Charleston, SC


Penicillin Allergy & Cross-Reactivity


  1. 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.
  2. True IgE-mediated penicillin allergies that cause anaphylaxis are rare.
  3. An IgE-mediated penicillin allergy can diminish over time, as 80% of patients become tolerant after a decade.
  4. Patients with a documented penicillin allergy may be inappropriately exposed to alternative antibiotics, resulting in increased treatment failures, adverse effects, and antimicrobial resistance.
  5. Penicillins, cephalosporins, and carbapenems all share a beta-lactam core structure, thus raising the potential for cross-reactivity among these agents.

Group 1Group 2Group 3Group 4
Penicillin Cefoxitin CefuroximeAmoxicillin Ampicillin Cefaclor Cephalexin CefadroxilCeftriaxone Cefotaxime Cefuroxime Cefepime Cefpodoxime CeftarolineAztreonam Ceftolazane Ceftazidime

  Overview of Evidence
AuthorDesignIntervention & ComparisonOutcome
  Why Cross-Reactivity?
Nagakura, 1990   Mayorga, 1995Animal study-Studied 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 allergiclike 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%
Romano, 2006Prospective study (n=112)-Skin tested to penicillins and then skin tested to imipenem -If skin test to imipenem was negative, then challenged with IM dose-Only 1 patient of the penicillin skin-test positive patients had a positive skin test to imipenem -Cross-reactivity rate was 0.9% -None of the 110 patients with a negative imipenem skin test that underwent IM challenge had a reaction
Romano, 2007Prospective study (n=104)-Skin tested to penicillins and then skin tested to meropenem -If skin test to imipenem was negative, then challenged with IV dose-Only 1 patient of the penicillin skin-test positive patients had a positive skin test to meropenem -Cross-reactivity rate was 1% -All 103 patients with a negative meropenem skin test tolerated the IV challenge
Atanaskovic- Markovic, 2008Prospective study (n=108)-Children with penicillin allergy were skin tested to penicillin and meropenem -If skin test to meropenem was negative, then challenged with IV dose-Only 1 patient with a positive penicillin test reacted to the meropenem skin test -Cross-reactivity rate was 0.9% -All 107 patients with a negative meropenem skin test tolerated the IV challenge  


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


  1. Apter AJ, Kinman JL, Bilker WB, et al. Is There Cross-Reactivity Between Penicillins and Cephalosporins? Am J Med. 2006;119(4):354e11-19.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Chaudry SB, Veve MP, Wagner JL. Cephalosporins: A Focus on Side Chains and Beta-Lactam Cross-Reactivity. Pharmacy. 2019;7:1-16.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Nagakura N, Souma S, Shimizu T, Yanagihara Y. Anti-Ampicillin Monoclonal Antibodies and their CrossReactivities to Various Beta-Lactams. Br J Hosp Med. 1990;44:252-258.
  12. 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.
  13. 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.
  14. 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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