Cephalosporins can be prescribed safely for penicillin-allergic patients
How the “10% cross-reactivity” myth took hold. When the first-generation cephalosporins cephaloridine and cephalothin were introduced in the 1960s, allergic and anaphylactic reactions were reported in patients with previous allergic reactions to penicillins. Subsequent reports, which attributed up to 10% cross-reactivity between the 2 drug classes, involved these same first-generation cephalosporins plus cephalexin and cefadroxil and a second-generation drug, cefamandole. However, these studies were flawed because the penicillin test compounds had been contaminated with cephalosporins. Until 1982, penicillin was produced commercially using the cephalosporium mold.38
Many recent studies have established that the rate of cross-reactivity between penicillin and cephalosporins has been grossly overestimated. In fact, the rate of cross-reactivity between penicillin/amoxicillin and second- or third-generation cephalosporins is very low and may actually be lower than that between penicillins and other classes of antibiotics.44
The evidence for limited cross-reactivity. A summary of publications evaluating 38,846 children and adults with and without a history of penicillin allergy is presented in TABLE 1. The database included 2435 patients with a history of penicillin allergy and 961 patients with a history of penicillin allergy and positive skin-test results for penicillin or amoxicillin (total penicillin-allergic patients=3396). The allergic reaction rate is compared with 34,047 patients without a history of penicillin allergy and 1403 patients without a history of penicillin allergy and negative skin-test results for penicillin or amoxicillin (total penicillin-nonallergic patients=35,450).
When patients with a positive history of penicillin-allergy received first-generation cephalosporins, which share a chemical side chain similar to penicillin or amoxicillin (cephalothin, cephaloridine, cephalexin, cefadroxil, and cefazolin, plus the early second-generation cephalosporin, cefamandole), they exhibited a significant increased risk of an allergic reaction to the cephalosporin.
Second- and third-generation cephalosporins modified in size and the complexity of their side chains (eg, cefprozil, cefuroxime, ceftazidime, cefpodoxime, and ceftriaxone) were different enough from penicillin and ampicillin that they did not increase risk of allergic cross-reactivity (TABLE 1).
Many other studies have suggested that cross-reactive immune responses to cephalosporins depend on side chain structure;22,23,27,32,37,38,44-49 that is, cephalosporins with a 7-position side chain similar to benzylpenicillin are more likely to cross-react with penicillin (TABLE 2). Cephalosporins that share a similar 7-position or 3-position side chain are more likely to cross-react with each other.
Cephalosporin/penicillin cross-reactivity
Few studies have evaluated whether patients with primary hypersensitivity to cephalosporins will experience cross-reactivity with penicillin. Romano et al49 conducted skin tests and RASTs in patients with immediate allergic reactions to cephalosporins to examine responses to other cephalosporins and to classic penicillin determinants. About 1 in 5 patients allergic to a cephalosporin reacted to penicillin determinants, while most had positive results to other cephalosporins with the same or similar side-chains.
