PENICILLIN AND BETA-LACTAM ALLERGY MANAGEMENT DOCUMENT TYPE: GUIDELINE Site Applicability This guideline applies to BC Children’s Hospital and BC Women’s Hospital + Health Centre. Purpose This is a tool to aid identifying which beta lactam antibiotics have high and low risk of cross reactivity. Guideline Statements Beta-lactam allergies, particularly allergies to penicillin, are over reported. Thorough beta-lactam allergy assessments are an important step in determining if a patient has a true allergy. Unnecessary avoidance of beta-lactam antibiotics and use of alternative non first line antibiotics has been associated with increased patient morbidity including decreased effectiveness, increased adverse effects, longer hospital stays, and increased C. difficile infection rates. Alternative non beta-lactam antibiotics are often more expensive and broader spectrum and exposure can lead to colonization and infection with resistant organisms.1,2 Historically, cross reactivity rates between classes of beta-lactam antibiotics have been over estimated and based on older studies with flawed methodologies. However, as allergies have become better defined and the role of the antibiotic chemical structure on likelihood of cross reactivity is better understood, more recent data suggests cross reactivity between penicillins and other beta-lactams is much lower.3 For patients in which a true penicillin or other beta-lactam allergy cannot be ruled out based on history and assessment, the below information can be used to aid in determining which beta-lactam may be safe to administer. Note: this information is not meant to replace clinical judgement or meant to be an antibiotic treatment guideline. The information below is based on the most recent literature surrounding beta lactam cross reactivity and is meant as an aid in determining beta lactam alternatives with a low cross allergy risk. It is important to note that new intolerances (i.e. any allergy or adverse reaction reported in a drug allergy field) can occur after 0.5 to 4% of all antimicrobial courses depending on the specific agent. Expect a higher incidence of new intolerances in patients with three or more prior medication intolerances.4 A thorough allergy assessment should always be conducted in any patient reporting an allergy. Patient has a Penicillin Allergy: Penicillins are a group of antibiotics and include: Penicillin, Ampicillin, Amoxicillin, Cloxacillin, Piperacillin-Tazobactam Cross reactivity between the penicillins is primarily due to shared common antigenic determinants based on similarities in their core ring structure that is common to all penicillins and their side chains that distinguish between the penicillins. Therefore, cross reactivity cannot be based on side chain similarities alone. If a patient has a true allergy to a penicillin, all penicillins should be avoided.4-6 Cross reactivity between the penicillins and cephalosporins is primarily due to similarities in side chains and not similarities in the beta-lactam ring structure. If a patient has a true penicillin allergy, a cephalosporin with different side chains can be safely administered.6-12 Note cefazolin does not share a similar side chain with any other beta-lactam commonly used in Canada. Please refer to the cross reactivity chart (Appendix 1) to determine if cross allergy is possible between beta-lactams. Cross reactivity between penicillins and carbapenems is very low. Carbapenems would be a reasonable option when antibiotics are required in patients with an allergy to penicillins.13,14 C-0506-07-60011 Published Date: 28-Jan-2019 Page 1 of 5 Review Date: 28-Jan-2022 This is a controlled document for BCCH& BCW internal use only – see Disclaimer at the end of the document. Refer to online version as the print copy may not be current. PENICILLIN AND BETA-LACTAM ALLERGY MANAGEMENT DOCUMENT TYPE: GUIDELINE Patient has a Cephalosporin Allergy: Commonly Used Cephalosporins First Generation Second Generation Third Generation Fourth Generation Cefadroxil Cefaclor Cefotaxime Cefipime Cefazolin Cefoxitin Ceftriaxone Cephalexin Cefprozil Cefixime Cefuroxime Ceftazidime Unlike the penicillins, cross reactivity between the cephalosporins is typically not a class effect. Cross reactivity in cephalosporins is primarily based on the similarities between the structures’ side chains. Therefore, if a patient has a cephalosporin allergy, one can safely be given a different cephalosporin (or other beta lactam) that has dissimilar side chains.9 Note: cefazolin does not share a side chain with any other beta lactam commonly used in Canada. Please refer to the cross reactivity chart (Appendix 1) to determine if a cross allergy is possible between beta-lactams. References 1. Macy E. and Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study. J Allergy Clin Immunol 2014;133:790-796 2. Charneski, L., Deshpande, G. & Smith, S.W. (2011). Impact of an antimicrobial allergy label in the medical record on clinical outcomes in hospitalized patients. Pharmacotherapy, 31(8): 742-747. 3. Pichichero ME and Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients: A meta- analysis. Otolaryngology-Head and Neck Surgery 2007; 136:340-347 4. Macy E and Ngor E. Recommendations for the Management of Beta-Lactam Intolerance. Clinic Rev Allerg Immunol 2014; 47:46-55. 5. PL Detailed-document, Allergic Cross-reactivity Among Beta-lactam Antibiotics: An Update. Pharmacist’s Letter/Prescriber’s Letter. October 2013 6. Terico AT and Gallagher JC. Beta-lactam allergy and cross-reactivity. J Pharm Pract. 2014 Dec;27(6):530-44. 7. Pichichero, Michael E. A review of evidence supporting the American Academy of Pediatrics recommendations for prescribing cephalosporin antibiotics in penicillin allergic patients. Pediatrics. 2005(115):1048-55. 8. Pichichero ME. Use of selected cephalosporins in penicillin allergic patients. A paradigm shift. Diagnostic Microbiology and Infectious Disease. 2007(52):13-18. 9. Romano A et al. IgE-mediated hypersensitivity to cephalosporins: Cross-reactivity and tolerability of alternative cephalosporins. J Allergy Clin Immunol. 2015; 136 (3); 685-691 10. Campagna JD, Bond MC, Schabelman E, Hayes BD. 2012. The use of cephalosporins in penicillin-allergic patients: a literature review. J Emerg Med 42:612-620. 11. DePestel DD, Benninger MS, Danziger L, LaPlante KL, May C, et al. Cephalosporin use in treatment of patients with penicillin allergies. J Am Pharm Assoc. 2008; 48:530-540 12. Novalbos A, Sastre J, Cuesta J et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy. 2001;31(3):438-443 C-0506-07-60011 Published Date: 28-Jan-2019 Page 2 of 5 Review Date: 28-Jan-2022 This is a controlled document for BCCH& BCW internal use only – see Disclaimer at the end of the document. Refer to online version as the print copy may not be current. PENICILLIN AND BETA-LACTAM ALLERGY MANAGEMENT DOCUMENT TYPE: GUIDELINE 13. Kula B, Djordjevic G, and Robinson JL. A Systematic Review: Can one Prescribe Carbapenems to Patients with IgE-Mediated Allergy to Penicillins or Cephalosporins? CID 2014;59(8):1113-1122 14. Kula B, Djordjevic G, and Robinson JL. A Systematic Review: Can one Prescribe Carbapenems to Patients with IgE-Mediated Allergy to Penicillins or Cephalosporins? CID 2014;59(8):1113-1122 15. Pichichero ME and Zagursky R. Penicillin and Cephalosporin Allergy. Ann Allergy Asthma Immunol 112(2014):404-412 16. Frumin J and Gallagher JC. Allergic Cross-Sensitivity Between Penicillin, Carbapenem and Monobactam Antibiotics: What are the Chances? The Annals of Pharmacotherapy 2009 Feb; 43:304-315 17. NB Provincial Health Authorities Anti-Infective Stewardship Committee. Management of Penicillin and Beta-Lactam Allergy 2017. http://en.horizonnb.ca/media/927867/management_of_penicillin_and_beta_lactam_allergy.pdf (accessed December 3, 2018). 18. Coombs P GP. Classification of allergic reactions responsible for clinical hypersensitivity and disease. Clinical aspects of immunology, 1968 Oxford, UK Oxford University Press (pg 575-96). 19. Solensky R. and Khan DA. (Editors) Joint Task Force on Practice Parameters. Drug Allergy: an Updated Practice Parameter. Ann Allergy Asthma Immunol 2010; 105:259-273 C-0506-07-60011 Published Date: 28-Jan-2019 Page 3 of 5 Review Date: 28-Jan-2022 This is a controlled document for BCCH& BCW internal use only – see Disclaimer at the end of the document. Refer to online version as the print copy may not be current. PENICILLIN AND BETA-LACTAM ALLERGY MANAGEMENT DOCUMENT TYPE: GUIDELINE APPENDIX 1 Beta-lactam Cross Reactivity Chart 7, 11, 12,13,16 IMPORTANT NOTE: this document and chart can only be used to evaluate the risk of cross reactivity between beta lactams in patients with type I IgE mediated hypersensitivity reactions. This does NOT apply to type II, III, and IV hypersensitivity reactions. Please see Appendix 2 for information on other types of hypersensitivity reactions and their management. Cefaclor Cefixime Cefipime Cefprozil Cefoxitin Penicillin Cefazolin Imipenem Ampicillin Cefadroxil Cloxacillin Ertapenem Aztreonam Amoxicillin Piperacillin Cephalexin Cefotaxime Cefuroxime Ceftriaxone Ceftazidime Meropenem Amoxicillin x x x x x x x x Ampicillin x x x x x x x x Penicillins Cloxacillin x x x x Penicillin x x x x x Piperacillin x x x x Cefadroxil x x x x x 1st Generation Cefazolin Cephalosporins Cephalexin x x x x x Cefaclor x x x x x nd Cefprozil x x x x x 2 Generation Cephalosporins Cefoxitin x x Cefuroxime x Cefixime rd Cefotaxime x x 3 Generation Cephalosporins Ceftazidime x Ceftriaxone x x 4th Generation Cefepime Cephalosporins x x Ertapenem x x Carbapenems Imipenem x x Meropenem x x Monobactam Aztreonam x Key: X – beta-lactam antibiotics that have a similar structure/side chains and indicate a risk for cross reactivity C-0506-07-60011 Published Date: 28-Jan-2019 Page 4 of 5 Review Date: 28-Jan-2022 This is a controlled document for BCCH& BCW internal use only – see Disclaimer at the end of the document. Refer to online version as the print copy may not be current.