Lack of Allergic Cross-Reactivity to Cephalosporins Among Patients Allergic to Penicillins

Abstract

Purpose of the Study. To assess the safety of administering cephalosporins to penicillin-allergic patients.Study Population. Forty-one patients (age 19–72, 14 male/27 female) with confirmed penicillin allergy by history, skin testing and in some cases by penicillin or amoxicillin challenge.Methods. All subjects underwent skin testing for penicilloyl-polylysine (PPL), minor determinant mixture (MDM), benzylpenicillin (PG), and amoxicillin (AX). A wheal 3 mm greater than the saline control was considered positive. If the prick skin tests were negative, than intradermal (ID) tests were performed, where a wheal 5 mm greater than the negative control was considered positive. If the ID tests were negative, PG was administered intramuscularly beginning with 1000 U and increasing incrementally to as high as 1.2 million U. After completing this challenge, the subjects returned in 20 days and was skin tested again and challenged to PG in a similar fashion. In the case of amoxicillin allergy, oral AX was administered in progressively increasing doses from 25 mg up to 500 mg every 45 mins, unless a reaction occurred. Once the diagnosis of penicillin (PCN) allergy was confirmed, cephalosporin testing was performed for cefazoline, cefuroxime, and ceftriaxone at 25 mg/mL and 250 mg/mL by puncture test and at 2.5 mg/mL and 25 mg/mL for ID testing. If the cephalosporin skin testing was negative, doses of each was injected intramuscularly beginning with 25 mg increasing progressively to as much as 500 mg. The challenges occurred over as long as 2 days. All challenges were performed in a single-blinded manner.Results. Thirty-four patients had AX or amoxicillin/clavulanic acid allergy, 1 had AX and cloxacillin allergy, 3 had PG allergy and in 3 cases the drug was unknown. Thirty-eight had a positive skin test to some PCN or AX reagent. Fifteen (36.5%) had positive skin test to AX only with negative skin test to remaining PCN determinants. Ten (24.3%) had 1 or more positive skin tests to PCN determinants and negative to AX. Thirteen (31.7%) had positive skin test to PCN determinants and AX. In 3 subjects, the skin testing for PCN and AX was negative, but they had a positive oral challenge to AX. Two of them who were rechallenged with PCN had good tolerance to it. Four (9.7%) had the diagnosis of PCN allergy made during the rechallenge study 20 days after the initial study. One of these subjects had a systemic reaction during the intradermal test. Skin tests to cephalosporins were negative in 39 patients, equivocal by ID technique in 2 and all 41 tolerated 3 cephalosporins by the intramuscular route.Conclusion. This study indicates that penicillin-allergic patients may receive cephalosporins with a low risk of having an allergic reaction, as long as the cephalosporin has a different side chain from the PCN causing the allergic reaction and the drug is given under careful supervision.Reviewer’s Comments. More than a third of patients with positive skin testing to only AX had negative skin testing to major and minor determinants, which supports testing for AX in addition to standard PCN testing. About 10% of subjects with PCN allergy were diagnosed at rechallenge, which supports the need to include rechallenge in the evaluation of PCN allergy. Previous studies of cross-reactivity between PCNs and cephalosporins have noted as much as a four-fold risk for reactions in PCN-sensitive subjects versus controls. These studies were performed with cephalosporins with similar side chains to PG. Others report between 12% to 38% of PCN-allergic subjects reacted to cephalosporins with similar sidechains, but reactions to cephalosporins without similar side chains have not been described. Therefore, when it comes to cross-reactivity between PCNs and cephalosporins, they are not all alike in the level of risk and those with dissimilar side chains offer the lowest risk of cross-reactivity.