Drug allergy: A 2022 practice parameter update

Abstract

The Joint Task Force on Practice Parameters (JTFPP) is committed to ensuring that all guidelines are based on the best scientific evidence at the time of publication, and that such evidence is free of commercial bias to the greatest extent possible. Before confirming the selection of the workgroup chairpersons and members, the JTFPP discusses and resolves all relevant potential conflicts of interest (COI) of each potential workgroup member. The JTFPP recognizes that experts in a field are likely to have interests that could come into conflict with the development of a completely unbiased and objective guideline. Therefore, a process has been developed to acknowledge potential COI when making specific recommendations. To preserve the greatest transparency regarding potential COI, all members of the JTFPP and workgroup complete a COI disclosure form prior to beginning work on the practice parameter and again prior to the guideline submission for publication. These disclosure forms are published on the JTFPP website. During the review process there are additional measures to avoid bias. At the workgroup level, all the recommendations and discussion sections are reviewed by all workgroup members to ensure that content is appropriate and without apparent bias. If any recommendation or section is deemed to have apparent bias, it is appropriately revised, without the section author’s involvement, in an attempt to remove potential bias. In addition, the entire document is also reviewed by the JTFPP and any apparent bias is acknowledged and removed at that level. For each and every recommendation, a vote is required by the workgroup and JTFPP, and any member with any perceived COI is recused from that vote (and so explained in the document). Any dissenting votes that cannot be resolved are described and explained in the document. In a final stage of review, the practice parameter is sent to invited expert reviewers, selected by the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI). The document is also posted on the AAAAI and ACAAI websites for general membership and the public-at-large to review and offer comment. All reviewers must provide statements of potential COI. Although the JTFPP has the final responsibility for the content of the documents submitted for publication, each reviewer’s comments will be discussed and reviewers will receive written responses to comments when appropriate. The JTFPP members and workgroup members’ COI disclosure forms can be found at www.allergyparameters.org. The AAAAI and the ACAAI have jointly accepted responsibility for developing the “Drug allergy 2022: a practice parameter update.” The medical environment is rapidly changing, and not all recommendations will be appropriate or applicable to all patients and may change over time. Because this document incorporates the efforts of many participants, no single individual, including members serving on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of this practice parameter. Any request for information or interpretation of this practice parameter by the AAAAI or ACAAI should be directed to the executive offices of the AAAAI and the ACAAI. Practice parameters and guidelines are not designed for use by the pharmaceutical industry in drug development or promotion. The JTFPP understands that the cost of diagnostic tests and therapeutic interventions is an important concern that may appropriately influence the evaluation and treatment selected for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication may vary, for example, depending on third-party payer issues and product patent expiration dates. However, because a given test or a therapeutic intervention’s cost is so widely variable, and there is a relative paucity of pharmacoeconomic data, the JTFPP is not always able to consider cost when formulating recommendations. In extraordinary circumstances, when the cost benefit of an intervention is prohibitive as supported by pharmacoeconomic data, commentary may be provided. Drug allergy: A 2022 practice parameter updateAbbreviationsPrefaceGlossaryWhat’s new and what’s differentExecutive summary Classification of drug allergies Diagnostic tests Antibiotic allergyPenicillinCephalosporinsBeta-lactam cross-reactivitySulfonamidesFluoroquinolonesMacrolides NSAID hypersensitivity Cancer chemotherapeuticsPlatinsTaxanesTyrosine kinase inhibitors Immune checkpoint inhibitors BiologicsRituximabCetuximabInfliximabOmalizumab ExcipientsMethods and overview of the practice parameter development processList of consensus based statementsDiagnostic testing updates Drug challenges Testing for delayed HSRsOverviewTesting for delayed HSRsIn vivo testing (PT and dIDT)Ex vivo and in vitro testing PharmacogenomicsPharmacogenomics of drug allergyImmediate and accelerated reactionsDelayed reactionsSummary of pharmacogenomicsAntibiotic allergy updates Beta-lactamsPenicillinPenicillin skin testingPreventing reacquisition of a penicillin allergy labelCephalosporinsCarbapenemsMonobactams (aztreonam)Drug allergy history-based beta-lactam allergy pathways Sulfonamides Fluoroquinolones and macrolidesFluoroquinolonesMacrolidesNSAID hypersensitivity updates Aspirin/NSAID hypersensitivity phenotypes Aspirin-exacerbated respiratory diseaseManagement of AERD—challenge and desensitizationManagement of AERD—aspirin as therapy NSAID-exacerbated cutaneous diseaseManagement of NSAID-exacerbated cutaneous disease Multiple NSAID-induced urticaria and angioedemaManagement of NSAID-induced urticaria and angioedema Single NSAID induced urticaria, angioedema, and anaphylaxisManagement of single NSAID reactors Other NSAID hypersensitivity subtypes Common NSAID hypersensitivity clinical scenariosUrgent requirement for aspirin in a patient with an acute coronary syndromeA patient requiring NSAID use for pain NSAID hypersensitivity in children Clopidogrel hypersensitivityCancer chemotherapeutic hypersensitivity Platins Taxanes Asparaginase Tyrosine kinase inhibitorsAdverse reactions to ICIsBiologic hypersensitivity Rituximab Cetuximab Infliximab Tocilizumab OmalizumabExcipients allergyReferences This practice parameter provides an updated approach to the diagnosis and management of various drug reactions. Evidence has evolved since the previous drug allergy practice parameter1Joint Task Force on Practice ParametersDrug allergy: an updated practice parameter.Ann Allergy Asthma Immunol. 2010; 105: 259-273Google Scholar and currently supports the ability to risk stratify most patients based on reaction phenotype. Evaluation of suspected drug allergy focuses on preferential use of drug challenges as opposed to skin testing in many circumstances. Clarification of drug allergy history is a valuable resource that allergist-immunologists provide to patients with shared decision making regarding testing and management options central to each evaluation. These parameters will help clinicians better understand how and when to use drug challenges, including consideration for 1-, 2-, or multistep challenges. While currently, 2-step challenges are required for reimbursement in the United States, the literature supports the use of single-step challenges in certain situations, and we are optimistic that third-party payers will reimburse this procedure in the future. A proactive approach to delabeling penicillin allergy as well as use of safe antibiotic alternatives for patients with proven penicillin allergy is emphasized. Approaches to diagnosis and management of nonpenicillin drug reactions are discussed in updated sections on cephalosporins, sulfonamides, fluroquinolones, macrolides, aspirin, chemotherapeutic agents, and biologics. This comprehensive resource provides consensus-based statements (CBSs) throughout, as well as detailed background and discussion to assist implementation into clinical practice. Allergy: For the purpose of this practice parameter, the terms “allergy” and “hypersensitivity” will be used interchangeably, and both indicate an abnormal immune response. The inclusion of both types of nomenclature reflects the variable use of these terms in the collective literature on this topic. Delayed hypersensitivity reaction: Immunologic-mediated reaction occurring at least 6 hours after dosing, with majority occurring 1-2 weeks after drug initiation. Delayed intradermal testing (dIDT): Intradermal injection of nonirritating drug concentration on the volar aspect of the forearm followed by evaluation for induration 24 hours after application. Desensitization: A form of temporary induction of drug tolerance typically for IgE-mediated reactions through administration of multiple gradually increasing doses of a drug to allow for treatment. Maintaining exposure to the drug is required to continue temporary induction of tolerance. In this practice parameter, we preferentially use “induction of drug tolerance.” Direct challenge: Performing drug challenge without prior skin testing. Drug challenge: Procedure whereby drug is administered to determine tolerance. Preferred nomenclature compared with “drug provocation tests” or “test doses,” which imply intent to provoke a reaction. Drug challenge, 1-step: One treatment dose of the drug is administered, followed by observation for objective symptoms of reaction. Drug challenge, 2-step: One-tenth of the treatment dose of the drug is administered, followed 20-30 minutes later by 90% of the treatment dose if no symptoms occur. Drug challenge, multiple days: Treatment dose of the drug is administered daily at home for 5-10 days. Induction of drug tolerance: Administration of multiple gradually increasing doses of a drug to allow for treatment. Ongoing consistent exposure to the drug is required to maintain tolerance. Infusion reactions: Unpredictable adverse reactions unrelated to known side effects from a drug. They are commonly associated with mAbs. Latency period: Time from first exposure to a drug to the time reaction occurs. Nocebo effect: Objective or subjective symptoms occurring after administration of a placebo dose. Penicillin major determinant: Detects the greatest number of patients with IgE-mediated penicillin allergy through skin testing. This is penicilloyl-polylysine (PPL; Pre-Pen, ALK-Abelló, Hørsholm, Denmark). Penicillin minor determinants: Penicillin G, penicilloate, penilloate. Pharmacogenomics: The study of how genetic variations affect responses to medications. Phenotype: Observable clinical characteristics associated with interactions from specific exposures. Structurally dissimilar: Cephalosporins that have disparate R1 side chains from other cephalosporins or aminopenicillins. Verified allergy: A patient with a verified drug allergy has confirmed their allergy via skin testing and/or challenge. All of the updated sections contain significant new information and recommendations compared with the previous 2010 updated drug allergy practice parameter.1Joint Task Force on Practice ParametersDrug allergy: an updated practice parameter.Ann Allergy Asthma Immunol. 2010; 105: 259-273Google Scholar Compared with the previous update, there is an overall de-emphasis on the use of skin testing as compared with drug challenge, particularly for the majority of patients who present with nonanaphylactic, nonsevere cutaneous drug allergy histories. In addition, more emphasis is placed on risk stratification based on reaction phenotype as well as the role for shared decision making in diagnostic testing and management. Some of the most important changes in this updated practice parameter are as follows:•Recommendation to define a positive skin test as a wheal that is ≥3 mm than the negative control for prick/puncture or intradermal tests accompanied by a ≥5 mm flare•Suggestion to use of 1- or 2-step drug challenges for low-risk patients•Suggestion to use placebo challenges in patients with subjective symptoms or multiple reported drug allergies•Suggestion to consider dIDT and/or patch tests (PTs) to identify culprit drugs for specific phenotypes of delayed drug reactions where the implicated agent is uncertain•Recognition that most pharmacogenetic associations identified to date are currently unlikely to translate into clinical practice•Recommendation for proactive penicillin allergy delabeling•Recommendation against multiple-day challenges in evaluation of most cases of suspected penicillin allergy•Recommendation against penicillin skin testing prior to direct amoxicillin challenge in low-risk pediatric patients•Consideration for direct amoxicillin challenge in adults with low-risk penicillin allergy histories•Recognition that patients with selective allergic reactions to piperacillin-tazobactam may be identified with skin tests to piperacillin-tazobactam and may tolerate other penicillins•Suggestion to perform direct challenge to cephalosporins with dissimilar side chains in patients with nonanaphylactic cephalosporin allergy•Suggestion to perform skin tests to parenteral cephalosporins with nonidentical R1 side chains (prior to challenge) in patients with anaphylactic cephalosporin allergy•Specific guidance on administration of cephalosporins to patients with various phenotypes of penicillin allergy•Specific guidance on administration of penicillins to patients with various phenotypes of cephalosporin allergy•Suggestion to administer carbapenems without prior testing in patients with other beta-lactam allergies•Recommendation that allergist-immunologists collaborate with hospitals and health care systems to implement beta-lactam allergy pathways to improve antibiotic stewardship outcomes•Suggestion to use a 1-step trimethoprim-sulfamethoxazole (TMP-SMX) challenge rather than desensitization for low-risk patients where there is a need to delabel sulfonamide allergy•Suggestion to use 1- or 2-step drug challenge for nonanaphylactic reactions to fluoroquinolones or macrolides without preceding skin testing•Recommendation against aspirin challenge to confirm a diagnosis of aspirin-exacerbated respiratory disease (AERD) in cases of high diagnostic certainty based on history but that aspirin desensitization remains a therapeutic option when indicated•Suggestion for oral aspirin challenge only in patients where there is diagnostic uncertainty of AERD•Suggestion that COX-2 inhibitors may be used in any nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity phenotype when an NSAID is needed•Suggestion to use oral aspirin challenge in patients with NSAID-induced urticaria/angioedema to determine tolerance to other NSAIDs•Suggestion for 2-step aspirin challenge (not desensitization) for patients with a history of non-AERD aspirin allergy in acute need of aspirin for cardiovascular disease•Suggestion that patients with non-IgE chemotherapy or biologic reactions be treated with slowed infusion rate, graded dose escalation, and/or premedications without desensitization•Suggestion that for patients with immediate reactions to taxanes, the severity of the initial reaction may assist in risk stratification and management•Suggestion that patients with non-IgE reactions to mAbs may be treated with a slowed infusion, graded dose escalation, and/or premedication without desensitization•Recognition that excipient allergy is very rare but may be considered in patients with anaphylaxis to ≥2 structurally unrelated products that share a common excipient The primary focus of the drug allergy practice parameter historically has been to provide suggestions and recommendations for the proper diagnosis and management of the spectrum of drug hypersensitivity reactions (HSRs). Since the most recent update in 2010, which was a comprehensive review on the topic of drug allergy at the time, our understanding of several areas in the field has changed.1Joint Task Force on Practice ParametersDrug allergy: an updated practice parameter.Ann Allergy Asthma Immunol. 2010; 105: 259-273Google Scholar This current update is a focused update on sections that the workgroup deemed to have significant changes from (or were not addressed in) the 2010 parameter. This update is not meant to be a comprehensive overview of drug hypersensitivity reactions as was the 2010 update, but rather this parameter is a focused update that will provide important suggestions and recommendations for the management of a variety of drug HSRs. The classification for drug HSRs has evolved. Allergic drug reactions can be classified based on chronology, mechanism, and clinical phenotypes. The chronology of drug allergic reactions is generally simplified into either immediate or delayed reactions. Immediate reactions are generally considered to occur within 1 hour but in some cases ≤6 hours of exposure to the drug.2Demoly P. Adkinson N.F. Brockow K. Castells M. Chiriac A.M. Greenberger P.A. et al.International consensus on drug allergy.Allergy. 2014; 69: 420-437Google Scholar,3Muraro A. Lemanske Jr., R.F. Castells M. Torres M.J. Khan D. Simon H.U. et al.Precision medicine in allergic disease-food allergy, drug allergy, and anaphylaxis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology.Allergy. 2017; 72: 1006-1021Google Scholar Phenotypically, immediate drug reactions may present with urticaria, angioedema, bronchospasm, or in severe cases, anaphylaxis. Immediate reactions are often IgE-mediated, but IgE-independent reactions can also occur. Recently, MRGPRX2 on mast cells has been found to be responsible for non-IgE–mediated reactions to drugs such as vancomycin, neuromuscular blocking agents, and fluoroquinolones.4McNeil B.D. Pundir P. Meeker S. Han L. Undem B.J. Kulka M. et al.Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.Nature. 2015; 519: 237-241Google Scholar Delayed HSRs often evolve over days or, in some cases, weeks following exposure to the drug. There are numerous clinical phenotypes of delayed HSRs with the most common being benign (eg, morbilliform drug eruption) exanthems.5Khan D.A. Cutaneous drug reactions.J Allergy Clin Immunol. 2012; 130: 1225-e6Google Scholar More severe delayed drug HSRs include the well-described phenotypes of drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and Stevens-Johnson syndrome (STS)/toxic epidermal necrolysis (TEN).6Peter J.G. Lehloenya R. Dlamini S. Risma K. White K.D. Konvinse K.C. et al.Severe delayed cutaneous and systemic reactions to drugs: a global perspective on the science and art of current practice.J Allergy Clin Immunol Pract. 2017; 5: 547-563Google Scholar Collectively these syndromes are referred to as severe cutaneous adverse reactions (SCARs). The immunologic mechanisms for delayed HSRs are likely related to drug-specific T cells including TH1, TH2, and cytotoxic T cells, depending on the phenotype.6Peter J.G. Lehloenya R. Dlamini S. Risma K. White K.D. Konvinse K.C. et al.Severe delayed cutaneous and systemic reactions to drugs: a global perspective on the science and art of current practice.J Allergy Clin Immunol Pract. 2017; 5: 547-563Google Scholar Serum sickness-like reactions (SSLRs) are another phenotype of delayed drug reactions that have clinical manifestations very similar to immune complex–mediated serum sickness, but the immunopathology of SSLRs is still not entirely clear. SSLR are characterized by urticaria-like (lesions persist >24 hours) and erythema multiforme-like lesions, joint inflammation, and fever, but unlike serum sickness, nephrotoxicity and hypocomplementemia are rare. There are also a number of organ-specific delayed drug reaction phenotypes (often without cutaneous manifestations) including drug-induced cytopenias, liver injury, interstitial nephritis, and vasculitis to name a few. These primarily noncutaneous organ-specific reactions will not be addressed in this update but have been reviewed in the prior update.1Joint Task Force on Practice ParametersDrug allergy: an updated practice parameter.Ann Allergy Asthma Immunol. 2010; 105: 259-273Google Scholar The chronology of various drug HSRs is shown in Fig 1. In the United States, diagnostic tests for drug allergies are based primarily on immediate skin testing and drug challenges. Delayed drug skin testing including dIDT and PT have an evolving role in the diagnosis of certain phenotypes of delayed HSRs.7Barbaud A. Collet E. Milpied B. Assier H. Staumont D. Avenel-Audran M. et al.A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions.Br J Dermatol. 2013; 168: 555-562Google Scholar In vitro testing for drug allergy with tests such as basophil activation tests, lymphocyte transformation tests, and other testing does not have any well-validated commercial assays in the United States and will not be discussed in this parameter. While skin testing is often performed with drug hypersensitivity evaluations, the accuracy of skin tests for most drugs is unclear. Furthermore, there has not been agreement on what even constitutes a positive skin test. The workgroup now recommends that a positive prick/puncture or intradermal skin test is to be defined as a wheal that is ≥3 mm than the negative control accompanied by a ≥5 mm flare. Recently, studies have shown an optimal method for reproducible intradermal antibiotic skin testing.8Barbaud A. Weinborn M. Garvey L.H. Testi S. Kvedariene V. Bavbek S. et al.Intradermal tests with drugs: an approach to standardization.Front Med. 2020; 7: 156Google Scholar Fluid should be drawn out first by filling the syringe with a larger volume (0.05-0.07 mL) and expelling the excess fluid and air bubbles to obtain 0.02 mL, then injecting to produce a baseline 3-5 mm bleb. While immediate skin testing is often employed in the evaluation of drug HSRs, as will be discussed later in the parameter, skin testing primarily is of most value in patients with histories of drug-induced anaphylaxis. The majority of patients who have more benign, nonanaphylactic reactions may be managed without drug skin testing. Evidence for all testing modalities for delayed HSRs is limited and of low certainty, generally based on small case series without drug challenge; hence, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) cannot be reliably calculated. However, in certain situations such as a patient with DRESS syndrome where several causal agents are potentially implicated, delayed skin testing may be considered to help identify the potential culprit. While the accuracy of delayed drug skin testing is unclear, it appears to be safe when performed at least 6 weeks to 6 months following healing of the drug reaction.7Barbaud A. Collet E. Milpied B. Assier H. Staumont D. Avenel-Audran M. et al.A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions.Br J Dermatol. 2013; 168: 555-562Google Scholar In contrast to drug skin testing, drug challenges are considered the reference standard for determining tolerance to a drug. A number of terms have been used to describe this procedure including “drug provocation tests,” “graded challenges,” and “test doses.” The term “drug challenge” is recommended as this is in keeping with other allergic diseases (eg, food challenges, sting challenges). While “drug provocation” is commonly used in the international literature, we do not recommend this term as the intent is to show tolerance rather than to provoke a reaction. Drug challenges may be given in an incremental (graded) fashion but can also be administered as a single dose. Drug challenges can be performed for both immediate and delayed phenotypes of drug reactions. There are contraindications to drug challenges that are outlined later in this parameter. In most scenarios, drug challenges are performed when the clinical probability of a drug allergy is low. In these circumstances, drug challenges can be performed with a 1- or 2-step drug challenge. A 1-step challenge would involve administering a therapeutic dose of the drug as a single step. In contrast, a 2-step challenge would involve first administering a smaller dose, such as 10%-25% of the final dose with observation, followed by administration of the rest of the dose 20-30 minutes later. Patients with primarily subjective symptoms or those who have multiple reported drug allergies should be considered for placebo-controlled drug challenges.9Kao L. Rajan J. Roy L. Kavosh E. Khan D.A. Adverse reactions during drug challenges: a single US institution's experience.Ann Allergy Asthma Immunol. 2013; 110: 86-91.e1Google Scholar Most pharmacogenomic associations identified to date are currently unlikely to translate into clinical practice.10Khan D.A. Pharmacogenomics and adverse drug reactions: primetime and not ready for primetime tests.J Allergy Clin Immunol. 2016; 138: 943-955Google Scholar A few genetic associations with serious immunologically mediated HSRs have been described.11Garon S.L. Pavlos R.K. White K.D. Brown N.J. Stone Jr., C.A. Phillips E.J. Pharmacogenomics of off-target adverse drug reactions.Br J Clin Pharmacol. 2017; 83: 1896-1911Google Scholar,12White K.D. Chung W.H. Hung S.I. Mallal S. Phillips E.J. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response.J Allergy Clin Immunol. 2015; 136 (quiz 35): 219-234Google Scholar Screening for these specific HLA associations is helpful in reducing HSRs for a few drugs and specific populations. Currently, genetic testing is not typically used for diagnostic purposes; however, this may evolve as more routine single HLA markers and other genotyping strategies become available that associate with clinical evidence for use in both screening and allergy diagnosis. In recent years, many important updates regarding optimal diagnostic strategies for antibiotic allergies have been published. In this parameter, updates regarding beta-lactams including penicillins, cephalosporins, carbapenems, and monobactams will be discussed. In addition, important changes to diagnostic strategies for sulfonamides, fluoroquinolones, and macrolides will also be reviewed. Since the last practice parameter update on drug allergy, several lines of evidence have pointed to the fact that a label of penicillin allergy is not benign.13Castells M. Khan D.A. Phillips E.J. Penicillin allergy.N Engl J Med. 2019; 381: 2338-2351Google Scholar Patients with a history of penicillin allergy are more likely to be treated with less effective, more toxic, or more expensive antibiotics, leading to increased cost, antibiotic-associated infections, longer hospital stays, and even increased mortality.14Bertram C.M. Postelnick M. Mancini C.M. Fu X. Zhang Y. Schulz L.T. et al.Association of beta-lactam allergy documentation and prophylactic antibiotic use in surgery: a national cross-sectional study of hospitalized patients.Clin Infect Dis. 2021; 72: e872-e875Google Scholar, 15Blumenthal K.G. Kuper K. Schulz L.T. Bhowmick T. Postelnick M. Lee F. et al.Association between penicillin allergy documentation and antibiotic use.JAMA Intern Med. 2020; 180: 1120-1122Google Scholar, 16Blumenthal K.G. Shenoy E.S. Huang M. Kuhlen J.L. Ware W.A. Parker R.A. et al.The impact of reporting a prior penicillin allergy on the treatment of methicillin-sensitive Staphylococcus aureus bacteremia.PLoS One. 2016; 11e0159406Google Scholar, 17Blumenthal K.G. Lu N. Zhang Y. Li Y. Walensky R.P. Choi H.K. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study.BMJ. 2018; 361k2400Google Scholar, 18Macy E. Contreras R. Health care use and serious infection prevalence associated with penicillin "allergy" in hospitalized patients: a cohort study.J Allergy Clin Immunol. 2014; 133: 790-796Google Scholar, 19Blumenthal K.G. Lu N. Zhang Y. Walensky R.P. Choi H.K. Recorded penicillin allergy and risk of mortality: a population-based matched cohort study.J Gen Intern Med. 2019; 34: 1685-1687Google Scholar Cost and simulation model-based economic studies support that penicillin allergy assessment is a cost-saving intervention.20Sousa-Pinto B. Blumenthal K.G. Macy E. Pereira A.M. Azevedo L.F. Delgado L. et al.Penicillin allergy testing is cost-saving: an economic evaluation study.Clin Infect Dis. 2021; 72: 924-938Google Scholar,21Blumenthal K.G. Li Y. Banerji A. Yun B.J. Long A.A. Walensky R.P. The cost of penicillin allergy evaluation.J Allergy Clin Immunol Pract. 2018; 6: 1019-1027.e2Google Scholar Therefore, a proactive effort should be made to delabel penicillin allergy whenever possible, and strong efforts should be made to educate about the benefits of delabeling to patients and clinicians. There are multiple strategies for penicillin allergy delabeling that are primarily based on the history of the reaction and patient comorbidities. While penicillin skin testing has been the most carefully studied skin test reagent for drug allergy, we suggest penicillin skin testing primarily for patients with a history of anaphylaxis or a recent reaction suspected to be IgE-mediated (eg, immediate onset urticaria).22Sabato V. Gaeta F. Valluzzi R.L. Van Gasse A. Ebo D.G. Romano A. Urticaria: the 1-1-1 criterion for optimized risk stratification in beta-lactam allergy delabeling.J Allergy Clin Immunol Pract. 2021; 9: 3697-3704Google Scholar For most other patients with histories of penicillin allergy that are remote and benign, direct challenge without preceding skin testing is the preferred approach. Patient histories are not always accurate