Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy

Abstract

ImportanceFewer than 5% of patients labeled with a penicillin allergy are truly allergic. The standard of care to remove the penicillin allergy label in adults is specialized testing involving prick and intradermal skin testing followed by an oral challenge with penicillin. Skin testing is resource intensive, limits practice to specialist-trained physicians, and restricts the global population who could undergo penicillin allergy delabeling.ObjectiveTo determine whether a direct oral penicillin challenge is noninferior to the standard of care of penicillin skin testing followed by an oral challenge in patients with a low-risk penicillin allergy.Design, Setting, and ParticipantsThis parallel, 2-arm, noninferiority, open-label, multicenter, international randomized clinical trial occurred in 6 specialized centers, 3 in North America (US and Canada) and 3 in Australia, from June 18, 2021, to December 2, 2022. Eligible adults had a PEN-FAST score lower 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.InterventionsPatients were randomly assigned to either direct oral challenge with penicillin (intervention arm) or a standard-of-care arm of penicillin skin testing followed by oral challenge with penicillin (control arm).Main Outcome and MeasureThe primary outcome was a physician-verified positive immune-mediated oral penicillin challenge within 1 hour postintervention in the intention-to-treat population. Noninferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5 percentage points (pp).ResultsA total of 382 adults were randomized, with 377 patients (median [IQR] age, 51 [35-65] years; 247 [65.5%] female) included in the analysis: 187 in the intervention group and 190 in the control group. Most patients had a PEN-FAST score of 0 or 1. The primary outcome occurred in 1 patient (0.5%) in the intervention group and 1 patient (0.5%) in the control group, with an RD of 0.0084 pp (90% CI, −1.22 to 1.24 pp). The 1-sided 95% CI was below the noninferiority margin of 5 pp. In the 5 days following the oral penicillin challenge, 9 immune-mediated adverse events were recorded in the intervention group and 10 in the control group (RD, −0.45 pp; 95% CI, −4.87 to 3.96 pp). No serious adverse events occurred.Conclusions and RelevanceIn this randomized clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was noninferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label.Trial RegistrationClinicalTrials.gov Identifier: NCT04454229

Reliability and validation of an electronic penicillin allergy risk-assessment tool in a pregnant population

“…A systematic review revealed 96.5% of patients could be de-labelled without serious adverse reactions 3 . This is further supported by recent evidence whereby low risk penicillin allergy patients can safely receive direct oral challenge 4 .…”

A multicentre observational study to investigate feasibility of a direct oral penicillin challenge in de-labelling ‘low risk’ patients with penicillin allergy by non-allergy healthcare professionals (SPACE study): Implications for healthcare systems

“…Patient demographics, case complexity including co-morbidities, clinical setting, views, perspectives and behavioural factors amongst HCPs and patients and local research governance framework may have contributed to the differences in conversion rates seen in these studies. Specifically, the risk stratification employed in this study broadly aligns to the PEN-FAST tool employed by Copaescu et al 21 in the PALACE trial, although our approach did not include a scoring system. Copaescu et al deemed patients with psychological and neurological conditions as ineligible to be randomised, although did not list clinical instability and severe cardio-respiratory co-morbidities such as severe asthma, COPD or heart failure as an exclusion criterion.…”

The Penicillin Allergy Decision Rule—Something New for Penicillin Allergy

“…It is time to change the ordinary happening of penicillin allergy labels by using the new approach of direct challenges stratified by PEN-FAST scores. The data by Copaescu et al 3 firmly support this action, and the adult inpatient setting is an optimal setting to start. The PEN-FAST and direct challenge tools may help optimize the use of Fleming's revolutionary discovery.…”

“…2 It has also been associated with vital public health concerns of increased health care costs and antimicrobial resistance. 2 The admirable work by Copaescu et al 3 uses the validated Penicillin Allergy Decision Rule (PEN-FAST) tool in a randomized clinical trial comparing traditional penicillin skin testing (PST) with a direct challenge in patients reporting a penicillin allergy. This is a call to end the ordinary happening of accepting a penicillin allergy label and embrace the something new of delabeling low-risk patients with a direct challenge.…”

“…Although a previous randomized clinical trial had similar findings, 4 the present study is superior based on its larger sample size, use of a validated screening tool, and multicenter and multinational enrollment. As stated by Copaescu et al 3 in the Discussion of their article, the recent drug allergy practice parameters recommend considering a direct challenge in adults, but this was a conditional recommendation with low-quality evidence. 2 The current study should be practice changing to move to direct challenges in low-risk adults in place of PST, thus allowing more penicillin allergy evaluations to completed by clinicians not specialized in allergy/immunology.…”