Effect of Long-term, Low-Dose Erythromycin on Pulmonary Exacerbations Among Patients With Non-Cystic Fibrosis Bronchiectasis The BLESS Randomized Controlled Trial

Importance Macrolide antibiotics such as erythromycin may improve clinical outcomes in non-cystic fibrosis (CF) bronchiectasis, although associated risks of macrolide resistance are poorly defined. Objective To evaluate the clinical efficacy and antimicrobial resistance cost of low-dose erythromycin given for 12 months to patients with non-CF bronchiectasis with a history of frequent pulmonary exacerbations. Design, Setting, and Participants Twelve-month, randomized (1: 1), double-blind, placebo-controlled trial of erythromycin in currently nonsmoking, adult patients with non-CF bronchiectasis with a history of 2 or more infective exacerbations in the preceding year. This Australian study was undertaken between October 2008 and December 2011 in a university teaching hospital, with participants also recruited via respiratory physicians at other centers and from public radio advertisements. Interventions Twice-daily erythromycin ethylsuccinate (400mg) or matching placebo. Main Outcome Measures The primary outcome was the annualized mean rate of protocol-defined pulmonary exacerbations (PDPEs) per patient. Secondary outcomes included macrolide resistance in commensal oropharyngeal streptococci and lung function. Results Six-hundred seventy-nine patients were screened, 117 were randomized (58 placebo, 59 erythromycin), and 107 (91.5%) completed the study. Erythromycin significantly reduced PDPEs both overall (mean, 1.29[95% CI, 0.93-1.65] vs 1.97[95% CI, 1.45-2.48] per patient per year; incidence rate ratio [IRR], 0.57 [95% CI, 0.42-0.77]; P=. 003), and in the prespecified subgroup with baseline Pseudomonas aeruginosa airway infection (mean difference, 1.32[95% CI, 0.19-2.46]; P=. 02). Erythromycin reduced 24-hour sputum production (median difference, 4.3 g [interquartile range [IQR], 1 to 7.8], P=. 01) and attenuated lung function decline(mean absolute difference for change in postbronchodilator forced expiratory volume in the first second of expiration, 2.2 percent predicted [95% CI, 0.1% to 4.3%]; P=.04) compared with placebo. Erythromycin increased the proportion of macrolide-resistant oropharyngeal streptococci (median change, 27.7% [IQR, 0.04% to 41.1%] vs 0.04% [IQR, -1.6% to 1.5%]; difference, 25.5% [IQR, 15.0% to 33.7%]; P<.001). Conclusion and Relevance Among patients with non-CF bronchiectasis, the 12-month use of erythromycin compared with placebo resulted in a modest decrease in the rate of pulmonary exacerbations and an increased rate of macrolide resistance. Trial Registration anzctr.org.au Identifier: ACTRN12609000578202 JAMA. 2013; 309(12): 1260-1267 www.jama.com