長期使用Macrolide可以幫助減少COPD惡化

作者：作者：Laurie Barclay, MD
出處：出處：WebMD醫學新聞

November 21, 2008 — 根據發表於12月1日版美國呼吸暨重症照護期刊上的隨機雙盲安慰劑控制研究結果，長期使用紅黴素(erythromycin)可以有效減少慢性阻塞性肺部 疾病(chronic obstructive pulmonary disease，COPD)的惡化。

千里達West Indies大學的Terence A. R. Seemungal等人寫道，頻繁的COPD惡化是引起住院與死亡的重要原因，且與增加呼吸道發炎有關。Macrolides有呼吸道抗發炎作用，可減少COPD惡化的發生率。

本研究的目標是檢視長期使用Macrolide是否可降低COPD惡化的頻率；研究人員將COPD門診病患隨機指派接受紅黴素250 mg或者安慰劑，每天兩次，為期12個月；主要研究終點是中度和/或嚴重惡化的人數，定義是那些使用全身性類固醇或抗生素或是住院的惡化病例。

在這109名隨機選取的門診病患中，69(63%)人是男性，52 (48%)人目前有抽菸習慣，平均年紀是67.2 ± 8.6歲，平均一秒鐘最大呼氣量(FEV1)是1.32 ± 0.53，平均FEV1%預測值為50% ± 18%；在參與試驗前一年，38(35%)名病患有至少三次復發，治療組之間沒有差異。

在研究期間，206名中度到重度惡化者 中，125人屬於安慰劑組，有10名病患從安慰劑組退出，從Macrolide組退出的有9人；根據一般線性模式，接受Macrolide者，相較於接受 安慰劑者，其惡化比率為0.648 (95% 信心區間，0.489 – 0.859; P = .003)；相較於安慰劑組的病患，Macrolide的惡化期間比較短。

在這一年的研究中，Macrolide和安慰劑組的穩 定期FEV1、痰中的介白質6 (IL-6)、 IL-8、骨髓過氧化酶(Myeloperoxidase)、菌落(bacterial flora)、血清C反應蛋白質或者血清IL-6、或者這些參數在第一次惡化時與開始時的改變並無差異。

研究作者寫道，相較於安慰劑，Macrolide治療與顯著降低惡化有關，可以有效減少此類病患的過度疾病負擔；在一年的研究期間，治療的耐受性良好。

本研究的研究限制包括痰中發炎標記的明顯變異、可能高估順從性、無法偵測研究組之間的發炎標記和抗生素的差異，且缺乏生活品質資料； 在編輯評論中，榮民醫學中心和明尼蘇達大學的Ken M. Kunisaki醫師和Dennis E. Niewoehner醫師指出，需要確認研究發現。

Kunisaki醫師和Niewoehner醫師寫道，假設Macrolide治療以減少惡化是唯一的臨床好處，想必只能用於少數惡化風險最高的COPD病患，但全球可能有數百萬或上千萬的病患。

他們結論表示，在此狀況中，實際廣泛出現的Macrolides細菌抗藥性是註定的，因此需要減少此類藥物的抗菌性；然而，權衡利益與傷害之間的兩難，使得目前尚無明確答案。

英國肺臟基金會支持本研究。研究作者與 Kunisaki博士宣稱沒有相關資金上的往來。Niewoehner醫師報告與Boehringer Ingelheim、Pfizer、Adams Respiratory Therapeutics、AstraZeneca、Schering Plough、Sanofi Aventis、Sepracor和GlaxoSmithKline等藥廠有資金上的往來。

Long-Term Macrolide Use May Help Reduce COPD Exacerbations

By Laurie Barclay, MD
Medscape Medical News

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.