Applied Evidence

Cephalosporins can be prescribed safely for penicillin-allergic patients

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Practice recommendations
  • The widely quoted cross-allergy risk of 10% between penicillin and cephalosporins is a myth (A).
  • Cephalothin, cephalexin, cefadroxil, and cefazolin confer an increased risk of allergic reaction among patients with penicillin allergy (B).
  • Cefprozil, cefuroxime, cefpodoxime, ceftazidime, and ceftriaxone do not increase risk of an allergic reaction (B).

Undoubtedly you have patients who say they are allergic to penicillin but have difficulty recalling details of the reactions they experienced. To be safe, we often label these patients as penicillin-allergic without further questioning and withhold not only penicillins but cephalosporins due to concerns about potential cross-reactivity and resultant IgE-mediated, type I reactions. But even for patients truly allergic to penicillin, is the concern over cephalosporins justified? It depends on the specific agent. What is certain is that a blanket dismissal of all cephalosporins is unfounded.

The truth about the myth

Despite myriad studies spanning decades and involving varied patient populations, results have not conclusively established that penicillin allergy increases the risk of an allergic reaction to cephalosporins, compared with the incidence of a primary (and unrelated) cephalosporin allergy. Most people produce IgG and IgM antibodies in response to exposure to penicillin1 that may cross-react with cephalosporin antigens.2 The presence of these antibodies does not predict allergic, IgE cross-sensitivity to a cephalosporin. Even penicillin skin testing is generally not predictive of cephalosporin allergy.3

Reliably predicting cross-reactivity

A comprehensive review of the evidence shows that the attributable risk of a cross-reactive allergic reaction varies and is strongest when the chemical side chain of the specific cephalosporin is similar to that of penicillin or amoxicillin.

Administration of cephalothin, cephalexin, cefadroxil, and cefazolin in penicillin-allergic patients is associated with a significant increase in the rate of allergic reactions; whereas administration of cefprozil, cefuroxime, cefpodoxime, ceftazidime, and ceftriaxone is not.

Penicillin skin testing can accurately predict a penicillin-allergic reaction, but is not predictive for cephalosporin allergy unless the side chain of the penicillin or ampicillin testing reagent is similar to the cephalosporin side chain being evaluated. Patients who have a reaction to a penicillin or a cephalosporin that is not IgE mediated and not serious may receive repeated courses of that antibiotic and related antibiotics.

This article provides a comprehensive review of the frequency of allergic cross-reactivity between penicillin/amoxicillin and cephalosporin antibiotics, supporting the recent American Academy of Family Physicians evidence-based clinical practice guideline on treatment of acute otitis media recommending the use of cefuroxime, cefpodoxime, cefdinir, and ceftriaxone cephalosporins for patients allergic to penicillin.


We searched Medline and EMBASE databases for English-language articles using the keywords cephalosporin, penicillin, allergy, and cross-sensitivity for the years 1960 to 2005. Among 219 articles identified, 101 were included as source material for this review. Articles we excluded were reviews, republication of results, or ones irrelevant to our purpose.

Five articles described the rate of rashes following use of penicillin and cephalosporins,4-8 and 4 articles described rates of anaphylaxis.5,9-11 We included 26 articles for the evidence base evaluating penicillin/amoxicillin cross-allergy.3,12-36 Eleven articles relied on patient history of penicillin/amoxicillin allergy to categorize results and establish reaction rates and relative risks for the penicillin/amoxicillin allergic vs nonallergic when receiving cephalosporins.12-15,17-20,27,28,31 Fourteen articles relied on patient history of penicillin/amoxicillin allergy plus skin testing results to penicillin/amoxicillin to categorize patients.16,21-25,29,30,32-37 One article3 provided data on a subset where penicillin/amoxicillin allergy was established based on history, and a separate subset where penicillin/amoxicillin allergy was established by skin testing. Other articles related to antibiotic chemical structures, animal studies, monoclonal antibody studies, cross-reactive antibody studies, and antibiotic skin testing were also reviewed.


True incidence of reactions to cephalosporins

The most frequent reactions to cephalosporins are non-pruritic, non-urticarial rashes, which occur in 1.0% to 2.8% of patients;4-8 for most, the mechanism is idiopathic and not a contraindication for future use.38 Retrospective studies suggest a 1% to 3% incidence of immune or allergic reactions to cephalosporins independent of any history of penicillin/amoxicillin allergy.31 Anaphylactic reactions from cephalosporins are extremely rare, with the risk estimated at 0.0001% to 0.1%.31,38 A seminal study suggested approximately 0.004% to 0.015% of treatment courses with penicillin results in anaphylaxis.5,9-11 Several studies suggest that cephalosporin-induced anaphylaxis occurs no more frequently among patients with known penicillin allergy than among those without such allergy.23,27,38-41

Determining cross-reactivity

Penicillins and cephalosporins both possess a beta-lactam ring for antimicrobial activity. They differ in that the 5-membered thiazolidine ring of penicillin is replaced in the cephalosporins with a 6-membered dihydrothiazine ring. After degradation, penicillin forms a stable ring, whereas cephalosporins undergo rapid fragmentation of their rings.42 Immunologic cross-reactivity between the penicillin and cephalosporin beta-lactam rings is, therefore, very unlikely—an observation confirmed by monoclonal antibody analysis.43


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