Adverse reactions to penicillin and related drugs

Abstract

Penicillin, itself, is a simple chemical which only becomes antigenic when it rearranges chemically, in vivo or in vitro, to form the highly reactive intermediary compound called penicillenic acid. The penicillin molecule has a low molecular weight of 374 and is not antigenic. Penicillenic acid couples with proteins in the blood to produce penicilloyl-protein conjugates and other penicillin-derived protein conjugates. These are the antigens responsible for the clinical types of allergic reactions seen following therapy with penicillin. There are many drugs chemically similar to the basic structure of penicillin, and some of these drugs produce reactions that are clinically identical to the penicillin reactions. Most of these drugs share structural similarities to the penicillin molecule, including the presence of a beta lactam ring (Fig. 1). The side chains are different. Ampicillin, one of the drugs which is very similar, differs from penicillin only in the presence of a single added amino group, yet behaves differently in its antimicrobial spectrum as well as in the overall incidence of rashes, estimated at 5–10% for ampicillin, higher than the 1–3% estimate for penicillin. 1,2 Cross-reactivity among the penicillin aminoglycosides also occurs regularly. The exact incidence is impossible to know for certain but probably ranges from 5 to 15%. Other structurally related antibiotics besides ampicillin are oxacillin, dicloxacillin, methicillin, penicillamine, and the cephalosporin drugs. Only the penicillin structure has been studied in great enough detail to permit identification of the major chemical hapten in the clinical penicillin allergies. This has been identified as the penicilloyl haptenic grouping (Fig. 2). Gamma globulins and albumin are two proteins which couple to penicillenic acid, the reactive penicillin intermediate that binds covalently to proteins. The penicilloyl hapten coupled to protein is called the major antigenic determinant of penicillin allergy because 95% of the drug that undergoes rearrangement and protein coupling goes by this pathway to form the penicilloyl structure. The remainder of the penicillin that becomes antigenic or the 5% pathway is called the minor determinant because it is a minor percentage. This has assumed relevance in terms of skin testing for predicting various types of clinical reactions. Penicillin itself is one of the important ingredients of the minor skin test mixture.