Background: Approximately, 10% of people report a penicillin allergy; however, more than 90% can safely undergo delabeling after a detailed history, oral challenge, or other investigations such as penicillin skin testing (PST). Although PST is the gold standard, the results can be heterogeneous, and awaiting specialist assessment may take an inordinate amount of time. Therefore, oral provocation challenge has become acceptable for individuals with low-risk penicillin allergy histories. There also appears to be an association with increased prevalence of adverse drug reaction reporting in female individuals, which may translate to penicillin allergy prevalence; however, the evidence has not been assessed through a sex and gender lens. This systematic review will identify and synthesize the findings from studies that report measures of effectiveness and safety of interventions aimed at delabeling penicillin allergies in low-risk individuals. Information related to sex and gender will be extracted, where available, to understand potential differences in allergy reporting and patient outcomes.

Methods: The Cochrane Handbook for Systematic Reviews of Interventions and the Centre for Review and Dissemination's Guidance for Undertaking Reviews in Health Care will be used as frameworks for conducting this systematic review. The literature search will be conducted by a medical librarian (B. M. M.) and will consist of a search strategy to identify and retrieve published studies that meet our inclusion criteria. Studies that require penicillin skin testing (PST) as a step prior to other interventions will be excluded. Integrated knowledge translation involving co-design was carried out for this systematic review protocol creation. Data extraction will be conducted at four levels: (1) study level, (2) patient level, (3) intervention level, and (4) outcome level. A narrative descriptive synthesis of results and risk of bias of all included studies will be provided, and, if relevant, a meta-analysis will be performed.

Discussion: The dissemination of findings from this knowledge synthesis to various stakeholders is intended to inform on options for evidence-based interventions to aid in delabeling penicillin allergies in individuals with a low risk of experiencing a hypersensitivity reaction. Detailed reporting on the characteristics of delabeling interventions as well as the effectiveness of similar interventions will benefit policy makers considering the implementation of a penicillin allergy delabeling protocol. Additionally, findings from this systematic review will report on the current evidence regarding the role of sex and gender in both the prevalence and outcomes associated with the presence of penicillin allergies.

Systematic review registration: PROSPERO CRD42022336457.

Keywords: Allergy; Amoxicillin; Antibiotic; Beta-lactam; Delabeling; Hypersensitivity; Oral challenge; Penicillin; Testing.