Aug. 22, 2012DDisapproved in 1996 and now widely used drug now has a new use, significantly reducing the number of exacerbations of the disease and delaying the first exacerbation in patients with non-cystic fibrosis bronchiectasis by at least one less exacerbation than in the previous year. The “Effectiveness of Macrolide Therapy in Patients with Exacerbations of Bronchiectasis Controlled with Azithromycin” (EMBRACE) trial was conducted by New Zealand researchers. The results were published in the Aug. 18 issue of The Lancet. The issue is dedicated to respiratory medicine and was published just prior to the annual meeting of the European Respiratory Society in Vienna, Austria. Non-cystic fibrosis bronchiectasis is a chronic disease that is extremely debilitating and leads to a progressive decline in lung function. Patients present with respiratory inflammation, usually caused by neutrophil invasion, prolonged bacterial infections, recurrent pulmonary exacerbations and sputum-draining cough. Although the prevalence of this disease is unknown, “with modern diagnostic techniques, more is known about bronchiectasis. from 1993 to 2006, the number of bronchiectasis-related hospitalizations in the United States increased by 2 to 3 percent per year, with an average annual hospitalization rate of 16.5 per 100,000 for the same period. ” said lead researcher Conroy Wong, MD, PhD, of the Department of Respiratory Medicine at Middlemore Hospital in Auckland, New Zealand. Currently, there are few evidence-based treatment options for these patients. The macrolide antibiotic azithromycin has both anti-inflammatory and immunomodulatory properties. dr. Wong told Medscape Medical News, “The mechanism of action of macrolide antibiotics in bronchiectasis is multifaceted …… and the purpose of this study was not to evaluate its mechanism of action specifically, but Azithromycin appears likely to have both antibacterial and anti-inflammatory mechanisms of action. The present study implies that there was a decrease in bacteria on sputum culture (antibacterial effect) and a decrease in neutrophil counts in blood and sputum in the azithromycin group.” A randomized, double-blind, placebo-controlled trial at three centers in New Zealand examined whether azithromycin could reduce the number of disease exacerbations and improve lung function. Participants were ≥18 years of age, had at least one exacerbation of pulmonary disease requiring antibiotic therapy in the year prior to enrollment, and bronchiectasis was confirmed by high-resolution CT scan. 141 patients were enrolled from Feb. 12, 2008, to Oct. 15, 2009, and were subsequently randomly assigned to receive 500 mg of azithromycin or placebo three times a week for 6 months. The number of exacerbations during treatment was significantly less in the azithromycin group than in the placebo group (42 : 103). The study met one composite observational endpoint: the event-based exacerbation rates during the 6-month treatment period were 0.59% in 71 cases in the azithromycin-treated group and 1.57% in 70 cases in the placebo group. In addition, there was a 62% relative reduction in exacerbation rates (ratio, 0.38, 95% confidence interval [CI], 0.26 – 0.54; P < .0001). During the 6-month trial, patients in the azithromycin group had few episodes of disease; therefore, the researchers identified the time of first exacerbation as the time of first exacerbation in at least 25% of patients. That time was 104 days (95% CI, 48 - 186) in the azithromycin group and 21 days (95% CI, 11 - 48) in the placebo group (hazard ratio [HR], 0.34; P < .0001). median time to first exacerbation during the 12-month treatment and follow-up period was 239 days (95% CI, 190 - 331) in the azithromycin group and 85 days (95% CI, 52 - 113) in the placebo group (HR, 0.44). - 113) (HR, 0.44; P < .0001). Patients continued to benefit from treatment after the trial ended. according to dr. Wong, "The results of the current study showed that 6-month azithromycin treatment reduced the number of exacerbations and delayed the time to first exacerbation, and these benefits appear to persist for 6 months after treatment." The study did not meet the other 2 composite observational endpoints. Exertional expiratory volume in the first 1 second before bronchodilation was the same as at baseline in the azithromycin group and decreased by 0.04 L in the placebo group (95% CI, 0.03 - 0.12; P = .251). The two groups of St? George Respiratory Questionnaire total scores were close, with a difference between groups of C3.25 (95% CI, C7.21 - 0.72; P = .108). The risk of exacerbation was halved in the azithromycin group, with 31% of patients in the azithromycin group and 66% of patients in the placebo group reporting at least one exacerbation during treatment, respectively. The researchers concluded that azithromycin is a new option for preventing disease exacerbations in patients with non-cystic fibrosis bronchiectasis, although they also recommended that clinicians "be cautious in selecting patients on long-term azithromycin therapy because of increasing concerns about the development of macrolide resistance." In an accompanying commentary, Dr. Robert Wilson and Dr. Athol Wells of the Royal Brompton Hospital in London, UK, noted that this large prospective study provides "clear evidence of the efficacy of inexpensive therapies for non-cystic fibrosis bronchiectasis." They also urged attention to increasing resistance to macrolides and recommended additional studies to determine which patients would benefit most from azithromycin. "Prospective assessment of disease severity and prior consideration of longitudinal disease behavior patterns may provide the best opportunity for future studies to identify patients with bronchiectasis who would benefit most from intervention," Dr. Wong noted, "and with increased concern about macrolide resistance, researchers are already focusing on the non-antimicrobial efficacy of macrolides. New agents have been derived from azithromycin and erythromycin and are now in the early stages of development. These agents have no antibacterial efficacy and, therefore, less or no risk of resistance, although they appear to have anti-inflammatory and immunomodulatory effects."