基本原理：大环内酯类抗生素阿奇霉素可减少患有持续性症状性哮喘的成年人的病情加重。但是，由于大环内酯类化合物的多效性，可能会发生意想不到的细菌学后果，例如病原体定殖增加或对抗生素耐药性生物的传播，这使阿奇霉素维持治疗的长期安全性受到质疑。

目的：评估阿奇霉素对气道微生物群，病原体丰度和携带抗生素抗性基因的影响。

方法：采用16S rRNA测序和定量PCR评估阿马霉素对AMAZES（哮喘和大环内酯类药物：阿奇霉素功效和安全性）试验参与者的痰微生物学影响：一项为期48周，双盲，安慰剂对照的试验在患有持续性不受控制的哮喘的成年人中，每周三次口服500 mg阿奇霉素治疗。合并模板shot弹枪宏基因组测序，定量PCR和分离全基因组测序进行评估抗生素耐药性。

测量和主要结果：配对痰标本来自61例患者（n = 34安慰剂，n = 27阿奇霉素）。阿奇霉素不影响细菌负荷（P = 0.37），但会显着降低Faith的系统发育多样性（P = 260.026）和流感嗜血杆菌的负荷（P <0.0001）。阿奇霉素对肺炎链球菌，金黄色葡萄球菌，铜绿假单胞菌或卡他莫拉菌的水平没有显着影响。在检测到的89种抗生素抗性基因中，五个大环内酯类抗性基因和两个四环素抗性基因显着增加。

结论：在持续性不受控制的哮喘患者中，阿奇霉素与安慰剂相比减少了呼吸道流感嗜血杆菌的负荷，但并未改变总细菌负荷。大环内酯类药物的耐药性增加，反映了以前的研究。这些结果强调需要评估非抗生素大环内酯类药物作为持续治疗不受控制的哮喘患者的长期治疗效果的研究。

Rationale: The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.

Objectives: To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.

Methods: 16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.

Measurements and Main Results: Paired sputum samples were available from 61 patients (n = 34 placebo, n = 27 azithromycin). Azithromycin did not affect bacterial load (P = 0.37) but did significantly decrease Faith’s phylogenetic diversity (P = 0.026) and Haemophilus influenzae load (P < 0.0001). Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.

Conclusions: In patients with persistent uncontrolled asthma, azithromycin reduced airway H. influenzae load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.

https://www.atsjournals.org/doi/abs/10.1164/rccm.201809-1739OC