1996年獲批現(xiàn)已得到廣泛應(yīng)用的藥物如今有了新用途，它可以明顯減少疾病的加重次數(shù)，推遲非囊性纖維化支氣管擴(kuò)張癥患者的首次加重時間，至少可以比上一年減少一次加重次數(shù)。

    “使用阿奇霉素控制病情加重的支氣管擴(kuò)張癥患者的大環(huán)內(nèi)酯類藥物治療效果”（EMBRACE）試驗(yàn)由新西蘭研究人員進(jìn)行。結(jié)果發(fā)表在8月18日的《柳葉刀》雜志上。該期雜志為呼吸病學(xué)?？?，恰好在奧地利維也納舉辦的歐洲呼吸學(xué)會年會之前發(fā)表。

    非囊性纖維化支氣管擴(kuò)張癥是一種使人極度虛弱的慢性疾病，導(dǎo)致肺功能進(jìn)行性下降?；颊叱霈F(xiàn)呼吸道炎癥，通常由嗜中性粒細(xì)胞入侵、長期細(xì)菌感染、復(fù)發(fā)性肺病加重及排痰性咳嗽等引起。

    雖然這種疾病的流行情況尚不清楚，“但是，憑借現(xiàn)代診斷技術(shù)，人們對支氣管擴(kuò)張癥的了解越來越多。1993年至2006年，美國的支氣管擴(kuò)張癥相關(guān)住院人數(shù)每年增長2%－3%，同期年平均住院率為十萬分之十六點(diǎn)五，”首席研究員、新西蘭奧克蘭市Middlemore醫(yī)院呼吸病內(nèi)科Conroy Wong博士說。

    目前，針對這些患者的循證治療方案不多。大環(huán)內(nèi)脂類抗生素阿奇霉素既有抗炎性又有免疫調(diào)節(jié)功能。Dr. Wong告訴《醫(yī)景醫(yī)學(xué)新聞》，“大環(huán)內(nèi)脂類抗生素對支氣管擴(kuò)張癥的作用機(jī)制是多方面的……，本研究目的不是專門評價它的作用機(jī)制，但是，阿奇霉素看來很可能具有抗菌和抗炎這兩種作用機(jī)制。本研究暗示，痰培養(yǎng)時細(xì)菌減少（抗菌效果），阿奇霉素組血液和痰中的中性白細(xì)胞計(jì)數(shù)下降。”

    新西蘭3家中心的一項(xiàng)隨機(jī)雙盲安慰劑對照試驗(yàn)對阿奇霉素是否可以減少疾病加重次數(shù)、改善肺功能進(jìn)行了研究。參試者年齡≥18歲，參試前一年至少發(fā)生一次需要抗生素治療的肺病加重，支氣管擴(kuò)張癥由高分辨CT掃描確診。2008年2月12日至2009年10月15日，研究人員共納入患者141例，隨后隨機(jī)分配接受500mg阿奇霉素或安慰劑治療，一周3次，共6個月。阿奇霉素組治療期間加重次數(shù)明顯少于安慰劑組（42 : 103）。

    研究達(dá)到一項(xiàng)復(fù)合觀察終點(diǎn)：6個月治療期間，基于事件的加重率分別為：阿奇霉素治療組71例，0.59%；安慰劑組70例，1.57%。此外，加重率相對減少62%（比率，0.38，95%置信區(qū)間[CI]，0.26 － 0.54；P < .0001）。

    6個月試驗(yàn)期間，阿奇霉素組患者幾乎未有疾病發(fā)作，因此，研究人員將至少25%患者出現(xiàn)首次加重的時間確定為首次加重時間。該時間為，阿奇霉素組104天（95% CI，48 － 186），安慰劑組21天（95% CI，11 － 48）（危害比[HR]，0.34；P < .0001）。12個月治療和隨訪期首次加重中位時間，阿奇霉素組239天（95% CI，190 － 331），安慰劑組85天（95% CI，52 － 113）（HR，0.44；P < .0001）。

    試驗(yàn)結(jié)束后，患者繼續(xù)受益于治療。Dr. Wong稱，“本次研究結(jié)果顯示，6個月阿奇霉素治療減少加重次數(shù)，推遲首次加重時間，這些好處似乎可在治療后持續(xù)6個月。”

    研究未達(dá)到其他2個復(fù)合觀察終點(diǎn)。阿奇霉素組支氣管擴(kuò)張前1秒鐘用力呼氣量與基線相同，安慰劑組下降0.04L（95% CI，0.03 － 0.12；P = .251）。兩組圣？？喬治呼吸問卷總分?jǐn)?shù)接近，組間差異–3.25 （95% CI，–7.21 － 0.72；P = .108）。阿奇霉素組加重風(fēng)險減半，分別有31%的阿奇霉素組患者和66%的安慰劑組患者報告，治療期間至少出現(xiàn)一次加重。

    研究人員得出結(jié)論，阿奇霉素是預(yù)防非囊性纖維化支氣管擴(kuò)張癥患者疾病加重的新選項(xiàng)，不過，研究人員也建議臨床醫(yī)師“要謹(jǐn)慎選擇接受阿奇霉素長期治療的患者，因?yàn)樵絹碓蕉嗟娜藫?dān)心會出現(xiàn)大環(huán)內(nèi)脂類藥物抗藥性。”

    在隨刊評論中，英國倫敦皇家布朗普頓醫(yī)院的Robert Wilson博士和Athol Wells博士指出，這次大型前瞻性研究，為“非囊性纖維化支氣管擴(kuò)張癥便宜療法的良好療效提供了明確的證據(jù)。”他們還敦促注意增加大環(huán)內(nèi)脂類藥物的抗藥性，建議進(jìn)行更多研究，以確定阿奇霉素對哪些患者好處最大。“對疾病嚴(yán)重性的前瞻性評估和事先考慮縱向性疾病行為方式可以為未來研究確定干預(yù)受益最大的支氣管擴(kuò)張癥患者提供最佳的機(jī)會，”

    Dr.Wong指出，“隨著對大環(huán)內(nèi)脂類藥物抗藥性擔(dān)心的增加，研究人員已經(jīng)在關(guān)注大環(huán)內(nèi)脂類的非抗菌功效?，F(xiàn)在已經(jīng)從阿奇霉素和紅霉素中衍生出新的藥劑，目前正處于早期研制階段。這些藥劑沒有抗菌功效，因此，較少甚至沒有抗藥性風(fēng)險，不過，似乎有抗炎和免疫調(diào)節(jié)功效。”

    英文全文見下：

    Azithromycin Lessens Bronchiectasis Exacerbations

    August 22, 2012 — A new application of a drug that was approved in 1996 and has been widely used since significantly decreased the frequency of exacerbations and increased the time to first exacerbation in patients with noncystic fibrosis bronchiectasis and at least 1 exacerbation during the previous year.

    The Effectiveness of Macrolides in Patients with Bronchiectasis Using Azithromycin to Control Exacerbations （EMBRACE） trial was conducted by a team of researchers from New Zealand. The results were published in the August 18 issue of the Lancet. The issue is devoted to respiratory medicine and was released just ahead of the European Respiratory Society Annual Congress being held in Vienna, Austria.

    Noncystic fibrosis bronchiectasis is a highly debilitating chronic condition that results in a progressive decline in lung function. Patients experience inflammation of the airways caused by neutrophil invasion, chronic bacterial infection, recurrent pulmonary exacerbations, and a productive cough.

    Although the prevalence of this condition is not known, “with modern diagnostic techniques, bronchiectasis is increasingly being recognized. In the United States, the number of bronchiectasis-associated admissions increased by 2% to 3% per year between 1993 and 2006, and the mean annual rate of admission in this period was 16.5 per 100,000 people,” according to lead investigator Conroy Wong, **hB, from the Department of Respiratory Medicine at Middlemore Hospital in Auckland, New Zealand.

    Few evidence-based therapeutic options exist for these patients. Azithromycin, a macrolide antibiotic, has both antiinflammatory and immunomodulatory properties. As Dr. Wong explained to Medscape Medical News, “there are multiple potential mechanisms of action of the macrolide antibiotics in bronchiectasis… Our study was not designed to specifically evaluate the mechanism of action, but it seems likely that azithromycin acts by both antibiotic and antiinflammatory mechanisms. Our study hinted at a reduction in organisms cultured in sputum （antibiotic effect） and showed reduced blood and sputum neutrophil counts in the azithromycin group.”

    Whether azithromycin can decrease the frequency of exacerbations and improve lung function was tested in a randomized, double-blind, placebo-controlled trial conducted at 3 New Zealand centers. Trial participants were 18 years or older and had to have had at least 1 pulmonary exacerbation requiring antibiotic treatment in the previous year plus bronchiectasis diagnosed by high-resolution computed tomography scan. The researchers enrolled 141 patients from February 12, 2008 to October 15, 2009, and subsequently randomized them to receive azithromycin 500 mg or placebo 3 times a week for 6 months.

    The number of exacerbations during the treatment period was much lower in the azithromycin group than in the placebo group （42 vs 103）。

    The study met one of the coprimary end points: the rate of event-based exacerbations during the 6-month treatment period was 0.59 per patient in the 71 patients who received azithromycin and 1.57 per patient in the 70 patients who received placebo. In addition, a 62% relative reduction in the rate of exacerbations was seen （rate ratio, 0.38; 95% confidence interval [CI], 0.26 to 0.54; P < .0001）。

    Because few patients in the azithromycin group experienced an episode during the 6-month trial, researchers defined time to first exacerbation as the time until at least 25% of the patients had a first exacerbation. This time was 104 days （95% CI, 48 to 186） in the azithromycin group and 21 days （95% CI, 11 to 48） in the placebo group （hazard ratio [HR], 0.34; P < .0001）。 Over the 12-month treatment and follow-up period, median time to first exacerbation was 239 days （95% CI, 190 to 331） in the azithromycin group and 85 days （95% CI, 52 to 113） in the placebo group （HR, 0.44; P < .0001）。

    Patients continued to benefit from the treatment after the trial ended. According to Dr. Wong, “our results show that azithromycin treatment for 6 months decreases the frequency of exacerbations and increases the time to first exacerbation. These benefits seem to persist for 6 months after the treatment is completed.”

    The study did not meet the other 2 coprimary end points. Forced expiratory volume in 1 s before bronchodilation did not change from baseline in the azithromycin group; in the placebo group, it decreased by 0.04 L （95% CI, 0.03 to 0.12; P = .251）。 The total score on the St. George's Respiratory Questionnaire was similar in the azithromycin and placebo groups; the difference between the groups was –3.25 （95% CI, –7.21 to 0.72; P = .108）。

    The risk for an exacerbation was halved with azithromycin; 31% of the azithromycin group and 66% of the placebo group reported at least 1 exacerbation during the treatment period.

    The researchers conclude that azithromycin is a new option for the prevention of exacerbations in patients with noncystic fibrosis bronchiectasis, but recommend that clinicians take “a careful approach to the selection of patients for long-term azithromycin treatment because of increasing concerns about macrolide resistance.”

    In an accompanying comment, Robert Wilson, MD, and Athol Wells, MD, both from the Royal Brompton Hospital in London, United Kingdom, explain that this study provides “clear evidence for a beneficial effect of an inexpensive treatment for noncystic fibrosis bronchiectasis in a large prospective study.” They too urge caution in light of increasing macrolide resistance, and suggest additional study to determine which patients could benefit most from azithromycin. “The prospective assessment of disease severity and thea prioriconsideration of patterns of longitudinal disease behavior could provide the best chance in future studies to identify patients with bronchiectasis with the most to gain from an intervention.”

    Dr. Wong noted that “with increasing concerns about macrolide resistance, researchers have been focusing on the nonantibiotic effects of macrolides. There are new agents derived from azithromycin and erythromycin that are in early-phase development. These agents do not have antibiotic effects, therefore less or no risk of resistance, but appear to have the antiinflammatory and immunomodulatory effects.”