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β Lactam antibiotic hypersensitivity cross-reactivity

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  • 1. Β-lactam AntibioticHypersensitivity & Cross- Reactivity Nathan Hare MD 11/03/09
  • 2. Outline• Drug Allergy• Allergy Testing• Structures• Penicillins• Cephalosporins• Carbapenems• Monobactams http://www.3dchem.com/moremolecules.asp?ID=250&othername=Penicillin-g#
  • 3. Adverse Drug Reactions• Immune Mediated = “Allergy” – Immediate: likely IgE-mediated – Delayed: likely T-cell -mediated
  • 4. IgE-mediated Allergic Reactions Allergen IgE Y Y Y Y Y Histamine Symptoms Mast Cell
  • 5. Allergy Testing• Skin test – indirect measurement of specific IgE• Blood test – direct measurement of specific IgE – RAST is old name, based on radioactive technique – Currently done with a fluorescent technique
  • 6. Allergy Skin Testing Allergen IgE Y Y Y Y Y Histamine Positive Skin test -wheal -flareMast Cell -itching
  • 7. Measuring Specific IgE levels Y SpecificAllergen IgE Fluorescent Tag Y IgG Anti-IgE
  • 8. Β-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 anaphylactic deaths in the United States• Prevalence:1-10% per patient reports Schafer JA et. al. Pharmacotherapy 2007;27(4):542-545
  • 13. Penicillin Allergy: Patient History• May be unreliable – Sodhi et. al. Journal of Antimicrobial Chemotherapy (2004)54(6):1155-57.• 10-20% of the patients in the general population who report a history of penicillin allergy are truly allergic based on skin testing – Salkind AR et. al. JAMA 2001;285:2498-505
  • 14. Penicillin Hypersensitivity: History• 80-95% of patients with a history of penicillin allergy 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 allergy skin test in the US – Contained the major determinant benzylpenicilloyl-polylysine (BP) – Suspended by the US FDA in 2000 – No commercial BP (CBP) since 2004 – UNTIL NOW Schafer JA et. al. Pharmacotherapy 2007;27(4):542-545
  • 16. Penicillin Hypersensitivity: Diagnostic Testing• Skin test of major and minor determinants is the gold standard• Major determinant testing identifies ≥ 90% of potential reactors• Accuracy approaches 100% with addition of a minor determinant test Schafer JA et. al. Pharmacotherapy 2007;27(4):542-545
  • 17. Penicillin Hypersensitivity: Diagnostic Testing• In other words, 97-99% of patients with a negative skin test can tolerate penicillin1. 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 test results and negative RAST results – Wide disparity between positive skin test results for the minor determinants and RAST results – Should not be used alone to rule out Penicillin allergy Schafer JA et. al. Pharmacotherapy 2007;27(4):542-545
  • 19. Penicillin Hypersensitivity: Diagnostic Testing• Combined approach?• RAST testing with skin testing for minor determinants• Not tested in a controlled clinical trial Schafer JA et. al. Pharmacotherapy 2007;27(4):542-545
  • 20. Cross-Reactivity among Penicillin drugs• Virtually Complete
  • 21. Cephalosporin structure Penicillins Cephalosporins
  • 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 components may participate• Allergic reactions may occur because of sensitization to determinants shared with 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 ceftazidime Pegler S, Healy B. BMJ 2007;335:991
  • 26. Cephalosporin hypersensitivity•Compared with Penicillins, the lower reactivity of the β-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 not reliably predict the probability of allergic reactions to cephalosporins in patients with histories of penicillin allergy • Salkind et. al. JAMA. May 16, 2001;285(19):2498-2505.• Testing with the native drug alone has little predictive 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-related compounds – Early cephalosporin antibiotics contained trace amounts of penicillins – May have led to over-estimation of degree of cross-reactivity for Penicillin and Cephalosporin allergyKelkar PS and Li JTC. N Engl J Med. Sept. 13, 2001; 345(11):804-09
  • 31. Penicillin and Cephalosporin Cross-reactivity Penicillins Cephalosporins
  • 32. Penicillin and Cephalosporin Cross-reactivity• Cefamandole, Benzylpenicillin, and Ampicillin have similar side-chain structures, benzyl derivatives (as do 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 Cephalosporin Cross-reactivity• Cross-reacting IgE antibodies have been identified• Bind to Benzylpenicillin and Cephalothin Zhao 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 were challenged tolerated oral cefuroxime and IM ceftriaxone• 22 patients declined a challenge•Romano 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 or anaphylaxis to a cephalosporin• 86.7% (26/30) had a positive skin test to a cephalosporin only, but not to a penicillin Romano A. et. al. J Allergy Clin Immunol. 2000;106(6):1177-83.
  • 40. Penicillin Allergy in patients with Cephalosporin Allergy• 127 patients – History suggestive of immediate reaction to 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 β- lactam antibiotics• Ertapenem – Narrower spectrum – Once daily dosing Stein, GE. Clin Infect Dis 2005:41 (Suppl 5) S293-S302.
  • 42. Carbapenem Structure Imipenem Meropenem Ertapenem•Prescott WA et. al. Pharmacotherapy 2007:27(1):137-142
  • 43. Carbapenem-associated Hypersensitivity• Reported incidence 1-3% in the general population – Sodhi M et. al. J Antimicrob Chemother 2004;54:1155-7 – quoting package inserts for Meropenem and Imipenem
  • 44. Carbapenem Allergy in Penicillin-allergic Patients• “Carbapenems do not cross-react immunologically 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, VT N Hare