Prophylactic azithromycin for chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized clinical trials

Introduction According to the WHO, chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide due to acute exacerbations (AECOPD). Prophylactic azithromycin has been suggested as a preventive therapy; therefore, this study aims to find the optimal dose for the best clinical outcomes.Theory Azithromycin exerts antimicrobial, anti-inflammatory, and immunomodulatory effects that may reduce AECOPD risk.Methods We systematically searched the Cochrane Central Register of Controlled Trials, PubMed, Scopus, Web of Science, and ClinicalTrials.gov. Randomised controlled trials comparing prophylactic azithromycin with placebo/standard care were included according to the provided PICO framework. The outcomes were defined based on the GOLD Guidelines. Risk of bias was assessed using ROB 2 and certainty of evidence using GRADE.Results Six trials (n = 1,673) were included. Azithromycin significantly reduced AECOPD (OR 0.60, 95% CI 0.48–0.74; p < 0.00001). The analyses showed that 250 mg and 500 mg thrice-weekly for 3 months were superior to once-daily. Hospitalisations (OR 0.57, 95% CI 0.35–0.95; p = 0.03) and serious adverse events (OR 0.77, 95% CI 0.61–0.97; p = 0.03) were reduced. At 250 mg once-daily, there was a significant risk of resistance, compared to 250/500 mg thrice-weekly (OR 0.23, 95% CI 0.06–0.78, p = 0.02). The heterogeneity varied depending on the assessed outcome (I2 = 0% to 60%); accordingly, subgroup analyses were performed. The overall ROB2 summary showed low to moderate risk in most domains. GRADE showed high certainty of evidence in reducing AECOPD events.Discussion Compared with prior studies, these findings reinforce the therapeutic potential of intermittent dosing strategies for preventing AECOPD while maintaining an acceptable safety profile. Further trials are needed to define optimal duration and long-term outcomes.