Synthesis, characterization and immunochemical evaluation of cephalosporin antigenic determinants

Abstract

Lack of knowledge of the exact chemical structure of cephalosporin antigenic determinants has hindered clinical interpretation of adverse reactions to these drugs and delayed understanding of the mechanisms involved in the specific recognition and binding of IgE molecules to these antigenic determinants. We further resolve the relationship between structure and activity of proposed antigenic chemicals, including the rational design and synthesis of these haptenic structures. Comparative RAST inhibition studies of the synthesized molecules revealed that they were recognized by IgE antibodies induced by cephalosporin antibiotics. Thus, these data indicate that recognition is mainly directed to the acyl side chain and to the beta-lactam fragment that remains linked to the carrier protein in the cephalosporin conjugation course.

Management of allergy to penicillins and other beta‐lactams

“…The exact nature of these intermediate products has not been characterized [86,87], but the haptenization mechanism appears slower and possibly more complex than with penicillins [88,89]. Our knowledge of the immunological relevance of cephalosporin hapten-carrier conjugates remains incomplete.…”

“…Cross-reactivity as a result of antibody recognition is more closely related to side chain homology (and possibly the small beta-lactam fragment linked to the carrier protein during cephalosporin conjugation) rather than the central beta-lactam ring [86][87][88]. Therefore, cefadroxil, cefradine, cefaclor and cefalexin have significant cross-reactivity in patients with a previous history of allergic reaction to ampicillin/amoxicillin because of similarities in side chain structure (table 3a,b) [89].…”

Antibiotic allergy: Immunochemical and clinical considerations

“…Despite criticism [30,32,33] of interpretations of IgE recognition results obtained by our group after using cephalosporin derivatives that were likely derived, at least in part, by nucleophilic -lactam ring opening [27], and uncertainty about the nature of the resulting products [24,25], the critics continue using cephalosporins chemically modified the same way for serum immunoassays [29,30]. These labile products' uncertain number and nature have prompted questions [30,32,33] about interpretations of cephalosporin allergenic determinants identified in radioimmunoassay (RIA) hapten inhibition studies, and in particular, implication of R2 structures in IgE recognition and binding.…”

Hypersensitivity Reactions to Beta-lactams

“…Another study generating a complete panel of antibodies of different isotypes to AX showed that the side chain was the most important part of the molecule contributing to the epitope, with the whole structure necessary for optimal recognition. Studies carried out using human IgE antibodies showed that although differences in the side chain structure were important for IgE recognition, the whole structure including the protein carrier plus the BL was also necessary for the constitution of the complete antigenic determinant (Perez-Inestrosa et al 2005;Sánchez-Sancho et al 2003;Moreno et al 1995).…”

“…In depth studies of IgE, recognition to these resultant structures has involved the synthesis of well-defined structures comprising the entire acyl side chain of different cephalosporins and the aminoacidic residue included in the BL moiety of the cephalosporins studied, linked as amide functions to an aliphatic (n-butyric) chain (Sánchez-Sancho et al 2003;Montañez et al 2011). The results showed that the proposed skeleton epitopes involving the appropriate functionality and R1 side chain were selectively recognized by IgE from patients allergic to cephalosporins with the same or similar side chain structures.…”