Detection and side‐chain specificity of IgE antibodies to flucloxicillin in allergic subjects

Abstract

Unlike studies on the antigenicity of penicillins in laboratory animals, limited information is available on the allergenicity of penicillins in man, especially with regard to fine structural allergenic differences between the many different penicillins. Inconsistent with the earlier conclusions of others, our studies suggest that side-chain structures on the penicillin molecule are the major allergenic determinants in many reactions. Immediate allergic reactions to flucloxacillin were observed in a number of patients where diagnosis was confirmed by skin testing and detection of flucloxacillin-reactive IgE antibodies. Quantitative hapten inhibition studies revealed potent inhibition by flucloxacillin and three structurally related penicillins: oxacillin, cloxacillin and dicloxacillin. Analysis of the inhibition results showed that the side-chain group of flucloxacillin, 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl, is recognized by some antibodies and that the 5-methyl-3-phenyl-4-isoxazolyl group, with or without halogen substituents, accounts for the reactivity of other antibodies and for the cross-reactions seen with some other penicillins. Since it is the side-chain group that distinguishes the many different penicillins, and since the side-chain groups are recognized by IgE antibodies in many of the allergic reactions, it is becoming clear that specific assays are required for the detection of IgE antibodies to each of the different penicillins.

IgE and Drug Allergy: Antibody Recognition of ‘Small’ Molecules of Widely Varying Structures and Activities

“…The results were similar to earlier quantitative inhibition findings employing an immunoassay for cephalosporin-reactive IgE in the sera of patients allergic to cephalothin [20] and further suggested that as well as the methylene structure, the thiophene ring acts as a bioisostere of the benzene ring in the side chain of benzylpenicillin [19]. Another good example of the preferential recognition of the penicillin R side chain was provided by the demonstration of IgE antibodies complementary to phenylisoxazolyl R substituents in the sera of patients who experienced anaphylaxis following the administration of flucloxacillin [17]. In addition to recognition of flucloxacillin, pronounced crossreactivity was seen with three structurally related penicillins containing a phenylisoxazolyl side chain, dicloxacillin, cloxacillin and oxacillin.…”

“…Examination of the specificities of penicillin-reactive IgE antibodies in the serum from a number of allergic patients revealed a heterogeneous group of allergenic determinants consisting exclusively, or in part, of the side chain groups of penicillins, the β-lactam ring and the thiazoline ring [16][17][18][19][20]. In some patients the entire penicillin molecule comprises the IgE-binding determinant structure.…”

“…The side chain of penicillins, particularly benzylpenicillin, phenoxymethylpenicillin, ticarcillin, the aminopenicillins ampicillin and amoxicillin and the isoxazolyl penicillins are frequently implicated as allergenic determinant structures by IgE antibodies in the sera of patients allergic to the drugs [5,17]. Note however, in addition to side chain recognition, IgE antibody responses recognize a heterogeneous group of determinants that sometimes include the β-lactam and thiazolidine rings of the penicillin nucleus [16].…”

Antibiotic allergy: Immunochemical and clinical considerations

“…This suggests the need to employ not only a wider variety of individual drugs but also drugs in different hapten-conjugate linkages in skin and antibody tests. We base this conclusion on findings that include demonstration of allergic sensitivity and positive skin and IgE tests to flucloxacillin but not to benzyl penicillin [16]; antibody recognition of the amoxicilloyl but not the amoxicillinanyl determinant in one allergic subject but the reverse recognition pattern in another patient [22]; and demonstration of fine structural recognition differences on R1 and R2 side chains of cefaclor by IgE antibodies from cefaclor-allergic subjects [14].…”

“…Given the need to consider side-chain determinants on individual -lactams; the possibility of cross-reactions resulting from recognition of core or shared side-chain structures [12][13][14][15][16][17][18]; and the known heterogeneity of penicillin and cephalosporin allergenic determinants [1,[12][13][14]17,18], test reagents in vivo and in vitro should not be confined to preparations like benzylpenicilloyl-polylysine (Prepen) and the so-called "minor" determinant mix (generally prepared from benzyl penicillin) [18]. In this context, and after reviewing studies [19][20][21] and guidelines from Europe [19], little long-term thinking seems to have occurred and little effort made to begin developing and standardizing a wider range of improved -lactam test agents.…”