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Long Term Macrolide Use May Help Reduce COPD Exacerbations

Laurie Barclay, MD

Medscape Medical News 2008. © 2008 Medscape

November 21, 2008 — Long-term use of erythromycin was effective in reducing exacerbations of chronic obstructive pulmonary disease (COPD), according to the results of a randomized, double-blind, placebo-controlled study reported in the December 1 issue of the American Journal of Respiratory and Critical Care Medicine.

"Frequent [COPD] exacerbations are a major cause of hospital admission and mortality and are associated with increased airway inflammation," write Terence A. R. Seemungal, from University of the West Indies in Trinidad and Tobago, and colleagues. "Macrolides have airway anti-inflammatory actions and may reduce the incidence of COPD exacerbations."

The goal of this study was to examine whether chronic macrolide therapy reduces the frequency of COPD exacerbations. Outpatients with COPD were randomly assigned to receive either erythromycin 250 mg or placebo twice daily for a 12-month period. The main study endpoint was the number of moderate and/or severe exacerbations, defined as those exacerbations that were treated with systemic steroids or antibiotics or that led to hospitalizations.

Of 109 randomized outpatients, 69 (63%) were men, and 52 (48%) were current smokers. Mean age was 67.2 ± 8.6 years, mean forced expiratory volume in 1 second (FEV₁) was 1.32 ± 0.53, and mean FEV₁% predicted was 50% ± 18%. In the year before recruitment, 38 patients (35%) had at least 3 exacerbations, with no differences between treatment groups.

Of 206 moderate to severe exacerbations that occurred during the study, 125 were in the placebo group. Ten patients withdrew from the placebo group and 9 from the macrolide group. The rate ratio for exacerbations for the patients receiving macrolide vs the patients receiving placebo was 0.648 (95% confidence interval, 0.489 – 0.859; P = .003) based on generalized linear modeling. Compared with patients in the placebo group, those in the macrolide group had a shorter duration of exacerbations.

The macrolide and placebo groups did not differ in stable FEV₁, sputum interleukin 6 (IL-6), IL-8, myeloperoxidase, bacterial flora, serum C-reactive protein, or serum IL-6 or in changes in these parameters from baseline to the first exacerbation during the 1-year study.

"Macrolide therapy was associated with a significant reduction in exacerbations compared with placebo and may be useful in decreasing the excessive disease burden in this important patient population," the study authors write. "The treatment was well tolerated over the 1-year study period."

Limitations of this study include significant variability of sputum inflammatory markers, possible overestimate of compliance, insufficient power to detect a difference between study groups in terms of inflammatory markers and bacterial agents, and lack of quality-of-life data.

In an accompanying editorial, Ken M. Kunisaki, MD, and Dennis E. Niewoehner, MD, from the Veterans Affairs Medical Center and the University of Minnesota in Minneapolis, note that the study findings require confirmation.

"Macrolide therapy for reduction of exacerbations, assuming that is the only clinical benefit, presumably would be indicated for only a small proportion of patients with COPD at highest risk for exacerbations," Dr. Kunisaki and Dr. Niewoehner write. "But this might still include millions or even tens of millions of patients on a global scale."

They conclude, "In this scenario, substantial, widespread emergence of macrolide bacterial resistance is virtually foreordained, with attendant reduction in the antimicrobial usefulness of this drug class. Balancing benefit against harm could pose a dilemma for which there might be no clear answers."

The British Lung Foundation supported this study. The study authors and Dr. Kunisaki have disclosed no relevant financial relationships. Dr. Niewoehner reports various financial relationships with Boehringer Ingelheim, Pfizer, Adams Respiratory Therapeutics, AstraZeneca, Schering Plough, Sanofi Aventis, Sepracor, and GlaxoSmithKline.

Am J Respir Crit Care Med. 2008;178:1098–1099, 1139–1147.