重症哮喘患者长期使用阿奇霉素可降低流感嗜血杆菌的发病率、增加抗生素耐药性
2019/09/09
摘要
依据:大环内酯类阿奇霉素可减少持续症状哮喘患者病情恶化。然而，由于大环内酯类药物的多效性，出现多种意想不到的细菌学结果，如增加病原体定植或耐药病原体的传播，引起对阿奇霉素维持治疗长期安全性的质疑。
目的：评估阿奇霉素对气道微生物、病原体量、耐药性基因的效应。
方法：采用16S rRNA测序和定量PCR技术进行评估阿奇霉素对AMAZES(哮喘和大环内酯:阿奇霉素疗效和安全性)试验参与者的痰微生物学的影响:一项为期48周、双盲、安慰剂对照试验，每周3次、每次口服500毫克阿奇霉素，用于持续不受控制的哮喘成人。采用联合模板猎枪元基因组测序、定量PCR、分离全基因组测序等方法评估抗生素耐药性。
测量方法及主要结果：61例患者的配对痰标本(34例使用安慰剂，27例使用阿奇霉素)。阿奇霉素不影响细菌负荷(P = 0.37)，但显著降低Faith的系统发育多样性(P = 0.026)及流感嗜血杆菌负荷(P < 0.0001)。阿奇霉素对肺炎链球菌、金黄色葡萄球菌、铜绿假单胞菌或莫拉克斯氏菌属卡他莫拉菌无明显影响。在检测到的89个耐药基因中，5种大环内酯耐药基因和2种四环素耐药基因显著增加。
结论：在持续难控制哮喘患者中，与安慰剂相比，阿奇霉素可降低气道流感嗜血杆菌负荷，但不会改变总体细菌负荷量。大环内酯类耐药性增加，支持既往研究。这些结果强调了研究大环内酯类药物以非抗生素用途作为长期治疗持续难控制哮喘患者疗效的必要性。
Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma.
Taylor SL,Leong LEX,Mobegi FM,Choo JM,Wesselingh S,Yang IA,Upham JW,Reynolds PN,Hodge S,James AL,Jenkins C,Peters MJ,Baraket M,Marks GB,Gibson PG, Rogers GB,Simpson JL.
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.
依据:大环内酯类阿奇霉素可减少持续症状哮喘患者病情恶化。然而，由于大环内酯类药物的多效性，出现多种意想不到的细菌学结果，如增加病原体定植或耐药病原体的传播，引起对阿奇霉素维持治疗长期安全性的质疑。
目的：评估阿奇霉素对气道微生物、病原体量、耐药性基因的效应。
方法：采用16S rRNA测序和定量PCR技术进行评估阿奇霉素对AMAZES(哮喘和大环内酯:阿奇霉素疗效和安全性)试验参与者的痰微生物学的影响:一项为期48周、双盲、安慰剂对照试验，每周3次、每次口服500毫克阿奇霉素，用于持续不受控制的哮喘成人。采用联合模板猎枪元基因组测序、定量PCR、分离全基因组测序等方法评估抗生素耐药性。
测量方法及主要结果：61例患者的配对痰标本(34例使用安慰剂，27例使用阿奇霉素)。阿奇霉素不影响细菌负荷(P = 0.37)，但显著降低Faith的系统发育多样性(P = 0.026)及流感嗜血杆菌负荷(P < 0.0001)。阿奇霉素对肺炎链球菌、金黄色葡萄球菌、铜绿假单胞菌或莫拉克斯氏菌属卡他莫拉菌无明显影响。在检测到的89个耐药基因中，5种大环内酯耐药基因和2种四环素耐药基因显著增加。
结论：在持续难控制哮喘患者中，与安慰剂相比，阿奇霉素可降低气道流感嗜血杆菌负荷，但不会改变总体细菌负荷量。大环内酯类耐药性增加，支持既往研究。这些结果强调了研究大环内酯类药物以非抗生素用途作为长期治疗持续难控制哮喘患者疗效的必要性。
（中日友好医院呼吸与危重症医学科 张鑫 摘译 林江涛 审校）
（Am J Respir Crit Care Med. 2019 Aug 1;200(3):309-317.）
（Am J Respir Crit Care Med. 2019 Aug 1;200(3):309-317.）
Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma.
Taylor SL,Leong LEX,Mobegi FM,Choo JM,Wesselingh S,Yang IA,Upham JW,Reynolds PN,Hodge S,James AL,Jenkins C,Peters MJ,Baraket M,Marks GB,Gibson PG, Rogers GB,Simpson JL.
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.
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重症哮喘患者多发合并疾病的经济负担：一项基于人群的为期20年的研究
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以流感收入院的哮喘患者全身及局部炎症表现特点
