β-Lactam allergenic determinants: fine structural recognition of a cross-reacting determinant on benzylpenicillin and cephalothin

Background: An appreciation of the structural heterogeneity of allergenic determinants on penicillins and cephalosporins reveals the importance of side-chain groups and their involvement in many allergies to β-lactam drugs. Although allergenic cross-reactions between penicillins and cephalosporins are known to occur, the precise molecular bases of such recognitions and cross-sensitivities have rarely been studied and identified. Objectives: The unexpected finding of a high incidence of positive IgE antibody reactions with both benzylpenicillin and cephalothin prompted serological and immunochemical studies to identify the chemical basis of antibody recognition of these drugs from the two different families of β-lactam antibiotics. Methods: Adsorption studies were employed to identify whether or not a single population of antibodies was involved in the recognition of benzylpenicillin and cephalothin. Identification of the fine structural features recognized by IgE antibodies was investigated by quantitative hapten inhibition studies employing carefully selected β-lactam drugs, analogues and some other structurally related chemicals. Results: Adsorption studies with penicilloic acid-solid phase clearly established that a single population of cross-reacting antibodies recognized both benzylpenicillin and cephalothin. Quantitative inhibition findings, especially with phenylacetic acid and 2-thiopheneacetic acid and with cephaloridine and cefoxitin, which have the same (2-thienyl)methyl side-chain as cephalothin, implicated the methylene group as the focus of the allergenic determinant recognized on benzylpenicillin and cephalothin. In addition to the methylene group, recognition graded into neighbouring structures including the amide group and extended weakly to the β-lactam ring. Conclusions: Results confirmed that structural features as small as a methylene group may be allergenically important. In the present case, this group, making up only part of the different side-chains on benzylpenicillin and cephalothin, together with neighbouring structures extending toward the β-lactam ring, accounted for the cross-reactivity seen between structures that, at first sight, appear to be not closely related. Such subtle, small, common structural features are likely to be immunologically recognized and implicated in allergic reactions to other drugs, including β-lactam antibiotics.