Effects of Antibiotic Duration on the Intestinal Microbiota and Resistome: The PIRATE RESISTANCE Project, a Cohort Study Nested Within a Randomized Trial

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 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 detected at similar abundance in patients receiving 7 and 14 days (median counts/million [mCPM]: 96 versus [vs] 71; p=.38). By D30, total ARG content in both groups was similar to that of controls at D7 (362 and 370 mCPM vs 314 mCPM, p=.24 and .19). There were no significant differences among antibiotic-treated patients at any timepoint in bacterial diversity or clustering, but Shannon species diversity was significantly reduced compared to controls through D14 (median 3.12 and 3.24 in the 7-day and 14-day groups vs 3.61 [controls]; p=.04 and .012). Fourteen-day antibiotic courses prompted a persistent trend toward reduced faecal phage content. 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. 407440_167359). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The present study was approved by the Cantonal Ethics Committee of Geneva (no. 2017-00108); all participants provided written informed consent before enrolment.