Administration of antibiotics before incising the skin (‘surgical antimicrobial prophylaxis’) is a critical infection prevention strategy in surgery. Extending doses of prophylaxis into the postoperative period is a common practice in cardiac surgery; however, the benefit has not been clearly established and may lead to emergence of antimicrobial resistance and patient harm. We present the protocol for a large international multicentre, adaptive, pragmatic, double-blind, three-arm, placebo-controlled, randomised, non-inferiority clinical trial to compare the incidence of surgical site infection after three different durations of postoperative surgical antimicrobial prophylaxis in patients undergoing cardiac surgery.

This adaptive, multi-arm multistage non-inferiority trial will compare intraoperative only (Arm A), to intraoperative and 24 hours (Arm B) and, to intraoperative and 48 hours (Arm C) of intravenous cefazolin and placebo as surgical antimicrobial prophylaxis in 9180 patients undergoing cardiac surgery. The adaptive design allows for potential dropping of any of the three arms if clear inferiority is indicated at any of the scheduled interim analyses. The trial will evaluate the clinical and cost-effectiveness of the three different antibiotic prophylaxis durations.

Ethics approval will be obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals and the key findings presented at national and international conferences. Patients and members of the public will also be involved in the dissemination and translation of the trial results.

NCT05447559.