摘要
      囊性纤维化（PwCF）患者的肺部恶化（PEx）部分与肺部感染有关。虽然较高的微生物多样性与较高的肺功能有关，但关于短期抗生素对微生物多样性变化的影响的数据是相互矛盾的。此外，普雷沃氏菌分泌β-内酰胺酶，这可能影响肺功能的恢复。我们假设亚治疗性和广谱抗生素暴露会导致微生物多样性下降。我们的第二个目的是通过通路分析评估β-内酰胺药代动力学（PK）、抗生素谱、微生物多样性和抗生素耐药性对肺功能恢复的协同作用。这是一项回顾性观察性研究，针对2016年至2020年间在国家儿童医院接受PEx静脉抗生素治疗的CF患者；在入院时收集呼吸样本和临床信息，进行PEx（E）、抗生素治疗结束（T）和随访（F）。进行宏基因组测序；PathoScope 2.0和AmrPlusPlus用于细菌和抗生素抗性基因（ARGs）序列的分类分配。M/W Pharm用于PK建模。在STATA中进行分类变量和连续变量的比较以及通路分析。22名普华永道会计师事务所经历了43次PEx。研究队列的平均年龄为14.6岁。只有12/43个β-内酰胺疗程具有治疗PK，18/43个疗程具有广谱PK。在治疗性PK组中，E和T之间的丰富度下降幅度更大（足够− 20.1与不足− 1.59，p = 0.025）和接受广谱抗生素（广谱- 14.5与窄− 2.8，第页 = 0.030）。与基于β-内酰胺PK（充足的13.6%对不足的15.1%）或抗生素谱（宽的11.5%对窄的16.6%）的PEx相比，我们没有检测到治疗结束时预测的1秒用力呼气容积百分比（ppFEV1）的增加差异在治疗中，我们没有发现α多样性的长期变化，也没有发现与亚治疗PK和窄谱抗菌药物相比，α多样性与肺功能的优越恢复有关。
Abstract
Persons with cystic fibrosis (PwCF) suffer from pulmonary exacerbations (PEx) related in part to lung infection. While higher microbial diversity is associated with higher lung function, the data on the impact of short-term antibiotics on changes in microbial diversity is conflicting. Further, Prevotella secretes beta-lactamases, which may influence recovery of lung function. We hypothesize that sub-therapeutic and broad spectrum antibiotic exposure leads to decreasing microbial diversity. Our secondary aim was to evaluate the concerted association of beta-lactam pharmacokinetics (PK), antibiotic spectrum, microbial diversity, and antibiotic resistance on lung function recovery using a pathway analysis. This was a retrospective observational study of persons with CF treated with IV antibiotics for PEx between 2016 and 2020 at Children’s National Hospital; respiratory samples and clinical information were collected at hospital admission for PEx (E), end of antibiotic treatment (T), and follow-up (F). Metagenomic sequencing was performed; PathoScope 2.0 and AmrPlusPlus were used for taxonomic assignment of sequences to bacteria and antibiotic resistance genes (ARGs). M/W Pharm was used for PK modeling. Comparison of categorical and continuous variables and pathway analysis were performed in STATA. Twenty-two PwCF experienced 43 PEx. The study cohort had a mean age of 14.6 years. Only 12/43 beta-lactam courses had therapeutic PK, and 18/43 were broad spectrum. A larger decrease in richness between E and T was seen in the therapeutic PK group (sufficient − 20.1 vs. insufficient − 1.59, p = 0.025) and those receiving broad spectrum antibiotics (broad − 14.5 vs. narrow − 2.8, p = 0.030). We did not detect differences in the increase in percent predicted forced expiratory volume in one second (ppFEV1) at end of treatment compared to PEx based on beta-lactam PK (sufficient 13.6% vs. insufficient 15.1%) or antibiotic spectrum (broad 11.5% vs. narrow 16.6%). While both therapeutic beta-lactam PK and broad-spectrum antibiotics decreased richness between PEx and the end of treatment, we did not detect longstanding changes in alpha diversity or an association with superior recovery of lung function compared with subtherapeutic PK and narrow spectrum antimicrobials.

https://www.nature.com/articles/s41598-023-27628-x