Oral Challenge Alone May Be Enough to Rule Out Penicillin Allergy

A direct oral penicillin challenge sufficed to remove an incorrect penicillin allergy label on people considered to have a low-risk history, the international PALACE trial found.

Just 0.5% of people with a record of low-risk penicillin allergy (PEN-FAST score <3) tested positive after either a physician-verified positive immune-mediated penicillin oral challenge alone or the standard practice of a skin test followed by oral challenge (RR 1.02, 90% CI 0.10-10.34), reported Ana Maria Copaescu, MD, of McGill University in Montreal, and coauthors in JAMA Internal Medicine.

Between the intervention and control groups, the risk difference (RD) was 0.0084 percentage points, and the 1-sided 95% CI fell within the prespecified range of noninferiority, according to the report.

“In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label,” Copaescu’s group concluded. They noted that oral challenge is already considered the necessary final step for allergy label removal, citing skin testing’s imperfect negative predictive value.

“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,” the investigators added.

In current practice, they said, many penicillin allergies that are self-reported “remain largely unquestioned,” and upwards of 95% of patients who are listed as having penicillin allergies actually see negative results on subsequent allergy tests and tolerate exposure to the antibiotic.

Overall, the CDC estimates that fewer than 1% of Americans are truly allergic to penicillin, whereas 10% of the population carries a penicillin allergy label. The agency warns that the unnecessary use of alternative antibiotics as an alternative to penicillin is associated with higher healthcare costs, increased risk of antibiotic resistance, and suboptimal antibiotic therapy.

PALACE was conducted from 2021 to 2022 at six centers, three in North America and three in Australia. Eligible patients were adults with a PEN-FAST score lower than 3 who had been referred to an allergy clinic.

Participants randomized to the intervention group received only an oral penicillin challenge, consisting of the lowest available therapeutic dose of oral penicillin. The control group underwent skin pricks followed by intradermal testing and, in case of a negative result, went on to a penicillin oral challenge. Positive reactions to the oral challenge consisted of a patient reaction within the first hour following administration.

A total of 377 patients were included in the analysis, with 187 patients in the intervention cohort and 190 in the control cohort. The average patient age was 51 years, and nearly two-thirds were women. The population was 93% white in both study arms.

Copaescu and colleagues reported 19 immune-mediated adverse events in the 5 days after the oral challenge, roughly split between groups and none of them serious.

More than 84% of the patients in both groups received a single dose of amoxicillin as part of their respective challenges. Researchers noted that the two patients with positive challenges exhibited mild cutaneous skin reactions after administration, both of which cleared after the patients received a single dose of an antihistamine.

Limitations to the study include its open-label design and questionable generalizability to higher-risk groups, as patients with a PEN-FAST score of 0 or 1 made up more than 94% of the participants included. Candidate participants who had a previous history of anaphylaxis from medication were also excluded.

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