Perioperative Intravenous Antibiotic Regimens and Surgical Site Infection After Colorectal Surgery: Clinical Associations and External Evaluation of Risk Prediction Models

Background/Objectives: Surgical site infection (SSI) remains a major complication after colorectal surgery. Comparative evidence for commonly used perioperative intravenous antibiotic regimens is limited, and risk prediction models require external evaluation before clinical use. We examined regimen–SSI associations and secondarily evaluated models using routine perioperative variables to distinguish patients with and without electronically recorded postoperative SSI. Methods: We analysed 732 adults from MIMIC-IV for regimen association and model development and 133 adults from ICU-based eICU-CRD for external model evaluation. SSI was identified using an electronic phenotype. Four intravenous antibiotic exposure groups were compared using multivariable logistic regression and exploratory interaction analyses. Predictors selected using LASSO screening followed by clinical refinement informed six models, which were assessed using discrimination, calibration, and classification metrics. Results: SSI was recorded in 146/732 patients (19.9%), with no evidence of an unadjusted association across observed exposure categories (p = 0.947). Logistic regression achieved an external ROC-AUC of 0.858 (95% CI 0.764–0.934; PR-AUC 0.560) and detected 17/21 SSI cases, but generated 27 false positives. Positive predictive value was 38.6%, with limited calibration (expected calibration error 0.236) and a Brier score of 0.197. Conclusions: These data provide no evidence of an overall association, nor evidence of equivalent prophylactic efficacy. Heterogeneous exposures and residual confounding preclude regimen-level causal conclusions. The small ICU-based external evaluation informs higher-acuity populations, not routine elective surgery. Uncertain SSI onset, limited calibration, and false-positive burden preclude clinical implementation. Prospective multicentre studies should evaluate risk-adapted surveillance, not model-directed antibiotic selection.