Limitations of skin testing
Penicillin skin testing in patients with a history of penicillin allergy does not reliably predict allergy to a cephalosporin unless the side chain of the penicillin or ampicillin reagent is similar to the cephalosporin side chain being tested.3 The positive and negative predictive values of skin testing results for cephalosporins are not well established; if the haptens that cause cephalosporin allergy were known, cross-reactivity with penicillins could be assessed directly. Cephalosporin skin testing works only for the specific drug and drugs with the same side chains, and can be done only if the drug is available in an IV or IM formulation.
Even a positive result does not guarantee a clinical reaction. When penicillin and cephalosporin skin tests or radioallergosorbent tests (RASTs) are positive, a clinical reaction is observed in only 10% to 60% of patients, depending on the reagent and study.50 For example, among 19 well-characterized patients allergic to penicillin who were studied for their sensitivity to the cephalosporins, cephaloridine and cefamandole (which have identical or very similar side chains to penicillin and were therefore potentially cross-reactive) only 2 (10.5%) reacted to cefamandole, while the other 17 patients tolerated both agents.26 In another study of clinical cross-reactivity between amoxicillin and cefadroxil in patients allergic to amoxicillin with good tolerance of penicillin, only 12% had an immediate allergic reaction to cefadroxil, despite the 2 drugs sharing an identical side chain.33 In a third study, allergenic cross-reactivity with cefadroxil and cefamandole was studied among 21 patients selectively allergic to amoxicillin; 8 (38%) had a positive response to cefadroxil (same side chain) and none to cefamandole (different side chain).32
Discussion
Sensible approach to penicillin-allergic patients
Question patients who report penicillin allergy. In many cases, penicillin may not actually have been taken, or patients may have had non-immunologic adverse events such as vomiting, diarrhea, or nonspecific rash; toxic effects; or contemporaneous side effects inappropriately attributed to the drug. These patients can receive penicillin, amoxicillin, or the cephalosporins.
Without the ability to detect patients with IgE antibody to penicillin prospectively or to distinguish true IgE immunologic reactions from idiopathic reactions in patients receiving cephalosporins, it is impossible to definitely claim that increased immune or IgE-mediated reactions to cephalosporins occur in true penicillinallergic (IgE) patients.
When a cephalosporin is/is not safe for a penicillin-allergic patient. Only IgE-mediated reactions—such as anaphylaxis or hypotension, laryngeal edema, wheezing, angioedema, or urticaria—are likely to become more severe with time. Therefore, with a patient who has had a true IgE-mediated reaction to a penicillin, avoid using cephalosporins with a similar side chain. You may, however, give cephalosporins that have different side chains. Cephalosporins may also be used for patients who have had non-IgE-mediated adverse reactions (“non-type I allergy”)21 to a penicillin, such as a non-pruritic, non-urticarial morbilliform or maculopapular rash.
How prevalent is primary cephalosporin allergy? Even if the patient is not allergic to penicillin, cephalosporins can cause allergic or immune-mediated reactions in approximately 1% to 3% of patients. A patient who had an allergic reaction to a specific cephalosporin probably should not receive that cephalosporin again. The risk of a reaction with a different cephalosporin is very low to nonexistent if the side chains of the 2 drugs are dissimilar.
Bottom line. Penicillin-allergic patients have indeed shown an increased incidence of allergic reactions to cephalothin, cephaloridine, cephalexin, cefadroxil, cefazolin, and cefamandole. However, the risk has been overestimated because most studies reporting this cross-reactivity were flawed (because penicillins were contaminated with cephalosporins) and then failed to account for the fact that penicillin-allergic patients have a 3-fold increased risk of allergic reactions even to nonrelated drugs.51
For patients truly allergic to penicillin, the risk of a reaction from a cephalosporin with side chains that differ from penicillin/amoxicillin (cefuroxime, cefpodoxime, cefdinir, and ceftriaxone, as endorsed by the AAFP) is so low that use is justified and medico-legally defensible by the currently available evidence.
CORRESPONDENCE
Michael E. Pichichero, MD, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, New York 14642. E-mail: Michael_pichichero@urmc.rochester.edu