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NIHR Signal Long-term macrolide antibiotics reduce risk of exacerbations of bronchiectasis

Published on 31 October 2019

doi: 10.3310/signal-000831

People with bronchiectasis (not caused by cystic fibrosis) who take long-term macrolide antibiotics are around 50% less likely to experience acute worsening of symptoms like cough and sputum production (an exacerbation) than people taking a placebo.

Bronchiectasis guidelines only recommend preventative macrolide antibiotics in people with frequent exacerbations who do not carry a bacterium (Pseudomonas aeruginosa). This review pooled data from three trials in 341 patients where erythromycin or azithromycin was taken for 6-12 months. Macrolides were effective in all patient subgroups examined, including those with Pseudomonas infection, and those who had less than two exacerbations a year. Despite the improvement in symptoms, the small improvement in quality of life was not clinically significant.

Preventative antibiotics might be an option for more patients, but the risk-benefit balance needs to be considered. This includes the risk of side effects, drug interactions and increased antibiotic resistance.

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Why was this study needed?

Bronchiectasis is a condition where the ends of the airways in the lungs are permanently dilated and inflamed. This allows the build-up of mucus that can get infected. Bronchiectasis has varied causes, including previous lung infections and immune system disorders, though often the cause cannot be identified. Cystic fibrosis is a common genetic condition that also causes bronchiectasis. Overall, bronchiectasis is thought to affect 1 in 1,000 people in the UK.

Macrolide antibiotics are sometimes used to prevent exacerbations of non-cystic fibrosis bronchiectasis, but guideline recommendations are based on small trials of varied design and including mixed patient groups. A 2018 Cochrane review concluded that macrolides might reduce frequency of exacerbations, but highlighted the need for research to inform the best treatment regimen and identify which patient groups benefit.

This systematic review gathered individual participant data from trials to try and answer this question.

What did this study do?

This systematic review identified double-blind randomised controlled trials comparing long-term macrolide antibiotics (given for three months or more) with placebo in adults with non-cystic fibrosis bronchiectasis.

The researchers identified three trials, including a total 341 patients (average age 60 years). Trials were published 2012-13 and came from The Netherlands, New Zealand and Australia. The main characteristics of these trials were:

  • 83 adults with three or more exacerbations per year evaluating roughly 12 months of azithromycin (250mg daily)
  • 117 adults with two or more exacerbations per year evaluating roughly 12 months of erythromycin (400mg twice daily)
  • 141 adults with one or more exacerbation per year evaluating six months of azithromycin (500mg three times weekly)

The researchers analysed the effect by patient characteristics, including age, prior exacerbation history, steroid use, and Pseudomonas infection. The main limitations are the multiple analyses and small subgroups which increase the possibility of chance findings.

What did it find?

  • Long-term macrolide therapy decreased the frequency of exacerbations compared with placebo (incidence rate ratio [IRR] 0.49, 95% confidence interval [CI] 0.36 to 0.66). This was from a meta-analysis of individual patient data with adjustment for age, sex, lung function at baseline and study.
  • Macrolides also reduced time to first exacerbation (IRR 0.46, 95% CI 0.34 to 0.61) at a median 280 days compared with 98 days in the placebo group.
  • Macrolides gave a small quality of life improvement of 2.93 points (95% CI 0.03 to 5.83) on the 100-point St George’s Respiratory Questionnaire. This fell just short of the 4-point clinically meaningful improvement.
  • Planned subgroup analysis showed that macrolides reduced exacerbations in most groups including those for who preventative macrolides are not normally recommended: those with only one or two exacerbations per year (IRR 0.37, 95% CI 0.16 to 0.88) and those with Pseudomonas aeruginosa infection (IRR 0.36, 95% CI 0.18 to 0.72).

What does current guidance say on this issue?

NICE provides guidelines on the management of acute exacerbations of bronchiectasis (not caused by cystic fibrosis) including first-choice options for oral or intravenous antibiotics. NICE advises against routine prescription of antibiotic prophylaxis, and suggest a trial only in people with repeated exacerbations. The potential adverse effects and the need for regular review are highlighted. A 2014 NICE evidence summary on the effect of long-term azithromycin is also available, informed by two of these three trials.

NICE endorses the recommendations of the British Thoracic Society, which advises considering long-term antibiotics for people with three or more exacerbations per year. Provided the patient is not colonised with Pseudomonas aeruginosa, azithromycin or erythromycin is advised first-line (inhaled colistin is recommended if they are colonised). 

What are the implications?

Like previous studies, this meta-analysis suggests that long-term macrolides may reduce exacerbation frequency in bronchiectasis. It benefits from analysing individual patient data, indicating that prophylaxis may help wider patient groups than previously thought.

However, there are limitations, including the small patient subgroups and the fact that most evidence has looked at azithromycin. This makes it difficult to consider this strong conclusive evidence, but it may be the best that can be currently obtained for this rare condition.

Any decisions on prophylaxis will need to be made on an individual basis, considering the potential risks. These include adverse effects and the risk of antibiotic resistance and reduced susceptibility in future infections.

Citation and Funding

Chalmers JD, Boersma W, Lonergan M et al. Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis. Lancet Respir Med. 2019;7(10):845-54.

Funding was provided by the European Respiratory Society.

Bibliography

British Lung Foundation. Bronchiectasis. London: British Lung Foundation; 2019.

Hill AT, Sullivan AL, Chalmers JD et al. British Thoracic Society Guideline for bronchiectasis in adults. Thorax. 2019;74:1-69.

Kelly C, Chalmers JD, Crossingham I et al. Macrolide antibiotics for bronchiectasis. Cochrane Database Sys Rev. 2018;(3):CD012406.

NHS Inform. Bronchiectasis. Edinburgh: NHS Inform; 2019.

NICE. Bronchiectasis (non-cystic fibrosis), acute exacerbation: antimicrobial prescribing. NG117. London: National Institute for Health and Care Excellence; 2018.

NICE. Non-cystic fibrosis bronchiectasis: long-term azithromycin. Evidence summary ESUOM38. London: National Institute for Health and Care Excellence; 2014.

Why was this study needed?

Bronchiectasis is a condition where the ends of the airways in the lungs are permanently dilated and inflamed. This allows the build-up of mucus that can get infected. Bronchiectasis has varied causes, including previous lung infections and immune system disorders, though often the cause cannot be identified. Cystic fibrosis is a common genetic condition that also causes bronchiectasis. Overall, bronchiectasis is thought to affect 1 in 1,000 people in the UK.

Macrolide antibiotics are sometimes used to prevent exacerbations of non-cystic fibrosis bronchiectasis, but guideline recommendations are based on small trials of varied design and including mixed patient groups. A 2018 Cochrane review concluded that macrolides might reduce frequency of exacerbations, but highlighted the need for research to inform the best treatment regimen and identify which patient groups benefit.

This systematic review gathered individual participant data from trials to try and answer this question.

What did this study do?

This systematic review identified double-blind randomised controlled trials comparing long-term macrolide antibiotics (given for three months or more) with placebo in adults with non-cystic fibrosis bronchiectasis.

The researchers identified three trials, including a total 341 patients (average age 60 years). Trials were published 2012-13 and came from The Netherlands, New Zealand and Australia. The main characteristics of these trials were:

  • 83 adults with three or more exacerbations per year evaluating roughly 12 months of azithromycin (250mg daily)
  • 117 adults with two or more exacerbations per year evaluating roughly 12 months of erythromycin (400mg twice daily)
  • 141 adults with one or more exacerbation per year evaluating six months of azithromycin (500mg three times weekly)

The researchers analysed the effect by patient characteristics, including age, prior exacerbation history, steroid use, and Pseudomonas infection. The main limitations are the multiple analyses and small subgroups which increase the possibility of chance findings.

What did it find?

  • Long-term macrolide therapy decreased the frequency of exacerbations compared with placebo (incidence rate ratio [IRR] 0.49, 95% confidence interval [CI] 0.36 to 0.66). This was from a meta-analysis of individual patient data with adjustment for age, sex, lung function at baseline and study.
  • Macrolides also reduced time to first exacerbation (IRR 0.46, 95% CI 0.34 to 0.61) at a median 280 days compared with 98 days in the placebo group.
  • Macrolides gave a small quality of life improvement of 2.93 points (95% CI 0.03 to 5.83) on the 100-point St George’s Respiratory Questionnaire. This fell just short of the 4-point clinically meaningful improvement.
  • Planned subgroup analysis showed that macrolides reduced exacerbations in most groups including those for who preventative macrolides are not normally recommended: those with only one or two exacerbations per year (IRR 0.37, 95% CI 0.16 to 0.88) and those with Pseudomonas aeruginosa infection (IRR 0.36, 95% CI 0.18 to 0.72).

What does current guidance say on this issue?

NICE provides guidelines on the management of acute exacerbations of bronchiectasis (not caused by cystic fibrosis) including first-choice options for oral or intravenous antibiotics. NICE advises against routine prescription of antibiotic prophylaxis, and suggest a trial only in people with repeated exacerbations. The potential adverse effects and the need for regular review are highlighted. A 2014 NICE evidence summary on the effect of long-term azithromycin is also available, informed by two of these three trials.

NICE endorses the recommendations of the British Thoracic Society, which advises considering long-term antibiotics for people with three or more exacerbations per year. Provided the patient is not colonised with Pseudomonas aeruginosa, azithromycin or erythromycin is advised first-line (inhaled colistin is recommended if they are colonised). 

What are the implications?

Like previous studies, this meta-analysis suggests that long-term macrolides may reduce exacerbation frequency in bronchiectasis. It benefits from analysing individual patient data, indicating that prophylaxis may help wider patient groups than previously thought.

However, there are limitations, including the small patient subgroups and the fact that most evidence has looked at azithromycin. This makes it difficult to consider this strong conclusive evidence, but it may be the best that can be currently obtained for this rare condition.

Any decisions on prophylaxis will need to be made on an individual basis, considering the potential risks. These include adverse effects and the risk of antibiotic resistance and reduced susceptibility in future infections.

Citation and Funding

Chalmers JD, Boersma W, Lonergan M et al. Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis. Lancet Respir Med. 2019;7(10):845-54.

Funding was provided by the European Respiratory Society.

Bibliography

British Lung Foundation. Bronchiectasis. London: British Lung Foundation; 2019.

Hill AT, Sullivan AL, Chalmers JD et al. British Thoracic Society Guideline for bronchiectasis in adults. Thorax. 2019;74:1-69.

Kelly C, Chalmers JD, Crossingham I et al. Macrolide antibiotics for bronchiectasis. Cochrane Database Sys Rev. 2018;(3):CD012406.

NHS Inform. Bronchiectasis. Edinburgh: NHS Inform; 2019.

NICE. Bronchiectasis (non-cystic fibrosis), acute exacerbation: antimicrobial prescribing. NG117. London: National Institute for Health and Care Excellence; 2018.

NICE. Non-cystic fibrosis bronchiectasis: long-term azithromycin. Evidence summary ESUOM38. London: National Institute for Health and Care Excellence; 2014.

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

Published on 14 August 2019

Chalmers, J. D.,Boersma, W.,Lonergan, M.,Jayaram, L.,Crichton, M. L.,Karalus, N.,Taylor, S. L.,Martin, M. L.,Burr, L. D.,Wong, C.,Altenburg, J.

Lancet Respir Med , 2019

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.

Expert commentary

There are relatively few large placebo-controlled clinical trials of antibiotic therapy in bronchiectasis, so guidelines on management are largely based on small and heterogeneous studies.

Current guidelines recommend macrolides only in patients with three or more exacerbations per year and not in patients with evidence of Pseudomonas aeruginosa infection, whereas this analysis shows that even patients with infrequent exacerbation and those with Pseudomonas infections can benefit clinically. The current European Respiratory Society bronchiectasis guidelines, therefore, need to be modified in the light of this new analysis. For patients who have predominantly Pseudomonas colonisation, currently inhaled antibiotics are recommended, but the evidence for their benefit is equivocal.

It now seems that macrolides are effective even in patients with predominant infection with Pseudomonas, so should be recommended as first-line treatment for these patients. However, the benefit of macrolides needs to be balanced by the adverse effects of chronic macrolide therapy, including deafness in elderly patients, cardiovascular effects, drug-drug interactions and the development of antibiotic resistance.

Professor Peter Barnes, Margaret Turner-Warwick Professor of Thoracic Medicine, Imperial College London

The commentator declares no conflicting interests