- Macrolides and Bronchiectasis
Macrolides and Bronchiectasis
Among patients with the lung disorder non-cystic fibrosis bronchiectasis, treatment with the antibiotic azithromycin or erythromycin resulted in improvement in symptoms but also increased the risk of antibiotic resistance, according to two studies appearing in the March 27 issue of JAMA.1
Bronchiectasis is characterized by abnormal widening of the bronchi (air tubes that branch deep into the lungs) and can cause recurrent lung infections, a disabling cough, shortness of breath, and coughing up blood. “If progressive, this process may lead to respiratory failure and the need for lung transplantation or to death,” according to background information in one study.
Macrolide (a class of antibiotics) antibiotics have antibacterial and anti-inflammatory properties that conceivably would provide effective treatment of bronchiectasis. These antibiotics have been shown beneficial in treating cystic fibrosis (CF), and findings from small studies suggest a benefit in non-CF bronchiectasis.
Josje Altenburg, M.D., of the Medical Centre Alkmaar, the Netherlands, and colleagues conducted a multicenter trial to investigate whether 1 year of low-dose macrolide treatment added to standard therapy is effective in reducing exacerbation frequency in patients with non-CF bronchiectasis.
The randomized, placebo-controlled trial was conducted between April 2008 and September 2010 in 14 hospitals in the Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year. Patients received azithromycin (250 mg daily) or placebo for 12 months.
Forty-three participants (52 percent) received azithromycin and 40 (48 percent) received placebo and were included in the modified intention-to-treat analysis. A total of 117 exacerbations treated with antibiotics were reported during 1 year of treatment, 78 of which occurred in the placebo group.
“During the treatment period, the median [midpoint] number of exacerbations in the azithromycin group was 0, compared with 2 in the placebo group. Of the 40 participants receiving placebo, 32 (80 percent) had at least 1 exacerbation during the study period. In the 43 participants receiving azithromycin, 20 (46.5 percent) had at least 1 exacerbation in the same period, yielding an absolute risk reduction of 33.5 percent. The number of patients needed to treat with azithromycin to maintain clinical stability was 3.0,” the authors write.
“Gastrointestinal adverse effects occurred in 40 percent of patients in the azithromycin group and in 5 percent in the placebo group but without need for discontinuation of study treatment. A macrolide resistance rate of 88 percent was noted in azithromycin-treated individuals, compared with 26 percent in the placebo group.”
“We conclude that macrolide maintenance therapy was effective in reducing exacerbations in patients with non-CF bronchiectasis. In this trial, azithromycin treatment resulted in improved lung function and better quality of life but involved an increase in gastrointestinal adverse effects and high rates of macrolide resistance,” the authors write.
In another study2, David J. Serisier, M.B.B.S., D.M., F.R.A.C.P., of Mater Adult Hospital, South Brisbane, Australia, and colleagues tested the hypothesis that low-dose erythromycin would reduce pulmonary exacerbations in patients with non-CF bronchiectasis with a history of frequent exacerbations.
The study consisted of a 12-month randomized controlled trial of erythromycin in currently nonsmoking, adult patients with non-CF bronchiectasis with a history of 2 or more infective exacerbations in the preceding year. The study was undertaken between October 2008 and December 2011 in a university teaching hospital.
Patients received twice-daily erythromycin ethylsuccinate (400 mg) or matching placebo. The primary measured outcome was the annualized average rate of protocol-defined pulmonary exacerbations (PDPEs) per patient. Secondary outcomes included macrolide resistance and lung function.
Six-hundred seventy-nine patients were screened, 117 were randomized (58 placebo, 59 erythromycin), and 107 (91.5 percent) completed the study. The researchers found that erythromycin significantly reduced PDPEs (76 for the erythromycin group vs. 114 for the placebo group; average 1.29 vs. 1.97 respectively, per patient per year). The number of patients treated with erythromycin who had zero PDPEs was 20 (vs. 16 for placebo), and 10 patients had more than 2 PDPEs (vs. 18, respectively).
Erythromycin also reduced PDPEs in the prespecified subgroup with baseline Pseudomonas aeruginosa airway infection. In addition, there were significantly fewer total respiratory events (total PDPEs plus non-PDPEs) in the erythromycin group (111 vs. 176 for placebo; average, 1.88 vs. 3.03 per patient per year).
“Erythromycin reduced 24-hour sputum production and attenuated [lessened] lung function decline compared with placebo. Erythromycin increased the proportion of macrolide-resistant oropharyngeal streptococci,” the authors write.
“In conclusion, long-term low-dose erythromycin significantly reduced exacerbations, protected against lung function decline, reduced sputum production, and significantly increased macrolide resistance in oropharyngeal streptococci.
The bacterial resistance caused by macrolide therapy mandates a cautious application of this therapy in clinical practice. Further studies are needed to evaluate the possibility that P aerugmosa-infected individuals with frequent exacerbations may represent an appropriate subgroup for limitation of this therapy.”
“The important issues for clinicians are to determine which patients with bronchiectasis should be prescribed a macrolide and which macrolide should be used,” writes J. Stuart Elborn, M.D., and Michael M. Tunney, Ph.D., of Queen’s University Belfast, United Kingdom, in an accompanying editorial.
“In the trials in this issue of JAMA, patients were recruited if they had frequent exacerbations, defined as at least 2 or 3 exacerbations in the previous year. Therefore, patients with bronchiectasis who have 2 or more exacerbations in the previous year should be considered for treatment.
Erythromycin and azithromycin are both effective for reducing exacerbations and have similar effects on antimicrobial resistance. The effect of long-term macrolide use on antibiotic resistance in these patients is not clear but should dissuade clinicians from prescribing macrolides for patients whose clinical characteristics differ from those for whom a positive effect was seen in these studies.”
1. JAMA. 2013;309(12):1251-1259
2. JAMA. 2013;309(12):1260-1267;
3. JAMA. 2013;309(12):1295-1296;
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