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.
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).
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.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre