Thirty-nine trials were included in this review with 4623 participants. Antimicrobials versus placebo or no treatment Overall, antimicrobial therapy shortened the mean duration of diarrhoea by about a day and a half compared to placebo or no treatment (MD -36.77 hours, 95% CI -43.51 to -30.03, 19 trials, 1013 participants, moderate quality evidence). Antimicrobial therapy also reduced the total stool volume by 50% (ROM 0.5, 95% CI 0.45 to 0.56, 18 trials, 1042 participants, moderate quality evidence) and reduced the amount of rehydration fluids required by 40% (ROM 0.60, 95% CI 0.53 to 0.68, 11 trials, 1201 participants, moderate quality evidence). The mean duration of fecal excretion of vibrios was reduced by almost three days (MD 2.74 days, 95% CI -3.07 to -2.40, 12 trials, 740 participants, moderate quality evidence).There was substantial heterogeneity in the size of these benefits, probably due to differences in the antibiotic used, the trial methods (particularly effective randomization), and the timing of outcome assessment. The benefits of antibiotics were seen both in trials recruiting only patients with severe dehydration and in those recruiting patients with mixed levels of dehydration. Comparisons of antimicrobials In head-to-head comparisons, there were no differences detected in diarrhoea duration or stool volume for tetracycline compared to doxycycline (three trials, 230 participants, very low quality evidence); or tetracycline compared to ciprofloxacin or norfloxacin (three trials, 259 participants, moderate quality evidence). In indirect comparisons with substantially more trials, tetracycline appeared to have larger benefits than doxycycline, norfloxacin and trimethoprim-sulfamethoxazole for the primary review outcomes.Single dose azithromycin shortened the duration of diarrhoea by over a day compared to ciprofloxacin (MD -32.43, 95% CI -62.90 to -1.95, two trials, 375 participants, moderate quality evidence) and by half a day compared to erythromycin (MD -12.05, 95% CI -22.02 to -2.08, two trials, 179 participants, moderate quality evidence). It was not compared with tetracycline.

Authors' conclusions: In treating cholera, antimicrobials result in substantial improvements in clinical and microbiological outcomes, with similar effects observed in severely and non-severely ill patients. Azithromycin and tetracycline may have some advantages over other antibiotics.

PubMed Disclaimer

Conflict of interest statement

None declared. Prof. Mohammed Abdus Salam is an author of some of the trials included in our review.

Figures

1
1
An antimicrobial treatment network based on antimicrobial drug or class. This figure describes the different comparisons in all included studies which compared one antimicrobial vs another antimicrobial (comparisons vs. placebo/ no treatment not included).
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Antimicrobial versus placebo/no treatment, Outcome 1 Diarrhoea duration.
1.2
1.2. Analysis
Comparison 1 Antimicrobial versus placebo/no treatment, Outcome 2 Stool Volume.
1.3
1.3. Analysis
Comparison 1 Antimicrobial versus placebo/no treatment, Outcome 3 Deaths.
1.4
1.4. Analysis
Comparison 1 Antimicrobial versus placebo/no treatment, Outcome 4 Clinical failure.
1.5
1.5. Analysis
Comparison 1 Antimicrobial versus placebo/no treatment, Outcome 5 Hydration requirements.
1.6
1.6. Analysis
Comparison 1 Antimicrobial versus placebo/no treatment, Outcome 6 Pathogen excretion duration.
1.7
1.7. Analysis
Comparison 1 Antimicrobial versus placebo/no treatment, Outcome 7 Bacteriological failure.
2.1
2.1. Analysis
Comparison 2 Sensitivity analysis: Antimicrobial versus placebo/no treatment by allocation concealment, Outcome 1 Diarrhoea duration.
2.2
2.2. Analysis
Comparison 2 Sensitivity analysis: Antimicrobial versus placebo/no treatment by allocation concealment, Outcome 2 Stool Volume.
2.3
2.3. Analysis
Comparison 2 Sensitivity analysis: Antimicrobial versus placebo/no treatment by allocation concealment, Outcome 3 Clinical failure.
2.4
2.4. Analysis
Comparison 2 Sensitivity analysis: Antimicrobial versus placebo/no treatment by allocation concealment, Outcome 4 Hydration requirements.
2.5
2.5. Analysis
Comparison 2 Sensitivity analysis: Antimicrobial versus placebo/no treatment by allocation concealment, Outcome 5 Pathogen excretion duration.
2.6
2.6. Analysis
Comparison 2 Sensitivity analysis: Antimicrobial versus placebo/no treatment by allocation concealment, Outcome 6 Bacteriological failure.
3.1
3.1. Analysis
Comparison 3 Sensitivity analysis: Antimicrobial versus placebo/no treatment by time outcome definitions, Outcome 1 Diarrhoea duration by outcome definitions.
3.2
3.2. Analysis
Comparison 3 Sensitivity analysis: Antimicrobial versus placebo/no treatment by time outcome definitions, Outcome 2 Clinical failure at 48/72/96 hours.
3.3
3.3. Analysis
Comparison 3 Sensitivity analysis: Antimicrobial versus placebo/no treatment by time outcome definitions, Outcome 3 Bacteriological failure 48/72/96 sub totals only.
4.1
4.1. Analysis
Comparison 4 Antimicrobial versus placebo/no treatment subgrouped by severity of dehydration, Outcome 1 Diarrhoea duration.
4.2
4.2. Analysis
Comparison 4 Antimicrobial versus placebo/no treatment subgrouped by severity of dehydration, Outcome 2 Stool Volume.
4.3
4.3. Analysis
Comparison 4 Antimicrobial versus placebo/no treatment subgrouped by severity of dehydration, Outcome 3 Clinical failure.
4.4
4.4. Analysis
Comparison 4 Antimicrobial versus placebo/no treatment subgrouped by severity of dehydration, Outcome 4 Hydration requirements.
5.1
5.1. Analysis
Comparison 5 Antimicrobial vs. placebo/no treatment subgrouped by antimicrobial resistance, Outcome 1 Bacteriological failure arms with no resistance only.
6.1
6.1. Analysis
Comparison 6 Azithromycin versus ciprofloxacin, Outcome 1 Diarrhoea duration.
6.2
6.2. Analysis
Comparison 6 Azithromycin versus ciprofloxacin, Outcome 2 Stool Volume.
6.3
6.3. Analysis
Comparison 6 Azithromycin versus ciprofloxacin, Outcome 3 Hydration requirements.
6.4
6.4. Analysis
Comparison 6 Azithromycin versus ciprofloxacin, Outcome 4 Clinical failure.
6.5
6.5. Analysis
Comparison 6 Azithromycin versus ciprofloxacin, Outcome 5 Bacteriological failure.
7.1
7.1. Analysis
Comparison 7 Azithromycin versus erythromycin, Outcome 1 Diarrhoea duration.
7.2
7.2. Analysis
Comparison 7 Azithromycin versus erythromycin, Outcome 2 Stool Volume.
7.3
7.3. Analysis
Comparison 7 Azithromycin versus erythromycin, Outcome 3 Hydration requirements.
7.4
7.4. Analysis
Comparison 7 Azithromycin versus erythromycin, Outcome 4 Clinical failure.
7.5
7.5. Analysis
Comparison 7 Azithromycin versus erythromycin, Outcome 5 Bacteriological failure.
8.1
8.1. Analysis
Comparison 8 Tetracycline versus doxycycline, Outcome 1 Diarrhoea duration.
8.2
8.2. Analysis
Comparison 8 Tetracycline versus doxycycline, Outcome 2 Stool Volume.
8.3
8.3. Analysis
Comparison 8 Tetracycline versus doxycycline, Outcome 3 Deaths.
8.4
8.4. Analysis
Comparison 8 Tetracycline versus doxycycline, Outcome 4 Hydration requirements.
8.5
8.5. Analysis
Comparison 8 Tetracycline versus doxycycline, Outcome 5 Pathogen excretion duration.
8.6
8.6. Analysis
Comparison 8 Tetracycline versus doxycycline, Outcome 6 Bacteriological failure.
9.1
9.1. Analysis
Comparison 9 Tetracycline versus quinolone, Outcome 1 Diarrhoea duration.
9.2
9.2. Analysis
Comparison 9 Tetracycline versus quinolone, Outcome 2 Stool Volume.
9.3
9.3. Analysis
Comparison 9 Tetracycline versus quinolone, Outcome 3 Deaths.
9.4
9.4. Analysis
Comparison 9 Tetracycline versus quinolone, Outcome 4 Clinical failure.
9.5
9.5. Analysis
Comparison 9 Tetracycline versus quinolone, Outcome 5 Hydration requirements.
9.6
9.6. Analysis
Comparison 9 Tetracycline versus quinolone, Outcome 6 Pathogen excretion duration.
9.7
9.7. Analysis
Comparison 9 Tetracycline versus quinolone, Outcome 7 Bacteriological failure.
10.1
10.1. Analysis
Comparison 10 Tetracycline versus TMP‐SMX, Outcome 1 Diarrhoea duration.
10.2
10.2. Analysis
Comparison 10 Tetracycline versus TMP‐SMX, Outcome 2 Clinical failure.
10.3
10.3. Analysis
Comparison 10 Tetracycline versus TMP‐SMX, Outcome 3 Pathogen excretion duration.
10.4
10.4. Analysis
Comparison 10 Tetracycline versus TMP‐SMX, Outcome 4 Bacteriological failure.
11.1
11.1. Analysis
Comparison 11 Tetracycline versus chloramphenicol, Outcome 1 Diarrhoea duration.
11.2
11.2. Analysis
Comparison 11 Tetracycline versus chloramphenicol, Outcome 2 Stool Volume.
11.3
11.3. Analysis
Comparison 11 Tetracycline versus chloramphenicol, Outcome 3 Clinical failure.
11.4
11.4. Analysis
Comparison 11 Tetracycline versus chloramphenicol, Outcome 4 Hydration requirements.
11.5
11.5. Analysis
Comparison 11 Tetracycline versus chloramphenicol, Outcome 5 Pathogen excretion duration.
12.1
12.1. Analysis
Comparison 12 Tetracycline versus furazolidone, Outcome 1 Diarrhoea duration.
12.2
12.2. Analysis
Comparison 12 Tetracycline versus furazolidone, Outcome 2 Stool Volume.
12.3
12.3. Analysis
Comparison 12 Tetracycline versus furazolidone, Outcome 3 Deaths.
12.4
12.4. Analysis
Comparison 12 Tetracycline versus furazolidone, Outcome 4 Clinical failure.
12.5
12.5. Analysis
Comparison 12 Tetracycline versus furazolidone, Outcome 5 Hydration requirements.
12.6
12.6. Analysis
Comparison 12 Tetracycline versus furazolidone, Outcome 6 Pathogen excretion duration.
12.7
12.7. Analysis
Comparison 12 Tetracycline versus furazolidone, Outcome 7 Bacteriological failure.
13.1
13.1. Analysis
Comparison 13 Doxycycline versus quinolones, Outcome 1 Diarrhoea duration.
13.2
13.2. Analysis
Comparison 13 Doxycycline versus quinolones, Outcome 2 Stool Volume.
13.3
13.3. Analysis
Comparison 13 Doxycycline versus quinolones, Outcome 3 Deaths.
13.4
13.4. Analysis
Comparison 13 Doxycycline versus quinolones, Outcome 4 Hydration requirements.
13.5
13.5. Analysis
Comparison 13 Doxycycline versus quinolones, Outcome 5 Bacteriological failure.
14.1
14.1. Analysis
Comparison 14 TMP‐SMX versus erythromycin, Outcome 1 Diarrhoea duration.
14.2
14.2. Analysis
Comparison 14 TMP‐SMX versus erythromycin, Outcome 2 Clinical failure.
14.3
14.3. Analysis
Comparison 14 TMP‐SMX versus erythromycin, Outcome 3 Bacteriological failure.
15.1
15.1. Analysis
Comparison 15 Short versus long duration of treatment, Outcome 1 Diarrhoea duration.
15.2
15.2. Analysis
Comparison 15 Short versus long duration of treatment, Outcome 2 Stool Volume.
15.3
15.3. Analysis
Comparison 15 Short versus long duration of treatment, Outcome 3 Hydration requirements.
15.4
15.4. Analysis
Comparison 15 Short versus long duration of treatment, Outcome 4 Pathogen excretion duration.
15.5
15.5. Analysis
Comparison 15 Short versus long duration of treatment, Outcome 5 Clinical failure.
15.6
15.6. Analysis
Comparison 15 Short versus long duration of treatment, Outcome 6 Bacteriological failure.

Update of

  • doi: 10.1002/14651858.CD008625

References

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Cash 1973 {published data only}
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References to studies awaiting assessment

References to ongoing studies

Khan_Ongoing {unpublished data only}
    1. Randomized, Double Blind, Controlled Clinical Trial to Evaluate the Efficacy of Multiple‐Dose Ciprofloxacin With Single Dose Azithromycin Therapy for Adults With Cholera Due to Multiply Resistant Strains of V. Cholerae O1 or O13. Ongoing study July 2007.
Saha_Ongoing {unpublished data only}
    1. Randomized, Open, Parallel Group Clinical Trial to Compare the Efficacy and Safety of a Single Dose of Ciprofloxacin Oral Suspension 20 Mg/Kg With a 3‐Day Course of Erythromycin Oral Suspension Administered in a Dose of 12.5 Mg/Kg Every 6 Hours (12 Doses) in the Treatment of Children,With Clinically Severe Cholera Due to V. cholerae O1 or O139.. Ongoing study May 2001.
Saha_Ongoing_B {unpublished data only}
    1. Randomized, Double‐Blind, Controlled Clinical Trial to Compare Efficacy of a Single Dose of Azithromycin Versus a Single Dose of Ciprofloxacin in the Treatment of Adults With Clinically Severe Cholera Due to V. cholerae O1 or O139. Ongoing study December 2002.

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