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Original Investigation
November 2016

Azithromycin for Acute Exacerbations of Asthma The AZALEA Randomized Clinical Trial

Author Affiliations
  • 1National Heart and Lung Institute, Imperial College London, London, England
  • 2Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, England
  • 3Institute for Lung Health, University of Leicester, Leicester, England
  • 4Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, Scotland
  • 5Respiratory Medicine, NHS Greater Glasgow and Clyde, Glasgow, Scotland
  • 6Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, England
  • 7Respiratory Medicine, Heart of England Foundation Trust, Birmingham, England
  • 8Severe and Brittle Asthma Unit, University of Birmingham, Birmingham, England
  • 9Respiratory Medicine and Allergy, King’s College London School of Medicine, London, England
  • 10Department of Asthma, Allergy and Respiratory Science, Guy’s and St. Thomas’ NHS Foundation Trust, London, England
  • 11Respiratory Medicine, Newcastle University, Newcastle, England
  • 12Respiratory Medicine, Imperial College Healthcare NHS Trust, London, England
  • 13Centre for Respiratory Medicine and Allergy, Medicines Evaluation Unit, University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, England
  • 14Respiratory Medicine, Portsmouth Hospitals NHS Trust, Portsmouth, England
JAMA Intern Med. 2016;176(11):1630-1637. doi:10.1001/jamainternmed.2016.5664
Key Points

Question  Does addition of azithromycin to standard care improve outcomes in adults requesting acute medical care for asthma attacks?

Findings  This randomized clinical trial found no statistically or clinically significant benefit in symptoms, lung function, or speed of recovery. For every 1 patient randomized, more than 10 had to be excluded because they had already received antibiotics.

Meaning  Widespread use of antibiotics despite guideline recommendations limited interpretation of the results of this study.


Importance  Guidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use.

Objective  To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit.

Design, Setting, and Participants  The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom–based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids.

Interventions  Azithromycin 500 mg daily or matched placebo for 3 days.

Main Outcomes and Measures  The primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of −0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score.

Results  Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference, −0.166; 95% CI, −0.670 to 0.337), nor on any day between exacerbation and day 10. No significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score.

Conclusions and Relevance  In this randomized population, azithromycin treatment resulted in no statistically or clinically significant benefit. For each patient randomized, more than 10 were excluded because they had already received antibiotics.

Trial Registration  clinicaltrials.gov Identifier: NCT01444469