重症哮喘患者长期阿奇霉素治疗可减少流感嗜血杆菌感染，增加了抗生素耐药性
2020/02/11
摘要
立题依据：大环内酯类抗生素阿奇霉素可减少患有持续性症状性成年人哮喘的急性加重。然而，由于大环内酯类药物的多效性，可能会出现非预期的细菌学后果：例如病原体定植的增加或对抗生素耐药性细菌的传播，这使阿奇霉素维持治疗的长期安全性受到质疑。
目的：探讨阿奇霉素对气道菌群、病原体丰度和耐药基因携带的影响。
方法：采用16S rRNA测序和定量PCR评估阿奇霉素对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48周、双盲、安慰剂对照试验，对患有持续性非控制性成人哮喘每周三次口服500mg阿奇霉素。采用混合模板鸟枪基因组测序、定量PCR和分离全基因组测序对抗生素耐药性进行评估。
测量指标和主要结果：61例患者（34例安慰剂，27例阿奇霉素）成对痰标本。阿奇霉素不影响细菌载量（P =0.37），但显著降低了Faith的系统发育多样性（P =0.026）和流感嗜血杆菌载量（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、卡他莫拉菌水平无显著影响。在检测到的89个抗生素耐药基因中，5个大环内酯类耐药基因和2个四环素类耐药基因显著增加。
结论：在持续性未控制的哮喘患者中，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，但未改变总细菌负荷。大环内酯类抗药性增加，反映了先前的研究。这些结果强调了评估非抗生素大环内酯类药物作为持续治疗未控制哮喘患者的长期治疗效果的研究的必要性。
Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma.
Taylor SL, et al. Am J Respir Crit Care Med. 2019 Aug 1.
Abstract
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.
立题依据：大环内酯类抗生素阿奇霉素可减少患有持续性症状性成年人哮喘的急性加重。然而，由于大环内酯类药物的多效性，可能会出现非预期的细菌学后果：例如病原体定植的增加或对抗生素耐药性细菌的传播，这使阿奇霉素维持治疗的长期安全性受到质疑。
目的：探讨阿奇霉素对气道菌群、病原体丰度和耐药基因携带的影响。
方法：采用16S rRNA测序和定量PCR评估阿奇霉素对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48周、双盲、安慰剂对照试验，对患有持续性非控制性成人哮喘每周三次口服500mg阿奇霉素。采用混合模板鸟枪基因组测序、定量PCR和分离全基因组测序对抗生素耐药性进行评估。
测量指标和主要结果：61例患者（34例安慰剂，27例阿奇霉素）成对痰标本。阿奇霉素不影响细菌载量（P =0.37），但显著降低了Faith的系统发育多样性（P =0.026）和流感嗜血杆菌载量（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、卡他莫拉菌水平无显著影响。在检测到的89个抗生素耐药基因中，5个大环内酯类耐药基因和2个四环素类耐药基因显著增加。
结论：在持续性未控制的哮喘患者中，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，但未改变总细菌负荷。大环内酯类抗药性增加，反映了先前的研究。这些结果强调了评估非抗生素大环内酯类药物作为持续治疗未控制哮喘患者的长期治疗效果的研究的必要性。
（中国医科大学附属第一医院 李文扬 摘译 杨冬 审校）
（Taylor SL, et al. Am J Respir Crit Care Med. 2019 Aug 1.）
（Taylor SL, et al. Am J Respir Crit Care Med. 2019 Aug 1.）
Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma.
Taylor SL, et al. Am J Respir Crit Care Med. 2019 Aug 1.
Abstract
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.
