Abstract
BACKGROUND: Open fractures, particularly Gustilo-Anderson grade III injuries, carry high risks of infection. This cohort study compared the effectiveness of three prophylactic antibiotic regimens in reducing a range of infection-related outcomes, including infection markers (ESR, CRP), wound colonization, clinical infections, fever, cellulitis, and abscess formation. METHODS: In this prospective cohort study, 600 patients aged 18–85 years with open fractures were enrolled at Shahid Bahonar Hospital, Iran (2020–2022). Participants were grouped by clinician-selected regimens: Group A (Cefazolin 1 g every 6 h + amikacin), Group B (Cefazolin 2 g every 8 h + amikacin), and Group C (Vancomycin 2 g every 12 h + amikacin). Multivariable logistic regression adjusted for confounders (age, fracture severity). Missing data (< 5%) were imputed. RESULTS: Of 978 patients screened, 600 completed follow-ups. Baseline demographics (mean age: 31.2 years; 82% male) were balanced. Group C had lower rates of elevated ESR (4.8% vs. 8.0% in Group A; adjusted RR = 0.61, 95% CI: 0.40–0.92), clinical infection (4.7% vs. 8.0%; RR = 0.58, CI: 0.38–0.89), and deep infection (2.7% vs. 5.3%; RR = 0.51, CI: 0.29–0.90). Minor adverse events (rash/nausea) were balanced across all groups (5.5% overall), with no significant differences in incidence or type between regimens. CONCLUSION: Vancomycin-amikacin was associated with reduced infection markers and complications compared to cefazolin regimens in this observational cohort, supporting its consideration in high-risk settings. Causality requires confirmation through randomized trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12891-025-09063-3.