Direct Oral Challenge Research Articles

In low-risk penicillin allergies, direct oral challenge was noninferior to skin testing followed by oral challenge.

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;183:944-952. 37459086.

A new pathway for penicillin delabeling in Norway

BackgroundPenicillin allergy is self-reported by 3–10% of patients admitted to hospital. The label is wrong in 90% of the cases and has severe health implications. Penicillin-delabeling can reverse the negative effects of the label, and pathways adapted to local practice are needed. No tools are available in Norway for penicillin delabeling outside an allergy clinic. ObjectiveTo create and validate the first penicillin delabeling pathway applicable outside an allergy clinic in Norway. MethodsAn interdisciplinary taskforce created a penicillin allergy delabeling program (PAD) adapted to the Norwegian health care system. This was validated in a prospective, single-center study. Very low-risk and low-risk patients underwent a direct oral penicillin challenge and high-risk patients were referred for allergologic evaluation. ResultsOne-hundred forty-nine patients declaring penicillin allergy were included. Seventy-four (50%) were very-low- and low risk patients suitable for a direct oral penicillin challenge resulting in only 1 mild reaction. Sixty high-risk patients were eligible for an oral penicillin challenge after allergologic evaluation; 3 patients reacted non-severely. ConclusionWe have created and demonstrated feasibility of the first penicillin delabeling program (PAD) applicable in a hospital setting outside an allergy clinic in Norway. Our data suggest this is safe and beneficial, with 49% patients delabeled through a direct oral penicillin challenge, performed without any serious adverse events, and an overall 87% delabeling rate.

Assessing Pediatric Cephalosporin Allergic Reactions Through Direct Graded Oral Challenges

Cephalosporins, β-lactam antibiotics, commonly cause allergic reactions. To assess the clinical characteristics and management of pediatric patients with suspected cephalosporin allergy using direct graded oral challenges (GOCs). Children referred for suspected cephalosporin allergy at 4 Canadian clinics were recruited over 10 years. Data on demographics, clinical reaction characteristics, and management were collected through a questionnaire. Patients underwent a direct GOC (initially 10% of the treatment dose, then 90% after 20 min), and reactions were monitored 1 week postchallenge. Families were contacted annually for up to 5 years to detect subsequent antibiotic reactions. Logistic regression analysis identified factors associated with positive GOC reactions. Among the 136 patients reporting cephalosporin allergy, 75 (55.1%) were males with a median age of 3.9 years (interquartile range 2.3-8.7). Cefprozil represented the most common cephalosporin linked to the index reaction (67.6% of cases). Of the 136 direct GOCs, 5.1% had an immediate and 4.4% a nonimmediate reaction, respectively. Positive GOCs conducted in children with a history of skin-limited nonsevere rashes were classified as mild, benign skin rashes. Positive GOCs were more likely in children with food allergies (adjusted odds ratio 1.14; 95% confidence interval [95% CI] 1.00-1.29). Direct GOCs are safe and effective for diagnosing pediatric cases that report nonvesicular skin-limited symptoms while being treated with cephalosporins.

Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot randomised controlled trial

BackgroundSelf-reported penicillin allergies are highly prevalent in hospitalised patients and are associated with poor health and health service outcomes. Critically ill patients have historically been underrepresented in prospective delabelling studies in part due to concerns around clinical stability and reliability of penicillin skin testing. Allergy assessment tools exist to identify low-risk penicillin allergy phenotypes and facilitate direct oral challenge delabelling. PEN-FAST is a clinical decision rule that has been validated to predict true penicillin allergy in a cohort of non-critically ill patients. There is however limited evidence regarding the feasibility, safety and efficacy of direct oral challenges and the use of delabelling clinical decisions rules in the intensive care setting.MethodsCritically ill patients in the intensive care unit (ICU) with low-risk penicillin allergy phenotypes (PEN-FAST score < 3) will be randomised 1:1 to direct oral penicillin challenge (single dose 250 mg oral amoxicillin or implicated penicillin) or routine care, followed by a 2-h observation period. Patients will receive a second oral challenge/observation prior to hospital discharge (with subsequent observation for 2 h). An assessment for antibiotic-associated adverse events will also be undertaken at 24 h and 5 days post each challenge/observation and again at 90 days post-randomisation. The primary outcome measures are feasibility (proportion of eligible patients recruited and protocol compliance) and safety (proportion of patients who experience an antibiotic-associated immune-mediated adverse event or serious adverse event).DiscussionWe will report the feasibility and safety of point-of-care penicillin direct oral challenge in this first randomised controlled trial of low-risk penicillin allergy in critically ill hospitalised patients. Upon completion of the project, important findings will inform the design of planned large prospective multi-centre clinical trials in Australian and international ICUs, further examining safety and efficacy and exploring antimicrobial prescribing-related outcomes following penicillin oral challenge.Trial registrationAustralian New Zealand Clinical Trials RegistryRegistration Number: ACTRN12621000051842Date registered: 20/01/2021https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379735&isReview=true

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

Fewer 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. To 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. This 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. Patients 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). The 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). A 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. In 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. ClinicalTrials.gov Identifier: NCT04454229.

Description and accuracy of antibiotic allergy labels at North Shore Hospital.

Antibiotic allergy labels are common and associated with adverse care. Most people with an antibiotic allergy label are found to be non-allergic on investigation. The aims of this study were to evaluate the burden and accuracy of antibiotic allergy labels at North Shore Hospital and to identify and assess beta-lactam specific allergies, and the potential impact of an inpatient antibiotic allergy service. An evaluation of documented inpatient adverse drug reaction (ADR) labels. Structured assessment of beta-lactam allergies was undertaken using the Austin Health tool. Three hundred and seven patients were reviewed; 78 patients had an antibiotic allergy label, with 102 individual labels. Fifty-five of these 78 patients underwent structured assessment. Forty-four patients had a beta-lactam-specific antibiotic allergy label. Using the Austin Health tool, 9/44 (20%) of beta-lactam-specific allergy labels could have been removed following a history alone and a further 16/44 (36%) would have been appropriate for direct oral challenge. Antibiotic allergy label accuracy was 64% for beta-lactam antibiotics, and 69% for non-beta-lactams. The prevalence of antibiotic specific allergies in our centre was similar to New Zealand and Australian statistics.1,2 Our study showed that a significant proportion of inpatients with a beta-lactam-specific allergy could be de-labelled on history or with a single dose challenge.

Obstetric and Allergy Providers' Attitudes Towards Penicillin Allergy Testing in Pregnancy: A Single Hospital System Survey Study [ID: 1378292

INTRODUCTION: Penicillin (PCN) allergy affects 10% of the U.S. population. The American College of Obstetricians and Gynecologists recommends PCN allergy testing in pregnancy when available. The objective of this study is to explore obstetric and allergy providers' knowledge and attitudes toward penicillin allergy testing and identify current barriers. METHODS: Single hospital system survey-based study of all obstetric and allergy providers. All obstetric and allergy providers were emailed an anonymous survey of their knowledge, current practice pattern, and perceived barriers to PCN allergy testing. Institutional review board approval was obtained for this study. RESULTS: From January 1, 2021 to July 31, 2022, 2,795 of 20,500 initial prenatal visits (14%) had a listed beta-lactam allergy. Of these 2,795 patients, 300 (11%) were referred for allergy testing. Fifty-four obstetric providers completed surveys. Thirty-nine percent of obstetric providers had never referred a patient for PCN allergy evaluation. Twenty-seven percent of obstetric providers self-identified lack of provider knowledge in testing process as a complete barrier to testing, and one-third of providers perceived lack of time in clinic to discuss referral as a barrier. Twenty-one allergy providers completed the survey. All allergy provider responders were willing to perform allergy testing in pregnant women, with 63% performing a direct oral challenge to confirm results. Forty-one percent of allergy providers preferred to defer testing until the third trimester. CONCLUSION: Allergy providers are willing and able to perform penicillin allergy testing in pregnancy, but testing is limited by obstetric provider referrals. Current barriers include obstetric provider knowledge about testing and resources to allow efficient discussion of testing benefits in clinic.

Penicillin de-labelling in vancouver, British Columbia, Canada: comparison of approaches, outcomes and future directions

BackgroundInaccurate penicillin allergy labels lead to inappropriate antibiotic prescriptions and harmful patient consequences. System-wide efforts are needed to remove incorrect penicillin allergy labels, but more health services research is required on how to best deliver these services.MethodsData was extracted from five hospitals in Vancouver, British Columbia, Canada from October 2018-May 2022. The primary outcomes of this study were to outline de-labelling protocol designs, identify the roles of various healthcare professionals in de-labelling protocols and identify rates of de-labelling penicillin allergies and associated adverse events at various institutions. Our secondary outcome was to describe de-labelling rates for special populations, including pediatric, obstetric and immunocompromised subpopulations. To achieve these outcomes, participating institutions provided their de-labelling protocol designs and data on program participants. Protocols were then compared to find common themes and differences. Furthermore, adverse events were reviewed and percentages of patients de-labelled at each institution and in total were calculated.ResultsProtocols demonstrated a high level of variability, including different methods of participant identification, risk-stratification and roles of providers. All protocols used oral and direct oral challenges, heavily involved pharmacists and had physician oversight. Despite the differences, of the 711 patients enrolled in all programs, 697 (98.0%) were de-labelled. There were 9 adverse events (1.3%) with oral challenges with mainly minor symptoms.ConclusionsOur data demonstrates that de-labelling programs effectively and safely remove penicillin allergy labels, including pediatric, obstetric and immunocompromised patients. Consistent with current literature, most patients with a penicillin allergy label are not allergic. De-labelling programs could benefit from increasing clinician engagement by increasing accessibility of resources to providers, including guidance for de-labelling of special populations.

CATALYST: challenging antibiotic allergy status.

To develop a transferable process, CATALYST (challenging antibiotic allergystatus), to assess and challenge penicillin allergy status of inpatients within an NHS Foundation Hospital. A multidisciplinary team (MDT) steering group reviewed existing literature and protocols enabling penicillin allergy assessment, challenge and de-labelling. Using this, they identified five key steps forming the basis of CATALYST: clinical assessment of the nature of allergy; inclusion/exclusion criteria; consent; direct oral penicillin challenge; and removal of allergy label. A pharmacist-led pilot was conducted to assess the process, during which a continuous PDSA (plan-do-study-act) cycle was observed. This included formally auditing endpoint data such as accuracy of allergy status in medical records post-intervention. CATALYST was successfully developed with key resources produced to support clinicians. It was piloted in 304 patients, with 172 patients excluded and 132 successful allergy challenges. There was one incident of an adverse event (acute kidney injury) in the 132 successful patients, which occurred as a delayed reaction following 22 days of penicillin therapy. Only 64% of permanent records (held by GP) were appropriately updated when audited at the end of the pilot. CATALYST is a transferable process to facilitate safe assessment, challenge and removal of spurious penicillin allergy labels. Handover between care sectors forms a key element of allergy removal to ensure all records are updated and work is needed to ensure this process is done effectively.

Relationship of Reaction History to Positive Penicillin Skin Tests

Previous data suggest that up to one-third of patients classified as allergic based on positive penicillin skin tests have a vague reaction history. Direct oral challenge (DOC) has been recommended for patients with a low-risk reaction history. A variety of published models stratify reaction risk to guide the use of DOC. To reassess the proportion of penicillin skin test-positive patients with vague or low-risk reaction histories and evaluate the relationship between the reaction risk history and the likelihood of positive skin test results. We identified patients who underwent penicillin allergy evaluation over a 5-year period. We recorded drug reaction history, demographic variables, skin testing, and challenge results. Matched controls whose skin tests were negative were identified for skin test-positive patients. Drug reaction histories were assigned a risk category based on 2 previously published risk stratification models. We used logistic regression to investigate whether reaction history risk was associated with positive skin test results. Penicillin skin testing was performed in 3382 patients; 207 (6.1%) were positive. Positive skin tests were more frequent in outpatients (P < .001), younger patients (P < .001), and female patients (P < .001). Percentages of each risk category in each model were similar in cases versus matched controls. The likelihood for positive skin tests increased with a high-risk reaction history in one stratification model. Our data confirm that a substantial proportion of patients who self-report penicillin allergy and have positive skin test results have a low-risk history and imply that penicillin skin testing is associated with a poor positive predictive value.

Direct oral amoxicillin challenge for the outpatient evaluation of brazilian children and adolescents with low risk reactions

Antibiotic allergy labels contribute to longer hospitalizations, development of drug-resistant strains and are associated with increased costs and resource burdens for outpatient and hospital healthcare. Amoxicillin Direct Oral Challenge (DOC) may be safe and effective to delabeling low risk patients.

Direct Oral Challenges to Remove Beta-Lactam Allergy Label in Patients with Hematologic Malignancy

Patients with hematologic malignancy are at high risk for infection. Prior studies show that patients with a beta-lactam allergy label have worse outcomes compared with those who are non-allergic. Direct oral challenge can safely de-label eligible patients. We aimed to evaluate the effect of removing beta-lactam allergy via direct oral challenge in the outcome of patients with hematologic malignancy.

Assessing Allergic Reactions to Cephalosporins in Children

Cephalosporins, a beta-lactam antibiotic, commonly cause pediatric adverse allergic drug reactions. We assessed the clinical characteristics and management of pediatric patients with suspected cephalosporin allergies using direct graded oral challenges (GOC).

Penicillin Allergy Testing and Clearance in the Operational Setting: A Proof of Concept

Direct oral challenge for penicillin allergy has increasingly become a safe, cost-effective option especially in healthcare systems with limited access to allergy subspecialists. The military healthcare system has unique constraints in not only a paucity of allergists but

Inpatient Direct Oral Penicillin Challenge – A Large Prospective Cohort Study

Penicillin allergies are associated with inferior patient and antimicrobial stewardship outcomes. The long-term implementation (3.5 years) of a whole-of-hospital program to assess the safety of inpatient delabeling by direct oral challenge for low-risk penicillin allergies in hospitalized inpatients at Austin Hospital and the Peter MacCallum Cancer Centre, Australia was described here.

559. Inpatient Allergy Delabeling of Pediatric Patients with Low-Risk Penicillin Allergy Status through Direct Graded Oral Amoxicillin Challenge

Abstract Background Only 1% of patients with penicillin allergy are truly allergic but it remains the most common drug allergy reported. Studies show that direct oral challenge is a safe method to delabel low-risk patients using institutional screening stratification tools. There is no verified universal screening tool to perform this function, underscoring the need to address this clinical gap. This study aims to assess the efficacy of our institutional screening questionnaire at correctly stratifying penicillin allergy risk status and determine whether direct graded oral amoxicillin challenge can be safely used to delabel patients with low-risk penicillin allergy status. Figure 1Flow chart showing patient categorization based on penicillin allergy risk status and subsequent disposition following screening. Methods This was a pilot prospective study to verify penicillin allergy status among patients 3-18 years old in our institution from September 2021-March 2022. Patients were stratified using institutional screening questionnaire to no-risk, low-risk and high-risk penicillin allergy status. Low-risk patients underwent direct graded oral amoxicillin challenge using an institutional algorithm and delabeled based on their response to the testing. No-risk patients were delabeled without challenge testing. High-risk patients were referred to allergy. Results Ninety-two patients were identified with penicillin allergy. Forty (43.5%) of the 92 patients were screened using our institutional screening questionnaire. Of the 40 screened patients, 6 (15%) were identified as no-risk, 28 (70%) were identified as low-risk, and 6 (15%) were identified as high-risk. Twenty-four (86%) of the 28 low-risk patients were eligible for direct amoxicillin oral challenge. Seventeen (71%) of the 24 consented to the challenge testing but only 12 (70%) underwent direct amoxicillin oral challenge. Eleven (92%) of the 12 who underwent oral challenge were successfully delabeled. Five (83%) of the 6 no-risk patients were successfully delabeled. Three (50%) of 6 high-risk patients were referred to allergy. Overall, 16 (40%) of the 40 patients who were screened were successfully delabeled. Conclusion Our institutional risk stratification screening tool is effective at identifying penicillin allergy risk status and direct graded oral amoxicillin challenge is a safe initiative to delabel patients with low-risk penicillin allergy status. Disclosures All Authors: No reported disclosures.

The Evolution of Our Understanding of Penicillin Allergy: 1942-2022

This article reviews our evolving understanding of penicillin hypersensitivity at the 80th anniversary of penicillin's clinical introduction. Penicillin breakdown products covalently bond to serum proteins, leading to classic drug hypersensitivity. Penicillin remains the most frequently reported drug "allergy." Adverse reactions were presumed, in retrospect incorrectly, to implicate a risk for anaphylaxis, and therefore skin testing for IgE became the focus. Skin test positivity may wane over time. This insight has led to the radical conclusion that penicillin hypersensitivity may not be "forever." Atopic background, other drug allergies, family history, gender, and race are apparently not risk factors for penicillin hypersensitivity. Confirmed penicillin hypersensitivity has declined since the 1960s, potentially due to "cleaner" penicillin products and lower dose oral, instead of parenteral, use. Avoiding penicillins, without evaluation, caused unanticipated problems that have been appreciated only recently including longer hospital stays, increased cost of care, suboptimal outcomes from serious infections, and greater toxicities and costs with alternative antibiotics. There are personal and public health advantages with broadly implemented penicillin allergy delabeling based on a reaction history-based risk assessment. Limited skin testing followed by an oral challenge, if negative, for higher-risk histories, and direct oral challenges in lower-risk individuals are currently the reference standard tests to confirm current tolerance.

Use of a penicillin allergy clinical decision rule to enable direct oral penicillin provocation: an international multicentre randomised control trial in an adult population (PALACE): study protocol

IntroductionPenicillin allergies are highly prevalent in the healthcare setting and associated with the prescription of second-line inferior antibiotics. More than 85% of all penicillin allergy labels can be removed by...

Use of clindamycin as an alternative antibiotic prophylaxis

BackgroundClindamycin serves as an alternative surgical prophylactic antibiotic in patients with penicillin (PCN) or cephalosporin allergy labels. In the previous reports, the use of clindamycin was associated with higher incidences of surgical site infections (SSIs). We aimed to determine the characteristics of PCN or cephalosporin allergic reactions to stratify patient's risk and indicate subsequent management; leading to de-labeling of PCN or cephalosporin allergy. MethodsWe conducted a prospective cohort study of patients receiving clindamycin as surgical antibiotic prophylaxis from September 2021 to March 2022. Data were collected from electronic medical records; included demographic data, antibiotic allergy labels, allergic reaction, and allergy testing. ResultsClindamycin was administered in 445 patients who underwent 451 operations. Among these patients, 53.0% (n = 236) were female with a median age of 15 years (range; 0.5–57.0 years). PCN and cephalosporin allergies were labelled in 83.8% (n = 373) and 25.6% (n = 114) patients, respectively; 11.4% (n = 51) of patients were allergic to both classes of the antibiotics. There were 191 (51.2%) and 73 (64.0%) possible hypersensitivity reactions (HSRs) in PCN and cephalosporin groups, respectively. The most common reactions were rash (PCN: n = 99, 26.5%; cephalosporin: n = 35, 30.7%), and hives (PCN: n = 71, 19.0%; cephalosporin: n = 24, 21.1%). Severe reactions included angioedema (PCN: n = 7, 1.9%; cephalosporin: n = 5, 4.4%), anaphylaxis (PCN: n = 8, 2.1%; cephalosporin: n = 7, 6.1%), bronchospasm (cephalosporin: n = 1, 0.9%), airway involvement (PCN: n = 1, 0.3%; cephalosporin: n = 1, 0.9%), serum sickness (PCN: n = 1, 0.3%), blisters (PCN: n = 1, 0.3%), and drug reaction with eosinophilia and systemic symptoms (DRESS) (PCN: n = 1, 0.3%). Low-risk history of allergy included gastrointestinal side effects (PCN: n = 9, 2.4%; cephalosporin: n = 3, 2.7%), positive family history (PCN: n = 7, 1.9%; cephalosporin: n = 1, 0.9%), and remote history of allergy (PCN: n = 2, 0.5%). There were 201 (53.9%) and 53 (46.5%) unknown reactions in PCN and cephalosporin groups, respectively. In the overall cohort, 3 patients (0.7%) were skin tested for drug allergy (PCN: n = 2, 0.5%; cephalosporin: n = 2, 1.8%). ConclusionClindamycin was largely administered in patients with non-severe HSRs, low-risk history or unknown reactions to PCN or cephalosporin, whom cefazolin could have been administered safely. Obtaining a detailed history of antibiotic allergy, allergy testing and/or direct oral challenge can de-label unsubstantiated PCN or cephalosporin allergy and ultimately reduce the incidence of SSIs by optimizing the rate of more effective antibiotic administration.

Safety of direct oral challenge to amoxicillin in pregnant patients at a Canadian tertiary hospital

Penicillin allergy assessment during pregnancy relies heavily on penicillin skin testing (PST).1 Recently, Trubiano et al2 have published a validated, point-of-care penicillin allergy clinical decision tool called PEN-FAST, which predicts the chance of a positive skin test with a negative predictive value of 96.3%. However, even after negative skin testing, very few pregnant patients receive oral challenge to penicillin because of unfounded risks.3 A 2019 systematic review evaluating PST and desensitization in 231 pregnant women reported that of 203 who underwent PST, 170 tested negative.