Penicillin Cephalosporin Cross-Reactivity

Penicillin, Penicillin Cephalosporin Cross-Reactivity
Reproduced with permission from the Northwestern Medicine Antimicrobial Stewardship Program

According to the CDC:

  1. Approximately 10% of all U.S. patients report having an allergic reaction to a penicillin class antibiotic in their past.
  2. However, many patients who report penicillin allergies do not have true IgE-mediated reactions. When evaluated, fewer than1% of the population are truly allergic to penicillins.1
  3. Approximately 80% of patients with IgE-mediated penicillin allergy lose their sensitivity after 10 years.1
  4. Broad-spectrum antibiotics are often used as an alternative to penicillins. The use of broad-spectrum antibiotics in patients labeled “penicillin-allergic” is associated with higher healthcare costs, increased risk for antibiotic resistance, and suboptimal antibiotic therapy.1
  5. Correctly identifying those who are not truly penicillin-allergic can decrease unnecessary use of broad-spectrum antibiotics.1

The Northwesten Medicine Antimicrobial Stewardship Program created a B-lactam allergy side chain chart (pictured above) as well as a clinical pathway for assessing B-lactam allergy risk, to assist medical providers in determining appropriate cephalosporin therapy in patients with penicillin allergy. They note:2-5

  • The cross-reactivity between B-lactams with IgE-mediated hypersensitivity may be predicted by similarities of R-side chains.
  • The rate of cross-reactivity between a penicillin and cephalosporin due to antibody recognition is <2% in those who are skin test positive; <1% in patients not skin tested.
  • Non-IgE-mediated hypersensitivity reactions (maculopapular rash, acute interstitial nephritis, immune-mediated hepatitis) have been reported with anti-staphylococcal penicillins (e.g. nafcillin).
    • Cefazolin is an option as it has a dissimilar R1 side chain to penicillins and cephalosporins.19
  • Cross-reactivity with carbapenems is very unlikely (<1%).
  • Cross-reactivity with aztreonam is absent, except for ceftazidime

Further Reading

Diagnosis and Management of Group A Streptococcal Pharyngitis and Associated Complications Date Release: Dec 2017. This issue reviews the signs and symptoms of GAS pharyngitis, as well as associated complications, and provides recommendations for appropriate treatment that focuses on reducing the severity and duration of symptoms, reducing the incidence of nonsuppurative complications, and reducing transmission.

Evidence-Based Evaluation And Management Of Patients With Pharyngitis In The Emergency Department Date Release: Sep 2015. This issue reviews the various international guidelines for pharyngitis and notes controversies in diagnostic and treatment strategies, specifically for management of suspected bacterial, viral, and fungal etiology.


  1. Joint Task Force on Practice Parameters representing the 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 Oct;105(4):259-273.
  2. Torres MJ, Blanca M. The complex clinical picture of beta-lactam hypersensitivity: penicillins, cephalosporins, monobactams, carbapenems, and clavams. Med. Clin. North Am. 2010;94(4):805-820.
  3. Lee QU. Use of cephalosporins in patients with immediate penicillin hypersensitivity: cross-reactivity revisited. Hong Kong Med J 2014;20:428-36.
  4. Blumenthal KG, Youngster I, Shenoy ES, Banerji A, Nelson SB. Tolerability of Cefazolin after Immune-Mediated Hypersensitivity Reactions to Nafcillin in the Outpatient Setting. Antimicrob Agents Chemother. 2014;58(6):3137-3143.
  5. Zagursky RJ, Pichichero ME. Cross-reactivity in E-lactam Allergy. J Allergy Clin Immunol Pract. 2018;6:72-81.

Last Updated on January 25, 2023

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