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  • Cross-Allergy Among the 6-lactam Antibiotic Agents: RESULTS part 3

Risks of Prescribing Cephalosporins

Skin reactions to cephalosporins (e.g., urticaria, rash, pruritis) occur at a frequency of 1% to 3%. Anaphylaxis is rare (0.0001% to 0.1%). Because cephalosporins also contain the £-lactam ring (Figure 1), there is potential for cross-reactivity in penicillin-allergic patients. Complicating the issue is the fact that hypersensitivity reactions with cephalosporins may be due to the various side chains as well as the £-lactam nucleus. In addition, the original cephalosporins (cephalothin and cephaloridine) were contaminated with minute quantities of penicillin, which might have resulted in overestimates of cross-allergy.

Previous studies have indicated that the risk of allergy to cephalosporins is 4 to 8 times greater among patients with a reported penicillin allergy than among patients without a history of allergy. In an analysis of previous reports (the majority using older cephalosporins), 5.6% of patients with a positive result on penicillin skin testing had allergic reactions (including some cases of anaphylaxis) within 24 h of receiving a cephalosporin, whereas the frequency was only 1.7% among those with a negative skin test result (similar to the incidence in the general population). A similar summary incorporating 2 newer cross-allergy studies found a reaction rate of 4.4%. This is lower than the 10.9% (14/128) cross-reactivity rate observed in a recent investigation in which patients with a history of immediate reactions to a penicillin and a positive skin test result were challenged with skin tests to a variety of cephalosporins. Nine (64%) of the 14 patients had positive results to cefamandole and/or cephalothin, which have side chains similar to those of the penicillin agents used for skin testing (benzylpenicillin, ampicillin). If these patients are excluded, the incidence of cross-reactivity to cefuroxime, ceftazidime, ceftriaxone or cefotaxime was 3.9% (5/128). Thus, higher-generation cephalosporins appear to have a lower propensity (less than 4%) than first-generation cephalosporins (specifically, cefazolin and cephalexin) to cross-react in penicillin-allergic patients. These figures must also be interpreted in light of the fact that some patients may be predisposed to allergic reactions and may have reacted on this basis, rather than experiencing a true cross-reaction.
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Patients with negative results to penicillin skin tests are not at greater risk for allergy to cephalosporins and may receive these drugs. One study showed no cross-reactivity among 41 patients with documented allergy (mostly IgE-mediated) to penicillin G, amoxicillin or cloxacillin who were given cefazolin, cefuroxime, and ceftriaxone. None of these cephalosporins has a side chain similar to the penicillin that provoked the allergic reaction. The risk is higher for penicillin- allergic patients who received cephalosporins with a similar side chain (e.g., ampicillin and cephalexin, penicillin G and cephalothin) and has ranged from 12% to 38%.

In a chart review of patients undergoing orthopedic surgery, 73% of those reporting penicillin allergy received cefazolin preoperatively. Only 1 of the 300 patients may have had an allergic reaction associated with cefazolin administration. Although the authors noted that those who had had severe or anaphylactic reactions were probably among those given an alternative antibiotic, this study did support the safety of cefazolin, a first-generation cephalosporin, for surgical prophylaxis in most patients with a claim of penicillin allergy.

It is generally recommended that clinicians avoid cephalosporins and use an alternative class of antibiotic for patients with a history of immediate IgE-mediated reaction to penicillin, unless penicillin skin testing has been performed and the result is negative. This restrictive approach has been recently challenged, however, on the basis that the risk of cross-allergy with third-generation cephalosporins is thought to be insignificant and the potential of cross-allergy with first- or second-generation cephalosporins exists only if the cephalosporin has a similar side chain to the culprit penicillin. Unfortunately, the specific penicillin to which the patient previously reacted is not always known. Romano and others proposed skin testing with cefuroxime or ceftriaxone at a concentration of 2 mg/mL, followed by administration of the agent if the result of the test is negative.
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Recommendation: Obtain a thorough history of the penicillin allergy. Patients with a history of non-IgE- mediated reactions to penicillin may receive cephalosporins. If the patient has a history of IgE-mediat- ed allergy to penicillin, cephalosporins should be avoid­ed whenever possible. If a cephalosporin is required, it should be administered under close supervision. Skin testing to cephalosporins has been proposed. Alternative­ly, in nonurgent situations, penicillin skin testing may be performed, and the cephalosporin administered if the result is negative.

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