By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Medicine, Division of Infectious Diseases, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A multicenter, randomized clinical trial that compared direct oral penicillin challenge in low-risk patients to skin testing followed by oral challenge found no significant differences. Direct oral penicillin challenge appears to be a safe and effective way to delabel a penicillin allergy.
SOURCE: 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; Jul 17:e232986. [Online ahead of print].
A penicillin allergy label can have important negative implications for patients. The use of alternative agents to penicillin and other β-lactams can lead to higher costs and an increased risk of adverse events, and can promote the development of antimicrobial resistance. Therefore, delabeling a penicillin allergy could be highly impactful for both patients and the healthcare system. Copaescu et al sought to determine whether a direct oral penicillin challenge would be equivalent to penicillin skin testing followed by oral challenge in low-risk patients.
The study was a multicenter, randomized clinical trial conducted in the United States, Canada, and Australia. Patients included were at least 18 years of age and referred to an allergy clinic with a low-risk penicillin allergy. Risk status was determined using PEN-FAST, a clinical decision rule that stratifies penicillin allergy in adults. Those with a PEN-FAST score of ≤ 3 were eligible for inclusion. For reference, anaphylaxis that requires treatment represents a PEN-FAST score of 3. Patients were excluded if they reported anaphylaxis to penicillin or other drugs, or if they reported an adverse reaction to penicillin (e.g., headache or nausea) rather than a true allergy.
Patients were randomized 1:1 to either direct oral penicillin challenge (the intervention group) or intradermal testing and, if negative, then an oral penicillin challenge (control group). The primary outcome was a physician-verified positive oral penicillin challenge, defined as an immediate reaction occurring within one hour following ingestion of the penicillin consistent with an immune-mediated reaction. The investigators calculated that noninferiority would be achieved if the 95% confidence interval (CI) of the risk difference was ≤ 5 percentage points.
There were 187 patients randomized to the intervention group and 190 to the control group. The two groups were similar with regard to their baseline characteristics. The vast majority had a PEN-FAST score of 0-1 (94% in the intervention group, 97% in the control group). The primary outcome occurred in one patient in the intervention group and one in the control group. This result met the noninferiority margin of five percentage points. In the five days after the penicillin challenge, nine immune-mediated adverse events occurred in the intervention group and 10 occurred in the control group. There were no serious adverse reactions in either group. The two patients who experienced the primary outcome both developed a mild cutaneous skin reaction that resolved after a single dose of an antihistamine. Finally, the penicillin allergy label was removed in 186 of 187 participants (99.5%) in the intervention group and 186 of 190 (97.9%) in the control group. Four patients in the control group were excluded from the oral challenge because of a positive intradermal skin test.
COMMENTARY
Approximately 10% of people report being allergic to penicillin, making it the most common drug allergy.1 Of these, less than 5% are truly allergic. The delabeling of a penicillin allergy can be very beneficial from efficacy, safety, and healthcare cost perspectives. Thus, the study by Copaescu et al is welcome news for all clinicians involved with antibiotic stewardship. It provides high-quality evidence that direct oral challenge is an effective and safe method of assessing low-risk penicillin allergies.
Delabeling a penicillin allergy has become a high priority for many antibiotic stewardship programs, in concurrence with recent World Health Organization (WHO) recommendations.2 One hopes the present study will be used to inform future versions of antibiotic stewardship guidelines, such as those from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.3 Further research is warranted to explore whether direct oral challenge can abrogate non-β-lactam antibiotic allergies in low-risk patients, as well as in other populations (e.g., inpatients and children).
Despite a robust design, the study has a few limitations. First, 94% of the patients had a PEN-FAST score of 0 or 1, which limits the generalizability of the findings to those with a score of 2. Second, the open-label design of the trial could have affected the assessment of the primary outcome, since patients in the intervention group did not have skin testing performed. Finally, conducting the trial in high-income countries might limit the generalizability to other geographic locations.
Skin testing for penicillin allergy is a labor-intensive and expensive intervention that currently is not available for large numbers of patients in high- , middle- , and low-income countries. The success of direct oral challenge for low-risk patients with a penicillin allergy is a positive development that it is hoped will be widely recognized and implemented.
REFERENCES
- Warrington R, Fanny Silviu-Dan F. Drug allergy. Allergy Asthma Clin Immunol 2011;7 (Suppl 1):S10.
- World Health Organization. Antimicrobial stewardship programmes in health-care facilities in low- and middle-income countries: A WHO practical toolkit. World Health Organization. Oct. 22, 2019. https://www.who.int/publications/i/item/9789241515481
- Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis 2016;62:e51-e77.