Lack of Benefit of Azithromycin Use in Acute Asthma Exacerbations

According to a study recently published in JAMA Internal Medicine, there are no clinical benefits from adding azithromycin (500 mg for 3 days) to standard treatment for adults who presented to emergency departments with acute asthma exacerbations requiring a corticosteroid course.

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Furthermore, no differences in the scores of self-reported symptoms, quality of life, lung function, or speed of symptom resolution were observed.

Most patients with asthma experience an exacerbation during the past year. Respiratory viral and bacterial infections can cause asthma exacerbations and asthma itself can increase the risk of certain infections. To this end, researchers hypothesized that azithromycin might benefit patients with asthma exacerbation due to its antimicrobial and anti-inflammatory properties.

The study, deemed the Azithromycin Against Placebo in Exacerbation of Asthma (AZALEA) study was a randomized, double-blind, placebo-controlled clinical trial. It was carried out from September 2011 to April 2014 at 31 United Kingdom medical centers and included 199 patients after screening 4582 subjects.

A diary card for asthma symptoms (0=no symptoms to 6=severe symptoms) was used to monitor the severity of asthma symptoms over time. After comparing the azithromycin group to the placebo group, the primary outcome of diary card symptom score at day 10 was 2.09 ± 1.71 and 2.2 ± 1.51, respectively. These scores were 4.14 ± 1.38 and 4.18 ± 1.48, respectively, at time of exacerbation before administration of study treatments. Moreover, multilevel modeling did not identify any significant difference in symptom scores at day 10 (difference, −0.166; 95%CI, −0.670 to 0.337), nor on other days. The authors noted that the azithromycin group had a higher frequency of adverse events than the placebo group (gastrointestinal, 35 vs 24; cardiac, 4 vs 2).

Because treatment practice guidelines recommended against routine antibiotic use, receiving recent antibiotics was a major cause of exclusion from the study. As stated in the accompanying invited commentary by Brusselle and Van Braekel, this exclusion, as well as the anti-inflammatory activity of corticosteroids, might have caused some selection bias toward underestimating the clinical benefit of antibiotics.

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However, these results found that antibiotics were commonly used for acute asthma exacerbations and identify important opportunities for antibiotic stewardship.

In addition, it is worth mentioning that a previous study of patients with asthma exacerbations found a clinical benefit with telithromycin.

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Those patients had more reductions in asthma symptoms, improvement of lung function, and more rapid symptom resolution. In that study, 60% of patients tested positive for at least 1 of the following atypical bacteria: Chlamydophila pneumoniae or Mycoplasma pneumoniae. In contrast, only 5% of patients in the AZALEA trial tested positive for at least 1 of these atypical bacteria.

Two invited commentaries recommended several strategies to optimize antibiotic use for acute asthma exacerbations.

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Brusselle and Van Braekel recommended raising patients’ and health care providers’ awareness about antibiotic use in asthmatics; avoiding routine use of antibiotics in asthma exacerbations, as recommended by treatment practice guidelines; conducting large clinical trials to identify which cases with asthma exacerbations might benefit from treatment with antibiotics; and validation and development of biomarkers to guide targeted antibiotic therapy. On the other hand, Mehrotra and Linder recommended reframing the rationale against antibiotic use from a public health issue to an individual patient issue; utilizing interventions based on social and behavioral science to a greater extent; and utilizing telemedicine to reduce unnecessary ambulatory care visits in the first place.

In conclusion, this new study did not find a clinical benefit from adding azithromycin to corticosteroids for patients with acute asthma exacerbations. A worrisome finding is the overuse of antibiotics; therefore, antibiotic stewardship strategies are critical in these cases.

Dr. Khalid Eljaaly, PharmD, BCPS, MS is a postdoctoral pharmacy fellow in infectious diseases/antibiotic stewardship in the College of Pharmacy at the University of Arizona in Tucson, and a faculty member in the clinical pharmacy department, King Abdulaziz University, Jeddah, Saudi Arabia. He completed his PGY2 pharmacy residency at Beth Israel Deaconess Medical Center in Boston, a hospital affiliated with Harvard Medical School. He is a member of the stewardship committee in the SIDP and a member of Social Media Committee in both the SIDP and Infectious Diseases Practice and Research Network of the American College of Clinical Pharmacy. He is an active member of the Contagion® Editorial Advisory Board.

References

1. 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):1630-1637. doi:10.1001/jamainternmed.2016.5664.
2. Brusselle GG, Van Braeckel E. AZALEA Trial Highlights Antibiotic Overuse in Acute Asthma Attacks. JAMA Intern Med. 2016;176(11):1637-1638. doi:10.1001/jamainternmed.2016.6046.
3. Johnston SL, Blasi F, Black PN, et al; TELICAST Investigators. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med. 2006;354(15):1589-1600.
4. Mehrotra A, Linder JA. Tipping the Balance Toward Fewer Antibiotics. JAMA Intern Med. 2016;176(11):1649-1650. doi:10.1001/jamainternmed.2016.6254