Addition of macrolide antibiotics for hospital treatment of community-acquired pneumonia

Background Current guidelines recommend combining a macrolide with a β-lactam antibiotic for the empirical treatment of moderate-to-high severity community-acquired pneumonia (CAP); however macrolide use is associated with potential adverse events and antimicrobial resistance. Methods We analysed electronic health data from 8,872 adults in Oxfordshire, UK, hospitalised with CAP between 01-January-2016 and 19-March-2024, who received either amoxicillin or co-amoxiclav as initial treatment. We examined the effects of adjunctive macrolides on 30-day all-cause mortality, time to hospital discharge, and changes in Sequential Organ Failure Assessment (SOFA) score, using inverse probability treatment weighting to address confounding by baseline severity. Subgroup analyses by severity and sensitivity analyses with missing covariates imputed were performed. Results There was no evidence of an association between the use of additional macrolides and 30-day mortality, with marginal odds ratios of 1.05 (95%CI 0.75-1.47) for amoxicillin with vs. without macrolide, and 1.12 (0.93-1.34) for co-amoxiclav with vs. without macrolide. No evidence of difference was found in time to discharge from additional macrolides to amoxicillin (restricted mean days lost +1.76 [-1.66,+5.19]), or co-amoxiclav (+0.44 [-1.63,+2.51]). There was also no evidence that macrolide use was associated with SOFA score decreases. Results were consistent across stratified analyses by pneumonia severity, and remained broadly similar in sensitivity analyses with missing data imputed. Conclusions At a population level, the addition of macrolides was not associated with improved clinical outcomes for CAP patients. The potential advantages of combining macrolides with a β-lactam antibiotic in CAP treatment should be balanced against the risks of adverse effects and antimicrobial resistance.