Introduction: ERS guidelines suggest long-term (LT) treatments with either macrolides or inhaled antibiotics in bronchiectasis patients who remain frequent exacerbators despite optimised management.

Methods: In view of the absence of a head-to-head comparison among these two interventions in the literature, we designed a systematic review of randomised controlled trials (RCTs) with a parallel group design testing the efficacy and safety of LT (? 6 months) inhaled antibiotics vs LT (? 6 months) macrolides or each intervention against placebo (PROSPERO CRD42023446134). A two-step meta-analysis (first pairwise, then network meta-analysis) was performed to compare the three interventions with exacerbation frequency as primary endpoint.

Results: 4 RCTs compared macrolides vs placebo, 9 inhaled antibiotics vs placebo. Both macrolides and inhaled antibiotics were superior to placebo in the pairwise comparison (IRR 0.50, 95% CI [0.36-0.68] and IRR 0.73 [0.64-0.84], respectively). The network meta-analysis model revealed that macrolides were superior to inhaled antibiotics in terms of reduction of exacerbation frequency (IRR 0.69, 95% CI [0.51-0.92]). The effect was mainly driven by azithromycin. Macrolides were also associated with a prolonged time to first exacerbation (HR 0.44, 95% CI [0.29-0.66]) and a lower prevalence of patients experiencing an exacerbation during the study period (OR 0.54, 95% CI [0.32-0.91]) compared to inhaled antibiotics.

Conclusions: Our data support the use of macrolides as first-line treatment in preference to inhaled antibiotics for frequent exacerbating patients with bronchiectasis.