Can patients with penicillin allergy be given an oral challenge instead of skin testing?


Can patients with penicillin allergy be given an oral challenge instead of having to conduct skin testing first?

The Study

In September 2023, the Journal of the American Medical Association (JAMA) Internal Medicine published a study that answered this question.

Less than 5% of people labeled penicillin allergic actually have a penicillin allergy. To get rid of the label, a patient needs pin pick and intradermal skin testing, followed by an oral challenge. Incorrect labels can interfere with medical care. This study examined the safety of an oral challenge without skin testing, reducing pain and the time needed to determine true allergy.

377 patients were randomized to the single oral challenge or the standard-of-care skin testing followed by oral challenge group. The study took place in 6 specialized outpatient centers across North America and Australia.

Study group participants were given a dose of oral penicillin (amoxicillin, penicillin VK) and monitored for one hour. Control group members received pin prick and intradermal skin testing before moving to the oral challenge. Both groups were also contacted on day 5 to report any additional symptoms.


  • Adults age 18 or older, labeled with penicillin allergy
  • Calculated PEN-FAST score less than 3
    • PEN-FAST is a prospectively derived and internationally validated clinical decision rule that enables point-of-care risk assessment for adults reporting penicillin allergies.


  • Anaphylaxis associated with any drug
  • Known history of chronic spontaneous urticaria or mast cell disease
  • History of non–IgE-mediated severe reactions such as severe delayed organ or skin reactions
  • Patients with self reported penicillin allergy if reaction was compatible with adverse effects such as nausea or headache

What Did They Find?

Primary Outcome

A positive oral penicillin challenge consistent with an immune-mediated reaction.


  • 187 people entered the intervention group and 190 in the control group
  • Majority of participants had a PEN-FAST of 0 or 1
  • 1 person in each group (0.5%) experienced the primary outcome
  • In the 5 days after the oral challenge, 9 participants in the intervention group and 10 participants in the control group also experienced the primary outcome.
  • No serious adverse events occurred.
  • Median age of participants was 51 years old


In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label.

What does this mean for the ED or Urgent Care?

The study proves that an oral challenge in a low risk patient is safe to perform in the outpatient setting and requires only 1 hour of observation. This is certainly an option for a patient requiring oral penicillin with no other options.

Read The Original Article

Mullins RJ, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med. 2023 Nov 7;183(20):2205-2212. doi: 10.1001/jamainternmed.2023.2986. PMID: 37459086.

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