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Background COVID-19 mRNA vaccination-associated acute-onset hypersensitivity reactions have caused anxiety and may be contributing to vaccine hesitancy. Objective 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 12-15-2020 and 3-11-2021 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) [1,961 (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 6/77 (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 preexisting drug “allergies” (2.11 ± 2.12 versus 1.02 ± 1.41 (p

Background There is a theoretical concern, unconfirmed by population-based challenge data, that clinically-significant immunologically-mediated hypersensitivity occurs between beta-lactams sharing side chains. Objective Determine the population-based “allergy” incidence associated with the use of beta-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 There were 1,167,713 courses of ACC administered to individuals with no sulfonamide antibiotic or ACC “allergy” and 4,771 (0.41%) new ACC “allergies” were reported. There were 130,032 courses of ACC administered to individuals with a sulfonamide antibiotic “allergy” and no ACC “allergy” and 904 (0.70%) new ACC “allergies” 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 (0.87%) new ACC “allergies” were reported. Conclusion The incidence of new ampicillin, cephalexin, or cefaclor “allergy” reports is minimally and non-specifically increased when a preexisting ACC or sulfonamide antibiotic “allergy” exists over the baseline incidence in the population. This argues against clinically-significant immunologically-mediated cross-reactivity between beta-lactams sharing exact side chains in individuals with pre-existing, but unconfirmed, beta-lactam “allergy”. Any previously reported, even unrelated, antibiotic “allergy” appears to be a risk factor for reporting a new antibiotic “allergy”.

It is now well-established that avoiding β-lactam antibiotics, when they are the drugs of choice, results in significantly worse long-term global outcomes for patients. Much of this avoidable morbidity has been caused by widespread warnings in electronic health care record systems not to use cephalosporins in the setting of penicillin allergy. High rates, up to 1000-fold higher than now seen, of immunologically mediated reactions were associated with early impure penicillin preparations. This instilled a rational fear of β-lactam-associated anaphylaxis in generations of physicians. In the late 1970s, several editorial comments regarding a potential increased risk to patients given cephalosporins who had a history of a penicillin allergy resulted in the warning that became imbedded in the culture of medicine. Over the past 40 years, compelling data have been developed that refute this warning and showed that the risks of avoiding cephalosporins outweighed the benefits. In late 2017, Kaiser Permanente Southern California completely removed all warnings not to use cephalosporins in the setting of a penicillin allergy. The results have recently been published in JAMA Network Open. This Rostrum article provides some of the backstory on the establishment and removal of this warning for physicians who trained over the past 30 years.

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.

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, AsthmaImmunology 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.

Biologic and other therapies used for the treatment of immune-mediated hypersensitivity conditions, and in people with immune-mediated hypersensitivity, can trigger a wide variety of immune-related adverse drug reactions and immunologically mediated drug hypersensitivities. These range from acute-onset immunoglobulin E-mediated allergies to delayed-onset T-cell-mediated hypersensitivities. Certain therapeutic and diagnostic agents can directly activate mast cells. Biologic agents used to treat immune-mediated hypersensitivity can also globally upregulate or downregulate the immune system leading to pathologic reactions, including cytokine storm and hypogammaglobulinemia.

Having a penicillin allergy label associates with worse healthcare outcomes and increased treatment costs.1-3 However, whether penicillin allergy testing is cost‐saving remains unclear, particularly as there is heterogeneity in the practice of such testing.4 Therefore, we developed an online questionnaire to assess the practice and cost perceptions of diagnostic tests used in penicillin allergy evaluation. Regarding cost perceptions, we asked respondents to estimate material, personnel, and facilities costs of performing each assessed diagnostic test. We also asked for estimates on the total paid amounts for each performed test (ie, perceived reimbursements by the State, insurance companies, or patients). Respondents provided a level of confidence (low, medium, or high) for each reported cost estimate. This questionnaire targeted drug allergy experts in Europe—we contacted European Network of Drug Allergy members by email, as well as first, last, and/or corresponding authors of publications in the field of drug allergy (our search was limited to publications of the last 10 years).

Introduction: About 8% of the United States population carries an unconfirmed penicillin 'allergy' in their medical record. Many physicians needlessly avoid other beta-lactam use in individuals with unconfirmed penicillin allergies. There is a significantly increased risk of developing serious antibiotic-resistant infections, and increased morbidity and mortality in those who report penicillin allergy. Areas covered: Within this study, we reviewed the relevant literature on self-reported beta-lactam allergy. We discuss how the myth of serious allergy to penicillin developed and then discuss and in detail clinically significant immunologically mediated hypersensitivity reactions. Following this discussion, we delineate the risks of not using a beta-lactam when it is the drug of choice and then discuss the epidemiology of beta-lactam-associated anaphylaxis, serious cutaneous adverse reactions, and serious systemic immunologically mediated reactions. Following these topics, we further discuss the consensus current best practices to de-label patients with reported penicillin allergy. Expert opinion: An unconfirmed allergy to penicillin offers considerable harm to patients. Many patients have low-risk allergy symptoms to penicillin who could likely tolerate the medication without having an allergic reaction. The current best practices to de-label reported penicillin allergy is the utilization of a single dose oral challenge, with 1 h of observation, in low-risk patients.

Background Without accurate data on deaths directly caused by asthma, prevention will be difficult. Objective To determine how often asthma could be confirmed as a proximal cause of death in a large well-defined population with active health plan membership and no acute barriers to medical care. Methods All deaths occurring in active Kaiser Permanente Southern California health plan members between 2007 and 2015 were identified. Asthma-coded deaths were manually audited for cause. Health care and asthma medication use in the 6 months before death were determined. Results There were 248 (0.80 per 100,000 patient-years) unaudited asthma-coded deaths. There were only 63 (26.5%) (0.20 per 100,000 patient-years) asthma-confirmed deaths. Individuals with asthma-confirmed deaths were younger, less likely to have ever smoked, and had fewer emergency visits in the 6 months before death compared with those with asthma excluded. Individuals with asthma-confirmed deaths used preventative inhalers at very low rates. We unexpectedly found that ever inclusion in the 2016 National Committee for Quality Assurance health effectiveness data and information set (HEDIS) for persistent asthma was associated with a higher risk of all-cause early death. Individuals with asthma-confirmed deaths were also unlikely to be in the HEDIS asthma dataset in the year they died, thus not targeted for outreach. Conclusions Audit-confirmed fatal asthma is more likely to occur in younger, nonsmoking, individuals, using very low rates of preventive inhalers. This will be a very difficult group to prospectively identify and manage effectively. Further research into the reasons for early death after HEDIS asthma dataset inclusion is warranted.

A new episode of urticaria and/or angioedema can be an anxiety-inducing event for both the patient and the physician(s) seeing them in primary care, urgent care, or the emergency department. These events are commonly mistaken for “allergic” reactions and often mistreated. The most common causes of new onset urticaria in older children and adults, with or without angioedema, and normal vital signs or hypertension, are post-infection or acute idiopathic urticaria. These patients are not helped by systemic steroids, which may cause morbidity. An IgE-mediated allergy is almost never the cause. These episodes are easy to manage and virtually never life-threatening. Acute idiopathic urticaria is treated with high-dose nonsedating antihistamines acute avoidance of alcohol and nonsteroidal anti-inflammatory drugs, and time. An epinephrine prescription is not indicated for onset acute urticaria or angioedema, unless there is a strong suspicion of anaphylaxis, and they have been acutely treated with epinephrine. When anaphylaxis is suspected, because of hypotension or hypoxia, the treatment of choice is intramuscular epinephrine and supportive care. An acute tryptase then needs to be obtained within 1 to 3 hours of symptom onset, prior to a referral to Allergy. Most angioedema, without itching or hives, is idiopathic. Treatment is supportive care and time. Antihistamines, epinephrine, and systemic corticosteroids are completely ineffective in treating idiopathic or bradykinin-mediated angioedema. Suspect hereditary or acquired angioedema if there is recurrent non-itchy swelling with abdominal pain triggered by mechanical trauma. Only check a C4 prior to a referral to Allergy for a formal diagnosis and long-term management.

As populations age, the prevalence of reported drug "allergy" increases, often leading to suboptimal care and increased morbidity because of unnecessary avoidance of safe and effective medications. Evaluation by a drug allergy specialist is often warranted when a patient has more than 2 unrelated drug "allergies" listed in the medical record. In this commentary, we clarify and propose standard terminology to use when evaluating patients with multiple drug allergy labels including and more specifically when diagnosing multiple drug intolerance syndrome and the much rarer multiple drug hypersensitivity syndrome. We review epidemiology and key features of multiple drug intolerance syndrome and multiple drug hypersensitivity syndrome. We summarize the methodologic and practical diagnostic workup and management of individuals with MDIS to assist with the accurate delabeling of drug "allergies" in the electronic health record.

BackgroundHaving 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.MethodsIn 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.ResultsPenicillin 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.ConclusionsPenicillin 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.

Key messages All individuals with an unconfirmed penicillin allergy should have their penicillin allergy evaluated, and if appropriate, tested to confirm current hypersensitivity or tolerance.

Antibiotics are the most common class of medications that individuals report allergy or intolerance to. Adverse reactions are reported at a predictable rate with all antibiotic use that vary by antibiotic. Antibiotic allergy incidence rates are sex dependent, higher in females than in males. Most of these events are not reproducible or immunologically mediated. Antibiotic allergy prevalence increases with increasing age and is more common in hospitalized populations and in populations that use more antibiotics. Determining potential mechanisms for the observed symptoms of the adverse reactions is the starting point for effective management of antibiotic hypersensitivity. Skin testing and direct challenges are the primary tools used to determine acute tolerance in 2017. Commercially available in vitro testing is not currently clinically useful in determining antibiotic hypersensitivity, with rare exceptions. Desensitization can be used when acute-onset immunologically mediated hypersensitivity is confirmed to safely administer a needed antibiotic. Desensitization is not possible when clinically significant T-cell-mediated delayed-type hypersensitivity is present. Effective management of antibiotic allergy is an important part of a comprehensive antibiotic stewardship program.

The effect that penicillin allergy testing has on future health care utilization is uncertain.Determine whether penicillin allergy testing affects future overall health care utilization as measured by outpatient department (OPD) visits, emergency department (ED) visits, and hospital days.Potential cases and control subjects were penicillin allergic Kaiser Permanente Southern California members who had at least 2 visits between 2010 and 2012 and at least 1 year of continuous health plan coverage before their index visit.It was possible to match 308 (73.2%) of the potential cases to 1251 unique controls, on the basis of age, sex, weighted Charlson comorbidity index, drug class allergies, OPD visits, ED visits, and hospital days during the years before their index visit. Cases and controls were then followed for an average of 3.6 and 4.0 years, respectively. Based on results analyzed using a generalized linear mixed model, cases were estimated to have 0.09 fewer OPD visits (P.001), 0.13 fewer ED visits (P = .29), and 0.55 fewer hospital days (P.001) per health plan coverage year during follow-up compared with controls. Cases were exposed to more penicillins and first- and second-generation cephalosporins and less clindamycin and macrolides.Penicillin allergy testing, primarily done in the setting of an outpatient Allergy consultation, was associated with significantly less health care utilization during 3.6+ years of follow-up and greater use of narrow-spectrum antibiotics. Penicillin allergy testing has a favorable cost-benefit ratio for the incremental cost of testing versus future health care utilization and improves antibiotic stewardship.

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.

Large health system databases have revolutionized our understanding of the epidemiology of adverse drug reactions and immunologically mediated drug hypersensitivity. Population-based background rates of newly reported drug intolerance with each therapeutic exposure could not have been determined without large health system databases. Large databases have increased our understanding of multiple drug intolerance syndrome. Large health care systems, such as Kaiser Permanente, with a single electronic medical record system that covers all inpatient, outpatient, and pharmacy interactions, are particularly valuable in understanding the population-based incidence of severe and nonsevere adverse drug reactions, the risks of delayed-onset adverse drug reactions, such as those caused by Clostridiodes difficile, which can occur months after antibiotic exposures, and the risks and benefits associated with "allergy" delabeling, specifically penicillin allergy delabeling, which may accrue in the years after the delabeling. There currently are limitations to using electronic data, specifically billing code data, when studying adverse drug reactions. It is critical to audit electronic health records, which have temporally associated the use of a drug and an adverse reaction because of high rates of miscoding or lack of true cause and effect. Pending improvements in drug hypersensitivity coding in International Classification of Diseases, Eleventh Revision may make large databases even more useful.

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. 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.

This cohort study assesses whether removal of a warning against use of cephalosporins in the electronic health record (EHR) of patients with penicillin allergy was associated with changes in the dispensing or administration of cephalosporins., Key Points Question Is removal of a warning to avoid cephalosporin use in patients with penicillin allergies associated with an increase in cephalosporin dispensing or administration? Findings In this cohort study of 4 398 792 patients who had received antibiotic treatment, after an alert in the electronic health record system to avoid prescribing of cephalosporins to patients with a penicillin allergy was removed at 1 of 2 health system sites, cephalosporin dispensing or administration increased significantly among patients with a penicillin allergy at that site compared with patients without a penicillin allergy at the same site and patients at the comparison site that retained the warning. Meaning In this study, removal of a warning in the electronic health record to avoid cephalosporin use in patients with penicillin allergies was associated with increased dispensing and administration of cephalosporin., Importance Electronic health records (EHRs) often include default alerts that can influence physician selection of antibiotics, which in turn may be associated with a suboptimal choice of agents and increased antibiotic resistance. Objective To examine whether removal of a default alert in the EHR to avoid cephalosporin use in patients with penicillin allergies is associated with changes in cephalosporin dispensing or administration in these patients. Design, Setting, and Participants This retrospective cohort study of a natural experiment included data on patients who had received antibiotic treatment in the hospital or outpatient setting in 2 regions of a large, integrated health system in California from January 1, 2017, to December 31, 2018. Of 4 398 792 patients, 4 206 480 met the eligibility criteria: enrollment in the health system during antibiotic use, availability of complete demographic data, and use of antibiotics outside of the washout period. Interventions or Exposures Oral or parenteral antibiotics dispensed or administered after removal of an EHR alert to avoid cephalosporin use in patients with a recorded penicillin allergy. Main Outcomes and Measures Probability that an antibiotic course was a cephalosporin. A multinomial logistic regression model was used to examine the change in rates of cephalosporin use before and after an EHR penicillin allergy alert was removed in 1 of the study regions. Temporal changes in use rates were controlled for by comparing changes in cephalosporin use among patients with or without a penicillin allergy at the site that removed the warning and among patients at a comparison site that retained the warning. Regression models were used to examine adverse events. Results Of the 4 206 480 patients who met all inclusion criteria, 2 465 849 (58.6%) were women; the mean (SD) age was 40.5 (23.2) years. A total of 10 652 014 antibiotic courses were administered or dispensed, divided approximately evenly between the period before and after removal of the warning. Before removal of an alert in the electronic health record system to avoid prescribing of cephalosporins to patients with a penicillin allergy at 1 of the 2 sites, 58 228 courses of cephalosporins (accounting for 17.9% of all antibiotic use at the site) were used among patients with a penicillin allergy; after removal of the alert, administration or dispensing of cephalosporins increased by 47% compared with cephalosporin administration or dispensing among patients without a penicillin allergy at the same site and patients at the comparison site that retained the warning (ratio of ratios of odds ratios [RROR], 1.47; 95% CI, 1.38-1.56) . No significant differences in anaphylaxis (9 total cases), new allergies (RROR, 1.02; 95% CI, 0.93-1.12), or treatment failures (RROR, 1.02; 95% CI, 0.99-1.05) were found at the course level. No significant differences were found in all-cause mortality (ratio of ratios of rate ratios [RRRR], 1.03; 95% CI, 0.94-1.13), hospital days (RRRR, 1.04; 95% CI, 0.99-1.10), and new infections (Clostridioides difficile: RRRR, 1.02; 95% CI, 0.84-1.22; methicillin-resistant Staphylococcus aureus: RRRR, 0.87; 95% CI, 0.75-1.00; and vancomycin-resistant Enterococcus: RRRR, 0.82; 95% CI, 0.55-1.22) at the patient level. Conclusions and Relevance In this cohort study, removal of a warning in the electronic health record to avoid cephalosporin use in patients with penicillin allergies was associated with increased administration and dispensing of cephalosporin. This simple and rapidly implementable system-level intervention may be useful for improvement in antibiotic stewardship.

β-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.Approximately 10% of the US population has reported allergies to the β-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 β-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.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 β-lactam antibiotics is an important tool for antimicrobial stewardship.

Limited population-based data on penicillin-, carbapenem-, monobactam-, and clindamycin-associated reported adverse reactions exist.To collect data on penicillin, carbapenem, monobactam, and clindamycin usage and associated adverse reactions.Data from January 1, 2009, to December 31, 2017, in Kaiser Permanente Southern California were collected.There were 6,144,422 unique individuals, mean age 33.6 ± 21.1 years, 52.2% females, with at least 1 health care visit during the 9-year study interval, for a total of 37,387,313 patient-years of follow-up. This population was exposed to 5,617,402 courses of oral penicillins, 370,478 courses of parenteral penicillins, 59,645 courses of parenteral carbapenems or monobactams, 817,232 courses of oral clindamycin, and 215,880 courses of parenteral clindamycin. New penicillin allergies were reported more commonly after parenteral (0.85%) compared with oral (0.74%) exposures (P.0001). There were 22 cases (1 in 255,320) of oral penicillin-associated anaphylaxis and 3 cases (1 in 123,792) of parenteral penicillin-associated anaphylaxis (P.001). There were 2 clindamycin-associated anaphylaxis cases, 1 (1 in 817,232) oral and 1 (1 in 215,880) parenteral. There were 2 (1 in 2,993,940) penicillin-associated serious cutaneous adverse reaction (SCAR) cases, but both also had co-trimoxazole coexposure within 45 days. There was 1 (1 in 1,033,112) clindamycin-associated SCAR. Clostridioides difficile infection was more common after parenteral exposures, and with extended-spectrum penicillins, beta-lactamase combinations, carbapenems, monobactam, and clindamycin exposures compared with oral penicillins or clindamycin.Only 1 of 1543 (0.065%) oral and 1 of 1030 (0.097%) parenteral penicillin-associated allergy reports were confirmed to be anaphylaxis. C. difficile was more common after parenteral versus oral penicillin, carbapenem, monobactam, and clindamycin exposures, and with broader spectrum antibiotic exposures.

All beta-lactam use is associated with a certain rate of adverse reactions. Many of these adverse reactions result in an allergy to the beta-lactam being entered into the patient's medical record. Unfortunately, only a small minority of these recorded allergies are clinically significant immunologically mediated drug hypersensitivity. An unconfirmed allergy to beta-lactams is a significant public health risk, because patients so labeled typically do not receive narrow-spectrum penicillins and cephalosporins when clinically indicated. The alternative antibiotics they receive result in poorer clinical outcomes, increased incidence of serious antibiotic-resistant infections, prolonged hospitalizations, and greater health care utilization. There is a wide variation in beta-lactam allergy incidence and prevalence around the world, based in part on the specific beta-lactams used and overused. There is a wide variation in specific protocols used to confirm current tolerance of beta-lactams and remove these inaccurate allergy reports. Harmonizing testing protocols, when possible, may lead to more widespread use of narrow-spectrum beta-lactams, when clinically indicated, and improve patient safety worldwide. Further research is needed to better understand the regional differences in reporting beta-lactam allergy as this relates to regional differences in beta-lactam use and overuse, the frequency of clinically significant immunologically mediated beta-lactam hypersensitivity, and the optimal testing strategies to confirm current tolerance, based on presenting clinical symptoms.

Radiocontrast-associated acute-onset hypersensitivity reactions now occur less frequently than before 1990, when high-osmolar, ionic, radiocontrast agents were widely used. Premedication with corticosteroids and antihistamines does not reliably prevent recurrent low-osmolar radiocontrast-associated acute hypersensitivity reactions. Corticosteroid prophylaxis for acute hypersensitivity currently causes more morbidity than benefit. The specific radiocontrast agent that is associated with a patient’s adverse reaction must be displayed in the drug intolerance or drug “allergy” field of their electronic health record to enable effective management and prevention of future reactions. The term iodine allergy should never be used in the context of radiocontrast-associated adverse reactions because it leads to poorer clinical outcomes. The time to onset of the reaction and the nature of the reaction must be noted in enough detail in the drug intolerance comment fields in the electronic health record to determine the potential mechanism for the reaction and to enable selection of the appropriate radiocontrast material for future exposures. Most individuals with a history of radiocontrast agent hypersensitivity can be effectively managed by selecting an alternative radiocontrast agent, without any premedication. Radiology Departments, catheterization laboratories, and all physicians who use parenteral radiocontrast media must have management plans in place to treat severe acute reactions when they occur. Patients should be informed that delayed-onset reactions, mostly benign rashes within one week of exposure, are as common or more common than acute reactions. Future radiocontrast-associated acute and delayed-onset reactions can be minimized, but never completely avoided, by using an appropriate alternative agent.

Unverified penicillin allergy is being increasingly recognized as a public health concern. The ideal protocol for verifying true clinically significant IgE-mediated penicillin allergy needs to use only commercially available materials, be well tolerated and easy to perform in both the inpatient and outpatient settings, and minimize false-positive determinations. This review concentrates on articles published in 2013 and 2014 that present new data relating to the diagnosis and management of penicillin allergy.Penicillin allergy can be safely evaluated at this time, in patients with an appropriate clinical history of penicillin allergy, using only penicilloyl-poly-lysine and native penicillin G as skin test reagents, if an oral challenge with amoxicillin 250 mg, followed by 1 h of observation, is given to all skin test negative individuals.Millions of individuals falsely labeled with penicillin allergy need to be evaluated to safely allow them to use penicillin-class antibiotics and avoid morbidity associated with penicillin avoidance. Further research is needed to determine optimal protocol(s). There will still be a 1-2% rate of adverse reactions reported with all future therapeutic penicillin-class antibiotic use, even with optimal methods used to determine acute penicillin tolerance. Only a small minority of these new reactions will be IgE-mediated.

Multiple drug intolerance syndrome (MDIS), defined as three or more unrelated drug intolerances reported in the medical record, is primarily an iatrogenic condition. All medications are associated with adverse reactions, these reactions are commonly misclassified as “allergies,” females are more likely to report adverse reactions than males, and drug “allergies” are very rarely confirmed or removed for the medical record. Thus, MDIS is most commonly found in elderly females with relatively high levels of healthcare and medication utilization. Immunologically mediated multiple drug hypersensitivity is extremely uncommon in individuals with multiple drug intolerance syndrome. The management of MDIS relies on avoidance of unnecessary drugs, substitution of alternative drugs when possible, and rechallenges when needed.

Penicillin is still the most commonly reported drug class allergy. An oral amoxicillin challenge is the current reference standard test for verifying a clinically significant IgE-mediated penicillin allergy or a delayed onset T cell–mediated penicillin hypersensitivity. Only a small minority of individuals with a penicillin allergy history, less than 5%, will have a positive oral challenge reaction. The risk of avoiding penicillins is currently much greater than the risk of penicillin allergy testing. Penicillin skin testing, using the major determinant penicilloyl-polylysine, is done to reduce the risk of serious acute oral challenge reactions in individuals with a recent history of a possible IgE-mediated reaction to penicillin or any history of penicillin-associated anaphylaxis. Currently available in vitro tests are not clinically useful in evaluating penicillin allergy. Oral penicillin desensitization can be used to enable individuals with clinically significant IgE-mediated penicillin allergy to safely use a single course of therapeutic penicillin. Individuals with T cell–mediated hypersensitivity cannot be desensitized.

Context The morbidity potentially associated with unverified penicillin allergy in pregnant women, with and without group B streptococcus (GBS) infections, is unknown. Penicillin allergy testing is safe during pregnancy but is done infrequently. Objective To determine morbidity associated with antibiotic use in a large cohort of pregnant women, with and without an unverified history of penicillin allergy, and with and without GBS. Design Retrospective. All pregnant women who delivered live infants in Kaiser Permanente Southern California between January 1, 2009, and December 31, 2014, were identified. Main outcome measures Penicillin allergy status at delivery, delivery method, maternal and infant hospital utilization, peripartum antibiotic exposures, new antibiotic-associated adverse drug reactions, and new Clostridium difficile infections. Results There were 170,379 unique women who had 201,316 pregnancies during the study period. There were 16,084 pregnancies in women with an active, but unverified, penicillin allergy at delivery. There were 42,524 pregnancies in GBS-positive women, and 3500 also had a penicillin allergy. Women with a penicillin allergy, with or without GBS, had significantly (about 10%) higher cesarean section rates and spent significantly more (about 0.1) days in the hospital after delivery. Among GBS-positive women, those with an unverified penicillin allergy were exposed to significantly more cefazolin, clindamycin, vancomycin, and gentamicin and had significantly higher rates of adverse drug reactions associated with all antibiotic use. Conclusions Unverified penicillin allergy is associated with more hospital utilization and additional morbidity. Penicillin allergy testing of pregnant women with a history of penicillin allergy may help reduce these unwanted outcomes.

Background Penicillin skin testing is rarely used to undiagnose penicillin "allergy" in the United States, partially because of concern that commercially available materials are inadequate. Objective We determined whether skin testing with only commercially available penicilloyl-poly-lysine and penicillin followed by an oral amoxicillin challenge, if skin test-negative, can safely identify clinically significant penicillin allergy. Methods Five hundred sequential persons with positive history of penicillin "allergy" were evaluated by skin testing with penicilloyl-poly-lysine and penicillin between June 8, 2010, and March 29, 2012. All persons with negative skin tests were given an oral amoxicillin challenge and observed for 1 hour. Results Persons undergoing penicillin allergy testing were representative of all health plan members with penicillin allergy. Only 4 persons (0.8%; 95% CI, 0.32%-2.03%) had a positive skin test result. Only 4 persons (0.8%; 95% CI, 0.32%-2.03%) had an acute objective oral amoxicillin challenge reaction. Fifteen persons (3.0%; 95% CI, 1.83%-4.98%) had subjective oral challenge reactions, either acute transient itching or dizziness. All were women and 11 (73.3%) had multiple drug intolerance syndrome. None had severe reactions or objective signs. These were not considered to be positive challenge reactions. Sixty-eight subjects (13.6%) who were negative on testing were exposed to 88 courses of penicillins during 90 days of follow-up. New reactions were reported after 4 courses (4.5%), 3 (75%) occurring in subjects with multiple drug intolerance syndrome. Conclusions Penicillin skin testing, using only penicilloyl-poly-lysine and penicillin, followed by oral amoxicillin challenge, if negative, can safely identify clinically significant IgE-mediated penicillin allergy in patients who use health care in the United States at this time.

International audience; AbstractDrug hypersensitivity reactions (DHRs) affect an unknown proportion of the general population, and are an important public health problem due to their potential to cause life-threatening anaphylaxis and rare severe cutaneous allergic reactions. DHR evaluations are frequently needed in both ambulatory and hospital settings and have a complex diagnosis that requires a detailed clinical history and other tests that may include in vitro tests and in vivo procedures such as skin tests and drug provocation tests. Although over the years both European and U.S. experts have published statements on general procedures for evaluating DHRs, a substantial discordance in their daily management exists. In this review, we highlight both the differences and the similarities between the European and U.S. perspectives. While a general consensus exists on the importance of skin tests for evaluating DHRs, concordance between Americans and Europeans exists solely regarding their use in immediate reactions and the fact that a confirmation of a presumptive diagnosis by drug provocation tests is often the only reliable way to establish a diagnosis. Finally, great heterogeneity exists in the application of in vitro tests, which require further study to be well validated.

Background: There is little prospective data on the antibiotics prescribed and the adverse reactions associated with their use after penicillin skin testing. Objective: Provide data on antibiotic use and new antibiotic “allergy” incidence after penicillin skin testing. Methods: All patients who had penicillin skin testing at our Medical Center between 1-1-2000 and 12-31-2004 were followed through 12-31-2009. All therapeutic antibiotic use and all new “allergies” listed in their electronic medical records were reviewed. Results: There were 1684 study subjects of whom 1191 (70.7%) were female. There were 118 (7.0%) positive to at least one penicillin skin test reagent and 3 (0.2%) were positive only to amoxicillin. The mean follow-up period was 4.5 ± 2.9 years. Subjects were exposed to a mean of 8.2 ± 10.5 therapeutic antibiotic courses during follow-up. The highest new antibiotic “allergy” incidence rates in skin test-negative subjects were noted for penicillins, 2.9%, and sulfonamides, 2.7%, p = 0.9097. Females had higher overall incidences of new antibiotic “allergy,” independent of skin test result. Penicillin skin test-negative females treated with penicillin had a nonsignificantly higher new penicillin “allergy” incidence, 3.3% per course versus 1.9% for males, p = 0.0644. Cephalosporins had new antibiotic “allergy” incidence rates not significantly different from tetracyclines, quinolones, macrolides, clindamycin, metronidazole, nitrofurantoin, and other antibiotics. Conclusions: Females had higher new antibiotic “allergy” incidence rates. New “allergy” to cephalosporins occurred no more frequently than with non-beta-lactam-antibiotics, independent of skin test result. Sulfonamide antibiotics were associated with the higher rates of new antibiotic “allergy” than cephalosporins.

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.

To assess acute sinusitis (AS) encounters in primary care (PC), urgent care (UC), and emergency department (ED) settings for adherence to recommendations to avoid low-value care.A retrospective, observational study of adult AS encounters (2010-2012) within a large integrated healthcare system.We compared ED and UC encounters with PC visits, adjusting for differences in patient characteristics.adherence to recommendations to avoid antibiotics and a computed tomography (CT) scan of the face, head, or sinuses.length of symptoms and adherence with AS recommendations.Of 152,774 AS encounters, 89.2% resulted in antibiotics and 1.1% resulted in a CT scan. Compared with PC encounters, ED encounters were less likely to result in antibiotics (adjusted odds ratio [AOR], 0.57; 95% CI, 0.50-0.65) but more likely to result in a CT scan (AOR, 59.4; 95% CI, 51.3-68.7), while UC encounters were more likely to result in both antibiotics (AOR, 1.12; 95% CI, 1.08-1.17) and CT imaging (AOR, 2.4; 95% CI, 2.1-2.7). Chart review of encounters resulting in antibiotics found that 50% were inappropriately prescribed for symptoms of ≤7 days' duration (95% CI, 41%-58%), while 35% were appropriately prescribed for symptoms of ≥14 days' duration (95% CI, 27%-44%). Only 29% (95% CI, 22%-36%) of encounters were consistent with guideline-adherent care.AS encounters in an integrated health system infrequently result in CT imaging, but antibiotic treatment is common. Differences exist across acute care settings, but improved antibiotic stewardship is needed in all settings.

Background The safety and utility of penicillin skin testing (PST) in pregnant women with a history of penicillin allergy and group B streptococcus (GBS) colonization have not been studied. Objectives To document the safety and utility of PST in pregnant women with a history of penicillin allergy and GBS colonization. Methods Pregnant GBS culture–positive women with a history compatible with an IgE-mediated or unknown reaction to a penicillin-class antibiotic were recruited for PST. If PST results were negative, penicillin-class antibiotics were recommended for GBS prophylaxis. Adverse reactions associated with PST or antibiotic use from the time of PST through delivery and 6 months post partum were reported. Results In 56 enrolled patients, there were only 2 mild adverse reactions (4%) associated with PST and 3 positive PST results (5%). Of the 53 PST-negative patients, 47 (89%) received at least 1 course of penicillin. There were 2 delayed-onset rashes associated with the use of intrapartum penicillins and 1 immediate-onset rash with intrapartum vancomycin therapy in a PST-positive woman. There were 7 reactions (6%) associated with 122 antibiotic courses administered. Conclusions Penicillin skin testing can be performed safely in pregnant women and, if the results are negative, allows penicillins to be used safely at delivery for GBS prophylaxis.