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 (400 mg) 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