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Objectives and questions: The current Dutch guideline recommends single-dose perioperative antibiotic prophylaxis for primary joint arthroplasty. This recommendation is based on registry data without patient-level analyses. The aim of this study was to determine whether single-dose antibiotic prophylaxis is non-inferior to multiple-dose prophylaxis in preventing periprosthetic joint infection (PJI) within three months after primary arthroplasty.

Material and methods: In this retrospective cohort study adult patients who underwent primary hip, knee, or shoulder arthroplasty between 2018 and 2025 at two independent treatment centers in the Netherlands were included. Patients received either single-dose or multiple-dose perioperative antibiotic prophylaxis. The primary outcome was PJI within three months, defined as 1. revision surgery for infection recorded in the local electronic health record, 2. revision surgery for infection recorded in the Dutch Arthroplasty Register (LROI), or 3. a postoperative wound infection registered in the national surveillance database (PREZIES) by the independent treatment center. The association between antibiotic regimen and PJI was assessed using univariate logistic regression analysis. Non-inferiority was evaluated by calculating the absolute risk difference in PJI rates between groups. A pre-specified non-inferiority margin of 0.5% was applied. Non-inferiority was concluded if the lower bound of the 95% confidence interval (CI) of the risk difference exceeded this margin.

Results: A total of 24,088 patients were included, of whom 15,229 received single-dose and 8,855 multiple-dose prophylaxis. The three-month PJI rate was 0.39% in the single-dose group and 0.28% in the multiple-dose group. The odds ratio for single-dose versus multiple-dose prophylaxis was 1.40 (95% CI 0.88–2.23; p = 0.16). The absolute risk difference was 0.11% (95% CI −0.04% to 0.26%), demonstrating non-inferiority (p < 0.001 for non-inferiority).

Discussion and conclusions: Single-dose perioperative antibiotic prophylaxis is non-inferior to multiple-dose prophylaxis in preventing PJI within three months following primary joint arthroplasty. These findings support the current shift toward single-dose prophylaxis in the Netherlands and contribute patient-level evidence to ongoing international discussions on antibiotic stewardship in arthroplasty surgery.