How to Define and Manage Low-Risk Drug Allergy Labels.

Risk stratification in drug allergy implies that specific risk categories (eg, low, moderate, and high) classify historical drug hypersensitivity reactions. These risk categories can be based on reaction phenotypic characteristics, the timing of the reaction and evaluation, the required reaction management, and individual characteristics. Although a multitude of frameworks have been described in the literature, particularly for penicillin allergy labels, there has yet to be a global consensus, and approaches continue to vary between allergy centers. Immune-mediated drug allergies can sometimes be confirmed using skin testing, but a negative drug challenge is required to demonstrate tolerance and remove the allergy from the electronic health record ("delabel" the allergy). Even for quintessential IgE-mediated drug allergy, penicillin allergy, recent data reveal that a direct oral challenge, without prior skin testing, is an appropriate diagnostic strategy in those who are considered low-risk. Drug allergy pathogenesis and clinical manifestations may vary depending on the culprit drug, and as such, the optimal approach should be based on risk stratification that considers individual patient and reaction characteristics, the likely hypersensitivity reaction phenotype, the drug class, and the patient's clinical needs. This article will describe low-risk drug allergy labels, focusing on ß-lactam and sulfonamide antibiotics, nonsteroidal anti-inflammatory drugs, iodinated contrast media, and common chemotherapeutics. This review will also address practical management approaches using currently available risk stratification and clinical decision tools.

Safety of Direct Drug Provocation for the Evaluation of Penicillin Allergy in Low-Risk Adults.

BACKGROUND: About 10% of patients have a penicillin allergy label, but less than 5% of them are actually allergic. Unnecessary penicillin avoidance is associated with serious medical consequences. Given the growing number of these labels, it is imperative that our diagnostic strategy for penicillin allergy be as efficient as possible. The validity of traditionally used skin tests (STs) has been questioned, whereas drug provocation testing (DPT), the criterion standard, without previous ST appears very safe in most cases. OBJECTIVE: To evaluate the safety of direct DPT without consideration for ST results and the validity of ST in the diagnosis of penicillin allergy. METHODS: In this prospective cohort study without a control group, we recruited patients consulting an allergist for penicillin allergy. Patients underwent ST followed by DPT regardless of ST results. Patients with anaphylaxis to penicillin within the past 5 years or a severe delayed reaction were excluded, as were those with significant cardiorespiratory comorbidity. RESULTS: None of the 1002 recruited patients had a serious reaction to DPT. Ten (1.0%) had a mild immediate reaction, of whom only 1 (0.1%) was considered likely IgE-mediated. The positive and negative predictive values of ST for an immediate reaction were 3.6% and 99.1%, respectively. CONCLUSIONS: In a low-risk adult population reporting penicillin allergy, ST has very poor positive predictive value. Direct DPT without ST is safe and appears to be an ideal diagnostic strategy to remove penicillin allergy labels that could be implemented in first-line practice.

A nurse-driven penicillin allergy risk score in the preoperative setting was associated with increased cefazolin use perioperatively.

STUDY OBJECTIVE: To characterize and assess the effects of a preoperative, nurse-driven penicillin allergy risk stratification tool on rates of perioperative cefazolin and second-line antibiotic use. DESIGN: Quasi-experimental quality improvement study of penicillin-allergic surgical patients undergoing procedures for which cefazolin is indicated. SETTING: Outpatient Perioperative Care Clinic (PCC) for preoperative surgical patients at a tertiary care center. PATIENTS: 670 and 1371 adult penicillin-allergic PCC attendants and non-attendants, respectively. INTERVENTION: A paper penicillin allergy risk stratification questionnaire was administered during the PCC visit. Nurses were educated on its use. MEASUREMENTS: Antibiotic (cefazolin, clindamycin, vancomycin) use rates in the 24 months before and 17 months after intervention implementation in November 2020 (November 2018 - April 2022) were assessed in penicillin-allergic PCC attendants with statistical process control charts. Multivariable logistic regression assessed antibiotic use rates pre- and post-intervention adjusting for age, sex, surgical specialty and penicillin allergy history severity. Similar analyses were done in penicillin-allergic PCC non-attendants. MAIN RESULTS: Of 670 penicillin-allergic PCC attendants, 451 (median [IQR] age, 66 (Sousa-Pinto et al., 2021 [14])) were analyzed pre-intervention and 219 (median [IQR] age, 66 (Mine et al., 1970 [13])) post-intervention. One month after implementation, process measures demonstrated an upward shift in cefazolin use for PCC attendants versus no shift or other special cause variation for PCC non-attendants. There were increased odds of cefazolin use (aOR 1.67, 95% CI [1.09-2.57], P = 0.019), decreased odds of clindamycin use (aOR 0.61, 95% CI [0.42-0.89], P = 0.010) and decreased odds of vancomycin use (aOR 0.56, 95% CI [0.35-0.88], P = 0.013) in PCC attendants post-intervention. This effect did not occur in PCC non-attendants. There was no increase in perioperative anaphylaxis post-intervention. CONCLUSIONS: A simple penicillin allergy risk stratification tool implemented in the preoperative setting was associated with increased use of cefazolin and decreased rates of second-line agents post implementation.

The Syphilis Pandemic Prior to Penicillin: Origin, Health Issues, Cultural Representation and Ethical Challenges.

Syphilis is currently a treatable disease, with a low incidence in most developed countries, although the prevalence has increased recently, especially among men-who-have-sex-with-men. In many of the least developed countries, however, syphilis is still a major health problem, although the problem is not comparable to the desperate situation worldwide less than 80 years ago. At that time, and for many centuries previously, syphilis dramatically affected the lives and health of individuals and threatened the well-being of many societies. This review examines the aetiology, transmission, and many manifestations of syphilis from a historical perspective, emphasizing morbidity, treatment, psychosocial and cultural manifestations, as well as ethical issues uncovered in the clinical search for knowledge about the manifestations of the disease.

Use of oral penicillin challenge in low-risk penicillin allergy.

Overview of: 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;183:944-52.

Penicillin allergy reassessment for treatment improvement: A dental office tool to support appropriate penicillin allergy labeling.

BACKGROUND: Dental appointments offer an opportunity to evaluate a documented penicillin (PCN) allergy and determine whether the patient might be a candidate for medical reassessment of their allergy. The authors gathered feedback on the Penicillin Allergy Reassessment for Treatment Improvement (PARTI) tool, designed to enhance dentist-patient communications regarding PCN allergies. METHODS: From January 2022 through May 2023, the authors conducted a mixed-methods study, collecting focus group data from patients with PCN allergies and surveying health care workers (HCWs) regarding the PARTI tool. Feedback focused on reassessment procedures, patient-centered allergy information, and medical records updates. Thematic analysis was used for focus group data. RESULTS: The study included 15 patients in focus groups and 50 HCW survey respondents representing diverse US regions. Patient demographic characteristics included varied races, the mean age was 52 years, and most of the patients were female (53.3%). Most patients had health care interactions within the preceding year, at which 86.6% of patients were asked about drug allergies. HCW respondents primarily consisted of pharmacists (30%) and dentists, dental hygienists, and dental assistants (28%). Feedback on the PARTI tool was constructive, with both patients and HCWs recognizing its potential benefits and providing insights for improvement. Many HCWs (68%) highlighted the importance of step 3 of the PARTI tool, that is, the section on PCN allergy testing. Feedback from participants was incorporated into the final PARTI tool. CONCLUSIONS: Patient and HCW feedback on the PARTI tool was used to finalize a tool for the dental office to provide to patients who are candidates for PCN allergy reassessment. The feedback will also be used to inform an upcoming pilot study in US dental offices, focused on the process for PCN allergy reassessment and health record documentation. PRACTICAL IMPLICATIONS: Deploying the PARTI tool in dental offices is pivotal, as mislabeling patients with PCN allergies could have severe consequences, such as hindering the prescription of lifesaving antibiotics for conditions like endocarditis, in the future. This implementation not only enhances communication between dentists and patients, but it is also crucial for ensuring improved patient safety and maintaining accurate medical records among health care settings.

A multicentre observational study to investigate feasibility of a direct oral penicillin challenge in de-labelling 'low risk' patients with penicillin allergy by non-allergy healthcare professionals (SPACE study): Implications for healthcare systems.

OBJECTIVE: The huge burden of inaccurate penicillin allergy labels (PALs) is an important driver of antimicrobial resistance. This is magnified by insufficient allergy specialists and lack of 'point-of-care' tests. We investigated the feasibility of non-allergy healthcare professionals (HCPs) delivering direct oral penicillin challenges (DPCs) for penicillin allergy de-labelling. METHODS: This prospective observational study was conducted in three hospitals in England across three settings (acute medical, pre-surgical and haematology-oncology). Patients with a PAL were screened and stratified as low risk/high risk. Low risk patients (non-immune mediated symptoms, benign rash, tolerated amoxicillin since and family history) underwent a DPC. RESULTS: N = 2257 PALs were screened, 1054 were eligible; 643 were approached, 373 declined, 270 consented and 259 risk stratified (low risk = 155; high risk = 104). One hundred and twenty-six low risk patients underwent DPC, 122 (96.8%) were de-labelled with no serious allergic reactions. Conversion rate from screening-to-consent was 12% [3.3% and 17.9% in acute and elective settings respectively; odds ratios for consent were 3.42 (p < 0.001) and 5.53 (p < 0.001) in haematology-oncology and pre-surgical setting respectively. Common reasons for failure to progress in the study included difficulty in reaching patients, clinical instability/medical reasons, lacking capacity to consent and psychological factors. INTERPRETATION: DPCs can be delivered by non-allergy HCPs. A high proportion of patients with PALs did not progress in the study pathway. Strategies to deliver DPC at optimal points of the care pathway are needed to enhance uptake. Elective settings offer greater opportunities than acute settings for DPC. The safety and simplicity of DPCs lends itself to adoption by healthcare systems beyond the UK, including in resource-limited settings.

Effectiveness, barriers and facilitating factors of strategies for active delabelling of patients with penicillin allergy labels: a systematic review protocol.

INTRODUCTION: Up to 15% of adult patients in the clinical setting report to be allergic to penicillin. However, in most cases, penicillin allergy is not confirmed. Due to the negative aspects associated with erroneous penicillin allergy, the implementation of active delabelling processes for penicillin allergy is an important part of antibiotic stewardship programmes. Depending on the clinical setting, different factors need to be considered during implementation. This review examines the effectiveness of different delabelling interventions and summarises components and structures that facilitate, support or constrain structured penicillin allergy delabelling. METHODS AND ANALYSIS: This review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The databases MEDLINE (via PubMed), EMBASE and Cochrane Library were searched for studies reporting on any intervention to identify, assess or rule out uncertain penicillin allergy. To improve completeness, two further databases are also searched for grey literature. Study design, intervention type, professional groups involved, effectiveness, limitations, barriers, facilitating factors, clinical setting and associated regulatory factors will be extracted and analysed. In addition, exclusion criteria for participation in the delabelling intervention and criteria for not delabelling penicillin allergy will be summarised. In case of failed protocols, these are highlighted and quantitatively analysed if possible. Two independent reviewers will perform the screening process and data extraction. Discordant decisions will be resolved through review by a third reviewer. Bias assessment of the individual studies will be performed using the Newcastle Ottawa Scale. ETHICS AND DISSEMINATION: Because individual patient-related data are not analysed, an ethical approval is not required. The review will be published in a peer-reviewed scientific journal.

Impact of penicillin allergy records on antimicrobial prescribing in hospitalised patients.

BACKGROUND: The overdiagnosis of penicillin allergy and misclassification of non-truly allergic reactions is a growing public health problem, associated with the overuse of broad-spectrum and restricted antimicrobials. We aimed to evaluate the impact of penicillin allergy status on antimicrobial prescribing. METHODS: A retrospective study of inpatients with a documented penicillin allergy receiving antimicrobials was conducted from 1 April to 1 July 2021. Antimicrobial prescribing and clinical characteristics were compared between patients with an active penicillin allergy label and those whose label was removed following antimicrobial stewardship team review. Antimicrobials were classified in two categories: i) 'Access' (recommended), ii) 'Watch and Reserve' (restricted) according to WHO AWaRe classification, a tool to guide appropriate antibiotic use. RESULTS: 437 patients with a documented penicillin allergy receiving antimicrobials were included. 353 patients with an active penicillin allergy label, more frequently received antimicrobials from the 'Watch and Reserve list' (283;80% vs 30;37%; p<0.001). In contrast, 84 patients who were de-labelled received more often antimicrobials from the 'Access list' (53;63% vs 64;18%; p<0.001). CONCLUSIONS: Penicillin allergy reviews and de-labelling strategies may reduce the use of restricted antimicrobials under the 'Watch and Reserve list'. This practice should be encouraged and reinforced in all hospitals.

Randomized Multicenter Trial for the Validation of an Easy-to-Administer Algorithm to Define Penicillin Allergy Status in Sexually Transmitted Infection Clinic Outpatients.

BACKGROUND: Approximately 15% of patients in sexually transmitted infection (STI) clinics report penicillin allergies, complicating treatment for syphilis and gonorrhea. Nonetheless, >90% do not have a penicillin allergy when evaluated. We developed and validated an algorithm to define which patients reporting penicillin allergy can be safely treated at STI clinics with these drugs. METHODS: Randomized controlled trial to assess feasibility and safety of penicillin allergy evaluations in STI clinics. Participants with reported penicillin allergy answered an expert-developed questionnaire to stratify risk. Low-risk participants underwent penicillin skin testing (PST) followed by amoxicillin 250 mg challenge or a graded oral challenge (GOC)-amoxicillin 25 mg followed by 250 mg. Reactions were recorded, and participant/provider surveys were conducted. RESULTS: Of 284 participants, 72 (25.3%) were deemed high risk and were excluded. Of 206 low-risk participants, 102 (49.5%) underwent PST without reactions and 3 (3%) had mild reactions during the oral challenge. Of 104 (50.5%) participants in the GOC, 95 (91.3%) completed challenges without reaction, 4 (4.2%) had mild symptoms after 25 mg, and 4 (4.2%) after 250-mg doses. Overall, 195 participants (94.7%) successfully completed the study and 11 (5.3%) experienced mild symptoms. Of 14 providers, 12 (85.7%) completed surveys and 11 (93%) agreed on the safety/effectiveness of penicillin allergy assessment in STI clinics. CONCLUSIONS: An easy-to-administer risk-assessment questionnaire can safely identify patients for penicillin allergy evaluation in STI clinics by PST or GOC, with GOC showing operational feasibility. Using this approach, 67% of participants with reported penicillin allergy could safely receive first-line treatments for gonorrhea or syphilis. Clinical Trials Registration. Clinicaltrials.gov (NCT04620746).

Predicting Penicillin Allergy: A United States Multicenter Retrospective Study.

BACKGROUND: Using the reaction history in logistic regression and machine learning (ML) models to predict penicillin allergy has been reported based on non-US data. OBJECTIVE: We developed ML positive penicillin allergy testing prediction models from multisite US data. METHODS: Retrospective data from 4 US-based hospitals were grouped into 4 datasets: enriched training (1:3 case-control matched cohort), enriched testing, nonenriched internal testing, and nonenriched external testing. ML algorithms were used for model development. We determined area under the curve (AUC) and applied the Shapley Additive exPlanations (SHAP) framework to interpret risk drivers. RESULTS: Of 4777 patients (mean age 60 [standard deviation: 17] years; 68% women, 91% White, and 86% non-Hispanic) evaluated for penicillin allergy labels, 513 (11%) had positive penicillin allergy testing. Model input variables were frequently missing: immediate or delayed onset (71%), signs or symptoms (13%), and treatment (31%). The gradient-boosted model was the strongest model with an AUC of 0.67 (95% confidence interval [CI]: 0.57-0.77), which improved to 0.87 (95% CI: 0.73-1) when only cases with complete data were used. Top SHAP drivers for positive testing were reactions within the last year and reactions requiring medical attention; female sex and reaction of hives/urticaria were also positive drivers. CONCLUSIONS: An ML prediction model for positive penicillin allergy skin testing using US-based retrospective data did not achieve performance strong enough for acceptance and adoption. The optimal ML prediction model for positive penicillin allergy testing was driven by time since reaction, seek medical attention, female sex, and hives/urticaria.

Examining cefazolin utilization and perioperative anaphylaxis in patients with and without a penicillin allergy label: A cross-sectional study.

STUDY OBJECTIVE: To compare the occurrence of cefazolin perioperative anaphylaxis (POA) in patients with and without a penicillin allergy label (PAL) to determine whether the prevalence of cefazolin POA differs based on the presence of a PAL. DESIGN: Cross-sectional study. SETTING: A large U.S. healthcare system in the Baltimore-D.C. region, July 2017 to July 2020. PATIENTS: 112,817 surgical encounters across inpatient and outpatient settings in various specialties, involving 90,089 patients. Of these, 4876 (4.3%) encounters had a PAL. INTERVENTIONS: Perioperative cefazolin administration within 4 h before surgery to 4 h after the procedure began. MEASUREMENTS: The primary outcome was cefazolin POA in patients with and without PALs. Potential POA cases were identified based on tryptase orders or diphenhydramine administrations within the initial cefazolin administration to 6 h postoperatively. Verification included two validation steps. The first checked for hypersensitivity reaction (HSR) documentation, and the second, led by Allergy specialists, identified POA and the probable culprit. The secondary outcome looked at cefazolin use trends in patients with a PAL, stratified by setting and specialty. MAIN RESULTS: Of 112,817 encounters, 1421 (1.3%) had possible cefazolin HSRs. Of these, 22 (1.5%) had POA, resulting in a 0.02% prevalence. Of these, 13 (59.1%) were linked to cefazolin and 9 (40.9%) attributed to other drugs. Only one cefazolin POA case had a PAL, indicating no significant difference in cefazolin POA prevalence between patients with and without PALs (p = 0.437). Perioperative cefazolin use in patients with PALs steadily increased from 2.6% to 6.0% between 2017 and 2020, specifically in academic settings. CONCLUSIONS: The prevalence of cefazolin POA does not exhibit significant differences between patients with and without PALs, and notably, the incidence remains remarkably low. Based on these findings, it is advisable to view cefazolin as an acceptable choice for prophylaxis in patients carrying a PAL.

What Parents Need to Know About Penicillin Allergy Labels.

This JAMA Pediatrics Patient Page describes why it is important for children to see their pediatrician for any concern about a reaction to penicillin before a child is considered to have a penicillin allergy.