EAACI/ENDA position paper on drug provocation testing.

In drug hypersensitivity, drug provocation testing (DPT), also called drug challenge, is the gold standard for investigation. In recent years, risk stratification has become an important tool for adjusting the diagnostic strategy to the perceived risk, whilst still maintaining a high level of safety for the patient. Skin tests are recommended before DPT but may be omitted in low-risk patients. The task force suggests a strict definition of such low-risk patients in children and adults. Based on experience and evidence from studies of allergy to beta-lactam antibiotics, an algorithm on how to adjust DPT to the risk, and when to omit skin tests before DPT, is presented. For other antibiotics, non-steroidal anti-inflammatory drugs and other drugs, skin tests are poorly validated and DPT is frequently necessary. We recommend performing DPT with chemotherapeutics and biologicals to avoid unnecessary desensitization procedures and DPT with skin tests negative contrast media. We suggest DPT with anesthetics only in highly specialized centers. Specifics of DPT to proton pump inhibitors, anticonvulsants and corticosteroids are discussed. This position paper provides general recommendations and guidance on optimizing use of DPT, whilst balancing benefits with patient safety and optimizing the use of the limited available resources.

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.

Implementation and outcomes of beta-lactam allergy management protocol at a comprehensive cancer center.

PURPOSE: Beta-lactam allergy (BLA) is associated with increased broad-spectrum antibiotic (Br-ABX) use and worse clinical outcomes. We evaluated our hospital-wide BLA protocol (BLA-P) that used following categories: intolerance, low-risk, and high-risk. METHODS: Hospitalized adult patients with listed BLA during 10/2021-12/2022 were eligible. Exclusions were critically ill, surgical, hospice or comfort care, or non-verbal patients. Assessment was counted each time a pharmacist evaluated BLA. Interventions were no further action (high-risk allergy, patient refusal, unstable clinical status), updated allergy label, or delabeled. Delabeling was done either based on antibiotic history (direct-delabeling), or via test-dose challenge for low-risk patients. Br-ABX usage was compared in the unique delabeled patients: the empiric antibiotic use 90 days post-delabeling versus pre-delabeling using McNemar test (SPSS). RESULTS: A total of 700 assessments in 631 patients were identified. 441 assessments in 377 patients (median 63 years-old, 41% male, 50% hematological cancer) met inclusion criteria. The assessments revealed 9% intolerance, 55% low-risk, 23% high-risk and 13% unknown reaction. Interventions resulted in no further action 7%, updated label 72%, and delabeling 21%. 65% of the delabeling was via direct-delabeling and 35% test-dose challenge. Among patients who received a test-dose challenge, 36/36(97%) had no documented allergic reactions, and 1/26(3%) developed a mild rash. The use of aztreonam (pre-delabeling 28% vs. post-delabeling 1.2%, p < 0.001) and meropenem (13% vs. 2.4%, p = 0.022) significantly decreased while cefepime (24% vs. 50%, p = 0.001) and piperacillin-tazobactam (3.7% vs. 22%, p < 0.001) increased after delabeling. CONCLUSION: BLA-P led to 21% delabeling, which resulted in increased preferred Br-ABX and decrease in aztreonam/meropenem use among delabeled patients.

ß-Lactam allergy delabeling is safe and saves costs in Primary Care.

OBJECTIVE: To determine whether the ß-lactam allergy delabeling was safe and cost-saving in Primary Care (PC) patients. DESIGN: We have conducted a retrospective chart review of PC patients with ß-lactam allergy label evaluated in our Allergy Unit between 2017 and 2022. SITE: Allergy Department. Hospital Virgen del Rocio (Sevilla). PARTICIPANTS: A total of 391 patients labeled for ß-lactam allergy in PC were studied. MAIN MEASUREMENTS: (a) Outcome evaluation of a ß-lactam allergy delabeling procedure. (b) A ratio between the total e-prescribed antibiotic cost and the number of treatment days (the experimental daily antibiotic cost or EDAC) before and after delabeling was analyzed in delabeled and truly allergic patients. RESULTS: The results of skin testing were positive in 9.2% of the reported cases (36 of 391 patients). The reactions to oral provocation challenge (OPC) occurred in 2.14% of the patients who underwent negative skin testing to offending ß-lactam (in 15 of 699 OPC). A total of 307 patients (78.5%) were delabeled; 70 (17.9%) had a ß-lactam selective response and 14 (3.59%) reacted to both penicillin and cephalosporin. The EDAC before and after the procedure in delabeled patients was significantly lower (0.88 € vs 0.62 €, p<10-3), than that observed in truly allergic group (0.87 € vs. 0.76 €, p=not significant). CONCLUSION: To delabel ß-lactam allergy in Primary Care patients is safe in most patients, cost-saving in antibioticotherapy, and allows identify the main clinical ß-lactam allergy phenotypes that benefit from this procedure.

Delabeling of Penicillin Allergy: Room for Improvement.

BACKGROUND: Penicillin allergy labels have been shown to be associated with suboptimal treatment, negative health outcomes, and increased antibiotic resistance. Many inpatients claim to have penicillin allergy, but studies show that allergy can be disproved and the label removed in up to 90% of cases. OBJECTIVES: The purpose of the study was to investigate the proportion of patients with a penicillin allergy label in a Danish hospital and to classify patients according to the risk of having penicillin allergy in "no risk," low, and high risk. METHODS: For 22 days, inpatients with penicillin allergy labels were interviewed, had their dispensed penicillin prescriptions examined, and were subsequently categorized into risk groups based on the risk evaluation criteria in national guidelines. RESULTS: In total, 260 patients had a penicillin allergy label (10% of the inpatients). Out of 151 included patients, 25 were "no risk" patients (17%), who could potentially have their penicillin allergy label removed without testing. 42 were low-risk patients (28%). 10 "no risk" patients and 20 low-risk patients had been prescribed and dispensed one or more penicillins despite an allergy label. CONCLUSION: Ten percent of inpatients have a penicillin allergy label in a Danish hospital. 17% of these could potentially have their penicillin allergy label removed without allergy testing.

Antibiotic Prescribing Practices Differ between Patients with Penicillin Intolerance and Penicillin Allergy Labels.

INTRODUCTION: Penicillin allergy labels are common. However, many penicillin allergy labels have been applied incorrectly and in fact represent penicillin intolerance. Patients with penicillin intolerance can receive penicillin antibiotics. The effect of penicillin intolerance labels on prescribing practices is uncertain. METHODS: This multicenter retrospective cohort study included consecutive general medicine patients admitted to two tertiary hospitals over a 12-month period. Electronic medical records were reviewed for allergy and prescribing practices. Instances of penicillin prescription to patients with previously labeled penicillin allergies underwent case note review. RESULTS: There were 12,134 individual hospital admissions included in the study. The number of admissions with a previous penicillin allergy label was 1,312 (10.8%) and with a penicillin intolerance label was 60 (0.5%). Penicillin allergy labels were associated with increased likelihood of being prescribed vancomycin (odds ratio 1.42, 95% confidence interval 1.16-1.75, p = 0.001) and moxifloxacin (odds ratio 20.0, 95% confidence interval 13.4-29.9, p < 0.001). Penicillin intolerance was not associated with increased likelihood of receiving these antibiotics. There were 75 admissions during which an individual with a penicillin allergy label was prescribed one of the specified penicillins and only one adverse reaction in this group. These cases included eight deliberate challenges and 15 cases in which allergy history clarification was sufficient to delabel the allergy. CONCLUSIONS: This study supports that prescribing practices differ between patients with penicillin allergy labels and intolerance labels. Penicillin challenges may be undertaken safely in the inpatient setting. Further studies are required to investigate how best to interrogate penicillin allergy labels in this cohort.

Penicillin Allergy Delabeling Program: an exploratory economic evaluation in the Australian context.

BACKGROUND: Internationally, clinical and economic advantages of low-risk penicillin delabelling have been explored, supporting changes to healthcare delivery systems where penicillin delabelling is embedded into inpatient usual care. AIMS: To determine if economic advantages of low-risk inpatient penicillin delabelling, described in the international literature, are realised in the Australian context. METHODS: This explorative economic evaluation had prospective patient data collection between January and August 2019, across two Australian health services. Part 1: determine the cost per effectively delabelled patient for Penicillin Allergy Delabeling Program inpatients (PADP cohort) compared with Outpatient Antibiotic Allergy Testing Service outpatients (OAATS cohort). Part 2: a cost analysis to compare hospital costs for inpatients with low-risk penicillin allergy who did (PADP cohort) and did not (usual care cohort) undergo PADP delabelling. RESULTS: Part 1: the PADP (n = 350) and OAATS (n = 27 patients, n = 36 individual visits) cohorts were comparable. In PADP, costs/proportion delabelled was $20.10/0.98, equating to $20.51 per effectively delabelled patient; in OAATS, it was $181.24/0.50, equating to $362. Compared with OAATS, PADP was associated with savings of $341.97 per effectively delabelled patient, indicating the outpatient testing was the dominated strategy, being more costly and less effective. Part 2: the PADP (n = 218) and usual care (n = 32) cohorts were comparable. Significantly favouring the delabelled PADP cohort, the mean difference per patient was -4.41 days (95% confidence interval: -7.64, -1.18) and -$9467.72 (95% confidence interval: -$15 419.98, -$3515.46). CONCLUSIONS: Consistent with international literature, delabelling low-risk penicillin allergies in the inpatient setting had economic advantages in the Australian context. Fully powered economic evaluations are urgently required to consolidate these findings.

Artificial intelligence and the potential for perioperative delabeling of penicillin allergies for neurosurgery inpatients.

PURPOSE OF THE ARTICLE: Patients with penicillin allergy labels are more likely to have postoperative wound infections. When penicillin allergy labels are interrogated, a significant number of individuals do not have penicillin allergies and may be delabeled. This study was conducted to gain preliminary evidence into the potential role of artificial intelligence in assisting with perioperative penicillin adverse reaction (AR) evaluation. MATERIAL AND METHODS: A single-centre retrospective cohort study of consecutive emergency and elective neurosurgery admissions was conducted over a two-year period. Previously derived artificial intelligence algorithms for the classification of penicillin AR were applied to the data. RESULTS: There were 2063 individual admissions included in the study. The number of individuals with penicillin allergy labels was 124; one patient had a penicillin intolerance label. Of these labels, 22.4% were not consistent with classifications using expert criteria. When the artificial intelligence algorithm was applied to the cohort, the algorithm maintained a high level of classification performance (classification accuracy 98.1% for allergy versus intolerance classification). CONCLUSIONS: Penicillin allergy labels are common among neurosurgery inpatients. Artificial intelligence can accurately classify penicillin AR in this cohort, and may assist in identifying patients suitable for delabeling.

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.

New diagnostic perspectives in the management of pediatric beta-lactam allergy.

Since overdiagnosis of beta-lactam (BL) allergy is common in the pediatric population, delabeling is a critical part of antimicrobial stewardship. Undesirable consequences of inaccurate BL allergy labeling can be handled by incorporating traditional delabeling or newer risk-based strategies into antibiotic stewardship programs. Conventional assessment of BL allergy relies upon a stepwise algorithm including a clinical history with skin testing followed by drug provocation tests (DPTs). However, a growing number of studies highlighted the suboptimal diagnostic value of skin testing in children. Recently, there has been a paradigm shift in the practice of BL allergy assessment due to recent challenging data which emphasize the safety and accuracy of direct DPTs in children with a suspicion of non-immediate mild cutaneous reactions such as maculopapular eruption, delayed urticaria, and possibly also for benign immediate reactions such as urticaria/angioedema. Identifying low-risk BL allergy patients, in whom skin tests can be skipped and proceeding directly to DPTs could be safe, has become a hot topic in recent years. New risk stratification and predictive modeling studies that have the potential to better predict BL allergy risk status have recently been introduced into the field of drug allergy, particularly in adults. However, in contrast to adults, risk assessment studies in children are rare, and optimal risk definitions are controversial. In the coming years, promising potential methods to elucidate the predictors of BL allergy in children will require multidimensional approaches that may include predictive analytics, artificial intelligence techniques, and point-of-care clinical decision tools.

Delabeling penicillin and other antibiotic allergies in solid organ transplantation patients.

BACKGROUND: Immunocompromised populations including solid organ transplant (SOT) recipients have a high likelihood of need for antibiotic therapy for treatment of infection as well as for prophylaxis. Antibiotic allergy is commonly reported and often leads to the use of alternative, second-line antibiotics, which have been associated with poor outcomes, increased adverse effects, and higher cost. Formal allergy assessment and allergy testing can serve as an important antimicrobial stewardship tool in optimizing antibiotic regimens for this patient population. METHODS: A PubMed search with relevant keywords was performed. Review of relevant professional society guidelines was also performed. RESULTS: Documented penicillin and sulfonamide allergies are common impediments to the treatment and prophylaxis of immunocompromised populations, but are rarely formally evaluated in practice; however, there is evidence that most patients with documented allergy to these antibiotics can, in fact, tolerate penicillins and sulfonamide antibiotics. Implementation of an antibiotic allergy evaluation and testing program has been shown to increase the use of first-line antibiotics and can be cost saving. CONCLUSION: Antibiotic allergies have significant clinical consequences, especially in immunocompromised populations. Evaluation of these allergies to prevent the avoidance of first-line antibiotics should be a standard part of the workflow for these patients, prior to transplant. Programs can be tailored to the available personnel and resources of the organization.

Safety and value of pretransplant antibiotic allergy delabeling in a quaternary transplant center.

BACKGROUND: Self-reported antibiotic allergies, also known as antibiotic allergy labels, are common and may lead to worse patient outcomes. Within immunocompromized patients, antibiotic allergy labels can lead to inappropriate use of antimicrobials and may limit options for prophylactic and therapeutic options in the posttransplant period. While antibiotic allergy delabeling is considered an important aspect of antibiotic stewardship protocols, evidence and awareness of its application in transplant recipients is limited. METHODS: We describe our experience with an antibiotic allergy delabeling intervention in the pretransplant evaluation period and its impact on posttransplant antimicrobial utilization. This was a retrospective analysis of patients with an antibiotic allergy label who underwent evaluation for solid organ or stem cell transplantation between 2015 and 2020. Patients included in this analysis were those who completed pretransplant antibiotic allergy delabeling through our Drug Allergy Clinic and were retained in care for 6 months after transplant. RESULTS: Twenty-six of 27 patients underwent pretransplant antibiotic allergy delabeling and safely received the delabeled antibiotic posttransplant. There were no reported side effects to the delabeled antibiotic within 6 months posttransplant. Specific examination of sulfonamide (sulfa)-antibiotic delabeling showed cost savings of $254 to $2910 per patient in the posttransplant period compared to the use of alternative antibiotics for prophylaxis protocol. CONCLUSION: Antibiotic allergy delabeling prior to transplant is safe, is of high value, and should be considered in the pretransplant evaluation period. More resources are needed for the development of delabeling guidelines and support for broad implementation of pretransplant antibiotic allergy delabeling programs.

A Comprehensive Prospective Study of the Costs Associated With Evaluation of ß-Lactam Allergy.

BACKGROUND AND OBJECTIVE: Being labeled as allergic to penicillin (unverified ß-lactam allergy) can result in patients receiving broader-spectrum antibiotics than necessary that may be more toxic, less effective, and/or more expensive than alternative options. Objective: We aimed to evaluate the real costs of evaluating ß-lactam allergy. METHODS: We performed a prospective real-life observational study designed to evaluate all adult patients who consulted for suspected ß-lactam allergy over a 1-year period. Direct and indirect costs were systematically recorded. Direct health costs were calculated based on the number of visits and all additional and diagnostic tests performed, direct nonhealth costs based on the number of visits and the distance from their homes to the Allergy Department, and indirect costs based on absenteeism. RESULTS: A total of 296 patients with suspected allergy to ß-lactams were evaluated in our outpatient clinic from June 1, 2017 to May 31, 2018. Total direct health care costs were €28 176.70, with a mean (SD) cost of €95.19 (37.20). Direct nonhealth costs reached €6551.73, that is, €22.13 (40.44) per patient. Indirect health costs reached €20 769.20, with a mean of €70.17 (127.40). In summary, the total cost was €55 497.63, that is, a cost per patient of €187.49 (148.14). CONCLUSIONS: When all possible costs are taken into account, the evaluation of ß-lactam allergy is not expensive and can reduce future expense arising from unnecessary use of more expensive and less effective antibiotics.

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.

Evaluating Penicillin Allergies Without Skin Testing.

PURPOSE OF REVIEW: An unconfirmed penicillin allergy is known to confer significant risk to patients. Only a small minority of patients labeled with penicillin allergy will be confirmed to be hypersensitive with the current reference standard test, an oral amoxicillin therapeutic dose challenge. Skin testing has been recommended prior to oral challenges to reduce the risk of severe acute challenge reactions. The rate of severe acute anaphylactic reactions with oral amoxicillin is currently extremely low. Unfortunately, penicillin skin testing, as commonly performed, has a high rate of false positive results. RECENT FINDINGS: Encouraging skin testing in all individuals with an unconfirmed penicillin allergy, prior to a confirmatory oral challenge, would be technically difficult, make testing all individuals with an unconfirmed penicillin allergy very unlikely, and ultimately increase the risk to patients because of suboptimal antibiotic use. Most patients, who are appropriate candidates for a direct oral amoxicillin challenge, to confirm current penicillin tolerance, can be safely identified by their clinical histories. Higher risk individuals, those with a history of anaphylaxis or other acute onset potentially IgE-mediated reaction such as hives within 6 h of the first dose of the last course of a penicillin, may benefit from properly performed puncture and intradermal skin testing, using commercially available penicilloyl-polylysine, prior to an oral challenge, if skin test negative. Direct oral amoxicillin challenges in low-risk individuals are well accepted by patients and a safe and effective part of penicillin allergy delabeling.

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.