Background: Surgical antimicrobial prophylaxis (SAP) is a cornerstone for reducing surgical site infections (SSIs), yet its implementation remains inconsistent. This study evaluates the impact of adherence to local SAP guidelines (GDSAP) versus surgeon-directed practices (SDSAP) on SSI outcomes. Methodology: A prospective cohort of 827 surgical patients in two Jordanian hospitals was evaluated. After filtering for eligibility and outcome availability, 464 patients were analysed—232 in each group (GDSAP vs. SDSAP). SSI by day 90 was the primary outcome. Data were collected through patient monitoring, medical records, and post-discharge surveillance. Missing data (<5%, except SSI at 33.4%) were imputed using Multivariate Imputation by Chained Equations (MICE). Logistic regression identified SSI predictors. Results: Groups were demographically and clinically balanced. Post-discharge antibiotic use was higher in SDSAP (75%) compared to GDSAP (59%) (P < 0.001). SSIs were more frequent in the SDSAP group (16%) than in GDSAP (7.4%) (P = 0.004; OR = 3.12; RR = 1.27). Multivariate analysis revealed anaemia (OR = 2.86), multiple comorbidities (OR = 1.93), and BMI (OR = 1.01) as significant SSI predictors. GDSAP adherence independently predicted lower SSI risk (OR = 0.41; P = 0.006). Conclusion: Adherence to SAP guidelines has significantly reduced SSI rates and reflects a decrease in post-discharge antimicrobial overuse. Hospitals should implement tailored SAP protocols and multidisciplinary stewardship to ensure safer surgical outcomes.
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