Professor of Paediatrics and Paediatric Respirology, Imperial College Consultant Paediatric Chest Physician, Royal Brompton & Harefield NHS Foundation Trust, National Heart and Lung Institute, UK; Paediatric Chest Physician, Royal Brompton Harefield NHS Foundation Trust, UK.
Paediatr Respir Rev. 2020 Apr;34:67-74. doi: 10.1016/j.prrv.2019.07.002. Epub 2019 Aug 16.
The first clinical indication of non-antibiotic benefits of macrolides was in the Far East, in adults with diffuse panbronchiolitis. This condition is characterised by chronic airway infection, often with Pseudomonas aeruginosa, airway inflammation, bronchiectasis and a high mortality. Low dose erythromycin, and subsequently other macrolides, led in many cases to complete remission of the condition, and abrogated the neutrophilic airway inflammation characteristic of the disease. This dramatic finding sparked a flurry of interest in the many hundreds of macrolides in nature, especially their anti-inflammatory and immunomodulatory effects. The biggest subsequent trials of azithromycin were in cystic fibrosis, which has obvious similarities to diffuse panbronchiolitis. There were unquestionable improvements in lung function and pulmonary exacerbations, but compared to diffuse panbronchiolitis, the results were disappointing. Case reports, case series and some randomised controlled trials followed in other conditions. Three trials of azithromycin in preschool wheeze gave contradictory results; a trial in pauci-inflammatory adult asthma, and a trial in non-cystic fibrosis bronchiectasis both showed a significant reduction in exacerbations, but none matched the dramatic results in diffuse panbronchiolitis. There is clearly a huge risk of antibacterial resistance if macrolides are used widely and uncritically in the community. In summary, Azithromycin is not the answer to anything in paediatric respiratory medicine; the paediatric respiratory community needs to refocus on the dramatic benefits of macrolides in diffuse panbronchiolitis, use modern - omics technologies to determine the endotypes of inflammatory diseases and discover in nature or synthesise designer macrolides to replicate the diffuse panbronchiolitis results. We must now find out how to do better!
大环内酯类药物的非抗生素益处的第一个临床迹象出现在远东地区，成人弥漫性泛细支气管炎患者中。这种疾病的特征是慢性气道感染，通常由铜绿假单胞菌引起，气道炎症、支气管扩张和高死亡率。小剂量红霉素，随后是其他大环内酯类药物，导致许多情况下疾病完全缓解，并消除了疾病特征性的中性粒细胞气道炎症。这一戏剧性的发现引发了人们对自然界中数百种大环内酯类药物的浓厚兴趣，尤其是它们的抗炎和免疫调节作用。随后在囊性纤维化中进行的最大规模的阿奇霉素试验，与弥漫性泛细支气管炎有明显的相似之处。肺功能和肺部恶化都有明显改善，但与弥漫性泛细支气管炎相比，结果令人失望。随后在其他疾病中出现了病例报告、病例系列和一些随机对照试验。阿奇霉素治疗学龄前喘息的三项试验结果相互矛盾；一项在炎症性成人哮喘中的试验和一项在非囊性纤维化支气管扩张症中的试验都显示出发作次数显著减少，但都没有达到弥漫性泛细支气管炎的显著效果。如果大环内酯类药物在社区中被广泛且不加批判地使用，那么抗菌药物耐药性的风险显然是巨大的。总之，阿奇霉素在儿科呼吸医学中不是什么问题的答案；儿科呼吸界需要重新关注大环内酯类药物在弥漫性泛细支气管炎中的显著益处，利用现代组学技术确定炎症性疾病的表型，并在自然界中发现或合成设计大环内酯类药物来复制弥漫性泛细支气管炎的结果。我们现在必须想办法做得更好！
