Shorter Versus Prolonged Systemic Perioperative Antibiotic Prophylaxis in Clean Orthopedic Surgery: A Systematic Review and Meta-Analysis

Background and Objectives: Surgical-site infection remains a major complication of clean orthopedic surgery, particularly when implants or instrumentation are used. Although shorter perioperative prophylaxis is generally accepted for most clean procedures, prolonged postoperative courses continue to be used in selected high-risk orthopaedic settings. This review evaluated whether comparative evidence supports such extension. Methods: PubMed/MEDLINE, Scopus, and Cochrane CENTRAL were searched from inception to 14 May 2026. Randomized trials and non-randomized comparative studies evaluating systemic prophylaxis duration were eligible for qualitative synthesis. The primary meta-analysis was restricted to randomized controlled trials with extractable surgical-site infection data. Risk ratios were pooled using a random-effects model. Subgroup, sensitivity, and publication-bias analyses were performed. Results: Thirty-six studies were included in the qualitative synthesis, and 11 randomized trials involving 3823 participants contributed to the primary meta-analysis. After incorporating the cluster-adjusted estimate from the cluster-randomized trial, prolonged prophylaxis did not demonstrate a statistically significant additional reduction in any surgical-site infection compared with shorter prophylaxis (RR = 1.07, 95% CI 0.86–1.34; prediction interval 0.83–1.38; I2 = 0.0%). A sensitivity analysis excluding the cluster-randomized trial produced a similar result (RR = 1.11, 95% CI 0.88–1.40). Exploratory procedure-based subgroup analyses did not identify a statistically significant interaction, although each subgroup contained few trials. Secondary analyses showed no statistically significant difference for superficial or non-deep infection (RR = 1.19, 95% CI 0.79–1.77) or deep or complicated infection (RR = 0.85, 95% CI 0.55–1.32). Conclusions: Prolonged systemic prophylaxis has not demonstrated a consistent additional surgical-site infection-prevention benefit compared with shorter regimens. However, sparse events, wide confidence intervals, clinical heterogeneity, and low certainty preclude conclusions of equivalence or noninferiority. Further adequately powered trials are needed in higher-risk procedures.