Penicillin Allergy Evaluation and Health Equity: A Call to Action.

Allergists have been at the forefront of addressing the burden of unverified penicillin allergy labels. Coordinated national efforts with infectious diseases, antimicrobial stewardship experts, and pharmacy societies to advocate for formal evaluation of patient-reported penicillin allergy have resulted in improvements in delabeling efforts. Given the poorer health outcomes associated with the penicillin allergy label and the potential health benefits that can be gained with delabeling, improving access to penicillin allergy evaluation is of the utmost importance. Health disparities are widely recognized to impact all aspects of health care, and multilevel interventions at the patient, clinician, and systems level are required to ensure equitable care delivery. Structural racism underpins many social determinants of health and is a key driver of racial and ethnic health disparities. In this Rostrum, we use a conceptual framework from the 2015 National Academy of Medicine report Improving Diagnosis in Health Care to explore how inequities are related to the evaluation of penicillin allergy. We use the National Institute on Minority Health and Health Disparities Strategies to Advance Health Disparities to elucidate areas of important study. Building upon existing efforts to address disparities in Allergy/Immunology, we highlight the urgent importance of understanding and eliminating health disparities in penicillin allergy evaluation and delabeling.

Assessment of the Frequency of Dual Allergy to Penicillins and Cefazolin: A Systematic Review and Meta-analysis.

Importance: Cefazolin is the preoperative antibiotic of choice because it is safer and more efficacious than second-line alternatives. Surgical patients labeled as having penicillin allergy are less likely to prophylactically receive cefazolin and more likely to receive clindamycin or vancomycin, which results in higher rates of surgical site infections. Objective: To examine the incidence of dual allergy to cefazolin and natural penicillins. Data Sources: MEDLINE/PubMed, Web of Science, and Embase were searched without language restrictions for relevant articles published from database inception until July 31, 2020. Study Selection: In this systematic review and meta-analysis, a search of MEDLINE/PubMed, Web of Science, and Embase was performed for articles published from database inception to July 31, 2020, for studies that included patients who had index allergies to a natural penicillin and were tested for tolerability to cefazolin or that included patients who had index allergies to cefazolin and were tested for tolerability to a natural penicillin. A total of 3228 studies were identified and 2911 were screened for inclusion. Data Extraction and Synthesis: Data were independently extracted by 2 authors. Bayesian meta-analysis was used to estimate the frequency of allergic reactions. Main Outcomes and Measures: Dual allergy to cefazolin and a natural penicillin. Results: Seventy-seven unique studies met the eligibility criteria, yielding 6147 patients. Cefazolin allergy was identified in 44 participants with a history of penicillin allergy, resulting in a dual allergy meta-analytical frequency of 0.7% (95% credible interval [CrI], 0.1%-1.7%; I2 = 74.9%). Such frequency was lower for participants with unconfirmed (0.6%; 95% CrI, 0.1%-1.3%; I2 = 54.3%) than for those with confirmed penicillin allergy (3.0%; 95% CrI, 0.01%-17.0%; I2 = 88.2%). Thirteen studies exclusively assessed surgical patients (n = 3884), among whom 0.7% (95% CrI, 0%-3.3%; I2 = 85.5%) had confirmed allergy to cefazolin. Low heterogeneity was observed for studies of patients with unconfirmed penicillin allergy who had been exposed to perioperative cefazolin (0.1%; 95% CrI, 0.1%-0.3%; I2 = 13.1%). Penicillin allergy was confirmed in 16 participants with a history of cefazolin allergy, resulting in a meta-analytical frequency of 3.7% (95% CrI, 0.03%-13.3%; I2 = 64.4%). The frequency of penicillin allergy was 4.4% (95% CrI, 0%-23.0%; I2 = 75%) for the 8 studies that exclusively assessed surgical patients allergic to cefazolin. Conclusions and Relevance: These findings suggest that most patients with a penicillin allergy history may safely receive cefazolin. The exception is patients with confirmed penicillin allergy in whom additional care is warranted.

Penicillin Allergy Testing Is Cost-Saving: An Economic Evaluation Study.

BACKGROUND: Having a penicillin allergy label is associated with the use of less appropriate and more expensive antibiotics and increased healthcare utilization. Penicillin allergy testing results in delabeling most allergy claimants and may be cost-saving. This study aimed to project whether penicillin allergy testing in patients reporting a penicillin allergy is cost-saving. METHODS: In this economic evaluation study, we built decision models to project the economic impact of 2 strategies for a patient with a penicillin allergy label: (1) perform diagnostic testing (drug challenges, with or without skin tests); and (2) do not perform diagnostic testing. The health service perspective was adopted, considering costs with penicillin allergy tests, and with hospital bed-days/outpatient visits, antibiotic use, and diagnostic testing. Twenty-four base case decision models were built, accounting for differences in the diagnostic workup, setting (inpatient vs outpatient) and geographic region. Uncertainty was explored via probabilistic sensitivity analyses. RESULTS: Penicillin allergy testing was cost-saving in all decision models built. For models assessing the performance of both skin tests and drug challenges, allergy testing resulted in average savings (in United States [US] dollars) of $657 for inpatients (US: $1444; Europe: $489) and $2746 for outpatients (US: $256; Europe: $6045). 75% of simulations obtained through probabilistic sensitivity analysis identified testing as the less costly option. CONCLUSIONS: Penicillin allergy testing was projected to be cost-saving across different scenarios. These results are devised to inform guidelines, supporting the adoption of policies promoting widespread testing of patients with a penicillin allergy label.

Perioperative Allergic Reactions: Allergy Assessment and Subsequent Anesthesia.

BACKGROUND: Evidence-based guidelines are needed in the United States to improve evaluation of perioperative allergic reactions including recommendations for subsequent anesthesia. OBJECTIVE: To identify causative agent(s) and evaluate patients' tolerability of subsequent anesthesia in patients evaluated by Allergy/Immunology (A/I) at Massachusetts General Hospital. METHODS: We performed a retrospective review of patients referred to the outpatient A/I clinic for perioperative allergic reactions between October 2003 and May 2017. Patient demographics, atopic history, and prior adverse drug reactions were reviewed. Patients underwent a comprehensive evaluation with testing including skin testing (ST), drug challenges (when appropriate), tryptase level measurement, and specific IgE to latex measurement. Tolerance of subsequent procedures requiring anesthesia was assessed. RESULTS: Of 123 patients referred, 74 (60%) were female and the mean age was 46 (±18) years. At least 1 causative agent was identified in 28 patients (24%, n = 28 of 118). Seventeen of 28 (61%) patients were ST positive to an antibiotic, including 13 (46%) positive to cefazolin; 3 patients (11%) had a positive latex specific IgE. Of 85 patients who had subsequent anesthesia with a known outcome, 78 (91%) did not have another perioperative allergic reaction. Two of 5 patients with an elevated baseline tryptase level did not tolerate subsequent anesthesia. CONCLUSION: The majority of patients safely received subsequent anesthesia after comprehensive A/I evaluation for their perioperative allergic reactions; however, improved algorithmic care is needed in the United States. Among ST-positive patients (24%), antibiotics (especially cefazolin) were the most common culprits. An elevated baseline tryptase level was associated with an increased risk of recurrent perioperative allergic reactions.

Penicillin Allergy Assessment in Pregnancy: Safety and Impact on Antibiotic Use.

BACKGROUND: Penicillin and other beta-lactam antibiotics are recommended for group B Streptococcus and cesarean section prophylaxis, but approximately 10% of pregnant patients report a penicillin allergy. OBJECTIVE: To assess the safety and impact of penicillin allergy evaluation in pregnant patients. METHODS: In this retrospective study of obstetrician-ordered Allergy/Immunology (AI) electronic consultations (e-consults) from September 20, 2017 through December 31, 2019, we reviewed the electronic health record for e-consult recommendation; patient demographic, obstetric, and allergy histories; and peripartum antibiotic utilization with indication. For patients whose electronic consultation recommended an in-person AI evaluation, testing outcomes were determined, and multivariable logistic regression models were used to compare antibiotic use between patients who did and did not receive an in-person AI evaluation. RESULTS: Of 389 obstetrician-ordered e-consults, 363 (93%) recommended an in-person AI evaluation; of these, 222 (61%) patients received an in-person AI evaluation. Of 220 (99%) patients skin tested, 209 (95%) had their penicillin allergy label safely removed. Compared with patients who did not receive an in-person AI evaluation despite it being recommended (n = 141), patients with in-person AI evaluation (n = 222) had reduced peripartum vancomycin (adjusted odds ratio [aOR], 0.07; 95% CI, 0.01-0.33), clindamycin (aOR, 0.17; 95% CI, 0.08-0.34), and gentamicin (aOR, 0.39; 95% CI, 0.19-0.78) use and increased penicillin (aOR, 18.0; 95% CI, 6.30-51.2) use. The fully AI evaluated patients had increased first-line antibiotic prophylaxis for group B Streptococcus (aOR, 26.9; 95% CI, 6.32-114) and cesarean section (aOR, 1.94; 95% CI, 1.06-3.52). CONCLUSIONS: In a sample of 220 pregnant patients with penicillin allergy histories and in-person AI evaluation, penicillin allergy testing was safe and associated with significantly reduced broad-spectrum antibiotic use and increased first-line beta-lactam antibiotic use.

Increasing Operational Capacity and Reducing Costs of Rituximab Administration: A Costing Analysis.

OBJECTIVE: Originator intravenous rituximab is an important rheumatology treatment but is costly, and administration requires several hours. Because biosimilar rituximab may cost less and subcutaneous rituximab requires a shorter visit, both may reduce costs and increase treatment capacity (infusions per year). METHODS: We implemented time-driven activity-based costing (TDABC), a method to assess costs and opportunities to increase capacity, throughout the care pathway for 26 patients receiving a total of 30 rituximab infusions. Using the TDABC estimates, we created a base case, which included provider time, salaries, infusion rates and times, and drug formulation, to simulate an induction cycle (two infusions). We varied these parameters in sensitivity analyses and assessed the impact of infusion rates and formulation (biosimilar vs. subcutaneous) on capacity before and after assuming a fixed budget. RESULTS: The base-case cost was $19 452; more than 90% was due to drug cost. In sensitivity analyses, varying projected biosimilar cost led to the greatest cost savings ($8,988 per cycle). Faster infusion rates and subcutaneous rituximab increased annual capacity (300% and 800%, respectively). With a fixed budget, subcutaneous rituximab led to a relative increase in capacity over biosimilar rituximab except when biosimilar cost savings relative to originator rituximab exceeded 40%; faster biosimilar infusion rates did not meaningfully affect these findings. CONCLUSION: Using TDABC, we demonstrate that rituximab cost is the primary driver of treatment cost, but capacity is largely driven by treatment time. Subcutaneous rituximab leads to higher capacity than biosimilar rituximab across a range of plausible costs; its use in rheumatology should be studied.

High-cost, high-need patients: the impact of reported penicillin allergy.

OBJECTIVES: More than 90% of patients who report a penicillin allergy have the allergy disproved when tested. Unnecessary use of alternative (non-beta-lactam) antibiotics can result in more treatment failures and adverse reactions. We described the prevalence and impact of a reported penicillin allergy in high-cost, high-need (HCHN) patients. STUDY DESIGN: Retrospective cohort. METHODS: We identified HCHN patients in a care management program of an urban academic medical center (January 1, 2014, to December 31, 2016). We used multivariable logistic regression models to determine the association between a reported penicillin allergy and antibiotic use. We used multivariable Poisson regression models to determine the association between a reported penicillin allergy, with or without multiple drug intolerance syndrome (MDIS; ≥3 reported drug allergies), and healthcare resource utilization (HRU). RESULTS: Of 1870 HCHN patients, 383 (20%) reported penicillin allergy, 835 (45%) had MDIS, and 290 (16%) had both. HCHN patients reporting penicillin allergy had an increased odds of beta-lactam alternative antibiotic use (adjusted odds ratio, 3.84; 95% CI, 2.17-6.80). HRU was significantly higher for patients reporting a penicillin allergy alone (adjusted relative risk [aRR], 1.13; 95% CI, 1.03-1.25) and with concurrent MDIS (aRR, 1.20; 95% CI, 1.08-1.34). CONCLUSIONS: HCHN patients had a high burden of reported drug allergy. A reported penicillin allergy conferred a 4-fold increased odds of beta-lactam alternative antibiotic use. Reporting penicillin allergy, with and without MDIS, was associated with significantly more HRU. HCHN care management programs should consider systematic drug allergy evaluations to optimize antibiotic use in these fragile patients.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome Identified in the Electronic Health Record Allergy Module.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but severe hypersensitivity reaction that remains poorly characterized in the United States. OBJECTIVE: To identify and describe DRESS syndrome cases in an integrated health care system using electronic health record (EHR) allergy module free-text searches. METHODS: We identified DRESS syndrome cases with rash, absolute eosinophil count of 500/L or more, organ involvement, and a European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples score of 2 or more by reviewing those patients from 1980 to 2016 whose EHR allergic reaction matched DRESS-related key words. Liver injury required alanine aminotransferase level of 100 U/L or more, and renal injury required creatinine increase by 0.5 mg/dL (or 50%) or more. Patient and DRESS characteristics were described, resource use was determined, and cost was estimated. RESULTS: Among 3,162,562 patients with 3,319,387 million allergy entries, 538 reactions matched key words, and 69 were DRESS syndrome cases (prevalence 2.18 per 100,000). Patients with DRESS had liver (42%) or renal (42%) injury; 11 (16%) had both liver and renal injury. Primary drug culprits were antibiotics (74%) (vancomycin [39%], ß-lactams [23%], fluoroquinolones [4%], tetracyclines [4%], and sulfonamides [3%]) and anticonvulsants (20%). Of 65 (94%) hospitalized patients with DRESS, 43 (66%) were hospitalized for DRESS syndrome management with median length of stay of 9 days (interquartile range, 6-17 days) and cost approximately $17,101 per patient. CONCLUSIONS: Using free-text search of the EHR allergy module identified a large US DRESS syndrome cohort. DRESS prevalence was 2.18 per 100,000 patients. Both liver and kidney injury were frequent, and vancomycin was the most common drug culprit. DRESS cases were morbid and resource-intensive.

The Cost of Penicillin Allergy Evaluation.

BACKGROUND: Unverified penicillin allergy leads to adverse downstream clinical and economic sequelae. Penicillin allergy evaluation can be used to identify true, IgE-mediated allergy. OBJECTIVE: To estimate the cost of penicillin allergy evaluation using time-driven activity-based costing (TDABC). METHODS: We implemented TDABC throughout the care pathway for 30 outpatients presenting for penicillin allergy evaluation. The base-case evaluation included penicillin skin testing and a 1-step amoxicillin drug challenge, performed by an allergist. We varied assumptions about the provider type, clinical setting, procedure type, and personnel timing. RESULTS: The base-case penicillin allergy evaluation costs $220 in 2016 US dollars: $98 for personnel, $119 for consumables, and $3 for space. In sensitivity analyses, lower cost estimates were achieved when only a drug challenge was performed (ie, no skin test, $84) and a nurse practitioner provider was used ($170). Adjusting for the probability of anaphylaxis did not result in a changed estimate ($220); although other analyses led to modest changes in the TDABC estimate ($214-$246), higher estimates were identified with changing to a low-demand practice setting ($268), a 50% increase in personnel times ($269), and including clinician documentation time ($288). In a least/most costly scenario analyses, the lowest TDABC estimate was $40 and the highest was $537. CONCLUSIONS: Using TDABC, penicillin allergy evaluation costs $220; even with varied assumptions adjusting for operational challenges, clinical setting, and expanded testing, penicillin allergy evaluation still costs only about $540. This modest investment may be offset for patients treated with costly alternative antibiotics that also may result in adverse consequences.

A value set for documenting adverse reactions in electronic health records.

Objective: To develop a comprehensive value set for documenting and encoding adverse reactions in the allergy module of an electronic health record. Materials and Methods: We analyzed 2 471 004 adverse reactions stored in Partners Healthcare's Enterprise-wide Allergy Repository (PEAR) of 2.7 million patients. Using the Medical Text Extraction, Reasoning, and Mapping System, we processed both structured and free-text reaction entries and mapped them to Systematized Nomenclature of Medicine - Clinical Terms. We calculated the frequencies of reaction concepts, including rare, severe, and hypersensitivity reactions. We compared PEAR concepts to a Federal Health Information Modeling and Standards value set and University of Nebraska Medical Center data, and then created an integrated value set. Results: We identified 787 reaction concepts in PEAR. Frequently reported reactions included: rash (14.0%), hives (8.2%), gastrointestinal irritation (5.5%), itching (3.2%), and anaphylaxis (2.5%). We identified an additional 320 concepts from Federal Health Information Modeling and Standards and the University of Nebraska Medical Center to resolve gaps due to missing and partial matches when comparing these external resources to PEAR. This yielded 1106 concepts in our final integrated value set. The presence of rare, severe, and hypersensitivity reactions was limited in both external datasets. Hypersensitivity reactions represented roughly 20% of the reactions within our data. Discussion: We developed a value set for encoding adverse reactions using a large dataset from one health system, enriched by reactions from 2 large external resources. This integrated value set includes clinically important severe and hypersensitivity reactions. Conclusion: This work contributes a value set, harmonized with existing data, to improve the consistency and accuracy of reaction documentation in electronic health records, providing the necessary building blocks for more intelligent clinical decision support for allergies and adverse reactions.

Decision-Making in Critical Limb Ischemia: A Markov Simulation.

BACKGROUND: Critical limb ischemia (CLI) is a feared complication of peripheral vascular disease that often requires surgical management and may require amputation of the affected limb. We developed a decision model to inform clinical management for a 63-year-old woman with CLI and multiple medical comorbidities, including advanced heart failure and diabetes. METHODS: We developed a Markov decision model to evaluate 4 strategies: amputation, surgical bypass, endovascular therapy (e.g. stent or revascularization), and medical management. We measured the impact of parameter uncertainty using 1-way, 2-way, and multiway sensitivity analyses. RESULTS: In the base case, endovascular therapy yielded similar discounted quality-adjusted life months (26.50 QALMs) compared with surgical bypass (26.34 QALMs). Both endovascular and surgical therapies were superior to amputation (18.83 QALMs) and medical management (11.08 QALMs). This finding was robust to a wide range of periprocedural mortality weights and was most sensitive to long-term mortality associated with endovascular and surgical therapies. Utility weights were not stratified by patient comorbidities; nonetheless, our conclusion was robust to a range of utility weight values. CONCLUSIONS: For a patient with CLI, endovascular therapy and surgical bypass provided comparable clinical outcomes. However, this finding was sensitive to long-term mortality rates associated with each procedure. Both endovascular and surgical therapies were superior to amputation or medical management in a range of scenarios.