Penicillin (PCN) Allergy 101

To wrap up US Antibiotic Awareness Week 2020, I figured I’d share a few pearls I learned at a grand rounds recently.

Penicillin allergy is commonly acquired in childhood when allergic symptoms are found and confused with symptoms of viral or bacterial illness.

Up to 20% of people in the general population are labeled as allergic to PCN by the time they reach adulthood. After formal allergy evaluation, <5% of people are found to be truly allergic.

Most clinicians avoid the use of cephalosporins (contraindication) and do not override these alerts due to fears and misunderstanding of the pathophysiology of cross-reactivity among beta lactams.

Well let’s address this fear now! For years, we were told that there is a 10% cross-reactivity between PCN and cephalosporins based on published data from the 1960’s and 1970s. Cefazolin has a unique side chain and VERY low cross-reactivity with PCN.

PCN + Cephalosporin Cross-Reactivity
PCN + Cephalosporins 2%
PCN + Carbapenem <1 %
PCN + Aztreonam 0%
Cefazolin has a unique side chain and VERY LOW cross-reactivity
40% of patients with anaphylaxis to PCN have cross-reactivity to cephalosporin*
Trubiano JA et al


  • Within 1-6 hours after exposure: urticaria, anaphylaxis
  • >6 hours: maculopapular exanthems
  • Delayed T-cell mediated reactions with systemic involvement: severe cutaneous reactions, SJS, TEN, DRESS, acute generalized exanthematous pustulosis (AGEP)


A penicillin-allergy label that is acquired in childhood is frequently not questioned and may lead to non-beta lactam exposure and adverse effects. This also causes a substantial public threat and economic burden due to use of broad-spectrum antibiotics that can lead to C. diff infection, antibiotic resistance, and prolonged hospital stays.

Antibiotic costs for individuals reporting PCN-allergy are up to 64% higher than those who do not report a PCN-allergy.

In a hospital setting, a history of PCN-allergy translates to:

  • 10% more hospital days
  • 30% higher incidence of VRE infections
  • 23% higher incidence of C. diff infections
  • 14% higher incidence of MRSA infections

What type of patients should we avoid giving cephalosporins to?

Those with anaphylaxis to beta lactams, drug rash with eosinophilia and systemic symptoms, toxic epidermal necrolysis, Stevens Johnsons syndrome

IgE mediated reaction Symptoms:

  • Cutaneous: itching, flushing, urticaria, angioedema
  • Respiratory: rhinitis, wheezing, dyspnea, bronchospasm
  • CV: arrhythmia, syncope, chest tightness
  • GI: abdominal pain, nausea, vomiting, diarrhea
  • The most severe IgE-mediated reaction is anaphylaxis

How do you go about clarifying PCN allergy?

  1. Verify allergy by asking additional questions
  2. What medications were you taking when reaction occurred?
  3. Can you describe the symptoms you experienced?
  4. How soon did you develop symptoms?
  5. How long ago did it happen?
  6. How was the reaction managed?
  7. What was the outcome?
  8. Have you ever been prescribed amoxicillin or other penicillin since your reaction? How did you tolerate antibiotics?
  9. Stratify risks

When should patient be referred to allergy service?

  • Patients with medium-high risk history
  • PCN is the drug of choice and there are no other alternatives (i.e. syphilis in pregnancy or neurosyphilis)
  • Patient has multiple antibiotic allergies limiting therapeutic options

PCN Allergy Evaluation

  • PCN Skin testing: rapid, sensitive, cost-effective
  • Evaluates for immediate allergic reactions to PCN
  • Pre-PEN is the ONLY FDA approved skin test for the diagnosis of PCN allergy

Low-Risk patient: isolated non-allergic symptoms, family history of a penicillin allergy, pruritus without rash, remote (>10 years) unknown reactions without features suggestive of an IgE-mediated reaction

  • Perform PO challenge with amoxicillin 500mg in clinic, observe for 2 hours

 Moderate-risk patients: skin prick test, intradermal test (if skin prick test is negative), PO amoxicillin challenge (confirmation test – given under clinician observation)

What to do after negative PCN allergy evaluation?

  • Congratulations! And THANK YOU for being a leader and practicing antimicrobial stewardship.
  • Once an amoxicillin challenge is tolerated, PCN allergy should be deleted from EHR
  • Continue to educate and reassure patients!

Download this reference copy to use the next time you see a patient with a PCN-allergy!


  1. Castells M et al.Penicillin Allergy. N Engl J Med. 2019 Dec 12;381(24):2338-2351. doi: 10.1056/NEJMra1807761
  2. Shenoy ES, Macy E, Rowe T, Blumenthal KG Evaluation and Management of Penicillin Allergy: A Review. JAMA 2019 Jan 15;321(2):188-199. doi: 10.1001/jama.2018.19283
  3. Is it Really a Penicillin Allergy?
  4. Macy, E., & Contreras, R. Healthcare Use and Serious Infection Prevalence Associated with Penicillin “Allergy” in Hospitalized Patients: A Cohort Study. Journal of Allergy and Clinical Immunology, 2014 133(3), 790-796
  5. Macy E, et al. Practical Management of Antibiotics Hypersensitivity. Allergy Clin Immunol Pract. 2017 May-Jun;5(3):577-586.
  6.  Trubiano JA, Stone CA, Grayson ML, et al. The 3 Cs of antibiotic allergy-classification, cross-reactivity, and collaboration. J Allergy Clin Immunol Pract. 2017 Nov – Dec;5(6):1532-1542. doi: 10.1016/j.jaip.2017.06.017.
  7. Blumenthal KG, Shenoy ES. Am I Allergic to Penicillin? JAMA. 2019;321(2):216. doi:10.1001/jama.2018.20470

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