Penicillin and cephalosporin cross-reactivity: role of side chain and synthetic cefadroxil epitopes

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 potential 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). Cross-reactivity 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.

Recent patents in allergy and immunology: New pyrazinones for the diagnosis of allergies to aminocephalosporins

“…2 A straightforward synthetic protocol for precisely defined pyrazinone structures corresponding to cefaclor and cefadroxil was developed, and they were used for quantification of specific IgE antibodies to such cephalosporins in immunoassays. [2][3][4] The pyrazinone determinant was designed according to our degradation hypothesis for α-aminocephalosporins after their protein conjugation, 3 briefly summarized in Figure 1B. Haptenation occurs through nucleophilic opening of the β-lactam ring by amino groups of lysines via amide formation (Figure 1A).…”

“…Further studies are still needed to evaluate whether this in vitro tool would represent a safe alternative to in vivo tests for determining cross-reactivity, since negative skin test is not enough for predicting tolerance. Based on the outstandingly observed specific IgE recognition from patients with α-aminocephalosporin immediate reactions, 3,4 these pyrazinone structures could be potentially involved in the sensitization of aminocephalosporin-allergic reactions; therefore, we claimed the use of these structures to diagnose patients with β-lactam immediate reactions, especially for α-aminocephalosporins. 2…”

“…Our patent covers pyrazinone derivatives as novel potential antigenic determinants of α‐aminocephalosporins to diagnose β‐lactam allergies 2 . A straightforward synthetic protocol for precisely defined pyrazinone structures corresponding to cefaclor and cefadroxil was developed, and they were used for quantification of specific IgE antibodies to such cephalosporins in immunoassays 2‐4 …”

“…Based on the outstandingly observed specific IgE recognition from patients with α‐aminocephalosporin immediate reactions, 3,4 these pyrazinone structures could be potentially involved in the sensitization of aminocephalosporin‐allergic reactions; therefore, we claimed the use of these structures to diagnose patients with β‐lactam immediate reactions, especially for α‐aminocephalosporins 2…”

“…Moreover, no recognition of pyrazinone 2 was observed in cefadroxil-tolerant patients with amoxicillin immediate reactions. 4 The latter result could be explained because the generated pyrazinone 2 is exclusively derived from cefadroxil, and amoxicillin would not structurally be transformed in pyrazinone. According to these results, we hypothesize that pyrazinone 1 may be recognized by IgE specific to cefaclor or cefprozil (cephalosporins with equal R 1 ) but to a lesser extent by IgE specific to ampicillin (penicillin containing the same R 1 ).…”