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.

Addressing the epidemic of antibiotic "allergy" over-diagnosis.

OBJECTIVE: An epidemic of antibiotic allergy is occurring. DATA SOURCES: Articles published since 2008. STUDY SELECTIONS: Articles on antibiotic allergy and stewardship. RESULTS: A number of overlapping factors contribute. The most important factor is antibiotic overuse. Antibiotics are commonly used in situations in which no antibiotics are indicated. Thirty percent to 50% of ambulatory antibiotic use may be inappropriate. The duration of indicated antibiotic use is often excessive, which leads to more side effects. All antibiotic use can result in adverse reactions, and a fraction of these will be dutifully recorded as an allergy in the electronic health record (EHR). Most EHRs are not well structured to accurately convey information on expected side effects that have occurred, metabolic or other contraindications, dose-related or situational toxicities, personal preferences, clinically significant immunologically mediated hypersensitivity, and other reasons a particular patient may not want or should not be given a specific drug or type of drug in the future. As populations age, their accumulated baggage of reported antibiotic allergies increase. Suspected antibiotic allergy is rarely confirmed with appropriate testing or rechallenge. Patients then receive suboptimal antibiotic therapy and experience more side effects, treatment failures, and serious antibiotic-resistant infections. Reporting an antibiotic allergy in the EHR is nominally done to improve patient safety, but unfortunately, this is often not the actual result. CONCLUSION: Audit and feedback, to help ensure adherence to Choosing Wisely recommendations and good antibiotic stewardship practices, can help reduce inappropriate antibiotic use. Restructuring EHRs to facilitate correct drug intolerance reporting, along with active antibiotic allergy delabeling programs, can help stem this epidemic.

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.

Evaluation and Management of Penicillin Allergy: A Review.

IMPORTANCE: ß-Lactam antibiotics are among the safest and most effective antibiotics. Many patients report allergies to these drugs that limit their use, resulting in the use of broad-spectrum antibiotics that increase the risk for antimicrobial resistance and adverse events. OBSERVATIONS: Approximately 10% of the US population has reported allergies to the ß-lactam agent penicillin, with higher rates reported by older and hospitalized patients. Although many patients report that they are allergic to penicillin, clinically significant IgE-mediated or T lymphocyte-mediated penicillin hypersensitivity is uncommon (<5%). Currently, the rate of IgE-mediated penicillin allergies is decreasing, potentially due to a decreased use of parenteral penicillins, and because severe anaphylactic reactions to oral amoxicillin are rare. IgE-mediated penicillin allergy wanes over time, with 80% of patients becoming tolerant after a decade. Cross-reactivity between penicillin and cephalosporin drugs occurs in about 2% of cases, less than the 8% reported previously. Some patients have a medical history that suggests they are at a low risk for developing an allergic reaction to penicillin. Low-risk histories include patients having isolated nonallergic symptoms, such as gastrointestinal symptoms, or patients solely with a family history of a penicillin allergy, symptoms of pruritus without rash, or remote (>10 years) unknown reactions without features suggestive of an IgE-mediated reaction. A moderate-risk history includes urticaria or other pruritic rashes and reactions with features of IgE-mediated reactions. A high-risk history includes patients who have had anaphylaxis, positive penicillin skin testing, recurrent penicillin reactions, or hypersensitivities to multiple ß-lactam antibiotics. The goals of antimicrobial stewardship are undermined when reported allergy to penicillin leads to the use of broad-spectrum antibiotics that increase the risk for antimicrobial resistance, including increased risk of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Broad-spectrum antimicrobial agents also increase the risk of developing Clostridium difficile (also known as Clostridioides difficile) infection. Direct amoxicillin challenge is appropriate for patients with low-risk allergy histories. Moderate-risk patients can be evaluated with penicillin skin testing, which carries a negative predictive value that exceeds 95% and approaches 100% when combined with amoxicillin challenge. Clinicians performing penicillin allergy evaluation need to identify what methods are supported by their available resources. CONCLUSIONS AND RELEVANCE: Many patients report they are allergic to penicillin but few have clinically significant reactions. Evaluation of penicillin allergy before deciding not to use penicillin or other ß-lactam antibiotics is an important tool for antimicrobial stewardship.

Practical Management of Patients with a History of Immediate Hypersensitivity to Common non-Beta-Lactam Drugs.

Immediate hypersensitivity reactions to medications are among the most feared adverse drug reactions, because of their close association with anaphylaxis. This review discusses a practical management approach for patients with a history of an immediate hypersensitivity to a non-beta-lactam medication, where reexposure to the implicated, or similar, medication is clinically necessary. Mechanisms associated with severe immediate hypersensitivity reactions include IgE-mediated mast cell activation, complement-mediated mast cell activation, and direct mast cell activation. Immediate hypersensitivity reactions may also be mediated by vasodilators, other pharmacologic mechanisms, or be secondary to underlying patient-specific biochemical abnormalities such as endocrine tumors or chronic spontaneous urticaria. The key features in the reaction history and the biochemistry of the implicated medication are discussed. Most individuals with a history of immediate hypersensitivity to a medication, who require reuse of that drug, can be safely retreated with a therapeutic course of the implicated drug after a full-dose challenge, graded challenge, or desensitization, with or without premedication and/or any preliminary diagnostic testing, depending on the specific situation.

Adverse reactions associated with oral and parenteral use of cephalosporins: A retrospective population-based analysis.

BACKGROUND: Few studies have provided population-based, route-specific data on allergy to cephalosporin or incidence of serious adverse drug reactions (ADRs). OBJECTIVE: We investigated the incidence of new reports of cephalosporin-associated "allergy" and serious ADRs. METHODS: We identified all members of the Kaiser Permanente Southern California health plan given cephalosporins (from January 1, 2010, through December 31, 2012), all new reports of cephalosporin-associated allergy, and all serious ADRs. RESULTS: There were 622,456 health plan members exposed to 901,908 courses of oral cephalosporins and 326,867 members exposed to 487,630 courses of parenteral cephalosporins over the 3-year study period. New reports of allergy to cephalosporin were more frequent among women (0.56%; 95% CI, 0.54% to 0.57%) than among men (0.43%; 95% CI, 0.41% to 0.44%) per course (P < .0001). The most frequent serious cephalosporin-associated ADRs were Clostridium difficile infection within 90 days (0.91%), nephropathy within 30 days (0.15%), and all-cause death within 1 day (0.10%). None correlated with history of drug allergy. Physician-documented cephalosporin-associated anaphylaxis occurred with 5 oral exposures (95% CI, 1/1,428,571-1/96,154) and 8 parenteral exposures (95% CI, 1/200,000-1/35,971) (P = .0761). There were 3 documented cephalosporin-associated serious cutaneous adverse reactions (95% CI, 0-1 in 217,291). All were associated with the use of another antibiotic at the same time as cephalosporin. CONCLUSIONS: Cephalosporins are widely and safely used, even in individuals with a history of penicillin allergy. Physician-documented cephalosporin-associated anaphylaxis and serious cutaneous adverse reactions are rare compared with C difficile infection within 90 days, nephropathy within 30 days, and all-cause death within 1 day.

Identification of Stevens-Johnson syndrome and toxic epidermal necrolysis in electronic health record databases.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) carry a high mortality risk. While identifying clinical and genetic risk factors for these conditions has been hindered by their rarity, large electronic health databases hold promise for identifying large numbers of cases for study, especially with the introduction in 2008 of ICD-9 codes more specific for these conditions. OBJECTIVE: The objective of this study is to estimate the validity of ICD-9 codes for ascertaining SJS/TEN in 12 collaborating research units in the USA, covering almost 60 million lives. METHODS: From the electronic databases at each site, we ascertained potential cases of SJS/TEN using ICD-9 codes. At five sites, a subset of medical records was abstracted and standardized criteria applied by board-certified dermatologists to adjudicate diagnoses. Multivariate logistic regression was used to identify factors independently associated with validated SJS/TEN cases. RESULTS: A total of 56 591 potential cases of SJS/TEN were identified. A subset of 276 charts was selected for adjudication and 39 (of the 276) were confirmed as SJS/TEN. Patients with the ICD-9 codes introduced after 2008 were more likely to be confirmed as cases (OR 3.32; 95%CI 0.82, 13.47) than those identified in earlier years. Likelihood of case status increased with length of hospitalization. Applying the probability of case status to the 56 591 potential cases, we estimated 475-875 to be valid SJS/TEN cases. CONCLUSION: Newer ICD-9 codes, along with length of hospitalization, identified patients with a high likelihood of SJS/TEN. This is important for identification of subjects for future pharmacogenomics studies.

Health care use and serious infection prevalence associated with penicillin "allergy" in hospitalized patients: A cohort study.

BACKGROUND: Penicillin is the most common drug "allergy" noted at hospital admission, although it is often inaccurate. OBJECTIVE: We sought to determine total hospital days, antibiotic exposures, and the prevalence rates of Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) in patients with and without penicillin "allergy" at hospital admission. METHODS: We performed a retrospective, matched cohort study of subjects admitted to Kaiser Foundation hospitals in Southern California during 2010 through 2012. RESULTS: It was possible to match 51,582 (99.6% of all possible cases) unique hospitalized subjects with penicillin "allergy" to 2 unique discharge diagnosis category-matched, sex-matched, age-matched, and date of admission-matched control subjects each. Cases with penicillin "allergy" averaged 0.59 (9.9%; 95% CI, 0.47-0.71) more total hospital days during 20.1 ± 10.5 months of follow-up compared with control subjects. Cases were treated with significantly more fluoroquinolones, clindamycin, and vancomycin (P < .0001) for each antibiotic compared with control subjects. Cases had 23.4% (95% CI, 15.6% to 31.7%) more C difficile, 14.1% (95% CI, 7.1% to 21.6%) more MRSA, and 30.1% (95% CI, 12.5% to 50.4%) more VRE infections than expected compared with control subjects. CONCLUSIONS: A penicillin "allergy" history, although often inaccurate, is not a benign finding at hospital admission. Subjects with a penicillin "allergy" history spend significantly more time in the hospital. Subjects with a penicillin "allergy" history are exposed to significantly more antibiotics previously associated with C difficile and VRE. Drug "allergies" in general, but most those notably to penicillin, are associated with increased hospital use and increased C difficile, MRSA, and VRE prevalence.

Penicillin and beta-lactam allergy: epidemiology and diagnosis.

Penicillin is the most common beta-lactam antibiotic allergy and the most common drug class allergy, reported in about 8% of individuals using health care in the USA. Only about 1% of individuals using health care in the USA have a cephalosporin allergy noted in their medical record, and other specific non-penicillin, non-cephalosporin beta-lactam allergies are even rarer. Most reported penicillin allergy is not associated with clinically significant IgE-mediated reactions after penicillin rechallenge. Un-verified penicillin allergy is a significant and growing public health problem. Clinically significant IgE-mediated penicillin allergy can be safely confirmed or refuted using skin testing with penicilloyl-poly-lysine and native penicillin G and, if skin test is negative, an oral amoxicillin challenge. Acute tolerance of an oral therapeutic dose of a penicillin class antibiotic is the current gold standard test for a lack of clinically significant IgE-mediated penicillin allergy. Cephalosporins and other non-penicillin beta-lactams are widely, safely, and appropriately used in individuals, even with confirmed penicillin allergy. There is little, if any, clinically significant immunologic cross-reactivity between penicillins and other beta-lactams. Routine cephalosporin skin testing should be restricted to research settings. It is rarely needed clinically to safely manage patients and has unclear predictive value at this time. The use of alternative cephalosporins, with different side chains, is acceptable in the setting of a specific cephalosporin allergy. Carbapenems and monobactams are also safely used in individuals with confirmed penicillin allergy. A certain predictable, but low, rate of adverse reactions will occur with all beta-lactam antibiotic use both pre- and post-beta-lactam allergy evaluations.

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

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

Advances in the Understanding of Drug Hypersensitivity: 2012 Through 2022.

Over the last decade there have been key advances in understanding mechanisms, risk, and consequences of both true immunological drug hypersensitivity and unverified drug allergy labels that have changed clinical practice. This has been facilitated by the widespread adoption of electronic health records (EHRs). The vast majority of EHR drug allergy labels are unverified and cause significant morbidity from unnecessary avoidance of optimal drug therapy. There has also been significant movement in our understanding of mechanisms of drug hypersensitivity that, in addition to advancing our understanding of the pathogenesis of immediate and delayed reactions, have guided preventive efforts, diagnostic procedures, and clinical management. More widespread adoption, including scale-up of "allergy" delabeling and appropriate management, specifically for antibiotics, opiates, radiocontrast, chemotherapeutics, biologics, and nonsteroidal anti-inflammatory medications, will be necessary to improve patient outcomes over the next decade. This will require further engagement and collaboration between primary care health care providers, allergists, and other specialists.

Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management.

BACKGROUND: Population-based data on the demographics and clinical characteristics of patients with multiple unrelated drug class intolerances noted in their medical records are lacking. OBJECTIVES: To provide population-based drug "allergy" incidence rates and prevalence, and to identify individuals with multiple drug intolerance syndrome (MDIS) defined by 3 or more unrelated drug class "allergies," and to provide demographic and clinical information on MDIS cases. METHODS: Electronic medical record data from 2,375,424 Kaiser Permanente Southern California health plan members who had a health care visit and at least 11 months of health care coverage during 2009 were reviewed. Population-based drug "allergy" incidence rates and prevalence were determined for 23 unrelated medication classes. RESULTS: On January 1, 2009, 478,283 (20.1%) health plan members had at least one reported "allergy." Individuals with a history of at least 1 "allergy" and females, in general, reported higher population-based new "allergy" incidence rates. Multiple drug intolerance syndrome was present in 49,582 (2.1%). The MDIS cases were significantly older, 62.4 ± 16.1 years; heavier, body mass index 29.3 ± 7.1; and likely to be female, 84.9%, compared with average health plan members. They had high rates of health care utilization, medication usage, and new drug "allergy" incidence. They sought medical attention for common nonmorbid conditions. CONCLUSIONS: Multiple drug intolerance syndrome is in part iatrogenic. It is associated with overweight elderly women who have high rates of health care and medication usage. Urticarial syndromes only explain a small fraction of MDIS cases. Multiple drug intolerance syndrome is associated with anxiety, but not predominately with immunoglobulin E (IgE)-mediated allergy or life-threatening illness. Multiple drug intolerance syndrome can be managed by medication avoidance and judicious rechallenge.

Population-Based Incidence, Severity, and Risk Factors Associated with Treated Acute-Onset COVID-19 mRNA Vaccination-Associated Hypersensitivity Reactions.

BACKGROUND: COVID-19 mRNA vaccination-associated acute-onset hypersensitivity reactions have caused anxiety and may be contributing to vaccine hesitancy. OBJECTIVE: To determine the incidence, severity, and risk factors for treated acute-onset COVID-19 mRNA vaccination-associated hypersensitivity reactions in a well-characterized population. METHODS: All Kaiser Permanente Southern California (KPSC) members who received COVID-19 mRNA vaccinations between December 15, 2020, and March 11, 2021, at a KPSC facility were identified and characterized, along with all treated acute-onset vaccination-associated hypersensitivity events. RESULTS: We identified 391,123 unique vaccine recipients (59.18% female, age 64.19 ± 17.86 years); 215,156 received 2 doses (53.54% Moderna), 157,615 only a first dose (50.13% Moderna) (1961 [1.46%] >2 weeks late getting a second dose), and 18,352 (74.43% Moderna) only a second dose. Only 104 (0.028%) (85.58% female, age 53.18 ± 15.96 years) had treated first dose events, 68 (0.030%) Moderna. Only 32 (0.014%) (93.75% female, age 57.28 ± 17.09 years) had treated second dose events, 21 (0.016%) Moderna. Only 2 (0.00033%) vaccinations resulted in anaphylaxis. Only 27 (20.77%) of those with treated first dose reactions failed to get a second dose. Only 6 of 77 (7.8%) with first dose reactions also had second dose reactions. Individuals with treated events were more likely to be female (P < .0001), younger (P < .0001), and had more pre-existing drug "allergies" (2.11 ± 2.12 vs 1.02 ± 1.41 [P < .0001] for average recipients). CONCLUSIONS: Treated acute-onset hypersensitivity events were mostly benign, more common with first COVID-19 mRNA vaccine doses, more likely to occur in younger females with typical risk factors associated with multiple drug intolerance syndrome, and very unlikely to be primarily immunologically mediated.

Population-Based Incidence of New Ampicillin, Cephalexin, Cefaclor, and Sulfonamide Antibiotic "Allergies" in Exposed Individuals with and without Preexisting Ampicillin, Cephalexin, or Cefaclor "Allergies".

BACKGROUND: There is a theoretical concern, unconfirmed by population-based challenge data, that clinically significant, immunologically mediated hypersensitivity occurs among ß-lactams sharing side chains. OBJECTIVE: To determine the population-based allergy incidence associated with the use of ß-lactams sharing exact R1 side chains (ampicillin, cephalexin, and cefaclor [ACC]), with or without a current ACC allergy or a sulfonamide antibiotic allergy for comparison. METHODS: All courses of ACC and trimethoprim-sulfamethoxazole used by any Kaiser Permanente California members in 2017 and 2018, with follow-up through January 2019, were identified along with their preexisting antibiotic allergy status and all new antibiotic-specific allergies reported within 30 days of course initiation. RESULTS: A total of 1,167,713 courses of ACC were administered to individuals with no sulfonamide antibiotic or ACC allergy and 4,771 new ACC allergies (0.41%) were reported. Moreover, 130,032 courses of ACC were administered to individuals with a sulfonamide antibiotic allergy and no ACC allergy, and 904 new ACC allergies (0.70%) were reported. There were 5,958 courses of ACC administered to individuals with an ACC allergy, 2,341 who also had sulfonamide antibiotic allergy, and 52 new ACC allergies (0.87%) were reported. CONCLUSIONS: The incidence of new ACC allergy reports is minimally and non-specifically increased among individuals with a preexisting ACC or sulfonamide antibiotic allergy compared to the baseline incidence in the population. This argues against clinically significant, immunologically mediated cross-reactivity among ß-lactams sharing exact side chains in individuals with preexisting but unconfirmed ß-lactam allergy. Any previously reported, even unrelated antibiotic allergy appears to be a risk factor for reporting a new antibiotic allergy.

Allergy Electronic Health Record Documentation: A 2022 Work Group Report of the AAAAI Adverse Reactions to Drugs, Biologicals, and Latex Committee.

The allergy section of the electronic health record (EHR) is ideally reviewed and updated by health care workers during routine outpatient visits, emergency room visits, inpatient hospitalizations, and surgical procedures. This EHR section has the potential to help proactively and comprehensively avoid exposures to drugs, contact irritants, foods, and other agents for which, based on an individual's medical history and/or genetics, there is increased risk for adverse outcomes with future exposures. Because clinical decisions are made and clinical decision support is triggered based on allergy details from the EHR, the allergy module needs to provide meaningful, accurate, timely, and comprehensive allergy information. Although the allergy section of the EHR must meet these requirements to guide appropriate clinical decisions and treatment plans, current EHR allergy modules have not achieved this standard. We urge EHR vendors to collaborate with allergists to optimize and modernize allergy documentation. A work group within the Adverse Reactions to Drugs, Biologicals, and Latex Committee of the American Academy of Allergy, Asthma & Immunology was formed to create recommendations for allergy documentation in the EHR. Whereas it is recognized that the term "allergy" is often used incorrectly because most adverse drug reactions (ADRs) are not true immune-mediated hypersensitivity reactions, "allergy" in this article includes allergies and hypersensitivities as well as side effects and intolerances. Our primary objective is to provide guidance for the current state of allergy documentation in the EHR. This guidance includes clarification of the definition of specific ADR types, reconciliation of confirmed ADRs, and removal of disproved or erroneous ADRs. This document includes a proposal for the creation, education, and implementation of a drug allergy labeling system that may allow for more accurate EHR documentation for improved patient safety.