Cephalosporin hypersensitivity Presented bySirapassorn Sornphiphatphong, MD. August1, 2014

1. Cephalosporin hypersensitivity

2. Overview
•Introduction
•Reactions
•Risk factors
•Chemical structure and classification
•Cross reactivity
•Diagnosis
–Skin testing
–Specific IgE
–Basophil activation test
•Drug provocation testing

3. Introduction
•Widely prescribed for common infections; bronchitis, otitis media, pneumonia, and cellulitis
•First-line prophylaxis for many surgical procedures
Kelkar PS, Li JT-C. N Engl J Med 2001;345:804-9

4. Reactions to cephalosporins
•Non-immediate reactions:
–Common reactions
–Maculopapular or morbilliform skin eruption, drug fever, positive coombs’ test
•Immediate reactions:
–Less common
–urticaria, angioedema, anaphylaxis, eosinophilia, rhinitis, bronchospasm
Onset within 1 hr
Kelkar PS, Li JT-C. N Engl J Med 2001;345:804-9

5. Reactions to cephalosporins
Skin reactions
•1-3%
•Severe skin reactions are rare and less common than with penicilins
•Exfoliative dermatitis, Stevens-Johnson syndrome have been reported
Serum sickness-like reaction
•Rash and arthritis has been reported in children received cefaclor
•No reports in adults
Kelkar PS, Li JT-C. N Engl J Med 2001;345:804-9

6. Reactions to cephalosporins
Anaphylaxis
•0.0001-0.1%
•Risk of anaphylaxis from cephalosporin may be increased in patients with history of allergy to penicillin
•A survey of pharmaceutical manufacturers reported
–17 cases of anaphylaxis from ceftriaxone from 1985-1990
–11 cases of anaphylaxis from cefoxitin from 1986-1990
Kelkar PS, Li JT-C. N Engl J Med 2001;345:804-9

7. Risk factors
•History of allergy to penicillin or cephalosporins
•History of atopy (allergic rhinitis, asthma, AD) not seem to be risk factor
•AD and/or asthma predisposed to severe and fatal reactions
Kelkar PS, Li JT-C. N Engl J Med 2001;345:804-9

8. Chemical structure and classification
•Semisynthetic derivatives of cephalosporin C; first isolated from the cultures of the fungus Cephalosporium acremonium
Inestrosa EP et al. Curr Opin Allergy Clin Immunol 5:323–330.
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

9. Chemical structure and classification
•5 generations
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

10. Possible allergens and cross-reactivity
•Sensitization to structurally similar R1 side chain groups (most common)
•Sensitization to structurally similar R2 side chain groups
•Sensitization to the core beta-lactam ring or its metabolites
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142 Solensky R et al. Ann Allergy Asthma Immunol 2010; 105:259-73

11. Immunochemistry
Perez-Inestrosa E et al. Curr Opon Allergy Clin Immuno 5:323-330

12. Perez-Inestrosa E et al. Curr Opon Allergy Clin Immuno 5:323-330

13. Perez-Inestrosa E et al. Curr Opon Allergy Clin Immuno 5:323-330

14. Perez-Inestrosa E et al. Curr Opon Allergy Clin Immuno 5:323-330

15. Cross-reactivity
•All penicillin allergic patient before 1980 had been treated with first-generation cephalosporins; cephalothin, cephaloridine (similar side chains with benzylpenicillin)
•Nagakura et al reported that nearly all monoclonal antibodies in mice recognize unique cephalosporin epitopes, with little/no recognition of penicillins
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

16. Identical/similar R1-side chains
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

17. Identical/similar side chains
Romano A et al. J Allergy Clin Immunol 2000;106:1177-83

18. Sensitization to structurally similar R2 side chain groups
•A patient with an anaphylactic reaction to cefoperazone and positive skin test results to both cefoperazone and cefamandole, which share an identical R2-side chain
Romano A et la.Allergy (2005) 60:1545–1546

19. Side chain
Romano A et al. Clin Exp Allergy 2005; 35:1234–1242

20. Identical R2-Side chain
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

21. Diagnosis
•Clinical history
•Physical examination
•Evaluation of immediate reactions
–Skin prick testing
–Intradermal testing
–Serum specific IgE
•Drug provocation testing

22. Skin testing: Benefit?
•Skin prick test and intradermal test can be used for diagnosis of IgE-mediated drug reactions1, 2
•Useful tool for immediate reaction hypersensitivity diagnosis3-5
•Positive skin test in suspected cephalosporin allergy varied from 30.7-84.2%3-5
2 Solensky R et al. Ann Allergy Asthma Immunol 2010; 105:259-73
3Romano A et la.Allergy (2005) 60:1545–1546
4Romano et al. Pediatrics 2008; 122;521
5Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142
1 Middleton 8th edition

23. Skin testing
NEJM 2001
•Skin testing
–Not been conclusively defined allergic determinants of cephalosporins
–Not commercially available reagents
–Not been established PPV, NPV of testing
Kelkar PS, Li JT-C. N Engl J Med 2001;345:804-9

24. Skin testing
Skin prick test
•Cephalosporin 2mg/ml
•on volar forearm
•20 min
•Positive when wheal >3mm in diameter
Intradermal test
•Using nonirritating whole drug intradermal skin test
•0.02 ml ID (1:10)
•on volar forearm
•20 min
•Positive when wheal >3-5 mm in diameter
Romano A et al. J Allergy Clin Immunol 2000;106:1177-83 Empedrad R et al (2003) J Allergy Clin Immunol 112(3):629–630
Romano A et la.Allergy (2005) 60:1545–1546
Romano et al. Pediatrics 2008; 122;521

25. Skin prick testing: reagents
•Penicilloylpolylysine: 5x10-5 mmol/L
•Minor determinant mixture: 2x10-2 mmol/L
•Benzylpenicillin: 10,000 IU/ml
•Ampicillin: 1, 20 mg/ml
•Amoxicillin: 1, 20 mg/ml
•Cephalosporin injectable 2 mg/ml (proved to be nonirritant in healthy subjects)
Romano A et al. J Allergy Clin Immunol 2000;106:1177-83 Empedrad R et al (2003) J Allergy Clin Immunol 112(3):629–630 Romano A et la.Allergy (2005) 60:1545–1546 Romano et al. Pediatrics 2008; 122;521 Solensky R et al. Ann Allergy Asthma Immunol 2010; 105:259-73

26. Skin testing
•Sensitivity, specificity?
•Validation?
•Screening?

27. Skin testing: screening?
•Yoon SY et al studied 1421 subjects
•4/1421 (0.28%) developed urticaria
•Sensitivity 0%, specificity 94.7%
•PPV 0%, NPV 99.7%
Yoon SY et al. Allergy 68 (2013) 938–944

28. Skin testing: timing? Retesting?
ICON on drug allergy, 2014
•The IgE antibody response is not permanent over time, and decreased antibody levels may occur months to years after the occurrence of a DHR
•Patients with severe immediate reactions to B- lactams and negative evaluation (skin tests and/or drug provocation test), retesting 2–4 weeks

29. Skin testing: timing? Retesting?
•In 2005, Romano A et al reported that skin test positivity rate increase from 76.3 to 85.5% after retesting 4 wk later
•In 2008, Romano A et al reported the rate of resensitization was 25% (1/4)
Romano A et al. Clin Exp Allergy 2005; 35:1234–1242 Romano et al. Pediatrics 2008; 122;521

30. Skin testing: timing? Retesting?
•Survival analysis evaluated skin testing at evaluation, 1 yr, 3 yr and 5 yr later
•More than 60% lose their skin- test positivity over time
•Cephalosporin hypersensitivity group became negative skin test sooner and more frequently
•Suggesting to retes after 2–4 weeks
Romano A et al. Allergy 69 (2014) 806–809
A: pen
B: Ceph

31. Skin testing: timing? Retesting?
•Similar percentages were obtained for both groups and for all investigated drugs
Markovic. Pediatr Allergy Immunol 2005: 16: 341–347

32. Skin testing: timing? Retesting?
•Not routinely do resensitization with oral penicillin
•Repeated penicillin skin testing may be considered in patients with a history of penicillin allergy who have tolerated a course of parenteral penicillin
Solensky R et al. Ann Allergy Asthma Immunol 2010; 105:259-73

33. Serum specific IgE
In 2000
•Penicilloyl G, Penicilloyl V, Ampicilloyl, Amoxicilloyl, Cefaclor
•Defined positive when ≥0.35 kU/L
In 2005
•1st Cephalosporin-specific IgE by sepharose-RIA (coupling to sepharose epoxy-activated 6B)
•Defined positive when ratio to healthy, nonatopic subjects >2
Romano A et al. J Allergy Clin Immunol 2000;106:1177-83 Romano A et al. Clin Exp Allergy 2005; 35:1234–1242

34. Basophil activation test
•Quantitative measurement of CD63, expressed on basophils after stimulation with the culprit drug
•Sensitivity 50-60%, specificity higher than 90%
•Limited data in using in cephalosporin allergy
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142 Sanz Ml et al. Clin Exp Allergy 2002; 32:277-286 Torres MJ et al. Clin Exp Allergy 2004; 34:1768-1775

35. Drug provocation testing
•Gold standard for the identification of the culprit drug
•Questionable history and negative or inconclusive diagnostic test results would be candidates for a graded challenge
ICON on drug allergy 2014
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

36. Graded challenge
•Progressively increasing doses of a drug until a therapeutic dose is reached
•Started with 1/100, 1/10 and full dose every 30- 60 min
•Helpful in disproving a diagnosis of cephalosporin allergy in a patient with a doubtful history and negative skin testing
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

37. Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

38. Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142

39. Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142