medRxiv. 2023 Jul 12:2023.07.10.23292374. doi: 10.1101/2023.07.10.23292374. Preprint.
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 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.
SIGNIFICANCE STATEMENT: Antimicrobial resistance is a threat to human health. Antibiotic combinations potentially reduce resistance. However, conflicting data exists on its effectiveness. To test the effect of antibiotic combination therapy on resistance, we conducted a meta-analysis of clinical evidence, comparing higher and lower numbers of antibiotics across various bacterial infections and antibiotic combinations. We update and expand on previous work that focused on specific infections and antibiotic combinations. Overall, we found no statistical evidence for a difference in the risk of resistance acquisition due to lack of power. Thus, despite the increasing threat of antibiotic resistance, it remains unresolved whether combination therapy de- or accelerates resistance evolution of bacterial pathogens beyond the well-known conditions where combination therapy is the standard of care.