Importance:The optimal choice of antibiotic prophylaxis in elective colorectal surgery remains uncertain, with most reviews emphasizing timing and route of administration rather than direct comparisons of antibiotic classes. Objective:To compare the outcomes associated with different antibiotic classes and class combinations administered within 24 hours before elective colorectal surgery. Data Sources:MEDLINE, Embase, Cochrane Central, and Scopus were searched from inception to July 17, 2025. Study Selection:Eligible studies were randomized clinical trials that enrolled adult patients undergoing elective colorectal procedures and were required to report on surgical site infection (SSI) within 30 days of surgery. Data Extraction and Synthesis:Data on SSIs, adverse events, all-cause mortality, and length of hospital stay were extracted when available by 2 independent reviewers. A frequentist random-effects model was used for network meta-analysis. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses, Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-Analyses of Health Care Interventions. Main Outcomes and Measures:The primary outcome was risk of SSI; secondary outcomes were 30-day mortality, adverse events, and length of hospital stay. Risk ratios (RRs) with 95% CIs were calculated for binary outcomes, and mean differences (MDs) with SDs were calculated for continuous outcomes. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Findings:A total of 105 randomized clinical trials involving 18 273 patients were included. The network included 32 distinct antibiotic nodes defined by antimicrobial class or combination. High to moderate certainty of evidence indicated that, compared with placebo or no antibiotic, several regimens were associated with reduced the risk of SSI. Regimens including broad-spectrum penicillin (RR, 0.26; 95% CI, 0.16-0.42), third-generation cephalosporins (RR, 0.27; 95% CI, 0.16-0.45), a combination of metronidazole and second-generation cephalosporins (RR, 0.27; 95% CI, 0.17-0.44), and tetracyclines (RR, 0.32; 95% CI, 0.20-0.53) were all associated with significant reductions. The antibiotics associated with a significant decrease in mortality compared with placebo were broad-spectrum penicillin (RR, 0.21; 95% CI, 0.05-0.90) and a combination of fluoroquinolones and penicillins (RR, 0.14; 95% CI, 0.03-0.79). No significant differences were observed between antibiotic classes regarding hospital length of stay or adverse events. The certainty of evidence ranged from very low to moderate across outcomes. Conclusions and Relevance:In this systematic review and network meta-analysis, several antibiotic regimens were associated with substantially reduced risk of SSIs after elective colorectal surgery compared with placebo. Broad-spectrum penicillins had the most consistent benefits, with moderate-certainty evidence supporting reductions in risk of both SSI and mortality.
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