Cefazolin prophylaxis is associated with lower surgical site infection risk than vancomycin following elective spine surgery

Background: (MSSA) and coagulase-negative staphylococci (CoNS). However, reported B-lactam allergies are commonly cited in clinical practice as a reason for substitution with vancomycin, which provides inferior coverage for MSSA and limited gram-negative activity. Prior single center studies suggest higher SSI risk with vancomycin, but large-scale evidence remains limited. Methods: A retrospective cohort analysis was conducted using the TriNetX US Collaborative Network (2015-2023). Adults undergoing elective spine surgery, including transforaminal or posterior interbody fusion (TLIF/PLIF), multilevel lumbar fusion, posterior cervical fusion, anterior cervical discectomy and fusions (ACDF), and microdiscectomy, were identified. Patients receiving perioperative cefazolin or vancomycin within 24 hours of surgery were included. 1:1 propensity score matching controlled for demographics, comorbidities, and infection risk factors. The primary outcome was 90-day SSI, assessed using ICD-10 diagnosis codes. Risk ratios (RR) were estimated using Cox proportional hazards models. Results: After matching, 12,996 patients were included across 5 procedure cohorts. Cefazolin prophylaxis was associated with lower or comparable SSI risk compared with vancomycin across all procedures. Statistically significant differences were observed for TLIF/PLIF (0.82% vs. 2.30%; RR 0.36, 95% CI 0.18-0.7; p = .0019) and microdiscectomy (0.34% vs. 0.69%; RR 0.50, 95% CI 0.27-0.93; p = .025). Nonsignificant trends favored cefazolin for posterior cervical fusion (0.88% vs. 1.41%), multilevel lumbar fusion (1.25% vs. 1.51%), and ACDF (0.30% vs. 0.54%). Conclusions: Cefazolin prophylaxis is associated with significantly lower SSI risk in elective spine procedures. These findings support cefazolin as the preferred perioperative antibiotic and emphasize the need for accurate B-lactam allergy assessment to optimize infection prevention and antimicrobial stewardship in spine surgery.