The Use of Cephalosporins in Penicillin-allergic Patients

A Literature Review

James D. Campagna, MD; Michael C. Bond; Esteban Schabelman; Bryan D. Hayes


J Emerg Med. 2012;42(5):612-620. 

In This Article


Our literature review indicates that the cross reactivity between penicillins and cephalosporins is overestimated and much lower than reported in early studies. The high cross reactivity found in the early studies probably was caused, at least in part, by contamination of the study drugs with penicillin during the manufacturing process. Before the 1980s, pharmaceutical companies used Acremonium (formally called Cephalosporium) to create both penicillins and cephalosporins.[31] Furthermore, the authors of the early studies loosely defined "allergy" and did not account for the fact that penicillin-allergic patients have an increased risk of adverse reactions to any medication.[2]

True penicillin allergies are less common than reported. Only IgE-mediated immunologic responses (manifested as bronchospasm, angioedema, a pruritic rash, urticaria, or hypotension) are likely to result in anaphylaxis (representing a true allergy). Several studies in this review confirm a very low rate of positive skin and radioallergosorbent tests (a blood test used to determine if a person is allergic to a specific substance) in those with a reported penicillin allergy.[14,23] This is further supported by the work of Surtee et al., who studied 132 patients with a purported history of penicillin allergy.[32] The allergy was confirmed by radioallergosorbent test in only 4 (3.03%) of the 132 patients. The remaining 128 patients were given a single dose of oral penicillin and experienced no allergic reaction. The amassed data indicate that the true incidence of an allergy to penicillin in patients believed to have such allergy is < 10%.[1] An international survey finds the incidence of anaphylaxis after administration of penicillins to be 0.015–0.004%, with a fatality rate of 0.02–0.0015%.[33]

The early in vitro studies did not clearly distinguish cross reaction of IgM or IgG antibodies to cephalosporin antibodies from a true cross allergy.[7,34] A true allergic response is an IgE-mediated hypersensitivity reaction. IgG- and IgM-mediated responses are not allergic responses and are known to develop in most patients who receive penicillin.[35] IgG and IgM antibodies may cross react with cephalosporin antigens in in vitro tests, but this does not represent an allergic cross reaction.[8,29,36–38]

The structural similarities between penicillins and cephalosporins led to the belief in a high rate of cross reactivity. Penicillins and cephalosporins are both small-molecular-weight compounds with a β-lactam ring that has various side chains.[39] The two groups differ in regard to the constituents and structure of the side chains as well as their degradation pathways.[39–41] However, similarities in the side chains does correlate with risk for cross reactivity.[2,42] A number of studies indicate that the R1 side chain off the β-lactam ring rather than the ring itself is the determining factor for the rate of cross reactivity.[8,9,11,13–16] In particular, the aminopenicillins, amoxicillin and ampicillin, have the same R-group side chains as several first- and second-generation cephalosporins (Figure 2). The highest observed cross reactivity rate (27%) is with cefadroxil, which has the same R-group side chain as amoxicillin. This statement is based on two studies that documented a total of 10 adverse events in 40 patients.[17,19] Based on these data, patients confirmed to be selectively allergic to amoxicillin or ampicillin, but who tolerate penicillin, should not be given cephalosporins with similar R1 side chains.

Figure 2.

Penicillin and cephalosporins known to have a risk of allergic cross reaction.17,19,34,37,47,49 These cephalosporins should be avoided in patients who are allergic to penicillin.
*First generation.
†Second generation.
Patients who are selectively allergic to amoxicillin or ampicillin should avoid the cephalosporins listed, because they have similar R1-group side chains.

Skin testing in penicillin-allergic patients cannot reliably predict an allergic response to a cephalosporin.[13,29] The meta-analysis by Anne and Reisman, encompassing published reports and post-marketing data from pharmaceutical companies, found that skin testing does not predict allergic response to cephalosporins in penicillin-allergic patients, particularly to compounds with dissimilar side chains.[29] However, skin testing may be useful in determining whether a true allergy to penicillin exists.[24]


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