Introduction
Penicillin allergy labels are common and lead to the use of less-preferred antibiotics, despite often being inaccurate. Reference Jeimy, Ben-Shoshan, Abrams, Ellis, Connors and Wong1 Use of alternative antibiotics may be associated with lesser efficacy and a higher risk of adverse outcomes, including toxicity, Clostridium difficile infection, and resistance. Reference Jeimy, Ben-Shoshan, Abrams, Ellis, Connors and Wong1 Pharmacist-led allergy assessments prompting de-labeling effectively reduce high-risk alternative antibiotic use. Reference Turner, Wrenn and Sarubbi2
Direct oral amoxicillin challenge in patients with low-risk penicillin allergies is safe and effective for removing penicillin allergy labels, while reducing time and resource allocation associated with penicillin skin testing. Reference Copaescu, Vogrin and James3 Duke University Hospital piloted an amoxicillin oral challenge protocol beginning August 2023 for patients with low-risk penicillin allergies in inpatient and outpatient settings. We evaluated outcomes of a direct oral challenge (DOC) with amoxicillin, including success rate, allergy de-labeling, and adverse events.
Methods
This retrospective, single-center evaluation included patients who received a one-time 250 mg oral amoxicillin challenge at Duke University Hospital from August 2023 to September 2024. Our institutional guideline recommends testing clinically stable patients with PEN-FAST score < 2 (representative of most subject’s scores enrolled in PALACE Reference Copaescu, Vogrin and James3 ) and a 96-hour H1 antagonist washout. The decision to proceed with DOC was made at the discretion of the treating physician. Patients were excluded if they were < 18 years of age, admitted to labor and delivery units, or challenged in the outpatient allergy clinic. Eligible patients were identified via electronic health record (EHR) query.
Data collected from EHR included demographics, comorbidities, allergy history, challenge tolerance, allergy de-labeling documentation, and adverse reactions. Safety was assessed by immediate tolerance and delayed adverse effects. Efficacy was assessed through reviewing allergy de-labeling and subsequent antibiotic use. Additional outcomes included beta-lactam use post-DOC and review of patients who were re-labeled or who were not de-labeled.
Data were analyzed using descriptive statistics.
Results
A total of 99 patients received DOC from August 2023 to September 2024, and 94 patients were included for further review. Five patients were excluded based on primary location or team: obstetrics (n = 2), pediatrics (n = 2), or allergy (n = 1). The median age was 63 years (IQR 47.25–71), and 53.2% (n = 50) were male. Eighty four percent of patients (n = 79) received DOC inpatient. Approximately 22% (n = 21) of patients had iatrogenic immunosuppression, and the most common was chemotherapy for active cancer in 9.6% (n = 9). Common allergic reactions were childhood exanthem (39.4%), unknown (22.3%), and urticaria (21.3%). Documented allergy occurred > 10 years ago in 88.3% (n = 83) of patients. Most patients had PEN-FAST scores of 0 (48.9%) or 1 (45.7%). Table 1 summarizes baseline demographics and allergy history.
Table 1. Baseline demographics and allergy history
Of 94 patients who underwent DOC, 93 (98.9%) tested negative, and 81 (86.2%) subsequently had their allergy removed from their medical record. Of the 12 patients with a negative test who were not de-labeled, 9/12 (75%) had no documented indication for allergy label retention, 2/12 (16.7%) had an index reaction to cephalosporins, and 1/12 (8.3%) experienced a delayed reaction. Nine (9.6%) patients were re-labeled within one year of DOC, with 7/9 (77.8%) lacking clear reason for re-labeling and 2/9 (22.2%) experienced a delayed reaction.
One patient (1.1%) exhibited an immediate reaction, and four (4.3%) exhibited delayed reactions. Delayed reactions included diffuse rash (n = 3) and swelling (n = 1), one requiring treatment with an antihistamine. Of the four patients who experienced delayed reactions, three patients had a PEN-FAST score of 1 and one patient had a PEN-FAST score of 2. The median time to delayed reaction was 7 days. All immediate and delayed reactions were non-severe and self-limiting, resolving after discontinuation of penicillin derivative where appropriate. Table 2 provides a summary of patients who experienced reactions.
Table 2. Patients with immediate or delayed reactions
Forty-nine (52.1%) patients received a penicillin antibiotic within 90 days after DOC, including three who experienced delayed reactions.
Discussion
Our findings support the use of DOC in practice to remove penicillin allergy labels and optimize antibiotics for patients with low-risk allergies. Despite the high success rate of DOC in our cohort, nearly 18% of patients either did not have their allergy removed from their medical record, or had their allergy added back to their medical record for unclear reasons. Notably, stewardship workflow at our institution involves a best practice alert (BPA) upon allergy re-entry. Upon further chart review, we believe BPAs failed to fire when patients electronically entered penicillin allergies while scheduling initial clinic visits, despite successful PO challenge. Additionally, patients often reported potential alternative causes for delayed reactions, presenting a challenge to discern the nature of the reaction through EHR review alone. These observations may signal a need to focus on patient empowerment and education regarding penicillin allergy de-labeling.
DOC has been increasingly adopted into clinical practice after findings in the PALACE study demonstrated non-inferiority to the historic standard of penicillin skin testing, which requires an abundance of time and resources. Reference Copaescu, Vogrin and James3–Reference Trubiano, Vogrin and Mitri4 The PALACE trial included patients with low-risk penicillin allergies, 95.8% with a PEN-FAST score 0–1, which influenced our institutional recommendations and is reflected in the majority of our cohort having a PEN-FAST score of 0–1 (94.6%). Reference Copaescu, Vogrin and James3 In the PALACE trial, .5% of participants experienced a positive challenge, defined as an immediate immune-mediated reaction within 1 hour of DOC. Reference Copaescu, Vogrin and James3 These findings align with our cohort, as one (1.1%) patient experienced an immediate reaction. The PALACE trial also evaluated delayed reactions up to 5 days post oral challenge and reported 22 (11.6%) patients experiencing any delayed adverse effect in the DOC cohort, 9 (4.7%) of which were immune-mediated. The median time to immune-mediated delayed reaction was 4 days. Reference Copaescu, Vogrin and James3 We collected delayed reactions at any time point after oral challenge and observed a similar rate of 4.3%; however, in the four patients with delayed reactions these occurred a median of 7 days post-DOC. Our cohort study supports the efficacy findings of the PALACE trial and, with longer follow-up than available in current literature, instills confidence that DOC for penicillin allergy removal is safe in low-risk patients for months following the trial period.
Prior to the PALACE study, other institutions published center-specific data supporting the safety and efficacy of DOC for penicillin allergy removal. Reference Trubiano, Vogrin and Copaescu5–Reference Kuruvilla, Shih, Patel and Scanlon6 However, most available data focuses on immediate reaction and allergy removal, and there is a lack of evidence focused on long-term outcomes for these patients. In our review, nearly 18% of patients currently have documented penicillin allergies despite passing DOC without an immediate or a delayed reaction. This indicates a need for systems to ensure a negative DOC is followed by prompt allergy removal, as well as education to avoid re-labeling because of patient or provider uncertainty. Moreover, our data is novel in that we reviewed outcomes of DOC in both the inpatient and ambulatory setting, where most validation data is outpatient-focused.
Our study has limitations. The retrospective nature of our observational study precluded our ability to collect data on definitive reasons for allergy labels being removed or re-entered to the EHR. Additionally, data from a single center may not be generalizable; however, characteristics and findings are consistent with previously published literature.
Our review supports current guidance and published data regarding the safety and efficacy of DOC for allergy removal in patients with low-risk penicillin allergies. It is imperative that institutions take necessary measures to ensure penicillin allergies are removed following successful DOC, and that patients and healthcare team members are informed to avoid unjust allergy re-labeling.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/ash.2025.10168.
Acknowledgments
Research reported in this publication was supported by the Duke Clinical and Translational Science Institute (CTSI). The content is solely the responsibility of the authors and does not necessarily reflect the official view of Duke University or the Duke CTSI.
Financial support
The authors received no financial support for the research, authorship, and/or publication of this article.
Competing interests
The authors declare no conflicts of interest related to this work.
Research transparency and reproducibility statement
This study was reviewed and approved by Duke University Health System Institutional Review Board. Informed consent was waived due to the retrospective design. All relevant methods, including patient selection criteria, PEN-FAST scoring, oral challenge protocol, and outcome definitions are described in sufficient detail to allow replication. De-identified data used for this analysis are available from the corresponding author upon reasonable request. No custom code was used for analysis. All data were analyzed using standard descriptive statistics in Microsoft Excel.
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