NIHR DC Discover

NIHR Signal Study shows no benefit of an antibiotic for acute asthma

Published on 21 December 2016

doi: 10.3310/signal-000354

The antibiotic azithromycin did not reduce symptoms or change other outcomes in adults seeking emergency care for an acute asthma attack. However people not already taking antibiotics were hard to find and the trial failed to enrol enough people to answer the research question.

In this UK-based trial, people with asthma who received azithromycin on top of standard treatment with corticosteroids had no better symptoms ten days later than people who received corticosteroids alone.

Almost half of almost 4,600 potential participants had already been given antibiotics.

This study shows that many people are being prescribed antibiotics to treat an asthma attack despite British guidance stating that antibiotics should not be routinely used. This raises questions about unnecessary use of antibiotics, with implications for antimicrobial resistance.

The findings do not exclude the fact that a positive effect of azithromycin might exist for those not recruited to the trial. Prior to more definitive studies, clinicians should continue to follow existing guidance that antibiotics should not be prescribed routinely to people with an asthma attack.

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Why was this study needed?

Asthma is a chronic inflammatory respiratory disease characterised by attacks of breathlessness and wheezing. Around 10% of adults in England have asthma, and about a third of these people (30% of men and 39% of women) have an asthma attack once a year.

Asthma attacks are often caused by viral infections, but can also be triggered by bacterial infections, allergens, drugs, air pollution and smoking.

Guidelines do not recommend routinely prescribing antibiotics to people with an acute asthma attack. However, the antibiotic azithromycin is believed to have an additional effect of reducing inflammation and has been used to treat acute asthma attacks.

This study aimed to determine if azithromycin improved symptoms or speed of recovery when added to standard steroid treatment in people experiencing an asthma attack.

What did this study do?

This double-blind randomised controlled trial (the AZALEA study) recruited adults who presented to one of 31 centres, mainly hospitals, in the UK with an asthma attack.

Overall, 4,582 people were screened for eligibility, with 2,044 (45%) excluded because they were already receiving antibiotics. Only 199 people of a planned 380 were enrolled from 31 centres around the UK in two years seven months.

A total of 199 people were recruited and randomised within 48 hours of presentation to three days of treatment with azithromycin 500 mg a day or placebo (mean age 40 years and 70% women). All participants also received a course of oral and/or intravenous corticosteroids.

Participants rated their symptoms using a diary card on a scale of 1 to 6 (where 0=no symptoms to 6=severe symptoms) when they presented with the asthma attack (baseline) and at 5 and 10 days after.

What did it find?

  • Among the 97 people who received azithromycin, the average symptom score fell from 4.14 (standard deviation [SD] 1.38) at baseline to 2.09 (SD 1.71) by 10 days later.
  • In the 102 people who received placebo, the average symptom score fell from 4.18 (SD 1.48) at baseline to 2.20 (SD 1.51) by 10 days.
  • At 10 days, the average symptom score was not significantly better in the azithromycin group than the placebo group (difference −0.166, 95% confidence interval −0.670 to 0.337).
  • Side effects were uncommon, although people in the azithromycin group experienced more gastrointestinal adverse events, such as diarrhoea (35 events compared with 24 events in the placebo group), and cardiac adverse events (4 events compared with 2 events).

What does current guidance say on this issue?

The 2016 British guideline on the management of asthma, produced by the British Thoracic Society and the Scottish Intercollegiate Guidelines Network, states that routine prescription of antibiotics is not indicated for people with acute asthma.

It recommends early administration of high-dose inhaled β2 agonists as first-line treatment of adults with acute asthma attack. Adequate doses of steroids should also be provided for all cases.

NICE has published guidelines on antimicrobial stewardship covering the systems and processes for improving and measuring the appropriate use of antimicrobial drugs. These include high level actions to encourage providers to select the optimal antimicrobial drug regimen, dose, duration of therapy, and route of administration. NICE is currently preparing guidelines on diagnosis and monitoring of asthma and on asthma management.

What are the implications?

There are few implications for practice based on the findings of this study alone as it did not have enough participants to confirm if the drug has an effect or not.

Recruiting participants to this study was difficult because for each randomised patient, more than ten were excluded at screening because they were already receiving antibiotics to treat their asthma attack. However, the authors state that this finding has “worrying implications regarding antibiotic stewardship”.

Citation and Funding

Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma: the AZALEA randomized clinical trial. JAMA Intern Med.2016;176(11):1630-37.

This study was funded by the Efficacy and Mechanisms Evaluation programme of the Medical Research Council, in partnership with the National Institute for Health Research (project number 10/60/27).

Bibliography

British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. SIGN 153. London: British Thoracic Society; 2016.

Brusselle GG, Van Braeckel E. AZALEA trial highlights antibiotic overuse in acute asthma attacks. JAMA Intern Med. 2016; 176(11):1637-38.

Johnston SL, Blasi F, Black PN, et al. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med. 2006;354(15):1589-600.

NHS Choices. Asthma. London: Department of Health; 2016.

NICE. Antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. NG15. London: National Institute for Health and Care Excellence; 2015.

Why was this study needed?

Asthma is a chronic inflammatory respiratory disease characterised by attacks of breathlessness and wheezing. Around 10% of adults in England have asthma, and about a third of these people (30% of men and 39% of women) have an asthma attack once a year.

Asthma attacks are often caused by viral infections, but can also be triggered by bacterial infections, allergens, drugs, air pollution and smoking.

Guidelines do not recommend routinely prescribing antibiotics to people with an acute asthma attack. However, the antibiotic azithromycin is believed to have an additional effect of reducing inflammation and has been used to treat acute asthma attacks.

This study aimed to determine if azithromycin improved symptoms or speed of recovery when added to standard steroid treatment in people experiencing an asthma attack.

What did this study do?

This double-blind randomised controlled trial (the AZALEA study) recruited adults who presented to one of 31 centres, mainly hospitals, in the UK with an asthma attack.

Overall, 4,582 people were screened for eligibility, with 2,044 (45%) excluded because they were already receiving antibiotics. Only 199 people of a planned 380 were enrolled from 31 centres around the UK in two years seven months.

A total of 199 people were recruited and randomised within 48 hours of presentation to three days of treatment with azithromycin 500 mg a day or placebo (mean age 40 years and 70% women). All participants also received a course of oral and/or intravenous corticosteroids.

Participants rated their symptoms using a diary card on a scale of 1 to 6 (where 0=no symptoms to 6=severe symptoms) when they presented with the asthma attack (baseline) and at 5 and 10 days after.

What did it find?

  • Among the 97 people who received azithromycin, the average symptom score fell from 4.14 (standard deviation [SD] 1.38) at baseline to 2.09 (SD 1.71) by 10 days later.
  • In the 102 people who received placebo, the average symptom score fell from 4.18 (SD 1.48) at baseline to 2.20 (SD 1.51) by 10 days.
  • At 10 days, the average symptom score was not significantly better in the azithromycin group than the placebo group (difference −0.166, 95% confidence interval −0.670 to 0.337).
  • Side effects were uncommon, although people in the azithromycin group experienced more gastrointestinal adverse events, such as diarrhoea (35 events compared with 24 events in the placebo group), and cardiac adverse events (4 events compared with 2 events).

What does current guidance say on this issue?

The 2016 British guideline on the management of asthma, produced by the British Thoracic Society and the Scottish Intercollegiate Guidelines Network, states that routine prescription of antibiotics is not indicated for people with acute asthma.

It recommends early administration of high-dose inhaled β2 agonists as first-line treatment of adults with acute asthma attack. Adequate doses of steroids should also be provided for all cases.

NICE has published guidelines on antimicrobial stewardship covering the systems and processes for improving and measuring the appropriate use of antimicrobial drugs. These include high level actions to encourage providers to select the optimal antimicrobial drug regimen, dose, duration of therapy, and route of administration. NICE is currently preparing guidelines on diagnosis and monitoring of asthma and on asthma management.

What are the implications?

There are few implications for practice based on the findings of this study alone as it did not have enough participants to confirm if the drug has an effect or not.

Recruiting participants to this study was difficult because for each randomised patient, more than ten were excluded at screening because they were already receiving antibiotics to treat their asthma attack. However, the authors state that this finding has “worrying implications regarding antibiotic stewardship”.

Citation and Funding

Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma: the AZALEA randomized clinical trial. JAMA Intern Med.2016;176(11):1630-37.

This study was funded by the Efficacy and Mechanisms Evaluation programme of the Medical Research Council, in partnership with the National Institute for Health Research (project number 10/60/27).

Bibliography

British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. SIGN 153. London: British Thoracic Society; 2016.

Brusselle GG, Van Braeckel E. AZALEA trial highlights antibiotic overuse in acute asthma attacks. JAMA Intern Med. 2016; 176(11):1637-38.

Johnston SL, Blasi F, Black PN, et al. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med. 2006;354(15):1589-600.

NHS Choices. Asthma. London: Department of Health; 2016.

NICE. Antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. NG15. London: National Institute for Health and Care Excellence; 2015.

Azithromycin for Acute Exacerbations of Asthma . The AZALEA Randomized Clinical Trial

Published on 19 September 2106

S Johnston, M Szigeti, M Cross, et al.

JAMA Intern Med Volume 176 Issue 11 , 2106

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.

Expert commentary

Does a short course of the antibiotic azithromycin help recovery in patients after an asthma attack? The AZALEA study set out to answer this question. The main finding of this study is that there were no clinically meaningful benefits of azithromycin in this setting. However, perhaps the most important finding was that current advice, which is not to prescribe antibiotics in patients with an asthma exacerbation, is not being followed in the UK. Nearly half of subjects screened for this study had already received antibiotics, whilst sputum cultures were negative in 94% of subjects screened.

Professor Ian Hall, Director Designate, Nottingham Biomedical Research Centre