A Nail in the Coffin for Coughin'?
Abstract & Commentary
By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips is a consultant to Cephalon and Ventus and serves on the speaker's bureau of Cephalon and Boehringer Ingelheim.
Synopsis: Erythromycin, 250 mg bid, reduced the number of exacerbations in patients with moderate COPD over a 1-year period.
Source: Seemungal TA, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;178:1139-1147.
This study reports the results of a randomized, placebo- controlled trial of erythromycin 250 mg bid in reducing COPD exacerbations over a 12-month period. The participants were fairly old (mean age, 67 years), had significant COPD (mean FEV1, 1.32 L), and were mostly (63%) men. About a third had experienced 3 or more exacerbations in the year before the study. In this study, exacerbations were defined as moderate or severe. A moderate exacerbation was defined as a sustained worsening of baseline respiratory symptoms for at least 2 days that required treatment with oral corticosteroids (prednisolone) and/or antibiotics. A severe exacerbation was defined by the requirement for hospital admission. The primary endpoints were exacerbation frequency and airway inflammation. Airway inflammation was assessed by serum IL-6 and sputum levels of IL-6, IL-8, and myeloperoxidase. The investigators randomized 109 patients, and 19 withdrew, so the final sample size was only 90. The placebo and treatment groups were quite comparable.
There were 125 moderate exacerbations in the placebo group and 81 in the erythromycin group. There were 14 severe exacerbations in the placebo group and 6 in the treatment group. Over the course of the year, the median frequency of exacerbation for the placebo group was 2, and for the treatment group was 1. Exacerbations were more frequent overall in those with a history of frequent exacerbations and with lower baseline FEV1 levels. In addition to being less frequent in the treatment group, exacerbations were shorter: 13 days for placebo vs 9 days for active treatment.
There was no difference between active and placebo treatment groups for serum or sputum markers of inflammation or for spirometric measures. There also did not appear to be any change between groups in the bacteria isolated from sputum over the course of the study.
With regard to side effects, the overall frequency was quite low, and was not significantly different between the groups.
Commentary
COPD is a chronic condition that is tedious to treat (and probably even more tedious to experience personally!). Exacerbations (which remain difficult to define, but we all know them when we see them) are a major cause of cost, impaired quality of life, and deterioration in lung function in these patients. As a result, efforts have been underway for some time to identify treatments or factors that can reduce or shorten exacerbations in COPD patients. The current study appears to identify an inexpensive, low side effect treatment that can cut the exacerbation rate in about half: 250 mg erythromycin bid.
In the editorial that accompanies this paper, Kunisaki and Niewoehner point out that there is an ongoing, NIH-funded study to assess the effects of chronic use of a different macrolide, azithromycin, on COPD exacerbations.1 Results of this study are likely to be available in the very near future. These findings, combined with those of the current report and the results of a Cochrane meta-analysis that showed a modest reduction in exacerbation frequency for cystic fibrosis patients treated with azithromycin,2 are likely to change the way we treat COPD. But some caution is in order. Kunisaki and Niewoehner note that bacterial resistance could be a real problem. They point out that even if only the subset of COPD patients at highest risk for exacerbations receive preventive treatment, "substantial, widespread emergence of macrolide bacterial resistance is virtually foreordained."
For now, in clinical practice, there are probably two reasonable options: Await the results of the NIH trial of azithromycin, or use erythromycin only in those patients at highest risk for exacerbation. And who are those? According to this work and others, patients with 3 or more exacerbations per year are at highest risk.3
References
1. Kunisaki KM, Niewoehner DE. Antibiotic prophylaxis for chronic obstructive pulmonary disease: Resurrecting an old idea. Am J Respir Crit Care Med 2008;178:1098-1099.
2. Southern KW, et al. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2004;(2):CD002203.
3. Seemungal T, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418-1422.
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