The latest word on penicillin allergy

Editor's note:Our April 18 cover story, "Staving off allergies," drew so many inquiries from readers about the issue of the risk of cross-sensitivity with penicillins and cephalosporins that we invited Michael E. Pichichero, M.D., the source of our information, to explain the subject in greater detail below.

Despite a myriad of studies over the past several decades using varied patient populations, the true increased risk of an allergic reaction to a cephalosporin in a patient with a penicillin allergy compared with a primary (and unrelated) cephalosporin allergy has not been clearly established. This article provides a comprehensive review of the frequency of allergic cross-reactivity between penicillin and cephalosporin antibiotics.

Penicillin-cephalosporin cross-reactivity Penicillins and cephalosporins have similar beta-lactam ring structures, are of low molecular weight, and are highly substituted on their side chains. They differ in that the five-membered thiazolidine ring of penicillin is replaced in the cephalosporins with a six-membered dihydrothiazine ring. After degradation, penicillin forms a stable penicilloate ring with preservation of the thiazolidine ring, whereas cephalosporins undergo rapid fragmentation of the beta-lactam and dihydrothiazine rings. Immunologic cross-reactivity between the penicillin and cephalosporin beta-lactam rings is therefore minimal, which is confirmed by monoclonal antibody analysis.

The rate of cross-reactivity between penicillin and most second-, third-, and fourth-generation cephalosporins is low and may actually be lower than that between penicillins and other classes of antibiotics. Several studies have suggested that the immune response to cephalosporins depends more on their side chain substituents; that is, cephalosporins with a side chain similar to benzylpenicillin are more likely to cross-react with penicillin and those with side chains like ampicillin are more likely to cross-react with ampicillin and amoxicillin.