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Cross Sensitivity Between Penicillins and Cephalosporins

Due to the potential for cross-sensitivity reactions, patients allergic to penicillin are generally not administered cephalosporins. This issue is complex because it has been difficult to quantify the amount of cross-sensitivity reactions that occur between penicillins and cephalosporins. Evaluating the allergenicity of each class individually and assessing how these compounds relate to one another may contribute to a better understanding of this cross-sensitivity.

The frequency of adverse reactions to penicillin in the general population ranges from 0.7% to 10%, with anaphylactic reactions occurring in about 0.004% to 0.015% of patients. Comparatively, the overall incidence of adverse reactions to cephalosporins ranges from 1% to 10%, with anaphylactic reactions occurring in less than 0.02% of patients. Common adverse reactions in both classes include maculopapular or morbilliform skin rash, eosinophilia, drug fever, and gastrointestinal symptoms. The less common anaphylactic reactions manifest as severe urticaria, laryngeal edema, angioedema, wheezing, or hypotension. These anaphylactic reactions are immune mediated. Specific IgE antibodies recognize and bind to various constituents of the penicillin or cephalosporin moiety and initiate the activation of mast cells resulting in release of its mediators. Skin testing for IgE mediated reactions can be useful to determine if a patient has a true allergy. Although recommended, the main drawbacks to skin testing are the limited availability and additional costs associated with these diagnostic tools.

The incidence of cross sensitivity between penicillins and cephalosporins has been reported to be as high as 10%. Manufacturers of all cephalosporins explicitly state in their product labeling that patients with previous hypersensitivity reactions to penicillins should be given cephalosporins cautiously as serious acute allergic reactions may occur. This concept of increased probability of cross sensitivity between penicillins and cephalosporins arose from the fact that both classes share a common beta-lactam ring and have a similar spectrum of allergic reactions. To date, numerous clinical studies have tried to quantify the actual rate of cross sensitivity with mixed results.

Initial studies reported extremely high rates of cross sensitivity between penicillins and first generation cephalosporins. In 1966, Thoburn et al reported a cross sensitivity rate of 18.2% in patients with a history of penicillin allergy who were subsequently challenged with cephalothin, a first-generation cephalosporin. The elevated rates of cross sensitivity seen in early trials may have been due to contamination with penicillin during the manufacturing process of cephalosporins. Early first generation cephalosporins, such as cephalothin, contained trace amounts of penicillin (0.05 units/gram of cephalothin). This small amount of penicillin may have contributed to an elevated cross sensitivity rate.

In 1978, Petz performed an extensive review of cephalosporin clinical trial data involving 15,708 study subjects. Petz recorded the number of allergic reactions to cephalosporins in penicillin allergic and non-allergic subjects. Subjects were treated with any one of the following agents: cephaloridine, cephalothin, cephalexin, cefazolin, or cefamandole. Overall, 701 patients were allergic to penicillin, and of these 57 (8.1%) had an allergic reaction to a cephalosporin. In the remaining 15,007 non-allergic patients, 285 (1.9%) patients had an allergic reaction to one of the cephalosporins. Thus, the author concluded that there is a four-fold increase in the risk of developing an allergic reaction to cephalosporins when given to patients with a history of penicillin allergy.

A recent review article by Kelkar et al in the September 2001 New England Journal of Medicine summarized several studies on the cross sensitivity between penicillins and cephalosporins. The authors concluded that the risk of an allergic reaction to a cephalosporin was up to eight times higher in patients with a history of penicillin allergy versus non-allergic patients. The authors also stated that patients with a history of anaphylactic reactions secondary to penicillin had a significantly higher rate of positive skin tests for penicillin allergy.

Currently, studies on the cross sensitivity between penicillins and cephalosporins have shifted from retrospective reviews of clinical data to performing prospective studies. For many years, the beta-lactam ring has been considered the main antigenic determinant of IgE mediated allergic reactions. However, recent focus has been on the side-chain moieties attached to the ring structure. Some cephalosporins share an identical side-chain with certain penicillin formulations. For example, cephalexin and ampicillin have identical side-chain structures, and amoxicillin and cephadroxil also have identical side-chain structures. These side-chain moieties appear to play a role in eliciting an antigenic IgE mediated allergic reaction. Multiple studies have tested the theory by challenging penicillin allergic patients with cephalosporin agents with the identical side-chains versus cephalosporins that have differing side-chains.

Miranda et al studied 21 patients with a history of amoxicillin allergy. The authors challenged these patients with cefadroxil, a cephalosporin with an identical side-chain, and cefamandole, a cephalosporin with a different side-chain. Eight patients (38%) had a positive response to cefadroxil manifesting as pruritus, erythema, or maculopapules. None of the patients reacted to cefamandole. In addition, Novalbos et al studied 41 patients with a history of penicillin allergy. The authors challenged these patients with 3 cephalosporins that did not share the same side-chain as penicillin. All patients tolerated the 3 cephalosporins when administered via the intramuscular route. Both studies found that patients with a history of penicillin allergy tolerated cephalosporins with a different side-chain.

A clear rate of cross sensitivity exists between the penicillins and cephalosporins. Patients with a penicillin allergy are at an increased risk of developing an adverse reaction to a cephalosporin. When determining if treatment with a cephalosporin is appropriate in a penicillin allergic patient, the following factors should be considered:

    1. Obtain a detailed history from the patient on the type of reaction
    2. Classify the reaction as non-life threatening versus anaphylactic
    3. Skin test patients to assess true allergy
    4. Choose a cephalosporin with different side chain moieties from the original offending agent

These factors may aid in directing therapy towards an appropriate beta-lactam antibiotic.


1. Salkind AR, Cuddy PG, Foxworth JW. Is the patient allergic to penicillin? JAMA 2001;285(19):2498-505.

2. Anne S, Reisman RE. Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol 1995;74:167-170.

3. Kelkar PS, Li JT. Cephalosporin allergy. New Engl J Med 2001;345(11):804-9.

4. Thoburn R, Johnson JE III, Cluff LE. Studies on the epidemiology of adverse
reactions IV: the relationship of cephalothin and penicillin allergy. JAMA 1966;194:345-8.

5. Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: a review. J Infec Dis 1978;137:S74-9.

6. Miranda A, Blanca M etal. Cross-reactivity between a penicillin and a cephalosporin with the same side chain. J Allergy Clin Immunol 1996;98(3):671-677.

7. Novalbos A, Sastre J et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to pencillins. Clin Exp Allergy 2001;31:438-43.


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