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The latest word on penicillin allergy
Despite a myriad of studies over the past several decades using varied patient populations, the true increased risk of an allergic reaction to a cephalosporin in a patient with a penicillin allergy compared with a primary (and unrelated) cephalosporin allergy has not been clearly established.
This article provides a comprehensive review of the frequency of allergic cross-reactivity between penicillin and cephalosporin antibiotics.
Penicillin-cephalosporin cross-reactivity Penicillins and cephalosporins have similar beta-lactam ring structures, are of low molecular weight, and are highly substituted on their side chains. They differ in that the five-membered thiazolidine ring of penicillin is replaced in the cephalosporins with a six-membered dihydrothiazine ring. After degradation, penicillin forms a stable penicilloate ring with preservation of the thiazolidine ring, whereas cephalosporins undergo rapid fragmentation of the beta-lactam and dihydrothiazine rings. Immunologic cross-reactivity between the penicillin and cephalosporin beta-lactam rings is therefore minimal, which is confirmed by monoclonal antibody analysis.
Four generations of the cephalosporin class of antibiotics are now in use. When the first-generation cephalosporins cephaloridine and cephalothin were introduced in the 1960s, anaphylactic reactions were reported in patients with previous allergic reactions to penicillins. These early reports, which attributed up to 10% cross-reactivity between the two drug classes, primarily involved the first-generation cephalosporins and the second-generation agent cefamandole and were later reported to be flawed in that the penicillin test compounds had been contaminated with cephalosporins and the reporters failed to take into account the nonspecific three-fold increase in adverse drug reactions known to occur in penicillin-allergic patients with or without similar chemical structures.
The rate of cross-reactivity between penicillin and most second-, third-, and fourth-generation cephalosporins is low and may actually be lower than that between penicillins and other classes of antibiotics. Several studies have suggested that the immune response to cephalosporins depends more on their side chain substituents; that is, cephalosporins with a side chain similar to benzylpenicillin are more likely to cross-react with penicillin and those with side chains like ampicillin are more likely to cross-react with ampicillin and amoxicillin.
Table 1 : Likelihood of cross-reactivity between penicillin and cephalosporins based on side chain position and group (cephalosporin generation)
Thus, cephalothin and cephaloridine have identical thiophene 2-acetic acid side chains that closely resemble the phenylacetic acid side chain of benzylpenicillin and, therefore, have an increased likelihood to have produced cross-reacting IgE antibodies. Similarly, cefadroxil, cephalexin, cefaclor, and cefprozil have side chains similar to ampicillin and amoxicillin, and, therefore, these antibiotics may induce IgE antibodies that cross-react. Penicillin and cephalospo-rin antibiotics with related and unrelated side chains are listed in Table 1.
Table 2 : Proportion of patients with allergic reactions to cephalosporins stratified by cephalosporin generation, penicillin allergy history, and penicillin skin test results
A recent evidence-based review was published in 2005. The literature search employed Medline and Embase plus a search of all references cited in the identified articles. Twenty-five articles formed the basis of calculation of attributable risk of penicillin allergy to predict cephalosporin cross-sensitivity. The penicillin-allergic-by-history group included 2,435 patients, and the group who were not penicillin-allergic by history included 38,932 patients. The attributable risk of a penicillin-allergic patient's experiencing a cross-reactive, allergic reaction was calculated to be 0.5% to first-generation, 0.2% to second-generation, and -0.8% to third-generation cephalosporins (see Table 2).
Cephalosporin-penicillin cross-reactivity Few studies have evaluated cross-reactivity with penicillin in patients with primary hypersensitivity to cephalosporins. To examine IgE responses, Romano et al. conducted skin tests and radioallergosorbent tests (RAST) in patients with immediate allergic reactions to cephalosporins. Responses to other cephalosporins and to classic penicillin determinants were also assessed. They found fewer than 20% of cephalosporin-allergic patients had IgE antibodies that cross-reacted to penicillin determinants. Most of the patients who had cross-reactive antibodies to the cephalosporins had the same or similar side-chain structures. For example, IgE antibodies to ceftazidime displayed cross-reactivity with cefuroxime, cefotaxime, and ceftriaxone.
Incidence of anaphylaxis Approximately 0.004% to 0.015% of treatment courses with penicillin result in anaphylaxis. Anaphylactic reactions from cephalosporins are even more rare, with the risk estimated at 0.0001% to 0.1%. In an evidence-based analysis there were 20 reported cases of anaphylaxis from a cephalosporin in penicillin-allergic patients compared with 23 cases in patients who were not penicillin-allergic. Thus, anaphylaxis induced by cephalosporins has been found to occur more frequently in patients without a known penicillin allergy than in those with a penicillin allergy.
Conclusion Patients with histories of penicillin or cephalosporin "allergies" usually have had nonimmunologic adverse events such as vomiting, diarrhea, or nonspecific rash; toxic effects; or contemporaneous side effects that have occurred during antibiotic treatment and were inappropriately attributed to the drug. In addition, in the literature the term allergic reaction has been applied in an uncritical manner to any adverse reaction and cross-sensitivity to any test of cross-reactive antibody.
The risks of penicillin and cephalosporin cross-allergy and cross-reactivity have been grossly overestimated for three decades. The original data published in the mid-1970s came from two studies evaluating only first-generation cephalosporins (and cefamandole); the penicillin test compounds were contaminated with cephalosporins; and the three-fold increased rate of nonspecific allergic reactions in penicillin-allergic patients was not factored into the calculations. Shared allergy between penicillin and cephalosporins is controlled by similarities in side-chain structure, not the shared beta-lactam rings.
Therefore, pharmacists must now relearn which cephalosporins are likely to cause an allergic reaction in a penicillin- or amoxicillin-allergic patient. This is a major paradigm shift. As a rule, the cross-allergy risk from first-generation cephalosporins is about 0.5%, and the risk from second-generation or third-generation cephalosporins is near zero.