Introduction
Penicillin allergy is one of the most commonly reported drug allergies, yet only a small fraction of patients with a documented allergy will actually exhibit a true hypersensitivity reaction. Understanding the nuances of cross-reactivity is critical for optimizing antibiotic selection and avoiding unnecessary use of alternative agents.
Key Points on Penicillin Allergy
- 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.
Pharmacology & Cross-Reactivity
Side Chain Theory
Cross-reactivity is determined by similarity in side chains, not the beta-lactam ring itself
Cephalosporin Cross-Reactivity
Cross-reactivity between penicillins and cephalosporins is about 2%
Cefazolin Safety
Cefazolin is NOT likely to cross react with penicillin (side chains NOT similar)
Carbapenem & Monobactam Safety
Cross-reactivity with carbapenems is <1%; with monobactams (aztreonam) is negligible
Side Chain Cross-Reactivity Groups
Drugs within each group may have cross-reactivity to each other due to similar side chains
| Group 1 | Group 2 | Group 3 | Group 4 |
|---|---|---|---|
|
Penicillin Cefoxitin Cefuroxime |
Amoxicillin Ampicillin Cefaclor Cephalexin Cefadroxil |
Ceftriaxone Cefotaxime Cefuroxime Cefepime Cefpodoxime Ceftaroline |
Aztreonam Ceftolozane Ceftazidime |
Clinical Pearl
The side chain is the most important determinant in penicillin immunogenicity. Matching side chain groups helps predict cross-reactivity risk, while drugs with dissimilar side chains (e.g., cefazolin) carry minimal risk even in patients with confirmed penicillin allergy.
Overview of Key Evidence
Why Cross-Reactivity? — Animal Studies
Nagakura (1990) & Mayorga (1995)
Animal studies on antibody formation with protein-beta-lactam conjugates
92% of antibodies recognized an epitope in which the side chain was the main constituent. The side chain is the most important determinant in penicillin immunogenicity.
Cephalosporin Cross-Reactivity
| Author / Year | Design (n) | Intervention | Key Findings |
|---|---|---|---|
| Goodman, 20019 |
Retrospective
n=2,933 |
Orthopedic patients with penicillin allergy receiving cefazolin prior to a procedure |
Cross-reactivity rate 0.33%
Only 1 patient may have had an allergic reaction to cefazolin |
| Daulat, 20047 |
Retrospective
n=606 |
Patients with penicillin allergy receiving cephalosporins (42% 1st gen, 21% 2nd gen, 37% 3rd/4th gen) |
Cross-reactivity 0.17%
Only 1 patient had a reaction (worsening eczema after cefazolin) |
| Apter, 20061 |
Retrospective
n=3,920 |
Patients with penicillin Rx followed by a cephalosporin Rx; allergic-like events within 30 days identified |
Cross-reactivity 1.1%
Anaphylaxis risk 0.001%
43 patients reacted; 70% had only urticaria |
| Romano, 201816 |
Prospective
n=252 |
IgE-mediated penicillin hypersensitivity patients; skin tests for 10 cephalosporins + oral challenges |
39.3% positive allergy tests
37.7% positive to aminocephalosporins sharing side chains with penicillins; all 244 tolerated cefuroxime axetil and ceftriaxone |
Carbapenem Cross-Reactivity
| Author / Year | Design (n) | Intervention | Key Findings |
|---|---|---|---|
| Romano, 200612 |
Prospective
n=112 |
Penicillin skin test → imipenem skin test; if negative, challenged with IM dose |
Cross-reactivity 0.9%
Only 1 positive skin test to imipenem; 110 patients tolerated IM challenge |
| Romano, 200713 |
Prospective
n=104 |
Penicillin skin test → meropenem skin test; if negative, challenged with IV dose |
Cross-reactivity 1%
Only 1 positive skin test; all 103 with negative tests tolerated IV challenge |
| Atanaskovic-Markovic, 20082 |
Prospective
n=108 |
Children with penicillin allergy; skin tested to penicillin and meropenem; if negative, challenged with IV dose |
Cross-reactivity 0.9%
Only 1 positive skin test; all 107 with negative tests tolerated IV challenge |
| Sánchez de Vicente, 202015 |
Prospective
n=137 |
Tolerance testing for cephalosporins and carbapenems in patients with confirmed penicillin allergy |
Imipenem: 0% positive
Cephalosporin: 0.79%
0/46 positive for imipenem; 1/137 for cefuroxime; 1/137 for ceftriaxone |
Clinical Conclusions
Bottom Line
Cross-reactivity between penicillins and cephalosporins is approximately 2% and with carbapenems is <1%. These rates are far lower than historically reported, supporting cautious use of these agents in patients with documented penicillin allergy.
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%.
Full Reference List
- 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 Histories 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.
- Sánchez de Vicente J, Gamboa P, García-Lirio E, et al. Tolerance to Cephalosporins and Carbapenems in Penicillin-Allergic Patients. J Investig Allergol Clin Immunol. 2020;30(1):75-76.
- Romano A, Valluzzi RL, Caruso C, et al. Cross-Reactivity and Tolerability of Cephalosporins in Patients with IgE-Mediated Hypersensitivity to Penicillins. J Allergy Clin Immunol Pract. 2018;6(5):1662-1672.
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