Millions of people with penicillin allergies will benefit from a clinical trial

Clinical decision rule for direct oral challenge in low-risk penicillin allergy patients.


In the United States, nearly 25 million people are allergic to penicillin, including pregnant women and surgery patients. It is a public health risk, resulting in antibiotic resistance and potentially fatal infections in hospitalized patients. Over 75% of penicillin allergy labels are applied by age three due to misinterpretation of a V. Most of these rashes were never allergic. Still, the labels have many negative repercussions in maturity.

Many low-risk penicillin allergy patients could remove their allergy label using a simple “direct oral challenge” treatment as part of the Penicillin Allergy Clinical Decision Rule (PALACE) project, a world-first multicenter randomized control trial.

In the PALACE study, researchers randomly assigned low-risk penicillin-allergic individuals to one of two techniques to remove their allergy label: skin testing followed by oral challenge with penicillin or going straight to oral challenge without first performing skin testing.

PALACE study protocol member and Vanderbilt University Medical Center principal investigator Elizabeth Phillips, MD, the John Oates Professor of Clinical Research, said, “The majority of patients labeled as penicillin allergic, more than 90%, have low-risk histories, meaning they did not have a history to suggest a severe or more recent reaction to a penicillin, We would expect more than 95% of these patients to have negative testing and be able to take penicillin in the future.”

The study included 382 participants evaluated using the PEN-FAST risk assessment instrument. Participants were randomized randomly to receive a direct oral penicillin challenge or the conventional technique (penicillin skin testing followed by an oral challenge).

Only one patient (0.5%) in each group reacted positively to the penicillin challenge, suggesting that the direct oral penicillin challenge is as effective as the traditional technique. Notably, no significant variations in adverse events were seen between the two groups, and no serious adverse events were noted.

The findings have far-reaching consequences for patients, as reliable identification of people with low-risk penicillin allergies helps ensure proper antibiotic prescriptions. Patients with a confirmed penicillin allergy are more likely to be prescribed second-line antibiotics, which are often less effective against specific illnesses and may have more side effects.

The PALACE study’s findings will influence clinical practice because many patients in the United States do not have direct access to an allergist who can perform specialized testing like skin testing. The ability to perform a direct oral challenge with penicillin in low-risk patients in any observed situation will make it easier for patients in the United States to obtain treatment securely.

Journal Reference:

  1. Copaescu AM, Vogrin S, James F, 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 Internal Medicine.DOI:10.1001/jamainternmed.2023.2986