Research in context
Evidence before this study
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 2000, to Sept 30, 2018, using the search strategy described in the appendix (p 1). No language restrictions were applied. Searches were supplemented with review of reference lists and by reviewing previous meta-analyses and guidelines. Clearly ineligible studies were excluded based on abstract review alone.
We identified 234 unique references, of which three randomised controlled trials compared long-term treatment with macrolide antibiotics (>3 months duration) versus placebo and had reduction of exacerbations as the primary outcome. We identified several existing aggregate meta-analyses that suggested that macrolides reduce the frequency of exacerbations of bronchiectasis. Neither the individual trials nor the existing meta-analyses reported on the effectiveness of macrolides in different subpopulations. Identifying which patients benefit from macrolides was identified as a key research priority in bronchiectasis. The current European Respiratory Society guidelines suggest consideration of macrolides for patients without Pseudomonas aeruginosa infection with a history of at least three exacerbations in the previous year.
Added value of this study
We report the first individual patient data meta-analysis of long-term macrolide therapy in bronchiectasis. Our data, from 341 patients enrolled in randomised clinical trials in the Netherlands, New Zealand, and Australia, suggest that macrolide treatment for 6–12 months results in a reduction in the frequency of exacerbations compared with placebo (adjusted incidence rate ratio 0·49, 95% CI 0·36–0·66). Additional benefits included prolongation of the time to first exacerbation and significant improvements in quality of life measured by the St George's Respiratory Questionnaire. Lung function was not significantly improved. Analyses in prespecified subgroups, including age, sex, disease severity, and baseline microbiology, suggested that macrolides effectively reduced exacerbations across all subgroups of patients. Importantly, macrolides had a significant and clinically meaningful impact in patients in whom macrolides are not currently considered as first-line treatment, including those with P aeruginosa infection and patients with fewer than three exacerbations per year.
Implications of all the available evidence
Our data suggest that macrolide therapy is highly effective in reducing the frequency of exacerbations in bronchiectasis. Given the strong evidence that exacerbations contribute to long-term morbidity and mortality in bronchiectasis, macrolides should be considered in patients with frequent or severe exacerbations. Current bronchiectasis guidelines recommend inhaled antibiotics as first-line treatment for patients with P aeruginosa infection and frequent exacerbations. In view of the high level of effectiveness of macrolides in reducing exacerbations in the subgroup with P aeruginosa infection, and of equivocal data on the effectiveness of inhaled antibiotics, macrolides could be considered as first-line therapy for patients with P aeruginosa infection. The magnitude of benefit was similar in patients with one or two exacerbations per year and in those with three exacerbations per year, in whom macrolides are recommended by international guidelines; this finding suggests an individualised discussion of the risks and benefits of macrolides should be had. Macrolides have important adverse events and the potential to induce antimicrobial resistance, so should be used judiciously. No studies were identified with a treatment duration of more than 1 year and so the longer-term efficacy and safety of macrolides is unknown.