Background

Shortening antibiotic-treatment durations is a key recommendation of antibiotic-stewardship programmes, yet it is based on weak evidence. We investigated whether halving antibiotic courses would reduce antibiotic-resistance genes (ARG) in the intestinal microbiomes of patients treated for gram-negative bacteraemia.

Methods

This nested prospective cohort study included adult patients hospitalized at Geneva University Hospitals (Switzerland) participating in the PIRATE randomized trial assessing non-inferiority of shorter antibiotic courses (7 versus 14 days) for gram-negative bacteraemia (‘cases’) and, simultaneously, hospitalized patients with similar demography and comorbidity yet no antibiotic therapy (‘controls’). Stool was collected from case and control patients on days 7, 14, 30 and 90 after antibiotic initiation (day 1) and days 7 and 14 after admission, respectively, and analysed by whole-metagenome shotgun sequencing. The primary outcome was ARG abundance at day 30; secondary outcomes included microbiota-species composition and clustering over time.

Findings

Forty-five patients and 11 controls were included and evaluable; ARG analyses were conducted on the 29 per-protocol patients receiving 7 (±2) days or 14 (±3) days of antibiotic therapy. At day 30, ARGs were not detected at similar abundance in patients receiving 7 and 14 days (median counts/million [mCPM]: 96 versus [vs] 71; p=.38). By day 30, total ARG content between both groups was not significantly different from that of controls at D7 (362 and 370 mCPM vs 314 mCPM, p=.24 and 0.19). There were no significant differences amongst antibiotic-treated patients at any timepoint in bacterial diversity or clustering, but Shannon species diversity was significantly reduced compared to controls through day 14 (median 3.12 and 3.24 in the 7-day and 14-day groups vs 3.61 [controls]; p=.04 and 0.012). Patients treated for 14 days had reduced faecal phage content during and after therapy compared to other patient groups.

Interpretation

Reducing antibiotic durations by half did not result in decreased abundance of ARGs in patients treated for gram-negative bacteraemia, nor did it improve microbiota species diversity.

Funding

The study was funded by the University of Geneva's Louis-Jeantet Foundation (grant no. S04_12) and the Swiss National Science Foundation (NRP Smarter Healthcare, grant no. 407,440_167359).

中文翻译：

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抗生素持续时间对肠道微生物群和耐药组的影响：PIRATE RESISTANCE 项目，一项嵌套在随机试验中的队列研究

背景

缩短抗生素治疗时间是抗生素管理计划的一项重要建议，但它基于薄弱的证据。我们研究了将抗生素疗程减半是否会减少革兰氏阴性菌血症患者肠道微生物组中的抗生素耐药基因 (ARG)。

方法

这项嵌套的前瞻性队列研究包括在日内瓦大学医院（瑞士）住院的成年患者，他们参与了 PIRATE 随机试验，评估较短抗生素疗程（7 天对 14 天）治疗革兰氏阴性菌血症（“病例”）的非劣效性，同时，具有相似人口统计学和合并症但未接受抗生素治疗的住院患者（“对照”）。分别在抗生素开始后第 7、14、30 和 90 天（第 1 天）和入院后第 7 天和第 14 天从病例和对照患者中收集粪便，并通过全基因组鸟枪法测序进行分析。主要结果是第 30 天的 ARG 丰度；次要结果包括微生物群物种组成和随时间的聚集。

发现

包括 45 名患者和 11 名对照者并进行评估；对接受 7 (±2) 天或 14 (±3) 天抗生素治疗的 29 名符合方案的患者进行 ARG 分析。在第 30 天，在接受 7 天和 14 天的患者中未检测到相似丰度的 ARG（中位数/百万 [mCPM]：96 对 [vs] 71；p =.38）。到第 30 天，两组之间的总 ARG 含量与第 7 天的对照组相比没有显着差异（362 和 370 mCPM 与 314 mCPM，p = .24 和 0.19）。在任何时间点，抗生素治疗的患者在细菌多样性或聚类方面没有显着差异，但与对照组相比，香农物种多样性在第 14 天显着降低（7 天和 14 天组的中位数为 3.12 和 3.24，而 3.61 [控制]；p =.04 和 0.012）。与其他患者组相比，治疗 14 天的患者在治疗期间和治疗后的粪便噬菌体含量减少。

解释

将抗生素使用时间减少一半并没有导致接受革兰氏阴性菌血症治疗的患者的 ARGs 丰度降低，也没有改善微生物群的多样性。

资金

该研究由日内瓦大学 Louis-Jeantet 基金会（授权号 S04_12）和瑞士国家科学基金会（NRP Smarter Healthcare，授权号 407,440_167359）资助。