Controversies in Drug Allergy: Drug Allergy Pathways

Abstract

Drug allergy pathways are standardized approaches for patients reporting prior drug allergies with the aim of quality improvement and promotion of antibiotic stewardship. At the International Drug Allergy Symposium during the 2018 American Academy of Allergy, Asthma, and Immunology/World Allergy Organization Joint Congress in Orlando, Florida, drug allergy pathways were discussed from international perspectives with a focus on beta-lactam allergy pathways and pragmatic approaches for acute care hospitals. In this expert consensus document, we review current pathways, and detail important considerations in devising, implementing, and evaluating beta-lactam allergy pathways for hospitalized patients. We describe the key patient and institutional factors that must be considered in risk stratification, the central feature of pathway design. We detail shared obstacles to widespread beta-lactam allergy pathway implementation and identify potential solutions to address these challenges.

Keywords: Adverse drug reaction; Allergy; Beta-lactam; Drug; Graded challenge; Guideline; Hypersensitivity; Penicillin; Policy; Quality improvement; Skin test; Stewardship; Test dose.

Figure 1.

Drug allergy pathways that include both history tools and guidance on beta-lactam prescriptions. A. Partners HealthCare System (Boston, MA, USA) Penicillin (A1) and cephalosporin (A2) hypersensitivity pathways with optional computerized clinical decision support (A3) (Boston, MA, USA). These pathways were originally used with a history tool at Massachusetts General Hospital (Figure 2A), with subsequent modification into an electronic App that is provider-facing and uses the patient-reported history and available patient records. This pathway is active throughout hospitals affiliated with Partners HealthCare System (PHS), and has been adopted by other hospitals in the US. The App uses patient-reported clinical history to group patients into one of the three reaction groups and is currently only available for use at PHS hospitals. Research studies on this pathway demonstrate its safety, and its association with an increase in beta-lactam antibiotic use and increase first-line therapies for some inpatient infections.^,, PHS hospitals performed over 1,000 drug challenges (test doses) per year with this infrastructure. * Antibiotic-stewardship program restricted antibiotics Abbreviations: PCN, penicillin B. Computerized clinical decision support system (Birmingham, UK) This computerized clinical decision support system (CDSS, Birmingham, UK) begins with an electronic questionnaire that is available as an App to assist providers in taking the allergy history. The computer uses entered information to stratify patients into high and low risk allergy groups (B1) with subsequent suggested actions (B2). High risk included patient acuity, high risk delayed reactions such as Stevens Johnson syndrome and organ involvement), and (1) rash <1 hour after first dose; 2) isolated hypotension, (3) upper or lower airway involvement, or (4) clinical features of anaphylaxis. Low risk patients are given direct amoxicillin challenge, with 1 hour observation. C. Australian Therapeutic Guidelines (Melbourne, Australia) Suggested management of patients reporting penicillin hypersensitivity in whom a beta-lactam antibiotic is definitely required (Therapeutic Guidelines, Melbourne, Australia). This is a national antibiotic prescribing document, available online for all physicians to reference in Australia. Most hospitals in Australia base their institutional guidelines on this national guideline.

Figure 1.

Drug allergy pathways that include both history tools and guidance on beta-lactam prescriptions. A. Partners HealthCare System (Boston, MA, USA) Penicillin (A1) and cephalosporin (A2) hypersensitivity pathways with optional computerized clinical decision support (A3) (Boston, MA, USA). These pathways were originally used with a history tool at Massachusetts General Hospital (Figure 2A), with subsequent modification into an electronic App that is provider-facing and uses the patient-reported history and available patient records. This pathway is active throughout hospitals affiliated with Partners HealthCare System (PHS), and has been adopted by other hospitals in the US. The App uses patient-reported clinical history to group patients into one of the three reaction groups and is currently only available for use at PHS hospitals. Research studies on this pathway demonstrate its safety, and its association with an increase in beta-lactam antibiotic use and increase first-line therapies for some inpatient infections.^,, PHS hospitals performed over 1,000 drug challenges (test doses) per year with this infrastructure. * Antibiotic-stewardship program restricted antibiotics Abbreviations: PCN, penicillin B. Computerized clinical decision support system (Birmingham, UK) This computerized clinical decision support system (CDSS, Birmingham, UK) begins with an electronic questionnaire that is available as an App to assist providers in taking the allergy history. The computer uses entered information to stratify patients into high and low risk allergy groups (B1) with subsequent suggested actions (B2). High risk included patient acuity, high risk delayed reactions such as Stevens Johnson syndrome and organ involvement), and (1) rash <1 hour after first dose; 2) isolated hypotension, (3) upper or lower airway involvement, or (4) clinical features of anaphylaxis. Low risk patients are given direct amoxicillin challenge, with 1 hour observation. C. Australian Therapeutic Guidelines (Melbourne, Australia) Suggested management of patients reporting penicillin hypersensitivity in whom a beta-lactam antibiotic is definitely required (Therapeutic Guidelines, Melbourne, Australia). This is a national antibiotic prescribing document, available online for all physicians to reference in Australia. Most hospitals in Australia base their institutional guidelines on this national guideline.

Figure 1.

Drug allergy pathways that include both history tools and guidance on beta-lactam prescriptions. A. Partners HealthCare System (Boston, MA, USA) Penicillin (A1) and cephalosporin (A2) hypersensitivity pathways with optional computerized clinical decision support (A3) (Boston, MA, USA). These pathways were originally used with a history tool at Massachusetts General Hospital (Figure 2A), with subsequent modification into an electronic App that is provider-facing and uses the patient-reported history and available patient records. This pathway is active throughout hospitals affiliated with Partners HealthCare System (PHS), and has been adopted by other hospitals in the US. The App uses patient-reported clinical history to group patients into one of the three reaction groups and is currently only available for use at PHS hospitals. Research studies on this pathway demonstrate its safety, and its association with an increase in beta-lactam antibiotic use and increase first-line therapies for some inpatient infections.^,, PHS hospitals performed over 1,000 drug challenges (test doses) per year with this infrastructure. * Antibiotic-stewardship program restricted antibiotics Abbreviations: PCN, penicillin B. Computerized clinical decision support system (Birmingham, UK) This computerized clinical decision support system (CDSS, Birmingham, UK) begins with an electronic questionnaire that is available as an App to assist providers in taking the allergy history. The computer uses entered information to stratify patients into high and low risk allergy groups (B1) with subsequent suggested actions (B2). High risk included patient acuity, high risk delayed reactions such as Stevens Johnson syndrome and organ involvement), and (1) rash <1 hour after first dose; 2) isolated hypotension, (3) upper or lower airway involvement, or (4) clinical features of anaphylaxis. Low risk patients are given direct amoxicillin challenge, with 1 hour observation. C. Australian Therapeutic Guidelines (Melbourne, Australia) Suggested management of patients reporting penicillin hypersensitivity in whom a beta-lactam antibiotic is definitely required (Therapeutic Guidelines, Melbourne, Australia). This is a national antibiotic prescribing document, available online for all physicians to reference in Australia. Most hospitals in Australia base their institutional guidelines on this national guideline.

Figure 1.

Drug allergy pathways that include both history tools and guidance on beta-lactam prescriptions. A. Partners HealthCare System (Boston, MA, USA) Penicillin (A1) and cephalosporin (A2) hypersensitivity pathways with optional computerized clinical decision support (A3) (Boston, MA, USA). These pathways were originally used with a history tool at Massachusetts General Hospital (Figure 2A), with subsequent modification into an electronic App that is provider-facing and uses the patient-reported history and available patient records. This pathway is active throughout hospitals affiliated with Partners HealthCare System (PHS), and has been adopted by other hospitals in the US. The App uses patient-reported clinical history to group patients into one of the three reaction groups and is currently only available for use at PHS hospitals. Research studies on this pathway demonstrate its safety, and its association with an increase in beta-lactam antibiotic use and increase first-line therapies for some inpatient infections.^,, PHS hospitals performed over 1,000 drug challenges (test doses) per year with this infrastructure. * Antibiotic-stewardship program restricted antibiotics Abbreviations: PCN, penicillin B. Computerized clinical decision support system (Birmingham, UK) This computerized clinical decision support system (CDSS, Birmingham, UK) begins with an electronic questionnaire that is available as an App to assist providers in taking the allergy history. The computer uses entered information to stratify patients into high and low risk allergy groups (B1) with subsequent suggested actions (B2). High risk included patient acuity, high risk delayed reactions such as Stevens Johnson syndrome and organ involvement), and (1) rash <1 hour after first dose; 2) isolated hypotension, (3) upper or lower airway involvement, or (4) clinical features of anaphylaxis. Low risk patients are given direct amoxicillin challenge, with 1 hour observation. C. Australian Therapeutic Guidelines (Melbourne, Australia) Suggested management of patients reporting penicillin hypersensitivity in whom a beta-lactam antibiotic is definitely required (Therapeutic Guidelines, Melbourne, Australia). This is a national antibiotic prescribing document, available online for all physicians to reference in Australia. Most hospitals in Australia base their institutional guidelines on this national guideline.

Figure 1.

Drug allergy pathways that include both history tools and guidance on beta-lactam prescriptions. A. Partners HealthCare System (Boston, MA, USA) Penicillin (A1) and cephalosporin (A2) hypersensitivity pathways with optional computerized clinical decision support (A3) (Boston, MA, USA). These pathways were originally used with a history tool at Massachusetts General Hospital (Figure 2A), with subsequent modification into an electronic App that is provider-facing and uses the patient-reported history and available patient records. This pathway is active throughout hospitals affiliated with Partners HealthCare System (PHS), and has been adopted by other hospitals in the US. The App uses patient-reported clinical history to group patients into one of the three reaction groups and is currently only available for use at PHS hospitals. Research studies on this pathway demonstrate its safety, and its association with an increase in beta-lactam antibiotic use and increase first-line therapies for some inpatient infections.^,, PHS hospitals performed over 1,000 drug challenges (test doses) per year with this infrastructure. * Antibiotic-stewardship program restricted antibiotics Abbreviations: PCN, penicillin B. Computerized clinical decision support system (Birmingham, UK) This computerized clinical decision support system (CDSS, Birmingham, UK) begins with an electronic questionnaire that is available as an App to assist providers in taking the allergy history. The computer uses entered information to stratify patients into high and low risk allergy groups (B1) with subsequent suggested actions (B2). High risk included patient acuity, high risk delayed reactions such as Stevens Johnson syndrome and organ involvement), and (1) rash <1 hour after first dose; 2) isolated hypotension, (3) upper or lower airway involvement, or (4) clinical features of anaphylaxis. Low risk patients are given direct amoxicillin challenge, with 1 hour observation. C. Australian Therapeutic Guidelines (Melbourne, Australia) Suggested management of patients reporting penicillin hypersensitivity in whom a beta-lactam antibiotic is definitely required (Therapeutic Guidelines, Melbourne, Australia). This is a national antibiotic prescribing document, available online for all physicians to reference in Australia. Most hospitals in Australia base their institutional guidelines on this national guideline.

Figure 1.

Drug allergy pathways that include both history tools and guidance on beta-lactam prescriptions. A. Partners HealthCare System (Boston, MA, USA) Penicillin (A1) and cephalosporin (A2) hypersensitivity pathways with optional computerized clinical decision support (A3) (Boston, MA, USA). These pathways were originally used with a history tool at Massachusetts General Hospital (Figure 2A), with subsequent modification into an electronic App that is provider-facing and uses the patient-reported history and available patient records. This pathway is active throughout hospitals affiliated with Partners HealthCare System (PHS), and has been adopted by other hospitals in the US. The App uses patient-reported clinical history to group patients into one of the three reaction groups and is currently only available for use at PHS hospitals. Research studies on this pathway demonstrate its safety, and its association with an increase in beta-lactam antibiotic use and increase first-line therapies for some inpatient infections.^,, PHS hospitals performed over 1,000 drug challenges (test doses) per year with this infrastructure. * Antibiotic-stewardship program restricted antibiotics Abbreviations: PCN, penicillin B. Computerized clinical decision support system (Birmingham, UK) This computerized clinical decision support system (CDSS, Birmingham, UK) begins with an electronic questionnaire that is available as an App to assist providers in taking the allergy history. The computer uses entered information to stratify patients into high and low risk allergy groups (B1) with subsequent suggested actions (B2). High risk included patient acuity, high risk delayed reactions such as Stevens Johnson syndrome and organ involvement), and (1) rash <1 hour after first dose; 2) isolated hypotension, (3) upper or lower airway involvement, or (4) clinical features of anaphylaxis. Low risk patients are given direct amoxicillin challenge, with 1 hour observation. C. Australian Therapeutic Guidelines (Melbourne, Australia) Suggested management of patients reporting penicillin hypersensitivity in whom a beta-lactam antibiotic is definitely required (Therapeutic Guidelines, Melbourne, Australia). This is a national antibiotic prescribing document, available online for all physicians to reference in Australia. Most hospitals in Australia base their institutional guidelines on this national guideline.

Figure 2.

Drug allergy history tools for non-allergists A. Massachusetts General Hospital history tool (US, inpatients) In the original (non-electronic app) guideline at the Massachusetts General Hospital, general inpatient providers were asked to follow these 3 steps, with allergy history questions. Future pathway iterations included the option electronic decision support tool (Figure 1A3). B. Rochester Health Penicillin allergy screening algorithm (US, inpatients) This penicillin allergy history screening algorithm was used to identify hospitalized patients who would benefit from penicillin skin testing. This algorithm assessed and categorized allergic reactions based on the Gell and Coombs classification scheme, time elapsed since the reported penicillin reaction, and whether a penicillin antibiotic had been subsequently tolerated. The algorithm did not apply to patients hospitalized in the cardiac, medical, or surgical intensive care unit, inability to provide informed consent, and pregnancy. C. Reassessing Antibiotic Side-effect Histories (RASH, Michael Garron Hospital, Toronto, Canada). RASH was performed by pharmacists in preoperative patients with subsequent allergy verification with an infectious diseases physician. Guideline-recommended prophylactic antibiotics often include cefazolin or cefoxitin, and patients with a reported penicillin allergy have a 50% increased odds of surgical site infection because their perioperative prophylaxis is inadequate.^, Patients were deemed unsafe to receive a perioperative cephalosporin if they had a self-reported or documented history of any of the following reactions to any beta-lactams: (i) type I-mediated reaction, compatible with anaphylaxis as demonstrated by symptoms of bronchospasm, hypotension or angioedema; and (ii) severe non-IgE-mediated reactions [including Stevens–Johnson syndrome/toxic epidermal necrolysis, drug-induced hypersensitivity syndrome (DHIS), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), renal failure, cytopenias, serum sickness or any other life-threatening reaction]. Additionally, any patients describing any symptoms specifically due to cefazolin exposure were also deemed inappropriate to receive cephalosporin prophylaxis. With this tool, a majority (55%) of patients received cefazolin prophylaxis.

Figure 2.

Drug allergy history tools for non-allergists A. Massachusetts General Hospital history tool (US, inpatients) In the original (non-electronic app) guideline at the Massachusetts General Hospital, general inpatient providers were asked to follow these 3 steps, with allergy history questions. Future pathway iterations included the option electronic decision support tool (Figure 1A3). B. Rochester Health Penicillin allergy screening algorithm (US, inpatients) This penicillin allergy history screening algorithm was used to identify hospitalized patients who would benefit from penicillin skin testing. This algorithm assessed and categorized allergic reactions based on the Gell and Coombs classification scheme, time elapsed since the reported penicillin reaction, and whether a penicillin antibiotic had been subsequently tolerated. The algorithm did not apply to patients hospitalized in the cardiac, medical, or surgical intensive care unit, inability to provide informed consent, and pregnancy. C. Reassessing Antibiotic Side-effect Histories (RASH, Michael Garron Hospital, Toronto, Canada). RASH was performed by pharmacists in preoperative patients with subsequent allergy verification with an infectious diseases physician. Guideline-recommended prophylactic antibiotics often include cefazolin or cefoxitin, and patients with a reported penicillin allergy have a 50% increased odds of surgical site infection because their perioperative prophylaxis is inadequate.^, Patients were deemed unsafe to receive a perioperative cephalosporin if they had a self-reported or documented history of any of the following reactions to any beta-lactams: (i) type I-mediated reaction, compatible with anaphylaxis as demonstrated by symptoms of bronchospasm, hypotension or angioedema; and (ii) severe non-IgE-mediated reactions [including Stevens–Johnson syndrome/toxic epidermal necrolysis, drug-induced hypersensitivity syndrome (DHIS), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), renal failure, cytopenias, serum sickness or any other life-threatening reaction]. Additionally, any patients describing any symptoms specifically due to cefazolin exposure were also deemed inappropriate to receive cephalosporin prophylaxis. With this tool, a majority (55%) of patients received cefazolin prophylaxis.

Figure 2.

Drug allergy history tools for non-allergists A. Massachusetts General Hospital history tool (US, inpatients) In the original (non-electronic app) guideline at the Massachusetts General Hospital, general inpatient providers were asked to follow these 3 steps, with allergy history questions. Future pathway iterations included the option electronic decision support tool (Figure 1A3). B. Rochester Health Penicillin allergy screening algorithm (US, inpatients) This penicillin allergy history screening algorithm was used to identify hospitalized patients who would benefit from penicillin skin testing. This algorithm assessed and categorized allergic reactions based on the Gell and Coombs classification scheme, time elapsed since the reported penicillin reaction, and whether a penicillin antibiotic had been subsequently tolerated. The algorithm did not apply to patients hospitalized in the cardiac, medical, or surgical intensive care unit, inability to provide informed consent, and pregnancy. C. Reassessing Antibiotic Side-effect Histories (RASH, Michael Garron Hospital, Toronto, Canada). RASH was performed by pharmacists in preoperative patients with subsequent allergy verification with an infectious diseases physician. Guideline-recommended prophylactic antibiotics often include cefazolin or cefoxitin, and patients with a reported penicillin allergy have a 50% increased odds of surgical site infection because their perioperative prophylaxis is inadequate.^, Patients were deemed unsafe to receive a perioperative cephalosporin if they had a self-reported or documented history of any of the following reactions to any beta-lactams: (i) type I-mediated reaction, compatible with anaphylaxis as demonstrated by symptoms of bronchospasm, hypotension or angioedema; and (ii) severe non-IgE-mediated reactions [including Stevens–Johnson syndrome/toxic epidermal necrolysis, drug-induced hypersensitivity syndrome (DHIS), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), renal failure, cytopenias, serum sickness or any other life-threatening reaction]. Additionally, any patients describing any symptoms specifically due to cefazolin exposure were also deemed inappropriate to receive cephalosporin prophylaxis. With this tool, a majority (55%) of patients received cefazolin prophylaxis.

Figure 3.

Beta-lactam structure and cross-reactivity examples Beta-lactam antibiotics include the penicillins, cephalosporins, carbapenems, and monobactams. This figure demonstrates the overall cross reactivitiy between classes sharing the core beta-lactam ring. Current data support that cross reactivity between penicillins and cephalosporins is higher for those that share common R1 side chains and in patients with severe reactions histories. This figure demonstrates a few examples of side chains where there has been clinical cross-reactivity observed. More comprehensive side chains cross-reactivity has been discussed elsewhere.^{, ,} * Except for shared side chains.^{,, †} Monobactams have no shared cross-reactivity, except for aztreonam and ceftazidime.