BackgroundPeriprosthetic joint infection (PJI) remains one of the most devastating complications following total joint arthroplasty. Appropriate prophylactic antimicrobial administration and antibiotic stewardship are major factors impacting the risk of PJI in total hip arthroplasty (THA). The purpose of our study was to evaluate whether cefazolin administration was superior to noncefazolin antibiotics in prevention of PJI after primary THA.Material and methodsA review of 9910 patients undergoing primary THA from 2013 to 2019 at a single institution was conducted. The primary outcome was PJI within 90 days of surgery. The Musculoskeletal Infection Society definition of PJI was used for this analysis. Groups were those receiving cefazolin + expanded gram-negative antimicrobial prophylaxis (EGNAP) and those receiving an alternative to cefazolin + EGNAP. Chi-square tests were conducted to determine statistical significance. Multivariate logistic regression was performed to eliminate confounders.Results9028 patients received cefazolin + EGNAP, and 882 patients received an alternative to cefazolin + EGNAP. PJI rate using the Musculoskeletal Infection Society criteria was 0.82% (81/9910). PJI rate in the cefazolin + EGNAP group was 0.75% (68/9028). In the group receiving an alternative to cefazolin + EGNAP, the PJI rate was 1.47% (13/882). This difference was statistically significant (P = .023). On multivariate analysis, the odds ratio for developing PJI when an alternative to cefazolin was used was 2.05 (P = .022). When comparing alternatives, there remained a statistically significant increased PJI rate when the alternative used was clindamycin (odds ratio 2.65, P = .007).ConclusionOur data demonstrate that in the presence of EGNAP in THA, there was a higher PJI rate when clindamycin was given as an alternative to cefazolin. The number of THA patients receiving alternatives to cefazolin must be minimized.Level of EvidenceIII, Retrospective Cohort Study.