Standardizing Safe Cefazolin Use in Total Joint Arthroplasty: A Multidisciplinary Triage Protocol

Cefazolin is the first-line perioperative antimicrobial for total joint arthroplasty (TJA) due to its efficacy against typical skin pathogens, favorable safety profile, and cost-effectiveness. Its use reduces the risk of periprosthetic joint infection (PJI) by over 30% compared to second-line antimicrobials. Approximately 15% of patients report a penicillin allergy, although true allergy is confirmed in only 1 to 10% of these cases. Cefazolin's unique molecular structure of the R1 side chain prevents immediate immunoglobulin E (IgE)-mediated cross-reactivity with penicillin or other cephalosporins. Severe cutaneous adverse reactions or delayed hypersensitivity reactions to beta-lactam antimicrobials are rare, less understood, and involve T-cell-mediated pathways. Despite evidence suggesting no immediate IgE-mediated cross-reactivity risk, it is still common practice to use second-line antimicrobials or preoperative allergy testing in patients with a reported penicillin allergy or cephalosporin allergy.

In January 2025, a multidisciplinary team implemented a novel algorithmic triage protocol for patients with penicillin allergy and cephalosporin allergy undergoing TJA. Patients who had a history of cefazolin allergy, anaphylaxis, or angioedema to any cephalosporin or severe cutaneous adverse reactions/delayed hypersensitivity reactions to any beta-lactam were referred for preoperative allergy testing. Patients who had an IgE-mediated reaction to penicillin (including anaphylaxis and angioedema) or a nonanaphylactic reaction to a noncefazolin cephalosporin were considered at no increased risk and received cefazolin without additional testing.

In 2024, 62 patients were referred for allergy testing, with only six being recommended to avoid cefazolin. Since the implementation of the new protocol in January 2025, no patients have been referred for beta-lactam allergies, and there have been no perioperative hypersensitivity reactions.

This standardized, multidisciplinary approach promotes safe cefazolin administration in patients who have listed penicillin allergy or cephalosporin allergy, thereby optimizing outcomes, reducing unnecessary health care utilization, and improving care across perioperative settings.