Direct Oral Penicillin Challenge Effective in Assessment of Low-Risk Allergy


This test provides a useful approach as it can be less intensive for time and resources, less costly, and it can be conducted outside of the specialist allergy setting.

Ana Maria Copaescu, MD
Credit: RI-MUHC

Ana Maria Copaescu, MD
Credit: RI-MUHC

The use of a direct oral penicillin challenge is shown to be both safe and efficacious when applied to patients for the purposes of assessing low-risk allergies to penicillin, according to recent findings.1

This new data resulted from a study conducted to explore the possibility that a direct oral penicillin challenge would be noninferior to the standard of care of skin testing for penicillin later added with oral challenge for those with the low-risk allergy.

The PEN-FAST clinically-validated decision rule provides point-of-care risk assessment for individuals with reported penicillin allergies, where a score under 3 reliably predicts low-risk allergies, boasting a negative predictive value of 96.3% (95% CI, 94.1% - 97.8%).2

This new research was authored by Ana Maria Copaescu, MD, from the Department of Medicine’s Division of Allergy and Clinical Immunology at McGill University Health Centre in Montreal.

“The aim of the Penicillin Allergy Clinical Decision Rule (PALACE) study was to evaluate whether risk-stratified direct oral challenge with penicillin was noninferior to penicillin prick and intradermal skin testing followed by an oral challenge in patients with low-risk penicillin allergy (PEN-FAST score <3),” Copaescu and colleagues wrote.

Background and Findings

The investigators' noted that the major aim of their research was to find whether a direct oral penicillin challenge could potentially be shown to be as efficacious as the conventional approach that involves penicillin skin testing followed later by an oral challenge in those with a low-risk allergy to penicillin.

The team’s research was done with a parallel design and 2 groups, adopting a noninferiority framework. Their research was also conducted openly over several different specialized centers on a wide-ranging, international scale.

The investigators used 6 specialized centers, and 3 were located in North America, in both the US and Canada, and the remaining 3 were noted as being in Australia. The research took place from June 2021 to December 2022, and they recruited adult study participants with an exhibited PEN-FAST score of less than 3.

The research team described the PEN-FAST tool as being clinically-derived and internationally validated, adding that it was designed for quick, on-the-spot assessment of risks linked to penicillin allergies in adult individuals.

Participants were randomly assigned to one of two groups: those who underwent a direct oral penicillin challenge (referred to as the intervention arm) and those who followed the standard protocol of penicillin skin testing followed by an oral penicillin challenge (referred to as the control arm).

The main measure of importance for the team was noted as being confirmation of a positive immune-mediated oral challenge by a clinician within a single hour following participants’-intervention. This was determined among those in the intention-to-treat population, with noninferiority being viewed as accomplished provided the one-sided 95% CI of the risk difference did not go over 5 percentage points.

Overall, the investigators recruited a total of 382 individuals, and among these 377 were used for the analysis, with a median age of 51 years. The team explained that 65.5% of them were female.

A total of 187 of the participants were placed into the intervention arm of the study, and 190 were placed into the control arm, with a majority of the patients reporting a PEN-FAST score of either 0 or 1. The primary outcome was seen in only 1 participant within the intervention arm and another single participant within the control arm.

The calculated risk difference for this primary outcome was 0.0084 percentage points with a 90% CI ranging from -1.22 points to 1.24 points. Notably, the 1-sided 95% CI was shown to have gone below the noninferiority threshold of 5 points.

At the time of the 5 day follow-up after the oral challenge, the investigators reported a total of 9 immune-mediated adverse events in the intervention arm and 10 in the control arm, leading to an RD of -0.45 pp (95% CI, -4.87 to 3.96 pp).

They also explained that there were not any serious adverse events found over the course of the study period.

“Compared with skin testing, a direct oral penicillin challenge is less resource and time intensive, is less expensive, and has the potential to be performed outside of the specialist allergy setting, providing a scalable approach to address low-risk, unverified penicillin allergy in diverse treatment settings internationally,” they wrote.


  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 Intern Med. 2023;183(9):944–952. doi:10.1001/jamainternmed.2023.2986.
  2. Trubiano JA, Vogrin S, Chua KYL, et al. Development and validation of a penicillin allergy clinical decision rule. JAMA Intern Med. 2020;180(5):745-752. doi:10.1001/jamainternmed.2020.0403.
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