Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics
- Kimberly G Blumenthal, MD, MSc
Kimberly G Blumenthal, MD, MSc
- Assistant Professor of Medicine
- Harvard Medical School
- Roland Solensky, MD
Roland Solensky, MD
- Oregon State University/Oregon Health and Science University College of Pharmacy
Penicillin allergy is the most common drug allergy reported by patients. Penicillins are one group within the family of beta-lactam antibiotics, which also includes cephalosporins, carbapenems, and monobactams. This topic will present diagnostic strategies used by allergy specialists for evaluating a patient with suspected or confirmed immediate (ie, immunoglobulin E [IgE]-mediated) allergy to penicillins. Studies of cross-reactivity between penicillins and other beta-lactam antibiotics are also reviewed.
●An algorithmic approach to the use of related antibiotics, with or without access to allergy consultation and penicillin skin testing, is discussed in detail separately (algorithm 1). (See "Choice of antibiotics in penicillin-allergic hospitalized patients".)
●Delayed reactions to penicillins, ranging from maculopapular drug eruptions to severe systemic reactions, are reviewed elsewhere. (See "Penicillin allergy: Delayed hypersensitivity reactions".)
Penicillin allergy is reported by up to 10 percent of patients. However, more than 90 percent of patients with a reported penicillin allergy do not have immunoglobulin E (IgE) antibodies when skin testing is performed, either because they were inappropriately labeled as allergic or because they had an earlier allergy that resolved with time [1-5]. Among patients with an IgE-mediated penicillin allergy that has been confirmed with skin testing, available studies suggest that 97 percent will tolerate cephalosporins and 99 percent will tolerate carbapenems, as reviewed in detail in this topic. However, despite these reassuring figures, beta-lactam drugs are among the leading causes of drug-induced anaphylaxis, and there are methodologic issues with the data that should be appreciated to understand the limitations of the literature.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Macy E, Burchette RJ. Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up. Allergy 2002; 57:1151.
- Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol 2006; 97:681.
- del Real GA, Rose ME, Ramirez-Atamoros MT, et al. Penicillin skin testing in patients with a history of beta-lactam allergy. Ann Allergy Asthma Immunol 2007; 98:355.
- Rimawi RH, Cook PP, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med 2013; 8:341.
- Raja AS, Lindsell CJ, Bernstein JA, et al. The use of penicillin skin testing to assess the prevalence of penicillin allergy in an emergency department setting. Ann Emerg Med 2009; 54:72.
- Asero R. Detection of patients with multiple drug allergy syndrome by elective tolerance tests. Ann Allergy Asthma Immunol 1998; 80:185.
- Apter AJ, Kinman JL, Bilker WB, et al. Is there cross-reactivity between penicillins and cephalosporins? Am J Med 2006; 119:354.e11.
- Mendelson L, personal communication.
- Bousquet PJ, Co-Minh HB, Arnoux B, et al. Importance of mixture of minor determinants and benzylpenicilloyl poly-L-lysine skin testing in the diagnosis of beta-lactam allergy. J Allergy Clin Immunol 2005; 115:1314.
- Romano A, Bousquet-Rouanet L, Viola M, et al. Benzylpenicillin skin testing is still important in diagnosing immediate hypersensitivity reactions to penicillins. Allergy 2009; 64:249.
- Moss RB, Babin S, Hsu YP, et al. Allergy to semisynthetic penicillins in cystic fibrosis. J Pediatr 1984; 104:460.
- 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.
- 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.
- 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.
- Daulat S, Solensky R, Earl HS, et al. Safety of cephalosporin administration to patients with histories of penicillin allergy. J Allergy Clin Immunol 2004; 113:1220.
- Goodman EJ, Morgan MJ, 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.
- Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: a review. J Infect Dis 1978; 137 Suppl:S74.
- Dash CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother 1975; 1:107.
- Fonacier L, Hirschberg R, Gerson S. Adverse drug reactions to a cephalosporins in hospitalized patients with a history of penicillin allergy. Allergy Asthma Proc 2005; 26:135.
- MacPherson RD, Willcox C, Chow C, Wang A. Anaesthetist's responses to patients' self-reported drug allergies. Br J Anaesth 2006; 97:634.
- Crotty DJ, Chen XJ, Scipione MR, et al. Allergic Reactions in Hospitalized Patients With a Self-Reported Penicillin Allergy Who Receive a Cephalosporin or Meropenem. J Pharm Pract 2017; 30:42.
- Beltran RJ, Kako H, Chovanec T, et al. Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care center. J Pediatr Surg 2015; 50:856.
- Pederson-Bjergaard J. Cephalothin in the treatment of penicillin sensitive patients. Acta Allergol 1967; 22:299.
- Abraham GN, Petz LD, Fudenberg HH. Immunohaematological cross-allergenicity between penicillin and cephalothin in humans. Clin Exp Immunol 1968; 3:343.
- Assem ES, Vickers MR. Tests for penicillin allergy in man. II. The immunological cross-reaction between penicillins and cephalosporins. Immunology 1974; 27:255.
- Batchelor FR, Dewdney JM, Weston RD, Wheeler AW. The immunogenicity of cephalosporin derivatives and their cross-reaction with penicillin. Immunology 1966; 10:21.
- Levine BB. Antigenicity and cross-reactivity of penicillins and cephalosporins. J Infect Dis 1973; 128:Suppl:S364.
- Girard JP. Common antigenic determinants of penicillin G, ampicillin and the cephalosporins demonstrated in men. Int Arch Allergy Appl Immunol 1968; 33:428.
- Mendelson LM, Ressler C, Rosen JP, Selcow JE. Routine elective penicillin allergy skin testing in children and adolescents: study of sensitization. J Allergy Clin Immunol 1984; 73:76.
- Sogn DD, Evans R 3rd, Shepherd GM, et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med 1992; 152:1025.
- 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.
- Warrington RJ, Burton R, Tsai E. The value of routine penicillin allergy skin testing in an outpatient population. Allergy Asthma Proc 2003; 24:199.
- Romano A, Guéant-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.
- 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.
- Warrington RJ, Simons FE, Ho HW, Gorski BA. Diagnosis of penicillin allergy by skin testing: the Manitoba experience. Can Med Assoc J 1978; 118:787.
- 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.
- Saxon A, Adelman DC, Patel A, et al. Imipenem cross-reactivity with penicillin in humans. J Allergy Clin Immunol 1988; 82:213.
- Kula B, Djordjevic G, Robinson JL. A systematic review: can one prescribe carbapenems to patients with IgE-mediated allergy to penicillins or cephalosporins? Clin Infect Dis 2014; 59:1113.
- Atanasković-Marković M, Gaeta F, Medjo B, et al. Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins. Allergy 2008; 63:237.
- Romano A, Viola M, Guéant-Rodriguez RM, et al. Brief communication: tolerability of meropenem in patients with IgE-mediated hypersensitivity to penicillins. Ann Intern Med 2007; 146:266.
- Romano A, Viola M, Guéant-Rodriguez RM, et al. Imipenem in patients with immediate hypersensitivity to penicillins. N Engl J Med 2006; 354:2835.
- Atanasković-Marković M, Gaeta F, Gavrović-Jankulović M, et al. Tolerability of imipenem in children with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol 2009; 124:167.
- Gaeta F, Valluzzi RL, Alonzi C, et al. Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol 2015; 135:972.
- Saxon A, Swabb EA, Adkinson NF Jr. Investigation into the immunologic cross-reactivity of aztreonam with other beta-lactam antibiotics. Am J Med 1985; 78:19.
- Adkinson NF Jr, Saxon A, Spence MR, Swabb EA. Cross-allergenicity and immunogenicity of aztreonam. Rev Infect Dis 1985; 7 Suppl 4:S613.
- Adkinson NF Jr. Immunogenicity and cross-allergenicity of aztreonam. Am J Med 1990; 88:12S.
- Vega JM, Blanca M, García JJ, et al. Tolerance to aztreonam in patients allergic to beta-lactam antibiotics. Allergy 1991; 46:196.
- Patriarca G, Schiavino D, Lombardo C, et al. Tolerability of aztreonam in patients with IgE-mediated hypersensitivity to beta-lactams. Int J Immunopathol Pharmacol 2008; 21:375.
- 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. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol 2010; 105:259.
- Liccardi G, Senna G, Russo M, et al. Evaluation of the nocebo effect during oral challenge in patients with adverse drug reactions. J Investig Allergol Clin Immunol 2004; 14:104.
- Demoly P, Romano A, Botelho C, et al. Determining the negative predictive value of provocation tests with beta-lactams. Allergy 2010; 65:327.
- GENERAL CONCEPTS
- Features of immediate reactions
- Antigenic components of penicillins
- Multiple antibiotic allergy syndrome
- Population differences
- Studies estimating the risk of cross-reactivity
- Allergy evaluation and penicillin skin testing
- - Negative result
- - Positive result
- Penicillin skin testing is not available
- Patients reporting a past reaction to amoxicillin or ampicillin
- - Selective allergy confirmed by skin testing
- Recommended approach
- MONOBACTAMS (AZTREONAM)
- TEST DOSING (OR GRADED CHALLENGE)
- Indications and precautions
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS