Promoting penicillin allergy de-labeling for children attending a hematology clinic.

BACKGROUND: Up to 10% of children are reported to be allergic to penicillin, but many allergy labels are unverified and may require formal testing. Inaccurate drug allergy labels are associated with a range of adverse clinical outcomes. Patients with hematological disorders may experience frequent and severe infections; those who have been incorrectly labeled penicillin allergic may benefit from allergy de-labeling (ADL) efforts to facilitate access to beta-lactam antibiotics. We developed a multidisciplinary, pharmacist-driven process that enabled non-allergist trained providers to assess and de-label penicillin allergies in a pediatric hematology center. METHODS: Volunteers, including physicians, advanced practice providers, nurses, and pharmacists, were trained in skin testing and oral challenge procedures. Patients were identified by review of electronic medical records for penicillin or penicillin-derivative allergy. Patient and family interviews were conducted in cases where a true penicillin allergy was deemed uncertain based on chart review. If allergy could not be de-labeled by chart review or interview alone, patients were offered skin and/or oral challenge testing. RESULTS: Fifty-nine patients were initially labeled as penicillin allergic. Allergy labels of 11 (19%) were removed by chart review only, and 15 (25%) after conducting interviews. A total of two (3%) patients were ineligible due to contraindications, and five (9%) declined participation. Twenty-six patients (44%) underwent allergy testing (50% skin testing, 50% oral challenge) of which 23 (88%) were negative. CONCLUSIONS: ADL was possible in most patients previously identified as penicillin allergic. Testing was well tolerated with no serious adverse effects.

Safe De-Labeling of Patients at Low Risk of Penicillin Allergy in Denmark.

INTRODUCTION: Penicillin allergy is suspected in 10% of hospital inpatients but can be disproved in 90% of cases. Direct oral provocation without preceding tests among low-risk patients has proven to be safe in studies of both children and adults and is gaining use across the world. The aims of this study were to investigate the rate of severe allergic reactions to direct oral drug provocation, without preceding tests, in penicillin allergy patients stratified to be at low risk, as well as to examine if these patients have barriers to penicillin allergy de-labeling and future use of penicillins. METHODS: Adult patients referred to a university hospital allergy clinic with a suspected penicillin allergy were prospectively risk evaluated. Patients stratified to be at low risk were offered a direct oral provocation with a single-dose amoxicillin followed by 4 days of continued treatment. The same risk stratification criteria were applied to a larger retrospective cohort. RESULTS: In the prospective study population, 202 patients had a direct oral drug provocation and 20 (10%) were positive. There were no cases of anaphylaxis or severe delayed hypersensitivity. Fifteen reactions were benign rashes with onset >1 day after initial dosing, and 13 of these were maculopapular rashes. The same low-risk criteria were applied retrospectively to patients in a drug provocation database, and 1,759 patients fulfilled the criteria; of these, 10% had positive provocations, and there were no cases of anaphylaxis or severe delayed hypersensitivity. De-labeled patients in the prospective study reported not to fear future penicillin intake, after prolonged provocation. CONCLUSION: The risk stratification criteria for identifying low-risk patients for the oral drug provocation test without prior skin testing were safe in terms of avoiding anaphylaxis or severe delayed hypersensitivity. Benign delayed skin reactions still occurred, and access to allergy advice and follow-up is necessary.

The challenge of de-labeling penicillin allergy.

BACKGROUND: Even though 8%-25% of most populations studied globally are labeled as penicillin allergic, most diagnoses of penicillin allergy are made in childhood and relate to events that are either not allergic in nature, are low risk for immediate hypersensitivity, or are a potential true allergy that has waned over time. Penicillin allergy labels directly impact antimicrobial stewardship by leading to use of less effective and broader spectrum antimicrobials and are associated with antimicrobial resistance. They may also delay appropriate antimicrobial therapy and lead to increased risk of specific adverse healthcare outcomes. Operationalizing penicillin allergy de-labeling into a new arm of antimicrobial stewardship programs (ASPs) has become an increasing global focus. METHODS: We performed an evidence-based narrative review of the literature of penicillin allergy label carriage, the adverse effects of penicillin allergy labels, and current approaches and barriers to penicillin allergy de-labeling. Over the period 1928-2018 in Pubmed and Medline, search terms used included "penicillin allergy" or "penicillin hypersensitivity" alone or in combination with "adverse events," "testing," "evaluation," "effects," "label," "de-labeling," "prick or epicutaneous," and "intradermal" skin testing, "oral challenge or provocation," "cross-reactivity," and "antimicrobial stewardship". RESULTS: Penicillin allergy labels are highly prevalent, largely inaccurate and their carriage may lead to unnecessary treatment and inferior outcomes with alternative agents as well as adverse public health outcomes such as antibiotic resistance. CONCLUSIONS: Operationalizing penicillin allergy de-labeling as an aspect of ASP has become an increasing global focus. There is a need for validated approaches that optimally combine the use of history and ingestion challenge with or without proceeding formal skin testing to tackle penicillin allergy efficiently within complex healthcare systems. At the same time, there is great promise for penicillin allergy evaluation and de-labeling as an individual and public health strategy to reduce adverse healthcare outcomes, improve antimicrobial stewardship, and decrease healthcare costs.

Penicillin allergy skin testing as an antibiotic stewardship intervention reduces alternative antibiotic exposures in hematopoietic stem cell transplant recipients.

BACKGROUND: Antibiotic allergy de-labeling using penicillin allergy skin testing (PAST) can reduce the use and cost of alternative, non-ß-lactam antibiotics in general inpatient populations. This strategy's role in hematopoietic stem cell transplant (HSCT) recipients is unclear. METHODS: This study aimed to determine the effect of a pre-transplant PAST protocol on antibiotic use, days of therapy (DOT), and cost in an immunocompromised population at a single center from 7/1/2010-2/1/2019. Patients who received chimeric antigen receptor (CAR) T-cell therapy and those who underwent transplantation in the outpatient setting were excluded. RESULTS: Of 1560 patients who underwent inpatient HSCT during the study period, 208 reported ß-lactam allergy (136/844 [16%] pre- and 72/716 [10%] post-implementation; P < .001). PAST was performed on 7% and 54% of HSCT recipients pre- and post-implementation, respectively. Only two positive PAST were noted. There were no adverse reactions to PAST. There were no significant differences in the disease and transplant characteristics between the two groups. Days of therapy and cost of alternative antibiotics significantly decreased post-implementation (mean 788 vs 627 days, P = .01; mean $24 425 vs $17 518, P = .009). CONCLUSION: Penicillin allergy skin testing adjudicates reported ß-lactam allergy in HSCT recipients, lowering use, DOT, and cost of alternative antibiotics and promoting effective formulary agents to treat immunocompromised HSCT recipients.

Management of Penicillin Allergy in the Perioperative Setting.

The selection of perioperative antibiotic prophylaxis is challenging in patients with a history of penicillin allergy; as such, we present a literature review exploring current best practices and the associated supporting evidence, as well as areas for future research. Guidelines recommend the use of alternative agents in patients with an IgE-mediated hypersensitivity reaction, but those alternative agents are associated with worse outcomes, including an increased risk of surgical site infection, and higher cost. More recent data suggest that the risk of cross-reactivity between penicillins and cephalosporins, particularly cefazolin, is extremely low, and that cefazolin can be used safely in most penicillin-allergic patients. Studies have therefore explored how best to implement first-line cefazolin use in patients with a penicillin allergy label. A variety of interventions, including preoperative allergy de-labeling with incorporation of penicillin skin testing, use of patient risk-stratification questionnaires, and utilization of clinician algorithms to guide antibiotic selection intraoperatively, have all been shown to significantly increase cefazolin utilization without a corresponding increase in adverse events. Further studies are needed to clarify the most effective interventions and implementation strategies, as well as to evaluate whether patients with severe delayed hypersensitivity reactions to penicillin should continue to be excluded from receipt of other beta-lactams.

Beta-Lactam Allergy De-labeling in a Pediatric Hospital.

OBJECTIVE: To assess the ability to de-label pediatric patients of their beta-lactam allergy by using a newly implemented institutional protocol and to identify potential barriers to the de-labeling process. METHODS: All patients with reported allergies to prespecified beta-lactam antibiotics were eligible for a -beta-lactam allergy interview. Following the interview, patients were grouped into 4 risk categories-no risk, low risk, moderate risk, and high risk-and assessed for intervention eligibility. Potential interventions included de-labeling based on the interview alone or proceeding to an oral amoxicillin challenge with or without penicillin allergy skin testing. RESULTS: Of the 62 patients eligible for beta-lactam allergy interviews, 40% (n = 25) were de-labeled. Among de-labeled patients, 60% (n = 15) were de-labeled on the basis of the interview alone. Additionally, no failures were documented in patients who underwent an oral amoxicillin challenge or penicillin skin testing. Barriers to performing oral amoxicillin challenges or penicillin skin testing included concomitant systemic steroid or antihistamine use, refusal of intervention, and insufficient resources to perform penicillin skin testing. CONCLUSIONS: There was a high frequency of patients de-labeled of their beta-lactam allergies in this study. Increased education to patients, parents, and providers on the de-labeling process, as well as increased personnel available to coordinate and perform de-labeling interventions, may result in more beta-lactam allergy de-labeling.

A multidisciplinary approach to verify and de-label of drug allergic histories in a university hospital in Thailand: a retrospective descriptive study.

BACKGROUND: Mislabeling of drug allergic histories causes avoidable negative impacts on patients and healthcare system. Although multidisciplinary adverse drug reaction (ADR) services to verify and de-label drug allergic histories have been operated in particular hospitals in Thailand, their performances have not been reported. This research aimed to examine the effectiveness of verification of drug allergic history and de-labeling (VD) services of the physician-led multidisciplinary ADR clinic. METHODS: This research was a retrospective descriptive study. Medical charts of patients with at least one drug allergic history who received VD services at the multidisciplinary clinic between January 2017 to December 2018, were reviewed. Data on the history of drug allergy, VD services, and results were analyzed and presented using descriptive statistics. RESULTS: Seventy patients' charts were reviewed, and 171 unconfirmed drug allergic histories were identified. 79.53% of the reported reactions involved skin and soft tissues. The most found adverse skin reactions were maculopapular rash, pruritic and erythematous rash, and angioedema. The remaining 20.47% were systemic reactions which included drug reaction with eosinophilia and systemic symptoms (DRESS), anaphylaxis, and nausea/vomiting was the most prevalent. Antituberculosis, beta-lactam antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs) were the most reported suspected drugs. Drug allergic history reviewing by physicians or pharmacists could confirm and de-label for 3 and 20 reactions, respectively. Seven and one reactions were confirmed by enzyme-linked immunospot assay and patch test, respectively. The provocation tests with the suspected or alternative drug were conducted in 64 reactions. Twelve reactions were confirmed, and 45 reactions were de-labeled. Totally, 65/171 (38.01%) allergic histories were successfully de-labeled, 23/171 (13.45%) were confirmed, and 83/171 (48.53%) were inconclusive. CONCLUSIONS: More than half of drug allergic histories were successfully confirmed or de-labeled by the multidisciplinary ADR team. The collaborative activities of various healthcare professionals, consisting of physicians, nurse, and pharmacists as presented in the study were effective in VD services and should be implemented in other healthcare settings.

Barriers to penicillin allergy de-labeling in the inpatient and outpatient settings: a qualitative study.

BACKGROUND: Penicillin allergy is the most commonly reported drug allergy in the US. Despite evidence demonstrating that up to 90% of labels are incorrect, scalable interventions are not well established. As part of a larger mixed methods investigation, we conducted a qualitative study to describe the barriers to implementing a risk-based penicillin de-labeling protocol within a single site Veteran's hospital. METHODS: We conducted individual and group interviews with multidisciplinary inpatient and outpatient healthcare teams. The interview guides were developed using the Theoretical Domains Framework (TDF) to explore workflows and contextual factors influencing identification and evaluation of patients with penicillin allergy. Three researchers iteratively developed the codebook based on TDF domains and coded the data using thematic analysis. RESULTS: We interviewed 20 clinicians. Participants included three hospitalists, five inpatient pharmacists, one infectious disease physician, two anti-microbial stewardship pharmacists, four primary care providers, two outpatient pharmacists, two resident physicians, and a nurse case manager for the allergy service. The factors that contributed to barriers to penicillin allergy evaluation and de-labeling were classified under six TDF domains; knowledge, skills, beliefs about capabilities, beliefs about consequences, professional role and identity, and environmental context and resources. Participants from all groups acknowledged the importance of penicillin de-labeling. However, they lacked confidence in their skills to perform the necessary evaluations, such as test dose challenges. The fear of inducing an allergic reaction and adding further complexity to patient care exacerbated their reluctance to de-label patients. The lack of ownership of de-labeling initiative was another significant obstacle in establishing consistent clinical workflows. Additionally, heavy workloads, competing priorities, and ease of access to alternative antibiotics prevented the prioritization of tasks related to de-labeling. Space limitations and nursing staff shortages added to challenges in outpatient settings. CONCLUSION: Our findings demonstrated that barriers to penicillin allergy de-labeling fall under multiple behavioral domains. Better role clarification, opportunities to develop necessary skills, and dedicated resources are needed to overcome these barriers. Future interventions will need to employ a systemic approach that addresses each of the behavioral domains influencing penicillin allergy de-labeling with stakeholder engagement of the inpatient and outpatient health care teams.

A potential cost savings analysis of a penicillin de-labeling program.

Introduction: Over 95% of patients documented as penicillin allergic can tolerate a penicillin without a reaction. Inaccurate documentation of penicillin allergy leads to more expensive alternative antibiotic prescriptions and an increased incidence of resistant infections. Objective: To understand the potential drug cost savings of a penicillin de-labeling program to a healthcare system. Methods: We evaluated patient visits with documented penicillin allergy who presented to the pediatric Emergency Department (PED) and 22 associated primary care clinics. Patients were included if they were discharged home with a non-penicillin antibiotic when the first-line treatment for the diagnosis would have been a penicillin. The potential cost savings were the sum of all visit-level cost differences between the non-penicillin prescription(s) and a counterfactual penicillin prescription. To factor in a 95% successful patient de-labeling rate, we repeatedly sampled 95% from the patients with the eligible visits 10,000 times to produce an estimate of the potential cost savings. Results: Over the 8-year period, 2,034 visits by 1,537 patients to the PED and 12,349 visits by 6,073 patients to primary care clinics satisfied eligibility criteria. If 95% of the patients could have been successfully de-labeled, it would have generated a cost saving of $618,653 (95% CI $618,617-$618,689) for all the corresponding payers in the system. Conclusions: Implementing a penicillin de-labeling program across a healthcare system PED and its associated primary care clinics would bring significant cost savings. Healthcare systems should rigorously evaluate optimal methods to de-label patients with reported penicillin allergy.

Safety, Outcomes, and Recommendations for Two-Step Outpatient Nonsteroidal Anti-Inflammatory Drug Challenges.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) outpatient challenge protocols are not standardized. They vary in clinical practice and can be time- and resource-intensive to perform. OBJECTIVE: To investigate the safety and outcomes of two-step outpatient NSAID challenges to evaluate patients with non-aspirin-exacerbated respiratory disease (AERD)-related NSAID hypersensitivity. METHODS: We conducted a retrospective study of patients with a history of NSAID allergy who underwent outpatient NSAID challenges under allergist supervision. Individuals with AERD were excluded. Patient demographics, NSAID reaction history, and drug challenge details and outcomes were collected. RESULTS: A total of 249 patients (mean age, 51.6 years; 63.5% female) underwent 262 NSAID challenges. Of these, 224 challenges were negative (85.5%). Thirty challenges resulted in an immediate reaction during the challenge procedure (11.5%) and eight resulted in delayed reactions (3.1%). Three individuals with immediate reactions required treatment with intramuscular epinephrine. Factors associated with a positive NSAID challenge included a prior reaction occurring within 5 years of drug challenge (odds ratio [OR] = 3.66; 95% confidence interval [CI], 1.67-8.44), a prior immediate reaction within 3 hours of NSAID ingestion (OR = 2.45; 95% CI, 1.12-5.57), a history of cross-reactive NSAID hypersensitivity to multiple NSAIDs (OR = 2.97; 95% CI, 1.23-6.91), and the presence of comorbid chronic spontaneous urticaria (OR = 2.95; 95% CI, 1.35-6.41). CONCLUSIONS: More than 85% of two-step non-AERD NSAID drug challenges were negative for an immediate or delayed reaction, which allowed patients to use at least one clinically indicated NSAID. Challenge reactions were generally mild. Two-step NSAID challenge protocols can be safely performed in the outpatient setting.

The democratization of de-labeling: a review of direct oral challenge in adults with low-risk penicillin allergy.

INTRODUCTION: Penicillin antibiotic allergy labels (AALs) are common and lead to significant negative health and health system outcomes. Direct oral challenge offers a rapid and cost-effective way of removing inaccurate AALs and improving outcomes. AREAS COVERED: A narrative review (Medline, May 2020) of direct oral challenge in low-risk penicillin allergy in adults is described, and the evidence for the safety and efficacy of this approach in inpatients, outpatients, and special patient groups is presented. EXPERT OPINION: Whilst the current literature demonstrates the safety and efficacy of direct oral challenge in de-labeling low-risk penicillin allergy in adults, novel approaches are needed to improve access to antibiotic allergy assessment and address the growing global need.

Penicillin Allergy Maybe Not? The Military Relevance for Penicillin Testing and De-labeling.

INTRODUCTION: Penicillin allergy is the most common drug allergy reported. About 8-10% of individuals in the USA have a documented penicillin allergy, yet 90% are not truly allergic to penicillin. A penicillin allergy "label" results in increased antibiotic-related adverse reactions and increased health care costs, thus impacting the overall "readiness" of the military. MATERIALS AND METHODS: A review of the current literature and approaches to penicillin allergy and "de-labeling" a patient who reports penicillin allergy was conducted and future strategies to identify and assess military beneficiaries were outlined. Military allergists had a formal discussion at the Tri-service Military Allergy Immunology Assembly regarding the state of penicillin allergy testing in military allergy clinics. RESULTS: A PubMed search yielded 5,775 results for "penicillin allergy" and 484 results for "penicillin allergy testing." There were two formalized penicillin testing programs in the military treatment facilities. In 2017, the military trained nearly 165,000 new recruits. If 5-10% reported a penicillin allergy and 90% were de-labeled, that would yield a $15-30 million cost savings annually. Further, de-labeling of the 9.4 million active duty, beneficiaries and retirees with a 90% success rate could result in even greater savings for the military health care system. CONCLUSION: A penicillin allergy label is a risk to military readiness secondary to associated increases in the length of hospitalizations and emergency department and medical visits. Penicillin de-labeling is a simple intervention that can improve readiness, significantly decrease health care costs and prevent antibiotic resistance, as well as antibiotic-associated adverse events. The military allergist should be "front and center" providing expertise guidance and leadership for clinic and hospital-based penicillin de-labeling efforts which are nested within the antibiotic stewardship programs.

Comparing Direct Challenge to Penicillin Skin Testing for the Outpatient Evaluation of Penicillin Allergy: A Randomized Controlled Trial.

BACKGROUND: Direct challenge (DC) may be a safe and effective alternative to penicillin skin testing (PST) in low-risk patients. OBJECTIVE: To complete a prospective, randomized, controlled trial comparing PST followed by a challenge to amoxicillin versus a 2-step DC to amoxicillin without preceding skin testing in a predefined low-risk patient population. METHODS: Penicillin allergy histories were reviewed in patients presenting to an outpatient allergy/immunology practice from April 2018 to August 2018. Patients 5 years or older with a cutaneous-only or unknown reaction (>1 year ago for those aged 5-17 years, >10 years ago for those 18 years or older) were randomized 1:1 to PST or 2-step DC. All children younger than 5 years underwent DC, and patients with extracutaneous reaction histories underwent PST. All groups were monitored 30 minutes after administration of amoxicillin. RESULTS: Penicillin allergy was reported in 363 of 2465 (14.7%) patients, of which 185 consented to further evaluation. Thirteen patients younger than 5 years underwent DC; all were negative. Thirteen patients with angioedema and/or extracutaneous symptoms underwent PST; 2 of 13 patients had positive PST result. A total of 159 patients were randomized to DC (49.7%) or PST (50.3%). PST result was negative in 70 of 80 (87.5%) patients. All 70 patients had a negative amoxicillin challenge. DC was negative in 76 of 79 (96.2%) patients; positive DC reactions were minor. Average time for patients undergoing PST was 72.7 ± 5.3 minutes and for patients undergoing DC was 66.7 ± 4.8 minutes. CONCLUSIONS: In low-risk patients, DC provided a safe and effective alternative to PST in delabeling penicillin allergy. Compared with PST, DC may also take less time, cost less money, and lead to fewer penicillin allergy evaluations with false-positive results.

Improving the Effectiveness of Penicillin Allergy De-labeling.

BACKGROUND: Approximately 10-20% of hospitalized patients are labeled as penicillin allergic, and this is associated with significant health and economic costs. OBJECTIVES: We looked at the effectiveness of penicillin allergy de-labeling in clinical practice with the aim of deriving risk stratification models to guide testing strategies. METHODS: Consecutive patients aged 15 years or more, referred to a Western Australian public hospital drug allergy service between 2008 and 2013 for beta-lactam allergy, were included. Follow-up surveys were conducted. Results of skin prick testing and intradermal testing (SPT/IDT) and oral challenge (OC), and follow-up of post testing antibiotic usage were the main outcomes. RESULTS: SPT/IDT was performed in 401 consecutive patients with immediate (IMM) (≤ 1 hour) (n = 151) and nonimmediate (NIM) (>1 hour) (n = 250) reactions. Of 341 patients, 42 (12.3%) were SPT/IDT+ to ≥ 1 penicillin reagents, including 35/114 (30.4%) in the IMM group and 7/227 (3.1%) in the NIM group (P < .0001). Of 355 SPT/IDT patients, 3 (0.8%), all in the IMM group, had nonserious positive OC reactions to single dose penicillin VK (SPT/IDT negative predictive value [NPV] 99.2%). Selective or unrestricted beta-lactam was recommended in almost 90% overall, including 238/250 (95.2%) in the NIM group and 126/151 (83.4%) in the IMM group (P = .0001). Of 182 patients, 137 (75.3%) were following the allergy label modifications (ALM) at the time of follow-up. CONCLUSIONS: Penicillin SPT/IDT/OC safely de-labels penicillin-allergic patients and identifies selective beta-lactam allergies; however, incomplete adherence to ALM recommendations impairs effectiveness. Infrequent SPT/IDT+ and absent OC reactions in patients with NIM reactions suggest OC alone to be a safe and cost-effective de-labeling strategy that could improve the coverage of penicillin allergy de-labeling in lower risk populations.