长期使用抗生素可减少支气管扩张加重

两项随机对照研究(BLESS和BAT)显示，非囊性纤维化支气管扩张患者使用小剂量大环内酯类抗生素12个月可显著减少肺部症状加重。然而，抗生素耐药问题可能会影响这种方法在临床实践中的应用。

BLESS是一项由澳大利亚南布里斯班Mater成人医院的David Serisier博士及其同事进行的单中心研究，纳入117例过去1年内具有≥2次感染性加重史的门诊患者。患者接受2次/d红霉素(400 mg)或安慰剂治疗。红霉素组和安慰剂组患者的平均年龄分别为61.1岁和63.5岁(JAMA 2013;309:1260-7)。

结果显示，红霉素组每例患者每年的肺部症状加重的年平均发生率为1.29，而安慰剂组为1.97(P=0.003)。红霉素治疗使年平均加重发生率相对降低43%。在铜绿假单胞菌呼吸道感染亚组患者中也观察到加重发生率显著降低。此外，红霉素可减少24 h痰量和改善肺功能。

BAT研究由荷兰阿尔克马尔医疗中心的Josje Altenburg博士及其同事在14个荷兰医院进行，纳入83例过去1年内具有3次或3次以上呼吸道感染史的门诊患者。患者随机接受250 mg/d阿奇霉素或安慰剂治疗。阿奇霉素组和安慰剂组患者的平均年龄分别为59.9岁和64.6岁(JAMA 2013;309:1251-9)。

结果显示，阿奇霉素组患者在研究期间发生至少1次加重的风险显著低于安慰剂组[46.5% vs. 80%，风险比(HR)=0.29]。阿奇霉素组1年后加重的中位数为0，而安慰剂组为2(P＜0.001)。为维持临床稳定，需接受阿奇霉素治疗的患者数量为3.0。与安慰剂相比，阿奇霉素治疗还可改善肺功能。

长期使用这些抗生素治疗的问题在于可能产生大环内酯类耐药。在BAT研究中，阿奇霉素组和安慰剂组的大环内酯类耐药发生率分别为88%和26%。在BLESS研究中，红霉素组大环内酯类耐药口咽部链球菌比例增加，中位增加27.7%，而安慰剂为0.04%(P＜0.001)。

BLESS研究获Mater成人呼吸研究信托基金资助。Serisier博士声明从阿斯利康等公司获得酬金、演讲费或差旅费。BAT研究获荷兰Foreest医学院和葛兰素史克资助。硫唑嘌呤片剂由荷兰梯瓦公司提供。Altenburg博士声明无经济利益冲突。

随刊述评：大环内酯类疗效和耐药并存

英国贝尔法斯特女王大学的J. Stuart Elborn博士和Michael Tunney博士指出，这两项研究表明，长期大环内酯类维持治疗对支气管扩张患者有益。不过，两项研究中的大环内酯类耐药率均较高，当然，在长期应用其他抗生素时也会出现这一耐药率高的问题。因此，在进行长期抗生素治疗时，需权衡其获益和风险(JAMA 2013;309:1295-6)。

这两项研究探讨的都是已知的致病菌，如共生口咽部链球菌(BLESS研究)及流感嗜血杆菌、铜绿假单胞菌和肺炎链球菌(BAT研究)。而我们知道在这些患者的痰液中还存在其他多种细菌，其他细菌的耐药问题也需要进一步研究。这两项研究未采用定量培养来确定痰液总细菌负荷或各种细菌密度的降低是否与加重频率的减少相关，因此作用机制尚不清楚。

虽然这些研究表明红霉素和阿奇霉素可降低肺部加重发生率和改善肺功能，但由于耐药问题的存在，可能难以将这些研究结果外推至更广泛的临床人群，并且要确定哪些患者可从长期大环内酯类抗生素治疗中得到最大益处也有难度。未来需开展进一步长期研究，以更好地确定支气管扩张患者中大环内酯类维持治疗、呼吸道微生物组(microbiome)和耐药基因组(resistome)及临床疗效之间的关系。

Elborn博士和Tunney博士均声明无经济利益冲突。

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By: SARA FREEMAN, Internal Medicine News Digital Network

Low-dose macrolide antibiotics given for 12 months significantly reduced pulmonary exacerbations in non–cystic fibrosis bronchiectasis, according to findings from two randomized, controlled trials.

However, antibiotic resistance concerns could temper the use of such an approach in clinical practice, the studies’ investigators cautioned.

In BLESS (Bronchiectasis and Low-Dose Erythromycin Study), the annualized mean rate of pulmonary exacerbations per patient per year was 1.29 in patients treated with erythromycin, compared with 1.97 in those given placebo (P = .003) (JAMA 2013;309:1260-7).

In the BAT (Bronchiectasis and Long-Term Azithromycin Treatment) study, the median number of exacerbations after 1 year was 0 in azithromycin-treated patients, compared with 2 in patients given placebo (P less than .001) (JAMA 2013;309:1251-9).

Both studies’ findings are consistent with those of the EMBRACE trial published last year (Lancet 2012;380:660-77), which showed a 500 mg-dose of azithromycin given for 6 months reduced the incidence of pulmonary exacerbations, compared with placebo, in patients who had at least one exacerbation in the past year.

"The BLESS and BAT trials provide robust evidence for a beneficial effect of long-term macrolide maintenance therapy in patients with bronchiectasis," observed Dr. J. Stuart Elborn and Michael Tunney, Ph.D., in an editorial accompanying the articles (JAMA 2013;309:1295-6).

"Given the paucity of evidence for treatments in bronchiectasis, the results of these studies and the recently published EMBRACE trial are welcome, because they provide a good evidence base for an effective therapy for bronchiectasis," added the commentators, both of Queen’s University Belfast, U.K.

Bronchiectasis is characterized by widening of the airways – specifically, the small and medium-size bronchi – mucosal thickening, and bronchial inflammation. Sufferers are usually dogged by a chronic cough and sputum production, impaired lung function, and infection-related exacerbations.

BLESS was a single-center trial conducted in Australia involving 117 outpatients with a history of two or more infective exacerbations in the past year. Patients were treated with twice-daily erythromycin (400 mg) or placebo. The mean ages of antibiotic- and placebo-treated patients were 61.1 years and 63.5 years, respectively.

Treatment with erythromycin resulted in a 43% relative reduction in the mean annualized exacerbation rate. Exacerbations also were significantly decreased in a pre-specified subgroup of patients with Pseudomonas aeruginosa airway infection.

Furthermore, "erythromycin reduced 24-hour sputum production and attenuated lung function," wrote Dr. David Serisier and his colleagues at Mater Adult Hospital in South Brisbane, Australia.

The BAT study was conducted in 14 Dutch hospitals and involved 83 outpatients with a history of three or more lower respiratory tract infections in the past year. Patients were randomized to a daily dose of 250 mg azithromycin or placebo. The mean ages of antibiotic- and placebo-treated patients were 59.9 years and 64.6 years, respectively.

The risk of patients experiencing at least one exacerbation during the trial was significantly lower if they had been treated with the antibiotic rather than being given placebo (46.5% vs. 80%, hazard ratio = 0.29).

"The number of patients needed to treat with azithromycin to maintain clinical stability was 3.0," Dr. Josje Altenburg, Medical Centre Alkmaar, the Netherlands, and associates reported. Azithromycin therapy also was associated with improved lung function, compared with placebo.

One concern with long-term treatment using these antibiotics is the possible development of macrolide resistance. Dr. Altenburg and colleagues reported a macrolide resistance rate of 88% with azithromycin, vs. 26% with placebo. In BLESS, Dr. Serisier and his coauthors observed an increased proportion of macrolide-resistant oropharyngeal streptococci, with a median increase of 27.7%, compared with 0.04% with placebo (P less than .001).

"The bacterial resistance caused by macrolide therapy mandates a cautious application of this therapy in clinical practice," Dr. Serisier and associates acknowledged. They added that the potential for resistance must "curb enthusiasm" for widespread erythromycin use.

"The benefits of long-term macrolide treatment for individual patients with bronchiectasis need to be balanced with increasing concerns regarding the development of resistance to both macrolides and other antibiotics among airway microbiota," Dr. Elborn and Dr. Tunney similarly observed in their accompanying editorial.

"Further long-term studies are required to better determine the relationship between maintenance macrolide treatment, the airway microbiome and resistome, and clinical efficacy in patients with bronchiectasis," they cautioned.

The Mater Adult Respiratory Research Trust Fund funded the BLESS trial. Dr. Serisier reported receiving honoraria, speaker fees, or travel support from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Pharmaxia, and Phebra. The BAT trial was supported by a research grant from the Foreest Medical School, Alkmaar, the Netherlands, and an unrestricted research grant from GlaxoSmithKline. Teva Netherlands provided the azathioprine tablets. Dr. Altenburg, Dr. Elborn, and Dr. Tunney had no disclosures.

Resistance balances out macrolide efficacy

Dr. J. Stuart Elborn comments: For years, there has been no specific, evidence-based treatment for non–cystic fibrosis bronchiectasis. Now, with the publication of three trials (BLESS, BAT, and EMBRACE), there is evidence of a benefit with prolonged macrolide antibiotic treatment.

However, the authors of BLESS and the BAT trial both reported high rates of macrolide resistance. This is, of course, a concern with any prolonged antibiotic use.

The researchers are to be commended for addressing the issue of resistance in their studies. They looked for "known pathogens," notably commensal oropharyngeal streptococci in BLESS, and Haemophilus influenzae, Pseudomonas aeruginosa, and Streptococci pneumoniae in the BAT trial. We now know there is a community of bacteria in the sputum of these patients, and resistance in other bacteria may also be an issue.

The studies did not use quantitative cultures to see if a decrease in the total sputum bacterial load or the density of individual species could be linked to the reduced exacerbation frequency, so the mechanism of the improvement is not clear.

Erythromycin and azithromycin have been clearly shown to reduce pulmonary exacerbation rates and improve lung function in these trials. The concern over antibiotic resistance remains. There will be some challenges in extrapolating the results to the wider clinical population and determining which patients could benefit most from long-term macrolide antibiotic treatment; but further evidence of this effective therapy is welcome.

Dr. J. Stuart Elborn is director of the center for infection and immunity, Queen’s University Belfast (U.K.).