Trial Reveals Antibiotic Overuse for Asthma Attacks

Nicola M. Parry, DVM

September 20, 2016

Addition of azithromycin treatment to standard medical care offers no statistically significant or clinically important benefit for patients with acute asthma exacerbations, according to results from the randomized Azithromycin Against Placebo for Acute Exacerbations of Asthma (AZALEA) trial, published online September 19 in JAMA Internal Medicine.

"This randomized clinical trial found no statistically or clinically significant benefit in symptoms, lung function, or speed of recovery," write Sebastian L. Johnston, MBBS, PhD, from the Imperial College London, United Kingdom, and colleagues. "However, for each patient randomized, more than 10 were excluded because they had already received antibiotics," they add.

The researchers conducted the double-blind, multicenter trial in 199 patients across 31 UK medical centers between September 2011 and April 2014.

The patients, ranging from 18 to 65 years, all had a history of asthma for more than 6 months, and recruitment within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids. The study excluded patients if they had used oral and/or systemic antibiotics within 28 days of enrollment.

For 3 days, one group of 97 patients received active treatment with azithromycin 500 mg daily, whereas the other group of 102 patients received placebo.

"The primary outcome was diary card summary symptom score, with symptoms including wheezing, breathlessness, and coughing assessed at 10 days after randomization," the authors note.

However, azithromycin treatment offered no significant therapeutic benefit. From exacerbation to day 10 after randomization, mean asthma symptom scores decreased from 4.14 to 2.09 in the azithromycin group, and from 4.18 to 2.20 in the placebo group (difference, −0.166; 95% confidence interval, −0.670 to 0.337).

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. Similarly, the authors report no significant between-group differences in secondary outcomes such as quality-of-life questionnaires, lung function measurements during the acute exacerbation, or time to a 50% reduction in asthma symptoms.

Adverse events (AEs) occurred infrequently in both groups, with more gastrointestinal AEs in the azithromycin group than in the placebo group (35 vs 24 events).

Interestingly, however, the authors note that recruitment of patients for this study proved challenging. Among the 4582 patients who were originally screened for participation, the researchers excluded 2044 (44.6%) from the trial because they had already received antibiotics, despite treatment guidelines recommending against their routine use.

Although this finding inevitably has implications for antibiotic stewardship, the authors also acknowledge that such high antibiotic use rates may have directly affected the study's outcome by excluding patients who might potentially have benefitted from antibiotic therapy for their asthma exacerbation.

In an accompanying editorial, Guy G. Brusselle, MD, PhD, and Eva Van Braeckel, MD, PhD, both from Ghent University Hospital, Belgium, highlight the need for new adjunct therapies to use with systemic corticosteroids to speed recovery from acute asthma exacerbations and prevent complications.

They contrast the negative results from the AZALEA trial with the positive results from the Telithromycin, Chlamydophila, and Asthma (TELICAST) study, which showed clinical benefit of telithromycin treatment compared with placebo in acute asthma attacks. "[A]ll patients randomized in the AZALEA trial were required to receive systemic corticosteroid treatment, whereas only 34% of randomized patients received corticosteroids in the TELICAST study."

However, Dr Brusselle and Dr Van Braeckel note that the powerful anti-inflammatory effects of systemic corticosteroids may have contributed to the negative results by masking the beneficial anti-inflammatory effects of macrolides.

Different prevalences of Chlamydophila pneumoniae infection in the two trials might also have contributed to the different outcomes of the two studies, they say: "[I]n the AZALEA study only 5% of the azithromycin-treated patients tested positive for current infection with Chlamydophila pneumoniae or Mycoplasma pneumoniae, whereas in the TELICAST study 60% of telithromycin-treated patients had a positive [immunoglobulin M] test result for one of these atypical organisms."

The heterogeneity of chronic asthma and acute asthma exacerbations may also have contributed to negative study results, they add.

The editorialists also note that selection bias in the AZALEA trial limited the external validity of the study, which randomly assigned less than half of all screened patients, because they were already receiving antibiotic therapy.

Further commenting on the high use of antibiotics in patients in the AZALEA trial, the editorialists report that 22% of acute asthma visits in the United States have been shown to result in an antibiotic prescription, and that this inappropriate use probably contributes to the rising problem of antibiotic resistance.

Dr Brusselle and Dr Van Braeckel therefore recommend a combination of four strategies to help combat inappropriate use of antibiotics in patients with acute asthma attacks: raising awareness of antibiotics overuse among clinicians and patients, following asthma guidelines that recommend against routine antibiotics use in asthma exacerbations, performing large trials to determine which patients with asthma attacks might benefit from treatment with antibiotics, and validating known biomarkers and developing new ones to help guide targeted antibiotic therapy.

"Restricting the use of antibiotics to those patients with acute exacerbations who will benefit the most" is paramount, they conclude.

This study was funded by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR). The trial was supported by the NIHR Comprehensive Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. One author has received funding from the European Research Council, Asthma UK, and the MRC Centre. Several coauthors have reported various financial relationships with various companies: Allergy Therapeutics, Almirall, AstraZeneca, Boehringer Ingelheim, Centocor, Chiesi, Diagenics, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Roche/Genentech, Sanofi Pasteur, Skyepharma, Stallergenes, Synairgen, Teva, Therevance, and Verona. One coauthor has nine licensed patents and one patent pending. The editorialists have disclosed no relevant financial relationships.

JAMA Intern Med. Published online September 19, 2016. Article abstract, Editorial extract

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