Marc Bonten

Diane Harper

eLife assessment
This is a methodologically state-of-the-art systematic review and meta-analysis of studies that addressed the question of whether the administration of multiple antibiotics simultaneously prevents antibiotic resistance development in individuals. The findings are solid. Rather than providing a precise answer, the synthesis of studies eligible for analysis leads to the conclusion that "our analysis could not identify any benefit or harm of using a higher or a lower number of antibiotics regarding within-patient resistance development." This article is important as it articulates the existing knowledge gap, but also serves as an example for careful future use of the meta-analysis methodology, when existing data just don't allow conclusions.

anonymous

Reviewer #2 (Public Review):
Summary:
The authors performed a systematic review and meta-analysis to investigate whether the frequency of emergence of resistance is different if combination antibiotic therapy is used compared to fewer antibiotics. The review shows that there is currently insufficient evidence to reach a conclusion due to the limited sample size. High-quality studies evaluating appropriate antimicrobial resistance endpoints are needed.
Strengths:
The strength of the manuscript is that the article addresses a relevant research question which is often debated. The article is well-written and the methodology used is valid. The review shows that there is currently insufficient evidence to reach a conclusion due to the limited sample size. High-quality studies evaluating appropriate antimicrobial resistance endpoints are needed. I have several comments and suggestions for the manuscript.
Weaknesses:
Weaknesses of the manuscript are the large clinical and statistical heterogeneity and the lack of clear definitions of acquisition of resistance. Both these weaknesses complicate the interpretation of the study results.
Comments on latest version:
The authors adressed all the comments that were shared in the previous peer review. I still believe that both clinical and statistical heterogeneity remains a problem with the interpretation of the meta-analysis. However, as the authors state, this is in line with the original research question as formulated on Prospero.

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

Figures and data

Study selection

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