Cefazolin Versus Cefazolin Plus Vancomycin Prophylaxis for Primary Tha Patients Without Documented Mrsa Colonization: An Asap Trial-Informed Propensity-Matched Analysis

Background Whether vancomycin should be routinely added to cefazolin for perioperative prophylaxis in primary total hip arthroplasty (THA) remains uncertain. The ASAP randomized trial of 1,850 THA patients reported no clear benefit to adding vancomycin to cefazolin in arthroplasty patients without known MRSA colonization, with numerically higher surgical site infection rates in the dual-prophylaxis arm. However, hip-specific estimates were limited by sample size. We evaluated whether similar infection-related patterns were observable in a large U.S. real-world THA cohort. Methods A retrospective propensity-score-matched cohort study was conducted using the TriNetX U.S. Collaborative Network. Adults ≥18 years undergoing primary THA who received day-of-surgery cefazolin plus vancomycin were compared with those who received cefazolin alone. To approximate ASAP eligibility, we excluded patients with prior periprosthetic joint infection, any infection within 30 days pre-operatively, and any documented or suspected MRSA carriage, pre-operative mupirocin use, or pre-operative S. aureus nucleic acid testing. Patients receiving clindamycin, daptomycin, or gentamicin were excluded. Cohorts were 1:1 propensity-score matched on age, sex, race, ethnicity, BMI, comorbidities, and antibiotic allergy status. Outcomes within 90 days included periprosthetic joint infection, surgical site infection (any, superficial, deep), sepsis, lower-limb cellulitis, acute kidney injury, all-cause readmission, and emergency department visits. Results After matching, 88,310 patients (44,155 per arm) were analyzed. The cefazolin plus vancomycin group had a higher coded incidence of 90-day peri-prosthetic joint infection (0.93% vs 0.72%; RR 1.29; p < 0.001), any surgical site infection (0.95% vs 0.75%; RR 1.26; p = 0.001), superficial SSI (RR 1.63; p < 0.001), deep SSI (RR 2.03; p < 0.001), sepsis (RR 1.27; p = 0.009), and 90-day readmission (16.1% vs 12.4%; RR 1.30; p < 0.001). Lower limb cellulitis, acute kidney injury, and emergency department visits did not differ significantly between groups. Conclusion In this large propensity-matched analysis of primary THA patients without documented MRSA colonization, cefazolin plus vancomycin was not associated with lower 90-day infection-related risk compared with cefazolin alone. Instead, dual prophylaxis was associated with higher coded rates of PJI, SSI, sepsis, and readmission. Viewed alongside the ASAP trial, these findings do not provide supportive evidence for routine dual prophylaxis in MRSA-unknown primary THA patients and reinforce the need for more selective, risk-based use of vancomycin. These findings should be interpreted as hypothesis-generating given the limitations of federated EHR data, including residual confounding by indication, incomplete capture of MRSA screening, inability to verify antibiotic timing, dosing, and reliance on administrative codes.