Challenging the norm: are cefixime challenges relevant in confirmed penicillin-allergic patients?

Background. Growing evidence suggests that cross-reactivity between penicillins and cephalosporins is mainly driven by R1 side-chain similarity rather than the beta-lactam core. Although cefuroxime, ceftriaxone and cefixime appear to have a low cross-reactivity risk, their use in patients with confirmed penicillin hypersensitivity (HS) remains inconsistent. We aimed to assess the prevalence of HS to cephalosporins with structurally distinct R1 side chains in patients with penicillin allergy. Methods. A retrospective analysis of patients who completed allergy workup between 2010 and 2024 at a tertiary center was conducted. Patients with confirmed penicillin HS - established by positive specific IgE, basophil activation test, lymphocyte transformation test, positive skin tests (ST), positive drug provocation tests (DPT), and/or reproducible severe reactions - were included. Patients underwent ceftriaxone ST and cefixime or cefuroxime DPT to assess tolerance to an alternative beta-lactam. Results. Among 241 patients with confirmed penicillin HS, 214 (88.8%) underwent alternative DPT with cefixime (n = 210) or cefuroxime (n = 4). One patient (0.4%) had a positive intradermal ST to ceftriaxone and was not challenged with the alternative cephalosporin. Two patients (0.9%) developed HS reactions during cefixime DPT. Overall, 98.8% of patients tolerated the selected cephalosporins (95% CI 96.3-99.7). A pediatric subgroup was included (n = 40, 16.6%), and no child reacted to the alternative cephalosporins. Conclusions. In this 14-year real-life cohort, 98.8% of the patients with confirmed penicillin HS tolerated a cephalosporin with a structurally distinct R1 side chain, supporting its' safe use in those cases and suggesting that routine hospital-based alternative DPT may be unnecessary in selected patients.