Infection and Immunity Theme, South Australia Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia; School of Medicine, Flinders University, Bedford Park, Adelaide, SA, Australia.
Institute of Pharmaceutical Science, King's College London, London, UK.
Lancet Respir Med. 2014 Dec;2(12):988-96. doi: 10.1016/S2213-2600(14)70213-9. Epub 2014 Oct 14.
Long-term macrolide treatment has proven benefit in inflammatory airways diseases, but whether it leads to changes in the composition of respiratory microbiota is unknown. We aimed to assess whether long-term, low-dose erythromycin treatment changes the composition of respiratory microbiota in people with non-cystic fibrosis bronchiectasis.
Microbiota composition was determined by 16S rRNA gene sequencing of sputum samples from participants in the BLESS trial, a 12-month, double-blind, placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg) in adult patients with non-cystic fibrosis bronchiectasis and at least two infective exacerbations in the preceding year. The primary outcome was within-patient change in respiratory microbiota composition (assessed by Bray-Curtis index) between baseline and week 48, comparing erythromycin with placebo. The BLESS trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000460303.
The BLESS trial took place between Oct 15, 2008, and Dec 14, 2011. Paired sputum samples were available from 86 randomly assigned patients, 42 in the placebo group and 44 in the erythromycin group. The change in microbiota composition between baseline and week 48 was significantly greater with erythromycin than with placebo (median Bray-Curtis score 0·52 [IQR 0·14-0·78] vs 0·68 [0·46-0·93]; median difference 0·16, 95% CI 0·01-0·33; p=0·03). In patients with baseline airway infection dominated by Pseudomonas aeruginosa, erythromycin did not change microbiota composition significantly. In those with infection dominated by organisms other than P. aeruginosa, erythromycin caused a significant change in microbiota composition (p=0·03 [by analysis of similarity]), representing a reduced relative abundance of Haemophilus influenzae (35·3% [5·5-91·6] vs 6·7% [0·8-74·8]; median difference 12·6%, 95% CI 0·4-28·3; p=0·04; interaction p=0·02) and an increased relative abundance of P aeruginosa (0·02% [0·00-0·33] vs 0·13% [0·01-39·58]; median difference 6·6%, 95% CI 0·1-37·1; p=0·002; interaction p=0·45). Compared with placebo, erythromycin reduced the rate of pulmonary exacerbations over the 48 weeks of the study in patients with P. aeruginosa-dominated infection (median 1 [IQR 0-3] vs 3 [2-5]; median difference -2, 95% CI -4 to -1; p=0·01), but not in those without P. aeruginosa-dominated infection (1 [0-2] vs 1 [0-3]; median difference 0, -1 to 0; p=0·41; interaction p=0·04).
Long-term erythromycin treatment changes the composition of respiratory microbiota in patients with bronchiectasis. In patients without P. aeruginosa airway infection, erythromycin did not significantly reduce exacerbations and promoted displacement of H. influenzae by more macrolide-tolerant pathogens including P. aeruginosa. These findings argue for a cautious approach to chronic macrolide use in patients without P. aeruginosa airway infection.
Mater Adult Respiratory Research Trust Fund.
长期大环内酯类药物治疗已被证明对炎症性气道疾病有益，但它是否会改变呼吸道微生物群的组成尚不清楚。我们旨在评估长期低剂量红霉素治疗是否会改变非囊性纤维化支气管扩张症患者的呼吸道微生物群组成。
通过 16S rRNA 基因测序确定 BLESS 试验参与者的微生物群落组成，这是一项为期 12 个月的双盲、安慰剂对照试验，对非囊性纤维化支气管扩张症成年患者每天两次给予红霉素乙琥酯（400mg），在过去一年中至少有两次感染性加重。主要结局是基线和第 48 周时呼吸微生物群组成的患者内变化（通过 Bray-Curtis 指数评估），将红霉素与安慰剂进行比较。BLESS 试验在澳大利亚和新西兰临床试验注册中心注册，编号为 ACTRN12608000460303。
BLESS 试验于 2008 年 10 月 15 日至 2011 年 12 月 14 日进行。从 86 名随机分配的患者中获得了配对的痰样本，安慰剂组 42 名，红霉素组 44 名。与安慰剂相比，红霉素治疗组在基线和第 48 周时的微生物群组成变化明显更大（中位数 Bray-Curtis 评分 0.52 [IQR 0.14-0.78] vs 0.68 [0.46-0.93]；中位数差异 0.16，95%CI 0.01-0.33；p=0.03）。在基线气道感染以铜绿假单胞菌为主的患者中，红霉素治疗并未显著改变微生物群组成。在以铜绿假单胞菌以外的病原体为主的感染患者中，红霉素治疗导致微生物群组成明显变化（p=0.03[相似性分析]），代表流感嗜血杆菌的相对丰度降低（35.3%[5.5-91.6] vs 6.7%[0.8-74.8]；中位数差异 12.6%，95%CI 0.4-28.3；p=0.04；交互作用 p=0.02），铜绿假单胞菌的相对丰度增加（0.02%[0.00-0.33] vs 0.13%[0.01-39.58]；中位数差异 6.6%，95%CI 0.1-37.1；p=0.002；交互作用 p=0.45）。与安慰剂相比，红霉素治疗降低了研究期间铜绿假单胞菌感染患者的肺部恶化率（中位数 1 [IQR 0-3] vs 3 [2-5]；中位数差异 -2，95%CI -4 至-1；p=0.01），但在没有铜绿假单胞菌感染的患者中则没有（1 [0-2] vs 1 [0-3]；中位数差异 0，-1 至 0；p=0.41；交互作用 p=0.04）。
长期红霉素治疗改变了支气管扩张症患者呼吸道微生物群的组成。在没有铜绿假单胞菌气道感染的患者中，红霉素治疗并未显著减少恶化，并促进了更能耐受大环内酯类药物的病原体（包括铜绿假单胞菌）对流感嗜血杆菌的取代。这些发现表明在没有铜绿假单胞菌气道感染的患者中应谨慎使用慢性大环内酯类药物。
Mater 成人呼吸研究信托基金。
