JFP_0206_AE_Pichichero.Final 1/23/06 1:26 PM Page 106 APPLIED EVIDENCE New research findings that are changing clinical practice Michael E. Pichichero, MD University of Rochester Cephalosporins can be Medical Center, Rochester, NY prescribed safely for penicillin-allergic patients Practice recommendations an allergic reaction to cephalosporins, ■ The widely quoted cross-allergy risk compared with the incidence of a primary of 10% between penicillin and (and unrelated) cephalosporin allergy. cephalosporins is a myth (A). Most people produce IgG and IgM antibodies in response to exposure to ■ Cephalothin, cephalexin, cefadroxil, penicillin1 that may cross-react with and cefazolin confer an increased risk cephalosporin antigens.2 The presence of of allergic reaction among patients these antibodies does not predict allergic, with penicillin allergy (B). IgE cross-sensitivity to a cephalosporin. ■ Cefprozil, cefuroxime, cefpodoxime, Even penicillin skin testing is generally not ceftazidime, and ceftriaxone do not predictive of cephalosporin allergy.3 increase risk of an allergic reaction (B). Reliably predicting cross-reactivity ndoubtedly you have patients who A comprehensive review of the evidence say they are allergic to penicillin shows that the attributable risk of a cross- U but have difficulty recalling details reactive allergic reaction varies and is of the reactions they experienced. To be strongest when the chemical side chain of safe, we often label these patients as peni- the specific cephalosporin is similar to that cillin-allergic without further questioning of penicillin or amoxicillin. and withhold not only penicillins but Administration of cephalothin, cepha- cephalosporins due to concerns about lexin, cefadroxil, and cefazolin in penicillin- potential cross-reactivity and resultant IgE- allergic patients is associated with a mediated, type I reactions. But even for significant increase in the rate of allergic patients truly allergic to penicillin, is the reactions; whereas administration of concern over cephalosporins justified? It cefprozil, cefuroxime, cefpodoxime, cef- depends on the specific agent. What is cer- tazidime, and ceftriaxone is not. tain is that a blanket dismissal of all Penicillin skin testing can accurately cephalosporins is unfounded. predict a penicillin-allergic reaction, but CORRESPONDENCE Michael E. Pichichero, MD, is not predictive for cephalosporin aller- University of Rochester The truth about the myth gy unless the side chain of the penicillin Medical Center, 601 Elmwood Despite myriad studies spanning decades or ampicillin testing reagent is similar to Avenue, Box 672, Rochester, and involving varied patient populations, the cephalosporin side chain being evalu- New York 14642. E-mail: Michael_pichichero@ results have not conclusively established ated. Patients who have a reaction to a urmc.rochester.edu that penicillin allergy increases the risk of penicillin or a cephalosporin that is not 106 VOL 55, NO 2 / FEBRUARY 2006 THE JOURNAL OF FAMILY PRACTICE JFP_0206_AE_Pichichero.Final 1/23/06 1:26 PM Page 107 Cephalosporins can be prescribed safely for penicillin-allergic patients ▲ IgE mediated and not serious may receive ■ Results repeated courses of that antibiotic and True incidence of reactions related antibiotics. to cephalosporins This article provides a comprehen- The most frequent reactions to cephalo- sive review of the frequency of allergic sporins are non-pruritic, non-urticarial cross-reactivity between penicillin/amox- rashes, which occur in 1.0% to 2.8% of icillin and cephalosporin antibiotics, sup- patients;4–8 for most, the mechanism is idio- porting the recent American Academy of pathic and not a contraindication for Family Physicians evidence-based clinical future use.38 Retrospective studies suggest a practice guideline on treatment of acute 1% to 3% incidence of immune or allergic otitis media recommending the use of reactions to cephalosporins independent of cefuroxime, cefpodoxime, cefdinir, and any history of penicillin/amoxicillin ceftriaxone cephalosporins for patients allergy.31 Anaphylactic reactions from allergic to penicillin. cephalosporins are extremely rare, with the risk estimated at 0.0001% to 0.1%.31,38 A seminal study suggested approximately ■ Methods 0.004% to 0.015% of treatment courses We searched Medline and EMBASE data- with penicillin results in anaphylaxis.5,9–11 bases for English-language articles using Several studies suggest that cephalosporin- the keywords cephalosporin, penicillin, induced anaphylaxis occurs no more allergy, and cross-sensitivity for the years frequently among patients with known 1960 to 2005. Among 219 articles iden- penicillin allergy than among those with- tified, 101 were included as source mate- out such allergy.23,27,38–41 rial for this review. Articles we excluded were reviews, republication of results, or Determining cross-reactivity ones irrelevant to our purpose. Penicillins and cephalosporins both possess Five articles described the rate of a beta-lactam ring for antimicrobial activi- rashes following use of penicillin and ty. They differ in that the 5-membered cephalosporins,4–8 and 4 articles described thiazolidine ring of penicillin is replaced in FAST TRACK rates of anaphylaxis.5,9–11 We included 26 the cephalosporins with a 6-membered Penicillin articles for the evidence base evaluating dihydrothiazine ring. After degradation, penicillin/amoxicillin cross-allergy.3,12–36 penicillin forms a stable ring, whereas compounds Eleven articles relied on patient history of cephalosporins undergo rapid fragmenta- contaminated with penicillin/amoxicillin allergy to categorize tion of their rings.42 Immunologic cross- cephalosporins results and establish reaction rates and rel- reactivity between the penicillin and ative risks for the penicillin/amoxicillin cephalosporin beta-lactam rings is, there- led to the allergic vs nonallergic when receiving fore, very unlikely—an observation con- erroneous cephalosporins.12–15,17–20,27,28,31 Fourteen arti- firmed by monoclonal antibody analysis.43 assumption of 10% cles relied on patient history of How the “10% cross-reactivity” myth cross-reactivity penicillin/amoxicillin allergy plus skin test- took hold. When the first-generation ing results to penicillin/amoxicillin to cate- cephalosporins cephaloridine and cepha- gorize patients.16,21–25,29,30,32–37 One article3 lothin were introduced in the 1960s, aller- provided data on a subset where peni- gic and anaphylactic reactions were report- cillin/amoxicillin allergy was established ed in patients with previous allergic based on history, and a separate subset reactions to penicillins. Subsequent reports, where penicillin/amoxicillin allergy was which attributed up to 10% cross-reactivity established by skin testing. Other articles between the 2 drug classes, involved these related to antibiotic chemical structures, same first-generation cephalosporins plus animal studies, monoclonal antibody stud- cephalexin and cefadroxil and a second- ies, cross-reactive antibody studies, and generation drug, cefamandole. However, antibiotic skin testing were also reviewed. these studies were flawed because the www.jfponline.com VOL 55, NO 2 / FEBRUARY 2006 107 JFP_0206_AE_Pichichero.Final 1/23/06 1:26 PM Page 108 APPLIED EVIDENCE penicillin test compounds had been contam- Many other studies have suggested inated with cephalosporins. Until 1982, that cross-reactive immune responses to penicillin was produced commercially using cephalosporins depend on side chain struc- the cephalosporium mold.38 ture;22,23,27,32,37,38,44–49 that is, cephalosporins Many recent studies have established with a 7-position side chain similar to ben- that the rate of cross-reactivity between zylpenicillin are more likely to cross-react penicillin and cephalosporins has been with penicillin (TABLE 2). Cephalosporins grossly overestimated. In fact, the rate of that share a similar 7-position or 3- cross-reactivity between penicillin/amoxi- position side chain are more likely to cross- cillin and second- or third-generation react with each other. cephalosporins is very low and may actual- ly be lower than that between penicillins Cephalosporin/penicillin and other classes of antibiotics.44 cross-reactivity The evidence for limited cross-reactivity. Few studies have evaluated whether A summary of publications evaluating patients with primary hypersensitivity to 38,846 children and adults with and with- cephalosporins will experience cross- out a history of penicillin allergy is present- reactivity with penicillin. Romano et al49 ed in TABLE 1. The database included 2435 conducted skin tests and RASTs in patients patients with a history of penicillin allergy with immediate allergic reactions to and 961 patients with a history of peni- cephalosporins to examine responses cillin allergy and positive skin-test results to other cephalosporins and to classic peni- for penicillin or amoxicillin (total peni- cillin determinants. About 1 in 5 patients cillin-allergic patients=3396). The allergic allergic to a cephalosporin reacted to reaction rate is compared with 34,047 penicillin determinants, while most had patients without a history of penicillin positive results to other cephalosporins allergy and 1403 patients without a histo- with the same or similar side-chains. ry of penicillin allergy and negative skin- test results for penicillin or amoxicillin Limitations of skin testing FAST TRACK (total penicillin-nonallergic patients=35,450). Penicillin skin testing in patients