Articles
Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis

https://doi.org/10.1016/S2213-2600(19)30191-2Get rights and content

Summary

Background

Bronchiectasis guidelines recommend long-term macrolide treatment for patients with three or more exacerbations per year without Pseudomonas aeruginosa infection. Randomised controlled trials suggest that long-term macrolide treatment can prevent exacerbations in adult patients with bronchiectasis, but these individual studies have been too small to do meaningful subgroup analyses. We did a systematic review and individual patient data (IPD) meta-analysis to explore macrolide benefit in subpopulations, including those in which macrolide therapy is not currently recommended.

Methods

We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 2000, to Sept 30, 2018, to identify double blind, randomised, placebo-controlled trials of macrolide antibiotics in adult patients with bronchiectasis. We applied no language restrictions. Randomised controlled trials were eligible if treatment was defined a priori as long term and had a primary or secondary outcome of bronchiectasis exacerbations. Studies in patients with cystic fibrosis bronchiectasis were excluded. The primary outcome of the meta-analysis was frequency of exacerbations requiring treatment with antibiotics. Secondary endpoints were time to first exacerbation, change in quality of life according to the St George's Respiratory Questionnaire (SGRQ), and change in FEV1. IPD meta-analysis was done using fixed effects models adjusting for age, sex, FEV1, and trial. We did prespecified subgroup analyses for each of the primary and secondary endpoints using one-step meta-analysis only. Subgroups were defined by age, sex, previous exacerbation frequency, smoking status, inhaled corticosteroid use at baseline, body-mass index at baseline, cause, C-reactive protein at baseline, baseline FEV1 percentage of predicted, SGRQ total score, and Pseudomonas aeruginosa in sputum culture at baseline. The meta-analysis is registered with the PROSPERO international register of systematic reviews, number CRD42018102908.

Findings

Of 234 identified studies, we included three randomised controlled trials, and IPD was obtained for 341 participants. Macrolide antibiotics reduced the frequency of exacerbations (adjusted incidence rate ratio [IRR] 0·49, 95% CI 0·36 to 0·66; p<0·0001). We also found that macrolide treatment improved the time to first exacerbation (adjusted hazard ratio 0·46, 0·34 to 0·61; p<0·0001) and was associated with improved quality of life measured by the SGRQ (mean improvement 2·93 points, 0·03 to 5·83; p=0·048). Macrolides were not associated with a significant improvement in FEV1 (67 mL at 1 year, −22 to 112; p=0·14). Effect estimates in prespecified subgroup analyses revealed a reduced frequency of exacerbations in all prespecified subgroups, including a high level of benefit in patients with P aeruginosa infection (IRR 0·36, 0·18–0·72; p=0·0044) and in patients with one to two exacerbations per year (0·37, 0·16–0·88; p=0·025). Studies were rated as low risk of bias across all domains.

Interpretation

Long-term macrolide treatment significantly reduces the frequency of exacerbations in patients with bronchiectasis, with similar benefits observed in all subgroups based on patient characteristics. This finding suggests that macrolides might be considered in patients in whom macrolides are not indicated according to the current guidelines, particularly if alternative approaches to reduce exacerbations have been unsuccessful. However, downsides of long-term macrolide treatment must also be taken into account.

Funding

European Respiratory Society.

Introduction

Bronchiectasis is a common chronic disease associated with frequent respiratory tract infections, chronic symptoms of cough, and sputum production.1 The disease has a devastating impact on patients' quality of life.2 In addition, exacerbations of bronchiectasis, which are characterised by increases in symptoms requiring antibiotic treatment, are a major driver of disease progression and associated mortality.3, 4

Bronchiectasis is characterised by a vicious vortex of bacterial infection, airway inflammation, and impaired mucociliary clearance, which each interact to promote lung damage.5, 6 Few evidence-based treatments exist for bronchiectasis, as reflected in the 2017 European Respiratory Society bronchiectasis management guidelines,7 which were unable to recommend any pharmacotherapy with a high quality of evidence. Macrolide antibiotics are among the most widely used chronic treatments to prevent exacerbations in bronchiectasis.8, 9 They are particularly attractive because there is evidence that they target each of the key components of bronchiectasis pathophysiology.10, 11 In addition to reducing bacterial burden, macrolides have well established immunomodulatory effects that include suppression of neutrophil-mediated lung damage and enhancement of cilia function to promote mucociliary clearance.10, 12, 13

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.

A few randomised controlled trials14, 15, 16, 17 have shown that the macrolide class of antibiotics significantly reduce exacerbations in bronchiectasis. Meta-analyses18, 19 of these trials based on aggregate data suggest a clear reduction in the frequency of exacerbations with macrolide therapy, along with other benefits. For example, the meta-analysis by Gao and colleagues18 identified nine trials with 559 participants of which six were conducted in adults. Macrolide therapy reduced the frequency of exacerbations by 58% and the proportion of patients experiencing exacerbations, with slight improvements in FEV1 and quality of life.18 Macrolides, however, were associated with increased adverse events, such as diarrhoea and abdominal discomfort, and with an increased risk of antibiotic resistance.9, 14 Hearing loss and cardiovascular effects have been detected in other patient populations but were not observed in bronchiectasis trials.9, 20, 21 On the basis of these observations, the most recent Cochrane review called for further research to identify specific patient groups who are most responsive to macrolides.22 A 2016 consensus statement23 by the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) of the European Respiratory Society (ERS), based on a survey of over 100 bronchiectasis experts and over 1000 patients, identified “further studies to define the optimal patient population to benefit from long-term macrolide therapy” as one of the 22 key research priorities in bronchiectasis.

We therefore undertook an individual participant data (IPD) meta-analysis of studies of long-term macrolides in adults, with the objective of identifying responsive patient subgroups.

Section snippets

Search strategy and selection criteria

We did a systematic review and one-step and two-step meta-analysis of individual participant data. Double-blind, randomised, placebo-controlled trials of macrolide antibiotics in adult patients (≥18 years) with bronchiectasis were eligible for inclusion if they also had long-term treatment (defined a priori as treatment duration of at least 3 months on the basis of the previous ERS guidelines) and had frequency of exacerbations as a primary or secondary outcome.7 Studies in patients with cystic

Results

234 potentially eligible studies were identified. After exclusion of 231 manuscripts that did not meet the inclusion criteria, three double-blind, randomised, placebo-controlled trials with a total of 341 participants were included (figure 1). We sought IPD for these three trials and obtained data for all eligible participants.

These trials were done in the Netherlands, New Zealand, and Australia. Two trials compared azithromycin versus placebo,14, 16 whereas the third trial compared

Discussion

This IPD meta-analysis shows that the use of macrolides in patients with bronchiectasis reduces the frequency of exacerbations (IRR 0·49, 95% CI 0·36–0·66) over 6–12 months and is associated with a significant improvement in quality of life measured with the SGRQ score; although this improvement did not exceed the minimum clinically important difference, the proportion of patients who achieved a clinically meaningful improvement in quality of life was increased in participants in the macrolide

References (38)

  • AT Hill et al.

    Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research

    Eur Respir J

    (2017)
  • R Boaventura et al.

    Treatable traits in bronchiectasis

    Eur Respir J

    (2018)
  • E Polverino et al.

    European Respiratory Society guidelines for the management of adult bronchiectasis

    Eur Respir J

    (2017)
  • C Kelly et al.

    Macrolide antibiotics for bronchiectasis

    Cochrane Database Syst Rev

    (2018)
  • J Altenburg et al.

    Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms

    Respiration

    (2011)
  • JD Chalmers

    Macrolide resistance in Pseudomonas aeruginosa: implications for practice

    Eur Respir J

    (2017)
  • AB Chang et al.

    Randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in Indigenous Australian infants: rationale and protocol

    Trials

    (2011)
  • J Altenburg et al.

    Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial

    JAMA

    (2013)
  • DJ Serisier et al.

    Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial

    JAMA

    (2013)
  • Cited by (110)

    • Bronchiectasis

      2023, Medicine (United Kingdom)
    • Bronchiectasis

      2023, Presse Medicale
    View all citing articles on Scopus

    Joint first authors

    View full text