Antimicrobial stewardship and how to approach a potential penicillin allergy

September 28, 2021 Providence Pulse Content Team

Author: Alyssa Christensen, Pharm.D., BCIDP, infectious diseases clinical pharmacy specialist, Providence Oregon
Jennifer Marfori, M.D., infectious diseases physician, Providence Medical Group


The patient-driven perception that penicillin allergies are common is not based in fact. True allergic reactions to penicillin are very rare. There are compelling reasons to consider using penicillin or an equivalent beta-lactam antibiotic when treating patients for most types of infections. Using an agent other than penicillin is associated with increased adverse events, antibiotic resistance and increased costs.

Below is a guide to help you determine which antibiotics are safe to use with penicillin allergies. You’ll also find advice on how to perform an oral amoxicillin challenge.

Less than 1% of the population has a true penicillin allergy. In actuality, 90% of patients who claim to have a penicillin allergy do not, according to the Centers for Disease Control and Prevention. True allergic reactions to penicillin or cephalosporins are due to the side chain moiety and not the beta-lactam ring.

Studies have shown that antibodies may wane over time, and the rate of positive allergy testing decreases over time. Only 10% may test positive after 10 years

Use of alternative agents in patients labeled as having a penicillin allergy can result in increased costs, antibiotic resistant infections (most often MRSA and VRE), C.difficile infections and surgical site infections.

AT-A-GLANCE GUIDE: Cross-reactivity of allergies

Similar side chains: Cross reactivity risk in patients with immediate (IgE) reactions: 40%

Dissimilar side chains: Cross reactivity risk in patients with immediate (IgE) reactions: 1.5%

* Cefazolin has a unique side chain and appears to be a selective allergy.


Consider an oral challenge when:

  • A penicillin or cephalosporin is the preferred therapy to treat the patient’s suspected infection.
  • There is no adequate beta-lactam substitute with a dissimilar side chain available.
  • Patients have experienced isolated hives/rash reactions in the past.
  • Patients have unknown or childhood reactions.
  • Patients who have a remote (≥10 years) history of potential anaphylactic allergies (e.g., hypotension, edema).

(Patients with severe non-type 1 reactions should not be re-challenged, e.g. SJS/TEN).

Supporting literature: pediatric patients

  • A 2020 study in a pediatric ER randomized the patients with recorded penicillin allergy to receive amoxicillin oral challenge (500 mg tablet or 520 mg solution).
    • 97.3% of patients tolerated the oral challenge and were de-labeled as penicillin allergic.
    • Of those reporting positive reactions, the reactions were limited to mild urticaria; all symptoms were resolved with administration of antihistamines. No patients experienced facial swelling, shortness of breath or other signs of anaphylaxis.
  • A 2019 randomized single-blind study tested the safety of oral amoxicillin challenge without prior skin testing in children with reported penicillin allergies.
    • 155 participants completed the amoxicillin challenge.
    • 4 out of 155, or 2.6%, experienced mild allergic reactions.

Oral challenge protocol for adults
Under Providence Oregon’s antimicrobial stewardship program, providers should:

  1. Administer 250 mg of oral amoxicillin.
  2. Monitor vital signs every 15 minutes for 60 minutes.
  3. Inspect skin for erythema, rash, wheals and urticarial rash and hives.

If amoxicillin is tolerated without issue, you can prescribe a beta-lactam.



  • True penicillin allergies are rare.
  • Alternative antibiotics used in patients with penicillin allergies are associated with worse outcomes and higher rates of adverse events.
  • Cephalosporins with unrelated side chains are completely safe for patients with penicillin allergies (e.g., ceftriaxone, cefpodoxime or cefdinir).
  • An oral challenge can be a safe and inexpensive strategy to de-label a penicillin allergy and increase use of preferred beta-lactam therapy.


For more information

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