Unpacking Oral Challenge Protocols: A Descriptive Epidemiologic Study of Reactions,Predictors,and Practices for Delabeling Low-Risk Penicillin Allergies Leveraging Data from a Systematic Review and Meta-Analysis

Abstract

Background: Oral challenges with amoxicillin or other penicillins are safe and effective for delabeling low-risk penicillin allergy histories. While approximately 90% of reported penicillin allergies can be safely delabeled, detailed data on reaction frequency, types, and timing during and after delabeling interventions remain limited. Such data are crucial to optimizing protocols and integrating oral challenges into routine practice. This study aims to characterize the interventions commonly used for oral challenge, classify reported reactions, and identify reported predictors of hypersensitivity reactions in randomized controlled trials and quasi-experimental studies involving an oral challenge for patients with low-risk penicillin allergies. Methods: This study leverages data from a systematic review and meta-analysis assessing the effectiveness of oral challenge interventions in patients with low-risk penicillin allergies. This descriptive analysis summarizes the adverse reactions experienced among patients in published studies who received oral challenge. Participant demographics, intervention protocols, frequency, type, and timing of post-challenge adverse reactions are reported. Reactions are categorized as immediate, delayed, or other, with frequencies summarized using descriptive statistics. A random effects meta-analysis quantifies a pooled adverse reaction rate. Predictors of hypersensitivity reactions were synthesized narratively. Results: Across 26 studies (2 randomized trials, 24 quasi-experimental studies) evaluating an oral challenge for patients with a low-risk penicillin allergy, the average participant age was 56 years, with a predominance of females (61%) and limited ethnic diversity with 88% reported or identifying as White. Amoxicillin was the most frequenty used oral challenge agent, typically administered as a single 250 mg oral dose. The incidence of reaction or non-delabeling was 4% (95% Confidence Interval 3%, 6%), I² = 43%, P = .0001. Cutaneous manifestations, such as rashes, were the most frequent reactions. Delayed reactions, primarily mild maculopapular rashes, were uncommon and managed with antihistamines or topical steroids. Risk factors for oral challenge reactions included higher baseline allergy burden and shorter intervals to oral challenge since the index reaction. Conclusion: Oral challenge strategies to delabel low-risk penicillin allergies can involve single doses of amoxicillin or other penicillins with monitoring protocols that can be managed in ambulatory settings. However, although these delabeling strategies are becoming more prevalent, continued study of standardized protocols and follow-up are essential for effective and replicable delabeling strategies. Future research should prioritize diverse populations and equity-driven frameworks to improve generalizability to all individuals and to resource limited settings.

Keywords

oral challenge penicillin allergy delabeling antimicrobial stewardship

Background

Oral challenge is widely recognized as a safe and effective method for assessing penicillin allergies in low-risk population.^1-3 However, there remains limited analysis on the timelines to and types of reactions that may occur during or after oral challenge interventions. This knowledge is essential not only for optimizing the safety and efficacy of oral challenge protocols but also for facilitating their integration into routine clinical practice.⁴ By improving understanding of the characteristics, timelines, and predictors of hypersensitivity reactions, this work seeks to empower healthcare providers to confidently remove inappropriate penicillin allergy labels. In doing so, it will help reduce the unnecessary avoidance of first-line antibiotics, enhance antimicrobial stewardship, and improve patient outcomes across diverse healthcare settings.^5-7 Specifically, this study aims to comprehensively describe the characteristics of oral challenge interventions, categorize the observed and reported reactions following oral challenge, and identify predictors of hypersensitivity reactions in studies designed to delabel penicillin allergies in patients with a low-risk of hypersensitivity.

Methods

This study leverages data from a previously published systematic review and meta-analysis focused on penicillin allergy delabeling in low-risk populations.³ Details of the methods are available in both the published study protocol⁸ registered in PROSPERO: CRD42022336457 and in a manuscript reporting the primary findings.³ Briefly, a comprehensive search strategy was conducted across multiple databases (PubMed, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, Ovid MEDLINE, Ovid EMBASE, ClinicalTrials.gov and medRxiv) between their inception and February 2024. Two independent reviewers initially screened titles and abstracts prior to that of relevant full-text articles. This descriptive analysis uses data from all identified randomized trials and quasi-experimental studies evaluating individuals classified as having a low-risk penicillin allergy history who underwent oral challenge interventions, as these participants were directly evaluated for tolerability based on post-challenge outcomes. Low-risk was defined in the initial systematic review using thematic analysis of all eligibility criteria for inclusion in oral challenge arms across the 26 studies in which seven major themes were identified: non-severe cutaneous reactions, unknown reaction, side effects or intolerance, absence of anaphylaxis or angioedema, no personal reaction experienced, non-life-threatening reaction, and tolerated since index reaction.³ Patients included in direct delabeling interventions without oral challenge were excluded from this analysis.

Baseline demographic and clinical characteristics, intervention protocols, and reported index reactions to penicillins (reason for penicillin allergy label) were extracted as described by the authors and reported by participants. The primary outcomes of interest for this study are the characteristics of reported reactions after oral challenge intervention, including the time to onset, classification of reported reactions, and potential predictors of hypersensitivity reactions. Any reaction to oral challenge or reported reason that led to lack of removal of the allergy label based on the discretion of the study authors were described as non-delabeled. The mean incidence of reactions (or non-delabeling) occurring after oral challenge administration was described in the original systematic review and meta-analysis but is also briefly reported herein. Given that none of the reactions were severe in nature, reactions were categorized into the following groups: (1) non-severe immediate reactions (within 1 hour of oral challenge), (2) delayed non-severe reactions (occurring more than 1 hour after oral challenge), and (3) other reported reactions.

Descriptive statistics, including means and ranges, were used to summarize patient demographics, intervention characteristics, and baseline reaction histories. A random-effects proportional meta-analysis was conducted,⁹ heterogeneity of results across studies was assessed using the χ² statistic and quantified using the I² statistic and the DerSimonian-Laird approach was used to estimate between study heterogeneity. All oral challenge arms across all intervention types were pooled together for the purpose of this meta-analysis. Factors associated with an increased risk of post-oral challenge reactions, as reported by study authors, were synthesized and described narratively.

Results

Population Characteristics

As described in the initial systematic review and meta-analysis, there were 26 studies (2 RCTs, and 24 quasi-experimental studies) identified that included an oral penicillin challenge among low-risk patients. The mean age was reported in 24 studies (85%) with an average age of 56 years, ranging from 34 to 73 years.^10-33 Most study participants were female (61%)^10-25,28-33 with two studies including exclusively pregnant people.^26,27 Five studies included both male and female participant demographic variables at baseline.^{10,17,19,25,29} Ten studies reported ethnicities of participants of which 88% were White.^{12-14,17,19,23-25,32,33}

Index Reactions Leading to Allergy Labeling

The self-reported index reactions were described in 18 (69%) of the studies;^{11,13,14,16-22,24,26-28,30-32,34} details regarding all reported index reactions can be found in Table 1. Although index reactions were reported, these included both low and high-risk individuals without further stratification by allergy risk or correlation with tolerability of the oral challenge. Based on the reported data, diffuse rash occurring more than 10 years prior (or timeline not described) was reported in 40% of participants across 8 studies^{11,14,17,19,21,22,26,27} followed by childhood exanthem in 35% (min 9%, max 76%) across 5 studies^{13,17,20,22,34} and urticaria in 29% across 9 studies (min 9%, max 42%).^{11,14,16,17,19,26-28,30,31} Other types of index reactions were reported across various studies as described in Table 1.

Table 1.

Baseline Self-Reported or Reported Reactions to Penicillins (Reported in 18 of 26 Studies).

First author	Year	Childhood exanthem	Immediate diffuse rash	Diffuse rash <10 years	Diffuse rash ≥10 years	Blistering or desquamating rash	Angioedema	Swelling	Urticaria	Laryngeal involvement	Respiratory compromise	Fever	Anaphylaxis	Hematologic	Unknown reaction <10 years	Unknown reaction >10 years	Liver or renal injury (severe)	Liver or renal injury (mild)	Gastrointestinal symptoms	Neurologic or CNS symptoms (severe)	Neurologic or CNS symptoms (mild)	Pruritis	Other
Chau, K	2021	9%	11%	9%	22%	4%	12%	7%	9%	4%	6%	1%	7%	0%	1%	9%	1%	1%	13%	1%	2%	—	10%
Duplessis, T	2019	28%	—	—	—	—	10%	3%	—	—	—	—	—	—	—	—	3%	—	33%	12%	—	—	12%
Fanizza FA	2022	—	—	—	—	—	—	—	—	—	—	—	—	—	—	36%	—	—	—	—	—	—	39%
Gateman, DP	2021	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	9%
Ham, Y	2021	—	50%	—	—	—	6%	—	28%	—	22%	—	—	—	—	—	—	—	6%	—	—	—	22%
Iammatteo, M	2019	—	5%	—	24%	—	4%	—	40%	2%	—	—	—	—	—	15%	—	—	1%	—	—	3%	7%
Kuruvilla, M	2019	—	—	—	—	4%	—	—	38%	—	—	—	38%	—	—	—	—	—	4%	—	—	38%	—
Livirya, S	2022	31%	—	—	—	7%	5%	—	—	—	4%	—	11%	—	—	24%	—	—	17%	—	—	—	4%
Mak, R	2022	—	—	—	49%	—	9%	—	34%	—	5%	—	—	—	15%	15%	—	—	—	—	—	—	—
Mustafa, S	2019	—	—	—	47%	—	—	—	30%	—	—	—	—	—	—	6%	—	—	—	—	—	—	—
Ramsey, A	2020	—	—	—	46%	—	—	—	42%	—	—	—	—	—	—	8%	—	—	—	—	—	4%	—
Rozario, C	2023	—	—	38%	—	—	—	4%	26%	—	—	—	1%	—	19%	—	—	—	—	—	—	—	7%
Sneddon, J	2021	—	—	—	37%	—	7%	—	—	—	—	—	—	—	—	38%	—	—	6%	4%	—	—	8%
Steenvoorden, L	2021	—	—	—	—	—	26%	—	28%	—	23%	—	20%	—	—	—	—	—	—	—	—	—	—
Stollings, J	2023	—	—	—	—	—	—	—	—	—	—	—	22%	—	—	—	—	—	—	—	—	—	0%
Trubiano, JA	2018	26%	—	—	30%	—	—	—	—	—	—	—	—	—	37%	—	—	—	—	—	—	—	9%
Tucker	2017	76%	—	—	—	—	—	—	—	—	—	—	—	—	—	20%	—	—	1%	—	—	—	2%
Zhang, BY	2021	—	—	—	68%	—	—	—	11%	—	—	—	—	—	—	25%	—	—	—	—	—	—	—

Note. Dash (—) indicates that data is not reported.

Oral Challenge Intervention Characteristics

In the 26 studies for which oral challenge in the setting of a low-risk penicillin allergy was performed, amoxicillin 250 mg as a single oral dose was an option in 42% of studies^{16,17,20,22-25,28,31,32,34} (Table 2). Amoxicillin 500 mg administered orally was described in 27% of studies;^{14,17,21,27,29,30,33} however, frequency of dosing varied from once daily to twice daily administration for multiple days. Graded oral challenge strategies were described in 19% of studies.^11-13,18,35 In the study by Alnaes et al,³³ the penicillin for which the index reaction occurred was used if known, otherwise amoxicillin was selected. Other penicillins for oral challenge were considered in fewer studies as can be seen in Table 2. With respect to provider monitoring, nurses were involved in 27%,^{14,15,17,20,22,25,35} pharmacists in 15%,^13,16,24,32 allergists or immunologists in 12%,^11,26,30 primary care providers in 4%,¹⁸ and other or non-defined providers in 38%.^{10,12,19,21,23,27,28,31,33,34} One study by Fransson et al²⁹ included patient self-completion.

Table 2.

Protocol Descriptions and Reported Reactions from 26 Studies Involving an Oral Challenge.

First author	Year	Index reactions described	Reactions to oral challenge (n=, (%))	Drug(s) used	Dose	Frequency	Provider	Comments
Alnaes	2023	No	1 (1)	Index penicillin (if known) Amoxicillin (if index not known)	NR 500 mg	ONCE	NR	Non-severe rash
Chau	2021	Yes	9 (5)	Penicillin Amoxicillin Amoxicillin	250 mg 250 mg 500 mg	ONCE ONCE BID for 5 days	Nurse	6 positive oral challenges and 3 non-immune-mediated reactions
Copaescu	2023	No	1 (1)	Penicillin VK Amoxicillin Flucloxacillin	Variable	NR	Other	1 immune mediated reaction in both arms
Devchand	2019	No	NR	NR	NR	NR	Nurse	No follow up once delabeling completed
duPlessis	2019	Yes	3 (9)	Amoxicillin	Graded oral challenge suspended in yogurt given 30 min apart until 1000 mg TID	24 hours, if continued use not required	Pharmacist	Only nausea, vomiting, or headache were reported reactions
Fanizza	2022	Yes	0 (0)	Amoxicillin	250 mg	ONCE	Pharmacist	No reactions were described
Fransson	2022	No	20 (10)	Amoxicillin	500 mg	ONCE or Twice daily	Patient self-completed	19 cutaneous symptoms, 1 hyperventilation 13 of 19 cutaneous reactions were experienced 3 days after oral challenge
Gateman	2021	Yes	3 (3)	Amoxicillin	Graded	ONCE	Primary care provider	3 pediatric patients had a reaction No adult patients had a reaction
Ham	2021	Yes	2 (7)	Amoxicillin	250 mg	ONCE	Pharmacist	Two patients retained their allergy label due to mild reactions in the two-step challenge
Iammatteo	2019	Yes	19 (12)	Amoxicillin	80 mg and 500 mg	80 mg ONCE, observe for 30 min then 500 mg ONCE	Other	4 described as allergic and 15 non-allergic reactions
Koo	2022	No	NR	Amoxicillin	250 mg	ONCE	Other	NR
Kuruvilla	2019	Yes	3 (15)	Amoxicillin	500 mg	ONCE	Allergist/immunologist	3 reactions reported: chest tightness, pruritis, and dizziness
Livirya	2022	Yes	4 (10)	Amoxicillin	250 mg	ONCE	Nurse	Description of reactions not reported Relabeling on follow-up
Mak	2022	Yes	4 (2)	Amoxicillin	500 mg	ONCE	Other	No immediate hypersensitivity, 4 delayed cutaneous reactions, 1 vomiting (unrelated to challenge)
Mustafa	2019	Yes	3 (4)	Amoxicillin	400 mg	ONCE	Allergist/immunologist	No reactions in penicillin skin test arm 3 cutaneous reactions (treated with antihistamines) in oral challenge arm
Ramsey	2020	Yes	3 (6)	Amoxicillin	Graded or 500 mg	30-minute intervals or ONCE	Nurse	1 rash with amoxicillin/clavulanate on day 17 of therapy 1 facial swelling and nausea/vomiting with amoxicillin/clavulanate on the day after challenge 1 from the skin testing group experienced a rash with cefazolin on day 17 of therapy
Rozario	2023	Yes	2 (2)	Amoxicillin	250 mg	ONCE	Other	Of the 79 patients who were delabeled, allergy label was only removed from EMR for 64 (81%) 2 cases of delayed reactions
Savic	2019	No	1 (2)	Amoxicillin	Incremental dose increase	ONCE	Nurse	1 patient with index reaction of widespread urticaria (not initially disclosed to research team) developed urticaria in hands after the second dose and stopped taking the amoxicillin
Sneddon	2021	Yes	1 (1)	Amoxicillin Flucloxacillin	500 mg	ONCE	Other	1 patient did not have a documented success or failure and was therefore deemed non-successful
Steenvoorden	2021	Yes	2 (4)	Amoxicillin	75 mg 250 mg	ONCE	Other	1 admitted patient had worsening of pre-existing bronchial obstruction symptoms, resolved with ipratropium bromide-salbutamol inhalation, was not delabeled 1 patient reported a mild maculopapular rash 2 days after oral challenge, not treated and was delabeled
Stevenson	2020	No	6 (4)	Amoxicillin	NR	NR	Other	Direct challenge was performed for both low and moderate risk cases, but specifics not described in text
Stollings	2023	Yes	NR	Amoxicillin	250 mg	ONCE	Pharmacist	NR
Trubiano	2022	No	20 (4)	Penicillin VK Amoxicillin	250 mg	ONCE	Nurse	10 immune mediated (9 delayed rash, 1 immediate rash, 1 decreased consciousness, 1 self-resolving throat tightness, 1 fever, and 1 unknown; none required epinephrine) and 10 non-immune mediated
Trubiano	2018	Yes	0 (0)	Penicillin VK Amoxicillin Amoxicillin	250 mg	ONCE ONCE BID	Nurse	No reactions reported
Tucker	2017	Yes	5 (2)	Amoxicillin	250 mg	ONCE	Not defined	NR
Zhang	2021	Yes	NR	Amoxicillin	NR	NR	Allergist/immunologist	No reactions reported

Note. BID = twice daily; EMR = electronic medical record; NR = not reported; TID = three times daily.

Incidence of Reaction to Oral Challenge

Of 26 studies in which participants received an oral challenge, the pooled weighted mean incidence of reaction or non-delabeling due to an experienced reaction, or non-delabeling at discretion of the study authors was 4% (95% Confidence Interval 3%, 6%), I² = 43.2%, P = .0001 (Figure 1). None of the reported reactions were severe in nature. The reaction rate varied across studies with 6 studies describing all participants as tolerating oral challenge. In 13 studies, between 1% to 5% of participants were not delabeled; in 5 studies 6% to 10% of participants were not delabeled. Reactions to oral challenge occurring at a rate greater than 10% were described in studies by Kuruvilla et al³⁰ and Iammatteo et al¹⁹; however, of the 19 reactions described in the Iammatteo study, 15 are deemed non-allergic in nature. Details regarding the reported reactions can be found in Table 2.

Figure 1.

Proportion meta-analysis of oral challenge reactions.

Immediate Reactions

In 2 RCTs, reactions to oral challenges were infrequent and non-severe. Copaescu et al¹² reported immune-mediated reactions in 0.5% of participants (one per study arm) while Mustafa et al¹¹ reported three mild cutaneous reactions, all resolving with oral antihistamines. Of 24 quasi-experimental studies, including two involving pregnant individuals, 13 reported no reactions, mild non-allergic symptoms, or non-severe cutaneous reactions, with seven studies (27%) reporting no reactions during oral challenge.^{15,22-24,26,29,32} Mak et al,²⁷ in a study of pregnant individuals, reported 4 delayed maculopapular rashes treated with topical steroids and oral antihistamines and 1 case of vomiting attributed to pregnancy. Ham et al¹⁶ found 98% of participants were delabeled, with two retaining their allergy label due to mild, non-IgE-mediated symptoms (lip tingling and gastrointestinal discomfort). Kuruvilla et al³⁰ observed 3 non-IgE-mediated reactions (pruritus, chest tightness, dizziness); all self-resolved without treatment. Rozario et al²⁸ reported that while 98% of participants were eligible for delabeling, only 64 of 79 who tolerated oral challenges opted to remove the allergy label from their electronic medical record.

Delayed Reactions

In 6 quasi-experimental studies, non-severe delayed reactions were reported. Chua et al¹⁷ report that 97% of participants completed the oral challenge successfully, with 6 documented reactions: 3 non-immune-mediated (fever with baseline urosepsis, vomiting, and pruritus without rash) and 3 delayed immune-mediated reactions suspected to be T-cell-mediated, occurring 5 to 7 days after oral challenge intervention. du Plessis et al¹³ reported no immediate reactions, but 3 cutaneous reactions occurred within 72 hours. Ramsey et al¹⁴ found 97.9% of participants tolerated the intervention with 1 delayed rash after 17 days and 1 case of facial swelling, nausea, and vomiting the day after challenge with amoxicillin-clavulanate, managed successfully with antihistamines. Trubiano et al²⁵ reported a 95.8% delabeling rate, with 10 presumed immune-mediated reactions (9 delayed rashes, 1 immediate rash, and others including throat tightness and fever), with none requiring epinephrine. Fransson et al²⁹ observed 19 of 20 reactions involved skin symptoms, with 13 occurring 3 days post-challenge. In the only study with 6-month follow-up,²⁰ 10% of participants had allergy labels re-applied without detailed explanations.

Other Reported Reactions

Unique patient factors contributed to reactions in 2 studies, and 1 study described broad treatment for notable reactions. In the Steenvorden et al³¹ study, a patient with bronchial obstruction experienced worsening respiratory symptoms, which resolved with ipratropium-salbutamol inhalation; this was deemed unlikely to be IgE-mediated, although the patient was not delabeled. In the study by Savic et al³⁵ one patient developed hand urticaria after the second dose of amoxicillin. Further questioning revealed a history of widespread urticaria, which the patient did not disclose, as they were eager to participate in testing. Tucker et al³⁴ studied marine recruits, of whom five (2%) experienced reactions: two with rashes, two with unknown reactions, and one case of hives; in these instances, epinephrine was administered empirically to prevent escalation although anaphylaxis was not reported.

Risk Factors that Correlated with Reaction to Oral Challenge

Two studies explored risk factors linked to positive oral challenges and defined populations deemed “low risk.” Iammatteo et al¹⁹ found a correlation between the number of baseline reported allergies or intolerances and oral challenge outcomes. Patients with allergic reactions had a median of 3 baseline allergies or intolerances (IQR 2.5-3.5), compared to 2 (IQR 1-4) in those with non-allergic reactions and 1 (IQR 1-2.5) in those with no reaction (P = .02).¹⁹ Stevenson et al¹⁰ evaluated 8 definitions of low risk, including timing and severity of index reactions. The optimal model, suited for outpatient settings, identified low-risk reactions as those occurring over 1 year prior with mild symptoms (eg, benign rash without mucosal involvement). Among these low-risk patients, 97.1% tolerated oral challenge without any cases of anaphylaxis.

Discussion

This study examines the characteristics of participants undergoing oral challenge to delabel low-risk penicillin allergies, the interventions used, and post-exposure adverse reactions. The findings support oral challenge as an effective, safe, and practical strategy, with low adverse reaction rates and high success in delabeling. In this adult population, the mean age was 56 years with a notable female predominance (61%), reflecting the higher reported prevalence of penicillin allergies in women. Ethnicity data were inconsistently reported, with most participants identifying as White and all studies were conducted in higher income countries. This underscores the need to fully ascertain participant ethnicity and include more diverse populations in future studies to ensure equitable access to care and improve the generalizability of rash assessments during penicillin oral challenge interventions across all skin tones, particularly as cutaneous reactions are the most reported reaction to oral challenge. Furthermore, availability of resources to conduct oral challenge interventions in low and middle-income countries requires further study to determine the best strategies to implement these interventions in resources limited settings.

Amoxicillin was the preferred agent for oral challenge, likely due to its accessibility, tolerability, and safety profile. Most studies used single-dose or short-duration challenges at doses of 250 or 500 mg, with less frequent use of graded challenges or other penicillins. Based on the ease of administration of a single dose of amoxicillin and its association with successful delabeling, the use of a single 250 mg dose is reasonable for assessing tolerability. Variability in dosing and provider roles suggests the need for standardized protocols. Nurses and pharmacists were commonly involved in monitoring, demonstrating the feasibility of non-physician healthcare professionals in scaling delabeling interventions.

No clear link emerged between the agent or dose used in oral challenges and the risk of reactions. However, based on tolerability information on follow-up with patients who were prescribed penicillins after oral challenge, there may be a correlation between the use of amoxicillin-clavulanate and intolerance or mild hypersensitivity reactions.¹⁴ This is supported by a study that used spontaneous reporting of adverse drug reactions in Italy by Salvo et al,³⁶ which found higher rates of gastrointestinal (13% vs 7%), hepatic (4% vs 1%), and hematologic (2% vs 1%) reactions with amoxicillin-clavulanate compared to amoxicillin, despite skin reactions being more common with amoxicillin (82% vs 76%). Furthermore, a study and case report show a correlation between oral challenge with amoxicillin/clavulanate and the development of hepatotoxicity and pancreatitis.^37,38 Therefore, amoxicillin-clavulanate is a beta-lactam characterized by a unique association with hepatopancreatic adverse drug reactions.

The absence of severe reactions supports oral challenge as a first-line strategy, even in vulnerable populations such as pregnant individuals who are assessed as having a low-risk penicillin allergy. This was supported by a cohort study conducted by Wong et al,³⁹ which evaluated penicillin oral challenges during the antepartum and postpartum phases and found the approach to be safe and effective in the antepartum phase. The authors also noted that deferring oral challenges to the postpartum period poses a significant barrier to penicillin allergy delabeling.³⁹ However, even though oral challenge was relatively well-tolerated across the studies included in this analysis, follow-up is important as mild delayed reactions such as maculopapular rashes were reported. Studies with extended follow-up indicated some relabeling, emphasizing the importance of patient education and robust follow-up to sustain benefits and understand long-term sequalae associated with delabeling interventions. One study suggested a correlation between the number of reported allergies and reaction likelihood, indicating potential for risk stratification.¹⁹ Timing since the index reaction and a benign nature of the reaction were also important factors, supporting their inclusion in future risk assessment tools.¹⁰ An area for focus in future study designs would be to consider potential predictors of hypersensitivity reactions as covariates in regression models across all studies to better understand factors that may impact both the presence of an allergy label and the true incidence of reaction.

This research has some limitations. Inconsistent reporting of demographics, comorbidities, and equity factors, along with heterogeneous challenge protocols, complicates cross-study comparisons. Many studies lacked standardized definitions for allergic versus non-allergic reactions, and long-term outcomes were often underreported. The inclusion of participants with low and high-risk baseline reactions without linkage to eligibility for oral challenge leads to the inability to clearly interpret how reported baseline reactions correlate with outcomes. Also, the underrepresentation of vulnerable and diverse populations limits generalizability. Most studies relied on short-term follow-up and patient-reported data, which are prone to recall bias. Further, the research was largely conducted in high-income countries with few randomized controlled trials, highlighting the need for more rigorous, standardized, and equity-informed studies in this field.

Conclusion

This descriptive analysis underscores the critical role of oral challenge interventions in improving antibiotic stewardship by safely delabeling low-risk penicillin allergies. Most oral challenge interventions involve a single 250 mg dose of amoxicillin, with most participants tolerating the challenge. Reactions were mild and primarily cutaneous in nature, with few delayed reactions having occurred. Implementing standardized, evidence-based protocols in diverse healthcare settings, including primary care and community pharmacies, is possible and has the potential to enhance accessibility to penicillin allergy assessment interventions.

Footnotes

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work has not received financial support. Mira Maximos has received a CIHR Doctoral award.

ORCID iDs

Mira Maximos

Ryan Pelletier

Sameer Elsayed

Colleen J. Maxwell

Sherilyn K. D. Houle

Brie McConnell

John-Michael Gamble

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