All Pharmacy Pearls

Introduction

Only 0.5% to 2% of patients with a documented penicillin allergy that are administered a penicillin will exhibit a hypersensitivity reaction, usually presenting as a rash or hives. True IgE-mediated penicillin allergies that cause anaphylaxis are rare. An IgE-mediated penicillin allergy can diminish over time, as 80% of patients become tolerant after a decade.

Patients with a documented penicillin allergy may be inappropriately exposed to alternative antibiotics, resulting in increased treatment failures, adverse effects, and antimicrobial resistance. Penicillins, cephalosporins, and carbapenems all share a beta-lactam core structure, thus raising the potential for cross-reactivity among these agents.

Key Points

  • Only 0.5–2% of patients with a documented penicillin allergy react when given a penicillin (usually rash or hives); true IgE-mediated anaphylaxis is rare.
  • IgE-mediated penicillin allergy wanes over time — about 80% of patients become tolerant after a decade.
  • Penicillins, cephalosporins, and carbapenems share a beta-lactam core, raising potential cross-reactivity — but it is far lower than early studies suggested (partly from penicillin-contaminated study drugs).
  • Cross-reactivity between cephalosporins is about 2% and with carbapenems is <1%.

Clinical Detail

Group 1Group 2Group 3Group 4
PenicillinAmoxicillinCeftriaxoneAztreonam
CefoxitinAmpicillinCefotaximeCeftolazane
CefuroximeCefaclorCefuroximeCeftazidime
CephalexinCefepime
CefadroxilCefpodoxime
Ceftaroline
  • The following drugs in each group may have cross-reactivity to each other due to similar side chains
  • Cross-reactivity between penicillins and cephalosporins is about 2%
  • Cefazolin is NOT likely to cross react with penicillin (side chains NOT similar)
  • Cross-reactivity with monobactams (i.e. aztreonam) is negligible
  • Cross-reactivity between penicillins and carbapenems is <1%

Evidence

AuthorDesignIntervention & ComparisonOutcome
Nagakura, 1990
Mayorga, 1995		Animal studyStudied antibodies formed when animals were immunized with protein-beta-lactam conjugates
  • 92% of the antibodies recognized an epitope in which the side chain was the main constituent
  • The side chain is the most important determinant in penicillin immunogenicity
Goodman, 2001Retrospective review (n=2933)Orthopedic patients with penicillin allergy receiving cefazolin prior to a procedure
  • Only 1 patient may have had an allergic reaction to cefazolin
  • Cross-reactivity rate with cefazolin was 0.33%
Daulat, 2004Retrospective review (n=606)Patients with penicillin allergy receiving cephalosporins
42% 1st gen., 21% 2nd gen., and 37% 3rd or 4th gen. cephalosporins
  • Only 1 patient had an allergic reaction that was documented as worsening of underlying eczema after being placed on cefazolin
  • Cross-reactivity was 0.17%
Apter, 2006Retrospective review (n=3920)Patients with a prescription for penicillin followed by a prescription for a cephalosporin
Identified allergic-like events within 30 days after each prescription
  • Only 43 patients who experienced an allergic-like reaction after both penicillin and cephalosporin
  • Cross-reactivity rate was 1.1%
  • 70% of these patients just had urticaria
  • The risk of anaphylaxis to cephalosporins was only 0.001%
Sánchez de Vicente, 2020Prospective study (n=137)Prospective study of 252 subjects with IgE-mediated hypersensitivity to penicillins
Serum specific IgE assays for cefaclor and skin tests for 10 cephalosporins
Oral challenges with cefuroxime axetil, ceftriaxone, cefaclor, and cefadroxil for subjects with negative skin tests
  • 0/46 patients showed positive skin tests for imipenem.
  • 0.79% (1/137) patients showed a positive skin test for cefuroxime.
  • 0.79% (1/137) patients showed a positive skin test for ceftriaxone.

Conclusions

  • True penicillin allergies are less common than reported, and anaphylaxis is uncommon.
  • Cross-reactivity among penicillins and cephalosporins is attributed to similarity in side chains.
  • Cephalosporin cross-reactivity with penicillins is much lower than reported in early studies partly due to contamination of study drugs with penicillin.
  • Cross-reactivity between cephalosporins is about 2% and with carbapenems is <1%.

References

  • Apter AJ, Kinman JL, Bilker WB, et al. Is There Cross-Reactivity Between Penicillins and Cephalosporins? Am J

    • Med. 2006;119(4):354e11-19.

  • Atanaskovic-Markovic M, Gaeta F, Medjo B, Viola M, Nestorovic B, Romano A. Tolerability of Meropenem in

    • Children with IgE-Mediated Hypersensitivity to Penicillins. Allergy. 2008;63:237-240.

  • Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing Inpatient Beta-Lactam Allergies: A Multihospital

    • Implementation. J Allergy Clin Immunol Pract. 2017;5(3):616-625.

  • Blumenthal KG, Huebner EM, Fu X, et al. Risk-Based Pathway for Outpatient Penicillin Allergy Evaluations. J

    • Allergy Clin Immunol Pract. 2019;7(7):2411-2414.

  • Campagna JD, Bond MC, Schabelman E, Hayes BD. The Use of Cephalosporins in Penicillin-Allergic Patients: A

    • Literature Review. J Emerg Med. 2012;42(5):612-620.

  • Chaudry SB, Veve MP, Wagner JL. Cephalosporins: A Focus on Side Chains and Beta-Lactam Cross-Reactivity.

    • Pharmacy. 2019;7:1-16.

  • Daulat S, Solensky R, Earl HS, Casey W, Gruchalla RS. Safety of Cephalosporin Administration to Patients with

    • Hstories of Penicillin Allergy. J Allergy Clin Immunol Pract. 2004;113(6):1220-1222.

  • DePestel DD, Benninger MS, Danziger L, et al. Cephalosporin Use in Treatment of Patients with Penicillin

    • Allergies. J Am Pharm Assoc. 2008;48:530-540.

  • Goodman EJ, Morgan MJ, Johnson PA, Nichols BA, Denk N, Gold BB. Cephalosporins can be Given to

    • Penicillin-Allergic Patients Who Do Not Exhibit an Anaphylactic Response. J Clin Anesth. 2001;13(8):561-564.

  • Mayorga C, Obispo T, Jimeno L, et al. Epitope Mapping of Beta-Lactam Antibiotics with the Use of

    • Monoclonal Antibodies. Toxicology. 1995;97:225-234.

  • Nagakura N, Souma S, Shimizu T, Yanagihara Y. Anti-Ampicillin Monoclonal Antibodies and their Cross-

    • Reactivities to Various Beta-Lactams. Br J Hosp Med. 1990;44:252-258.

  • Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Pettinato R, Gueant JL. Imipenem in Patients with

    • Immediate Hypersensitivity to Penicillins. N Engl J Med. 2006;354:2835-2837.

  • Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Valluzzi R, Gueant JL. Brief Communication: Tolerability of

    • Meropenem in Patients with IgE-Mediated Hypersensitivity to Penicillins. Ann Intern Med. 2007;146:266-269.

  • Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review.

    • JAMA. 2019;321(2):188-199.

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