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Clinical and Translational Allergy Open Access

RESEARCH

Penicillin and cephalosporin cross‑reactivity: role of side chain and synthetic cefadroxil epitopes Gador Bogas1,2†, Cristobalina Mayorga1,2,3†, Ángela Martín‑Serrano1,3, Rubén Fernández‑Santamaría1, Isabel M. Jiménez‑Sánchez1,3, Adriana Ariza1, Esther Barrionuevo1,2, Teresa Posadas1,2, María Salas1,2, Tahía Diana Fernández1,4, María José Torres1,2,3,5*† and María Isabel Montañez1,3† 

Abstract  Background:  Analysis of cross-reactivity is necessary for prescribing safe cephalosporins for penicillin allergic patients. Amoxicillin (AX) is the betalactam most often involved in immediate hypersensitivity reactions (IHRs), and cefadroxil (CX) the most likely cephalosporin to cross-react with AX, since they share the same R1 side chain, unlike cefuroxime (CO), with a structurally different R1. We aimed to analyse cross-reactivity with CX and CO in patients with confirmed IHRs to AX, including sIgE recognition to AX, CX, CO, and novel synthetic determinants of CX. Methods:  Fifty-four patients with confirmed IHRs to AX based on skin test (ST) and/or drug provocation test (DPT) were included. Serum sIgE to AX and benzylpenicillin was determined by Radioallergosorbent test (RAST). Two poten‑ tial determinants of CX, involving intact or modified R1 structure, with open betalactam ring, were synthesised and sIgE evaluated by RAST inhibition assay. Results:  Tolerance to CX (Group A) was observed in 64.8% cases and cross-reactivity in 35.2% cases (Group B). Crossreactivity with CO was only found in 1.8% cases from Group B. ST to CX showed a negative predictive value of 94.6%. RAST inhibition assays showed higher recognition to CX as well as to both synthetic determinants (66% of positive cases) in Group B. Conclusions:  Cross-reactivity with CX in AX allergic patients is 35%, being ST not enough for prediction. R1, although critical for recognition, is not the unique factor. The synthetic determinants of CX, 1-(HOPhG-Ser-Bu) and 2-(pyrazinone) are promising tools for determining in vitro cross-reactivity to CX in AX allergic patients. Keywords:  Amoxicillin, Betalactam, Cephalosporin, Cross-reactivity, Drug allergy, Antigenic determinant, Specific IgE Background Betalactams (BLs) are the drugs most frequently involved in immediate (IgE-mediated) hypersensitivity reactions (IHRs) [1–3], which could be explained by *Correspondence: [email protected] † Gador Bogas and Cristobalina Mayorga, María José Torres and María Isabel Montañez contributed equally to this work 1 Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009 Málaga, Spain Full list of author information is available at the end of the article

their ability to act as haptens due to their high chemical reactivity against proteins [4, 5]. BL chemical structure is formed by a 4-membered ring (the so-called BL ring) that in penicillins is fused to a 5-membered thiazolidine ring, and in cephalosporins to a 6-membered dihydrothiazine ring (Fig. 1). These drugs have a side ch