Penicillin and cephalosporin-based antibiotic regimens are the most effective prophylactic options for preventing colorectal surgical site infections (SSIs), according to a large systematic review and meta-analysis, offering direction for improving guideline-based practices.
Optimising antibiotic prophylaxis is central to reducing SSIs in colorectal surgery, where baseline infection rates range from 10-25% and contribute significantly to morbidity and healthcare resource use.
Understanding the relative effectiveness of different antibiotic classes is therefore crucial, and a recent preregistered systematic review with network meta-analysis addresses an important evidence gap that previous route-focused studies have not.
The review included 105 randomised controlled trials involving 18,273 adult patients undergoing elective colorectal surgery. These studies assessed antibiotic prophylaxis administered within 24 hours preoperatively and compared 32 antibiotic classes or combinations, and the results were published in the journal JAMA Network Open.
The primary outcome was SSI within 30 days, and secondary outcomes included all-cause mortality, adverse events and length of hospital stay.
Broad-spectrum penicillins, SSIs and mortality
Moderate–high-certainty evidence demonstrated that several regimens significantly reduced the risk of SSIs compared with placebo or no prophylaxis.
Broad-spectrum penicillins had the greatest and most consistent benefit (risk ratio [RR] 0.26; 95% CI 0.16–0.42), alongside third-generation cephalosporins (RR 0.27; 95% CI 0.16–0.45) and combinations of metronidazole with second-generation cephalosporins (RR 0.27; 95% CI 0.17–0.44). Tetracyclines were also associated with reduced risk (RR 0.32; 95% CI 0.20–0.53).
However, some commonly used combinations, such as metronidazole with penicillin or monobactams, showed little or no benefit. Evidence suggested some additional potential benefit for regimens such as metronidazole plus fosfomycin (RR 0.07; 95% CI 0.02–0.25), although data were limited and of lower certainty.
Broad-spectrum penicillins were the only antibiotic class associated with reductions in both SSIs and mortality. These agents reduced all-cause mortality in 43 trials involving more than 9,000 patients (RR 0.21; 95% CI 0.05–0.90), with similar but less certain findings for fluoroquinolone–penicillin combinations (RR 0.14; 95% CI 0.03–0.79).
No significant differences were observed between antibiotic regimens in length of hospital stay or overall adverse events, with evidence certainty ranging from low to moderate.
Findings and limitations
The findings support existing guidance that emphasises broad coverage with aerobic and anaerobic antibiotics, while indicating that choosing specific classes could further improve outcomes.
Broad-spectrum penicillins and cephalosporin–metronidazole combinations emerged as the most consistently effective options, supporting their preferential use when multiple guideline-endorsed antibiotic regimens are available.
However, interpretation of the results is tempered by several limitations. Most trials (75.2%) were at high risk of bias in at least one domain, particularly regarding allocation concealment and blinding.
Many comparisons relied on small sample sizes, contributing to imprecision, and outcome definitions – including SSIs and adverse events – varied across studies. Heterogeneity in reporting of comorbidities, cancer status and bowel preparation further limited subgroup analyses.
Clinical implications for SSI prevention
Despite these constraints, the class-based analytical approach enhances clinical applicability, particularly because antimicrobial spectra remain broadly consistent across generations. The absence of differences in adverse events or length of stay suggests that preventing SSIs should remain the primary driver of antibiotic selection in this setting.
The authors noted that future research should prioritise adequately powered, head-to-head randomised trials comparing leading regimens, including underexplored combinations such as metronidazole plus fosfomycin. They also emphasised that standardised outcome reporting and improved characterisation of patient populations would be critical to refining evidence-based recommendations.
Additionally, given the global challenge of antimicrobial resistance, they highlighted the need for studies evaluating the efficacy of prophylactic strategies alongside their ecological consequences to align infection prevention with stewardship priorities.
Reference
Motaghi S et al. Antibiotic prophylaxis strategies and surgical site infections in colorectal surgery: a systematic review and network meta-analysis. JAMA Netw Open. 2026;9(2):e2560095.
This article was originally published by our sister publication Hospital Healthcare Europe.
