What is the risk of using a cephalosporin in a patient with a penicillin allergy?

A 10-year-old boy in your practice has an allergy to penicillin, which his mother describes as hives. He has now developed an acute bacterial sinusitis that you wish to treat with antibiotics. He is otherwise healthy. You wonder about the risk of using a cephalosporin in an individual with a penicillin allergy. Historically, the classic recommendation for management of an individual with a penicillin allergy has been to avoid the use of cephalosporins. This recommendation was primarily based on the widespread belief that there was approximately 10% cross-reactivity between penicillins and cephalosporins, prompting cautionary statements to be placed on penicillin and cephalosporin pharmaceutical labels (1). More recently, it has been postulated that this 10% cross-reactivity figure may not be as accurate as once believed. First, early cephalosporins contained small amounts of penicillin (2,3), which may have been a confounding factor in earlier studies; as well, an allergic reaction to cephalosporin may be the result of a primary allergy to cephalosporin rather than the result of a cross-reactivity with penicillin (1,4). Determining the true risk of prescribing cephalosporins to a patient with a penicillin allergy becomes increasingly important because as more microorganisms become resistant to medications, our options for treatment decrease, and because avoiding medications for which patients are ‘questionably’ allergic may result in prescribing medications that may be less effective or have greater side effects (5). The situation is often complicated by confusion as to whether a child with a history of penicillin (or amoxicillin) allergy may have experienced a reaction more likely due to nonallergic mechanisms. Patients with a history of allergy to penicillin appear to have a greater risk of subsequently reacting to other drugs (6), raising the question as to whether a response to cephalosporins is a result of coexisting sensitivities. In a recent retrospective database study by Apter et al (5), whose participants included both children and adults, it was suggested that the absolute risk of an allergic reaction to cephalosporins in an individual allergy to penicillin is actually very low and the risk of severe consequences of an allergic reaction is even lower. Anaphylaxis occurred in less than 0.001% of patients taking a cephalosporin who had a previous history of a penicillin allergy. This same study by Apter et al (5) also demonstrated that the relative risk of a reaction in a patient with a penicillin allergy, who subsequently takes a cephalosporin, is increased compared with individuals who received cephalosporin with no prior history of a penicillin allergy (unadjusted RR = 10.0; CI 7.4 to 13.6), with 1.1% of patients having events after both penicillin and cephalosporin. However, there was a similarly increased risk when the penicillin-allergic patient was given a sulfonamide as the second medication when compared with those who received sulfonamide without a history of penicillin allergy (unadjusted RR = 7.2; CI 3.8 to 13.5), with 1.6% of patients having events after both penicillin and sulfonamide. As a result, Apter et al (5) concluded that cross-reactivity could not fully explain these results, and because the risk of very severe reactions in their study was low, they believed that cephalosporins could be considered for treatment of patients with a penicillin allergy. There is also evidence to support that certain cephalosporins are more likely than others to cross-react with penicillin. Atanaskovic-Markovic et al (4) demonstrated that cross-reactivity between cephalosporins and penicillins depends on the generation of cephalosporins with cross-reactivity being higher with earlier generation of cephalosporins, and varying between 0.3% and 23.9%. Pichichero (1), in a recent review of the evidence, stated that because the degradation process of the beta-lactam rings is different for penicillins than it is for cephalosporins, the similarity in structure of the beta-lactam rings as a predictor of cross-reactivity may be less important than once thought. Pichichero also cited that evidence is growing to support the idea that a cephalosporin's ability to generate an immune response is linked to the chemical structure of its side chain. He concluded that medications with similarly structured side chains may be more likely to cross-react than those with dissimilar structures; for this reason, he also proposed that skin testing for penicillin as a predictor of cephalosporin allergy is of questionable value unless the side chains of the penicillin and the cephalosporin are of similar structure (1). Prospective studies have been too small to evaluate the value of penicillin skin testing in assessing cephalosporin allergy in patients with a history of allergy to penicillin (6). The value of cephalosporin skin testing is also questionable because the individual degradation components have not been identified and because skin testing is usually conducted using the native compound (1). The American Academy of Pediatrics (7) supports the use of cefuroxime, cefpodoxime and cefdinir in penicillin-allergic patients for the treatment of sinusitis provided that the penicillin allergy does not involve a type I (immunoglobulin E [IgE]-mediated) reaction. Type I reactions include the most serious allergic reactions and may involve symptoms from urticaria to anaphylaxis. As an added precaution, cephalosporins with similar side chains to penicillin (eg, cephaloridine, cephalothin and cefoxitin) should be used with caution. If the allergy is to ampicillin or amoxicillin, caution should be used with cephalexin, cephradine, cefatrizine, cefadroxil, cefaclor and cefprozil (1). Cephalosporins that have dissimilar side chains do not appear more likely to cause allergic reactions in individuals with penicillin allergy than among those who have no history of allergy (1). Evidence suggests that there is an increased risk associated with the administration of a cephalosporin to an individual with a known penicillin allergy. However, it appears that this increased risk cannot be fully explained by cross-reactivity alone because other medications also show a similarly increased risk of reaction in penicillin-allergic patients. In addition, the risk of severe reaction appears to be very small, especially when a cephalosporin is selected whose side chain is quite different from the medication that caused the allergy. Although the value of penicillin skin testing as a predictor of reactivity to cephalosporins is controversial, patients with a history of allergy to penicillin and a positive skin test may be at greater risk to react to a cephalosporin than those who have only a history of allergy to penicillin (6). It does appear that cephalosporins may be safely prescribed for patients who have not had IgE-mediated (or other serious) reactions to penicillin. Skin testing should be considered if the reaction is consistent with an IgE-mediated mechanism or if the history is not clear (8). Recent practice parameters have suggested that in patients with a history of penicillin allergy who have positive penicillin skin test responses, three options are available: ‘receive an alternate (non-beta-lactam) antibiotic; receive a cephalosporin through graded challenge; or receive a cephalosporin through rapid desensitization' (9).

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