Azithromycin Lessens Bronchiectasis Exacerbations

Jenny Powers

August 22, 2012

August 22, 2012 — A new application of a drug that was approved in 1996 and has been widely used since significantly decreased the frequency of exacerbations and increased the time to first exacerbation in patients with noncystic fibrosis bronchiectasis and at least 1 exacerbation during the previous year.

The Effectiveness of Macrolides in Patients with Bronchiectasis Using Azithromycin to Control Exacerbations (EMBRACE) trial was conducted by a team of researchers from New Zealand. The results were published in the August 18 issue of the Lancet. The issue is devoted to respiratory medicine and was released just ahead of the European Respiratory Society Annual Congress being held in Vienna, Austria.

Noncystic fibrosis bronchiectasis is a highly debilitating chronic condition that results in a progressive decline in lung function. Patients experience inflammation of the airways caused by neutrophil invasion, chronic bacterial infection, recurrent pulmonary exacerbations, and a productive cough.

Although the prevalence of this condition is not known, "with modern diagnostic techniques, bronchiectasis is increasingly being recognized. In the United States, the number of bronchiectasis-associated admissions increased by 2% to 3% per year between 1993 and 2006, and the mean annual rate of admission in this period was 16.5 per 100,000 people," according to lead investigator Conroy Wong, MBChB, from the Department of Respiratory Medicine at Middlemore Hospital in Auckland, New Zealand.

Few evidence-based therapeutic options exist for these patients. Azithromycin, a macrolide antibiotic, has both antiinflammatory and immunomodulatory properties. As Dr. Wong explained to Medscape Medical News, "there are multiple potential mechanisms of action of the macrolide antibiotics in bronchiectasis.... Our study was not designed to specifically evaluate the mechanism of action, but it seems likely that azithromycin acts by both antibiotic and antiinflammatory mechanisms. Our study hinted at a reduction in organisms cultured in sputum (antibiotic effect) and showed reduced blood and sputum neutrophil counts in the azithromycin group."

Whether azithromycin can decrease the frequency of exacerbations and improve lung function was tested in a randomized, double-blind, placebo-controlled trial conducted at 3 New Zealand centers. Trial participants were 18 years or older and had to have had at least 1 pulmonary exacerbation requiring antibiotic treatment in the previous year plus bronchiectasis diagnosed by high-resolution computed tomography scan. The researchers enrolled 141 patients from February 12, 2008 to October 15, 2009, and subsequently randomized them to receive azithromycin 500 mg or placebo 3 times a week for 6 months.

The number of exacerbations during the treatment period was much lower in the azithromycin group than in the placebo group (42 vs 103).

The study met one of the coprimary end points: the rate of event-based exacerbations during the 6-month treatment period was 0.59 per patient in the 71 patients who received azithromycin and 1.57 per patient in the 70 patients who received placebo. In addition, a 62% relative reduction in the rate of exacerbations was seen (rate ratio, 0.38; 95% confidence interval [CI], 0.26 to 0.54; P < .0001).

Because few patients in the azithromycin group experienced an episode during the 6-month trial, researchers defined time to first exacerbation as the time until at least 25% of the patients had a first exacerbation. This time was 104 days (95% CI, 48 to 186) in the azithromycin group and 21 days (95% CI, 11 to 48) in the placebo group (hazard ratio [HR], 0.34; P < .0001). Over the 12-month treatment and follow-up period, median time to first exacerbation was 239 days (95% CI, 190 to 331) in the azithromycin group and 85 days (95% CI, 52 to 113) in the placebo group (HR, 0.44; P < .0001).

Patients continued to benefit from the treatment after the trial ended. According to Dr. Wong, "our results show that azithromycin treatment for 6 months decreases the frequency of exacerbations and increases the time to first exacerbation. These benefits seem to persist for 6 months after the treatment is completed."

The study did not meet the other 2 coprimary end points. Forced expiratory volume in 1 s before bronchodilation did not change from baseline in the azithromycin group; in the placebo group, it decreased by 0.04 L (95% CI, 0.03 to 0.12; P = .251). The total score on the St. George's Respiratory Questionnaire was similar in the azithromycin and placebo groups; the difference between the groups was –3.25 (95% CI, –7.21 to 0.72; P = .108).

The risk for an exacerbation was halved with azithromycin; 31% of the azithromycin group and 66% of the placebo group reported at least 1 exacerbation during the treatment period.

The researchers conclude that azithromycin is a new option for the prevention of exacerbations in patients with noncystic fibrosis bronchiectasis, but recommend that clinicians take "a careful approach to the selection of patients for long-term azithromycin treatment because of increasing concerns about macrolide resistance."

In an accompanying comment, Robert Wilson, MD, and Athol Wells, MD, both from the Royal Brompton Hospital in London, United Kingdom, explain that this study provides "clear evidence for a beneficial effect of an inexpensive treatment for noncystic fibrosis bronchiectasis in a large prospective study." They too urge caution in light of increasing macrolide resistance, and suggest additional study to determine which patients could benefit most from azithromycin. "The prospective assessment of disease severity and thea prioriconsideration of patterns of longitudinal disease behavior could provide the best chance in future studies to identify patients with bronchiectasis with the most to gain from an intervention."

Dr. Wong noted that "with increasing concerns about macrolide resistance, researchers have been focusing on the nonantibiotic effects of macrolides. There are new agents derived from azithromycin and erythromycin that are in early-phase development. These agents do not have antibiotic effects, therefore less or no risk of resistance, but appear to have the antiinflammatory and immunomodulatory effects."

The study was funded by the Health Research Council of New Zealand and the Auckland District Health Board Charitable Trust. The study authors, Dr. Wilson, and Dr. Wells have disclosed no relevant financial relationships.

Lancet. 2012;380:627-629, 660-667. Comment, Abstract