β Lactam antibiotic hypersensitivity cross-reactivity

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<ul><li> 1. -lactam AntibioticHypersensitivity &amp; Cross- Reactivity Nathan Hare MD11/03/09</li></ul> <p> 2. Outline Drug Allergy Allergy Testing Structures Penicillins Cephalosporins Carbapenems Monobactamshttp://www.3dchem.com/moremolecules.asp?ID=250&amp;othername=Penicillin-g# 3. Adverse Drug Reactions Immune Mediated = Allergy Immediate: likely IgE-mediated Delayed: likely T-cell -mediated 4. IgE-mediated Allergic ReactionsAllergenIgE Y Y Y YY HistamineSymptoms Mast Cell 5. Allergy Testing Skin test indirect measurement ofspecific IgE Blood test direct measurement ofspecific IgE RAST is old name, based on radioactivetechnique Currently done with a fluorescenttechnique 6. Allergy Skin Testing Allergen IgEYYYY YHistamine Positive Skin test -wheal -flareMast Cell -itching 7. Measuring Specific IgE levels YSpecificAllergenIgEFluorescentTag YIgGAnti-IgE 8. -Lactam Antibiotics 9. PenicillinsZhao Z et. al. Clin Exp Allergy. 2002 Nov;32(11):1644-50 10. Drug Hapten Immune Response 11. Gruchalla RS and Pirmohamed M. N Engl J Med. Feb 9;346(6):601-609 12. Penicillin Hypersensitivity Responsible for 75% of anaphylacticdeaths in the United States Prevalence:1-10% per patient reportsSchafer JA et. al. Pharmacotherapy 2007;27(4):542-545 13. Penicillin Allergy:Patient History May be unreliable Sodhi et. al. Journal of AntimicrobialChemotherapy (2004)54(6):1155-57. 10-20% of the patients in the generalpopulation who report a history ofpenicillin allergy are truly allergicbased on skin testing Salkind AR et. al. JAMA 2001;285:2498-505 14. Penicillin Hypersensitivity: History 80-95% of patients with a history of penicillinallergy will have negative skin-test results Kelkar PS and Li JTC. N Engl J Med. Sept. 13, 2001; 345(11):804-09 Quoting Levine BB, Zolov DM J Allergy 1969 15. Penicillin Hypersensitivity:Diagnostic Testing PrePen Was the only available penicillin allergyskin test in the US Contained the major determinantbenzylpenicilloyl-polylysine (BP) Suspended by the US FDA in 2000 No commercial BP (CBP) since 2004 UNTIL NOWSchafer JA et. al. Pharmacotherapy 2007;27(4):542-545 16. Penicillin Hypersensitivity:Diagnostic Testing Skin test of major and minordeterminants is the gold standard Major determinant testing identifies 90% of potential reactors Accuracy approaches 100% withaddition of a minor determinant testSchafer JA et. al. Pharmacotherapy 2007;27(4):542-545 17. Penicillin Hypersensitivity: Diagnostic Testing In other words, 97-99% of patients witha negative skin test can toleratepenicillin1. The diagnosis and management of anaphylaxis: An updated practice parameter. J Allergy Clin Immunol. 2005 Mar; (3 Suppl 2): S483-523.2. Schafer JA et. al. Pharmacotherapy 2007;27(4):542-545 18. Penicillin Hypersensitivity:Diagnostic Testing RAST testing Measures the major determinant only Strong correlation between negative skin testresults and negative RAST results Wide disparity between positive skin test resultsfor the minor determinants and RAST results Should not be used alone to rule out PenicillinallergySchafer JA et. al. Pharmacotherapy 2007;27(4):542-545 19. Penicillin Hypersensitivity:Diagnostic Testing Combined approach? RAST testing with skin testing for minordeterminants Not tested in a controlled clinical trialSchafer JA et. al. Pharmacotherapy 2007;27(4):542-545 20. Cross-Reactivity among Penicillin drugs Virtually Complete 21. Cephalosporin structurePenicillinsCephalosporins 22. El-Shaboury SR et. al. J Pharm Biomed Anal. 2007 Sep 21;45(1):1-19 23. El-Shaboury SR et. al. J Pharm Biomed Anal. 2007 Sep 21;45(1):1-19 24. Cephalosporin Hypersensitivity Number of potential haptens large Side chain and nuclear componentsmay participate Allergic reactions may occur becauseof sensitization to determinants sharedwith penicillins or to unique haptensKelkar PS and Li JTC. N Engl J Med. Sept. 13, 2001; 345(11):804-09Romano A. et. al. J Allergy Clin Immunol. 2000;106(6):1177-83. 25. Cephalosporin hypersensitivity Risk of anaphylaxis is low 0.1%-0.0001% based on retrospective analysis data from 210 clinical trials 2539 patients Treated with ceftazidimePegler S, Healy B. BMJ 2007;335:991 26. Cephalosporin hypersensitivityCompared with Penicillins, the lower reactivity of the -lactam ring slows haptenization Perez-Inestrosa E. et. al. Curr Opin Allergy Clin Immunol. 2005;5:323-330 27. Skin Testing: Cephalosporins Histories and penicillin test results do notreliably predict the probability of allergicreactions to cephalosporins in patients withhistories of penicillin allergy Salkind et. al. JAMA. May 16, 2001;285(19):2498-2505. Testing with the native drug alone has littlepredictive value Kelkar PS and Li JTC. N Engl J Med. Sept. 13, 2001; 345(11):804-09 28. Skin Testing: Cephalosporins Starting to define skin testing in more detail Romano A. et. al. Clin Exp Allergy 2005;35:1234-1242 1 to 3 mg/mL concentrations recommended for skin testingThe diagnosis and management of anaphylaxis: An updated practiceparameter. J Allergy Clin Immunol. 2005 Mar; (3 Suppl 2): S483-523. 29. Empedrad R et. al. J Allergy Clin Immunol. 2003 Sep;112(3):629-30. 30. Cephalosporins and Penicillin Cross-reactivity Cephalosporium mold Produces some penicillin-relatedcompounds Early cephalosporin antibiotics containedtrace amounts of penicillins May have led to over-estimation ofdegree of cross-reactivity for Penicillin andCephalosporin allergyKelkar PS and Li JTC. N Engl J Med. Sept. 13, 2001; 345(11):804-09 31. Penicillin and CephalosporinCross-reactivity Penicillins Cephalosporins 32. Penicillin and CephalosporinCross-reactivity Cefamandole, Benzylpenicillin, and Ampicillin havesimilar side-chain structures, benzyl derivatives (asdo most 1st generation cephalosporins) Romano A. et. al. Ann Intern Med. 2004;141(1):16-22.Zhao Z et. al. Clin Exp Allergy. 2002 Nov;32(11):1644-50El-Shaboury SR et. al. J Pharm Biomed Anal. 2007 Sep 21;45(1):1-19. 33. Penicillin and CephalosporinCross-reactivity Cross-reacting IgE antibodies havebeen identified Bind to Benzylpenicillin andCephalothinZhao Z et. al. Clin Exp Allergy. 2002 Nov;32(11):1644-50 34. Cephalosporin Allergy in Penicillin-allergic patients 15,987 patients treated with a cephalosporin 8.1% with history of penicillin allergy reacted 1.9% without history of penicillin allergy reacted Lin RY. Arch Intern Med 1992;152:930-7. As referenced in Kelkar PS and Li JTC. N Engl J Med. Sept. 13, 2001; 345(11):804-09 4.4% rate estimated by Kelkar and Li 35. Cephalosporins in Penicillin-allergic Patients 128 patients Anaphylaxis (81) or urticaria (47) to a penicillin A positive skin test to at least 1 penicillin Cephalosporin skin test 10.9% (14/128) positive 94/94 with negative skin tests who werechallenged tolerated oral cefuroxime andIM ceftriaxone 22 patients declined a challengeRomano A. et. al. Ann Intern Med. 2004;141(1):16-22. 36. Romano A. et. al. Ann Intern Med. 2004;141(1):16-22. 37. 2005 Anaphylaxis Practice ParameterThe diagnosis and management of anaphylaxis: An updated practiceparameter. J Allergy Clin Immunol. 2005 Mar; (3 Suppl 2): S483-523. 38. 2nd and 3rd Generation Cephalosporins Less likely to cross-reactPichichero ME and Casey JR. Otolaryngol Head Neck Surg. 2007 Mar;136(3):340-7 39. Patients with Cephalosporin Allergy: Penicillin Allergy? Patients with a history of urticaria oranaphylaxis to a cephalosporin 86.7% (26/30) had a positive skin test toa cephalosporin only, but not to apenicillin Romano A. et. al. J Allergy Clin Immunol. 2000;106(6):1177-83. 40. Penicillin Allergy in patients withCephalosporin Allergy 127 patients History suggestive of immediate reactionto a cephalosporin 51 diagnosed as allergic 39: Skin-test POS (21/39 were RAST-POS)* 2: Skin-test NEG, RAST-POS 9: Skin-test NEG, RAST-NEG, Challenge-POS *2/21 were Skin-test POS for penicillinsAntunez C. et. al. J Allergy Clin Immunol. 2006;117(2):404-10. 41. Carbapenems Imipenem Susceptible to renal dehydropeptidase-1 (DHP-1) Requires co-administration with cilastatin (DHP-1 inhibitor) Combination can induce seizures Meropenem Stable with regard to DHP-1 Does not seem to induce seizures more often than other -lactam antibiotics Ertapenem Narrower spectrum Once daily dosingStein, GE. Clin Infect Dis 2005:41 (Suppl 5) S293-S302. 42. Carbapenem Structure ImipenemMeropenem ErtapenemPrescott WA et. al. Pharmacotherapy 2007:27(1):137-142 43. Carbapenem-associatedHypersensitivity Reported incidence 1-3% in thegeneral population Sodhi M et. al. J Antimicrob Chemother2004;54:1155-7 quoting package inserts for Meropenemand Imipenem 44. Carbapenem Allergy inPenicillin-allergic Patients Carbapenems do not cross-reactimmunologically with penicillin.The diagnosis and management of anaphylaxis: An updated practiceparameter. J Allergy Clin Immunol. 2005 Mar; (3 Suppl 2): S483-523. 45. PCN-allergic patients treated with a Carbapenem 47% with positive skin tests to Carbapenems Saxon et. al. J Allergy Clin Immunol 1988 Aug;(82):213-7 Imipenem Skin testing only, no challenges 11% Cross-reactivity Prescott WA et. al. Clin Infect Dis 2004;38:1102-7 Imipenem or Meropenem 9% Cross-reactivity Sodhi M et. al. J Antimicrob Chemother 2004;54:1155-7 Imipenem or Meropenem 46. Imipenem-cilastatin 112 patients Immediate hypersensitivity reactions to penicillins Positive skin test to at least 1 penicillin reagent Imipenem-cilastatin skin testing (0.5 mg/mL) Positive: 1/112 (0.9%) Challenges with imipenem-cilastatin 110/110 with no clinical reactionRomano A et. al. N Engl J Med. 2006 Jun 29;354(26):2835-7 47. Meropenem 104 patients Immediate hypersensitivity reactions to penicillins Positive skin test to at least 1 penicillin reagent Meropenem skin testing (1mg/mL) Positive: 1/104 (0.9%) Only with ID test Challenges with meropenem 103/103 with no clinical reaction Romano A et. al. Ann Intern Med. 2007;146:266-269 48. Aztreonam Skin test 2 ml/mlThe diagnosis and management of anaphylaxis: An updated practiceparameter. J Allergy Clin Immunol. 2005 Mar; (3 Suppl 2): S483-523. 49. Review Cephalosporin cross-reactivity may be present in up to 10% of patients with documented penicillin allergy Less likely with 2nd and 3rd generation drugsThe diagnosis and management of anaphylaxis: An updated practiceparameter. J Allergy Clin Immunol. 2005 Mar; (3 Suppl 2): S483-523. 50. Review Carbapenem cross-reactivity Not likely Monobactam cross-reactivity Not likely 51. Thank you. Questions?Windsor, VTN Hare</p>

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