Azithromycin may not improve symptoms or lung function in adults with acute asthma exacerbation requiring systemic corticosteroids

EBM Focus - Volume 11, Issue 40

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Reference - AZALEA trial (JAMA Intern Med 2016 Sep 19 early online) (level 2 [mid-level] evidence)

  • Antibiotics are often prescribed for acute asthma exacerbations in adults, despite guideline recommendations against their routine use.
  • In the AZALEA trial, 199 adults presenting to the emergency department in the United Kingdom for acute asthma exacerbation requiring systemic corticosteroids were randomized to azithromycin 500 mg vs. placebo once daily for 3 days and followed until day 10. Patients with systemic antibiotic use during the previous 28 days were excluded.
  • Patients in the azithromycin group did not have improved symptoms or lung function compared to placebo at any point in this trial.
  • Over 4,500 patients were initially assessed for this trial and 44.6% of them were excluded for recent antibiotic use, highlighting the continued use of antibiotics for asthma exacerbation.

Asthma exacerbations in adults are usually caused by viral respiratory infections, but bacterial infections, allergens, pollutants, and other causes may also trigger them. Despite the relatively low likelihood of a bacterial etiology, and guideline recommendations against routine antibiotic therapy (British Guideline on Acute Asthma 2016, National Heart, Lung, and Blood Institute Guidelines for the Diagnosis and Management of Asthma 2007), antibiotics are often prescribed for asthma exacerbations, including 22% of emergency room visits in the United States (Acad Emerg Med 2008 Aug;15(8):736). Evidence directly assessing antibiotic efficacy for asthma exacerbations is limited (Cochrane Database Syst Rev 2001;(3):CD002741), and in the highest quality trial to date that does show a benefit, treatment with telithromycin 800 mg/day for 10 days reduced symptom severity by only a mean of 0.3 points on a 6 point scale (N Engl J Med 2006 Apr 13;354(15):1589). To better investigate the possible efficacy of antibiotic use for asthma exacerbation, the AZALEA trial (JAMA Intern Med 2016 Sep 19 early online) randomized 199 adults presenting to the emergency department in the United Kingdom for acute asthma exacerbation to azithromycin 500 mg vs. placebo once daily for 3 days and followed them until day 10. Only patients requiring systemic corticosteroids for the exacerbation were included in this trial, and patients were excluded if they had any systemic antibiotic therapy during the previous 28 days or had other serious cardiopulmonary conditions.

Patients recorded symptom severity on a 6 point scale in a diary once daily. Mean severity for the entire cohort of patients decreased from about 4.1 on day 1 to 2.1 on day 10, with no significant differences between treatment groups on any day. There were also no significant differences in time for 50% reduction in symptom severity or measures of lung function. Most patients provided samples for PCR analysis, and about half also had bacterial culture. Positive bacterial tests occurred in 10.6%, and positive viral tests occurred in 18.1%. Mean symptom severity was not significantly different between groups in subgroup analyses based on these test results (although sample size for any subgroup analysis was very small). The azithromycin group had more gastrointestinal adverse events, more cardiac adverse events (although these were infrequent), and fewer respiratory adverse events, but statistical analyses were not reported.

For adults with acute asthma exacerbation, azithromycin does not appear to have any benefit. It is worth noting that this trial only included patients requiring systemic corticosteroids, unlike the trial with telithromycin in which only 1/3 of the patients were treated with systemic corticosteroids. A caveat of the present trial is that it was underpowered, with only 199 of a planned 380 patients recruited. This target patient number, however, was based on looking for a difference on the symptom severity scale that may be too small to be clinically meaningful. It is also noteworthy that 95.7% out of 4,582 patients presenting with acute exacerbation were excluded. The single most common reason for exclusion was systemic antibiotic use during the previous 28 days, which excluded 44.6% of potential participants. While it is possible that some patients already treated with antibiotics had bacterial pneumonia or some similar comorbidity justifying antibiotic treatment, it is likely that the vast majority of patients given antibiotics did not need them. It is concerning that almost half of the patients presenting to the emergency department for asthma exacerbation had recently taken systemic antibiotics, despite guidelines recommending against its routine use. The AZALEA trial provides additional evidence supporting these recommendations and will hopefully lead to a reduction in unnecessary antibiotic prescriptions.

For more information, see the Asthma exacerbation in adults and adolescents topic in DynaMed Plus. DynaMed users click here.