Cephalosporin use in treatment of patients with penicillin allergies
Daryl D. DePestel, PharmD; Michael S. Benninger, MD; Larry Danziger, PharmD; Kerry L. LaPlante, PharmD; Chandler May, MD, JD, MS, FCLM; Allan Luskin, MD; Michael Pichichero, MD; James A. Hadley, MD, FACS
J Am Pharm Assoc (2003) 2008;48:530-540. doi:10.1331/JAPhA.2008.07006


Objective  To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients.

Data sources  Published articles were identified through Medline and EMBASE (1960–2007) using the search terms penicillin and allergy and cephalosporin and cross-reactivity. Additional sources were identified from the authors’ personal collection and the reference bibliographies.

Study selection  The articles found in the search were limited to the English language and screened for relevance. Review articles and republication of results were excluded. A total of 44 articles reported evidence of cross-reactivity between cephalosporins and penicillins in human and animal studies. Additional references provided background and perspective.

Data synthesis  Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious, non-life-threatening penicillin reaction. Exclusions include type I anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and other potentially life-threatening responses to medication. Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions. Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity.

Conclusion  Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported. Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect. Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed.

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 American Academy of Pediatrics, Subcommittee on Management of Sinusitis and Committee on Quality Improvement. Clinical practice guidelines: management of sinusitis.  Pediatrics.  2001;108:798–808[erratum in Pediatrics. 2001;108:A24; Pediatrics. 2002;109:40.][PubMed]
 American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Follow-up management of children with tympanostomy tubes.  Pediatrics.  2002;109:328–9.[PubMed][CrossRef]
 American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media.  Pediatrics.  2004;113:1451–65.[PubMed]
Anon JB, Jacobs MR, Poole MD, et al. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis.  Otolaryngol Head Neck Surg.  2004;130:1–45.[PubMed]
Gell PGH, Coombs RRA.Classification of allergic reactions underlying disease. In:  Clinical aspects of immunology.  Philadelphia:  F.A. Davis;  1963:317–37.
Shulman ES.  Development of a monoclonal anti-immunoglobulin E antibody (omalizumab) for the treatment of allergic respiratory disorders.  Am J Respir Crit Care Med.  2001;164:S6–11.[PubMed]
Daly AK.  Pharmacogenetics of the cytochromes P450.  Curr Top Med Chem.  2004;4:1733–44.[PubMed]
Dalhoff A, Janjic N, Echols R. Redefining penems.  Biochem Pharmacol.  2006;71:1085–95.[PubMed]
Kelkar PS, Li JT.  Cephalosporin allergy.  N Engl J Med.  2001;345:804–9.[PubMed]
Platt R. Adverse effects of third-generation cephalosporins.  J Antimicrob Chemother.  1982;10(suppl C):135–40.[PubMed]
Gadde J, Spence M, Wheeler B, Adkinson NF Jr. Clinical experience with penicillin skin testing in a large inner-city STD clinic.  JAMA.  1993;270:2456–63.[PubMed]
Lin RY.  A perspective on penicillin allergy.  Arch Intern Med.  1992;152:930–7.[PubMed]
Petz LD.  Immunologic reactions of humans to cephalosporins.  Postgrad Med J.  1971;47(suppl):64–9.[PubMed]
Robinson JL, Hameed T, Carr S. Practical aspects of choosing an antibiotic for patients with a reported allergy to an antibiotic.  Clin Infect Dis.  2002;35:26–31.[PubMed]
Arndt KA, Jick H. Rates of cutaneous reactions to drugs: a report from the Boston Collaborative Drug Surveillance Program.  JAMA.  1976;235:918–23.[PubMed]
Levine LR.  Quantitative comparison of adverse reactions to cefaclor vs. amoxicillin in a surveillance study.  Pediatr Infect Dis.  1985;4:358–61.[PubMed]
Sanders CV, Greenberg RN, Marier RL.  Cefamandole and cefoxitin.  Ann Intern Med.  1985;103:70–8.[PubMed]
Norrby SR.  Side effects of cephalosporins.  Drugs.  1987;34(suppl 2):105–20.[PubMed]
Forrest D, Schellenber R, Their VV, et al. Introduction of a practice guideline for penicillin skin testing improves the appropriateness of antibiotic therapy.  Clin Infect Dis.  2001;32:1686–90.
Silviu-Dan F, McPhillips S, Warrington RJ.  The frequency of skin test reactions to side-chain penicillin determinants.  J Allergy Clin Immunol.  1993;91:694–701.[PubMed]
Solley GO, Gleich GJ, Van Dellen RG.  Penicillin allergy: clinical experience with a battery of skin-test reagents.  J Allergy Clin Immunol.  1982;69:238–44.[PubMed]
Sullivan TJ, Wedner HJ, Shatz GS, et al. Skin testing to detect penicillin allergy.  J Allergy Clin Immunol.  1981;68:171–80.[PubMed]
Warrington RJ, Tse KS, Gorski BA, et al. Diagnosis of penicillin allergy by skin testing: the Manitoba experience.  Can Med Assoc J.  1978;118:787–91.[PubMed]
Weiss ME, Adkinson NF.  Immediate hypersensitivity reactions to penicillin and related antibiotics.  Clin Allergy.  1998;18:515–40.
Pichichero ME.  A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients.  Pediatrics.  2005;115:1048–57.[PubMed]
De Weck AL, Schneider CH, Gutersohn J. The role of penicilloylated protein impurities, penicillin polymers and dimers in penicillin allergy.  Int Arch Allergy Appl Immunol.  1968;33:535–67.[PubMed]
Batchelor FR, Dewdney JM, Weston RD, Wheeler AW.  The immunogenicity of cephalosporin derivatives and their cross-reaction with penicillin.  Immunology.  1966;10:21–33.[PubMed]
Shibata K, Atsumi T, Horiuchi Y, Mashimo K. Immunological cross-reactivities of cephalothin and its related compounds with benzylpenicillin (penicillin G).  Nature.  1966;212:419–20.[PubMed]
Hamilton-Miller JM, Abraham EP.  Specificities of haemagglutinating antibodies evoked by members of the cephalosporin C family and benzylpenicillin.  Biochem J.  1971;123:183–90.[PubMed]
Petersen BH, Graham J. Immunologic cross-reactivity of cephalexin and penicillin.  J Lab Clin Med.  1974;83:860–70.[PubMed]
Nagakura N, Shimizu T, Masuzawa T, Yanagihara Y. Anti-cephalexin monoclonal antibodies and their cross-reactivities to cephems and penams.  Int Arch Allergy Appl Immunol.  1990;93:126–32.[PubMed]
Mayorga C, Obispo T, Jimena L, et al. Epitope mapping of beta-lactam antibiotics with the use of monoclonal antibodies.  Toxicology.  1995;97:225–34.[PubMed]
Stewart GT.  Cross-allergenicity of penicillin G and related substances.  Lancet.  1962;1:509–10.[PubMed]
Thoburn R, Johnson JE 3rd, Cluff LE.  Studies on the epidemiology of adverse drug reactions. IV. The relationship of cephalothin and penicillin allergy.  JAMA.  1966;198:345–8.[PubMed]
Greico M. Cross allergencitiy of the penicillins and cephalosporins.  Arch Intern Med.  1967;119:141–6.[PubMed]
Pedersen-Bjergaard J. Significance of the penicilloyl radical in penicillin allergy.  Acta Allergol.  1967;22:466–84.[PubMed]
Girard JP.  Common antigenic determinants of penicillin G, ampicillin and the cephalosporins demonstrated in men.  Int Arch Allergy Appl Immunol.  1968;33:428–38.[PubMed]
Assem ES, Vickers MR.  Tests for penicillin allergy in man. II. The immunological cross-reaction between penicillins and cephalosporins.  Immunology.  1974;27:255–69.[PubMed]
Martin JA, Igea JM, Fraj J, et al. Allergy to amoxicillin in patients who tolerated benzylpenicillin, aztreonam, and ceftazidime.  Clin Infect Dis.  1992;14:592–3.[PubMed]
Igea JM, Fraj J, Davila I, et al. Allergy to cefazolin: study of in vivo cross reactivity with other betalactams.  Ann Allergy.  1992;68:515–9.[PubMed]
Vega JM, Blanca M, Garcia JJ, et al. Immediate allergic reactions to amoxicillin.  Allergy.  1994;49:317–22.[PubMed]
Audicana M, Bernaola G, Urrutia I, et al. Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin.  Allergy.  1994;49:108–13.[PubMed]
Miranda A, Blanca M, Vega JM, et al. Cross-reactivity between a penicillin and a cephalosporin with the same side chain.  J Allergy Clin Immunol.  1996;98:671–7.[PubMed]
Sastre J, Quijano LD, Novalbos A, et al. Clinical cross-reactivity between amoxicillin and cephadroxil in patients allergic to amoxicillin and with good tolerance of penicillin.  Allergy.  1996;51:383–6.[PubMed]
Roman A, Quarantino D, Venuti A, et al. Selective type-1 hypersensitivity to cefuroxime.  J Allergy Clin Immunol.  1998;101:564–5.[PubMed]
Blanca M, Fernandez J, Miranda A, et al. Cross-reactivity between penicillins and cephalosporins: clinical and immunologic studies.  J Allergy Clin Immunol.  1989;83:381–5.[PubMed]
Romano A, Mayorga C, Torres MJ, et al. Immediate allergic reactions to cephalosporins: cross-reactivity and selective responses.  J Allergy Clin Immunol.  2000;106:1177–83.[PubMed]
Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins.  Clin Exp Allergy.  2001;31:438–43.[PubMed]
Anne S, Reisman R. Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy.  Ann Allergy Asthma Immunol.  1995;74:167–70.[PubMed]
Apicella M, Perkins R, Salsaw S. Cephaloridine treatment of bacterial infections.  Am J Med Sci.  1966;251:266–76.[PubMed]
Dash C. Penicillin allergy and the cephalosporins.  J Antimicrob Chemother.  1975;1(3 suppl):107–18.[PubMed]
Daulat S, Solensky R, Earl H, et al. Safety of cephalosporin administration to patients with histories of penicillin allergy.  J Allergy Clin Immunol.  2004;113:1220–2.[PubMed]
Goodman E, Morgan M, Johnson PA, et al. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response.  J Clin Anesth.  2001;13:561–4.[PubMed]
Griffith R, Black H. Cephalothi: a new antibiotic: preliminary clinical and laboratory studies.  JAMA.  1964;189:823–8.[PubMed]
Marks J, Garrett R. Cephalexin in general practice.  Post Grad Med J.  1970;46(suppl):113–7.
Pichichero M, Pichichero D. Selecting skin testing reagents to predict amoxicillin and cephalosporin allergy.  Pediatr Asthma Allergy Immunol.  1997;11:79–93.
Romano A, Gueant-Rodriguez RM, Viola M, et al. Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins.  Ann Intern Med.  2004;141:16–22.[PubMed]
Saxon A, Beall G, Rohr A. Immediate hypersensitivity reactions to beta-lactam antibiotics.  Ann Intern Med.  1987;107:204–15.[PubMed]
Shepherd G, Burton D. Administration of cephalosporin antibiotics to patients with a history of penicillin allergy.  J Allergy Clin Immunol.  1993;91:262.
Stewart G. Hypersensitivity and toxicity of beta-lactam antibiotics.  Postgrad Med J.  1967;43(suppl 43):31–6.[PubMed]
Walters E, Romansky M, Johnson A. Cephalothin-laboratory and clinic studies in 109 patients.  Antimicrob Agents Chemother.  1963:161:247–53.[PubMed]
Weinstein L, Kaplan K, Chang T. Treatment of infections in man with cephalothin.  JAMA.  1964;189:829–34.[PubMed]
Hasdenteufel F, Luyasu S, Renaudin JM, et al. Anaphylactic shock associated with cefuroxime axetil: structure-activity relationships.  Ann Pharmacother.  2007;41:1069–72.[PubMed]
Trcka J, Seitz CS, Bröcker EB, et al. Aminopenicillin-induced exanthema allows treatment with certain cephalosporins or phenoxymethyl penicillin.  J Antimicrob Chemother.  2007;60:107–11.[PubMed]
Apter AJ, Kinman JL, Bilker WB, et al. Is there cross-reactivity between penicillins and cephalosporins? Am J Med.  2006;119:254.e11–19.
 Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of anaphylaxis: an updated practice parameter.  J Allergy Clin Immunol.  2005;115(3 suppl):S483–523.[PubMed]
Simons FE, Frew AJ, Ansotequi IJ, et al. Risk assessment in anaphylaxis: current and future approaches.  J Allergy Clin Immunol.  2007;120(1 suppl):S2–24.[PubMed]
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No Cross-Reactivity With Cephalosporins in Patients With Penicillin Allergy. J Investig Allergol Clin Immunol 2015;25(3):216-7.
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