The effect of combining antibiotics on resistance: A systematic review and meta-analysis

Author:

Siedentop Berit12ORCID,Kachalov Viacheslav N23ORCID,Witzany Christopher1ORCID,Egger Matthias456ORCID,Kouyos Roger D23ORCID,Bonhoeffer Sebastian1ORCID

Affiliation:

1. Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zürich

2. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich

3. Institute of Medical Virology, University of Zurich

4. Institute of Social and Preventive Medicine (ISPM), University of Bern

5. Population Health Sciences, University of Bristol

6. Centre for Infectious Disease Epidemiology and Research, Faculty of Health Sciences, University of Cape Town

Abstract

When and under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.We searched CENTRAL, EMBASE and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to November 24 th , 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. A patient was considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.42 trials were eligible and 29, including 5054 patients, were qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio (OR) for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68-2.25), with substantial between-study heterogeneity ( I 2 =77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall, is compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.

Publisher

eLife Sciences Publications, Ltd

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