1. Β-lactam Antibiotic
Hypersensitivity & 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
-flare
Mast Cell
-itching

7. Measuring Specific IgE levels
Y
Specific
Allergen IgE
Fluorescent
Tag
Y
IgG
Anti-IgE

8. Β-Lactam Antibiotics

9. Penicillins
Zhao 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
penicillin
1. 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 haptens
Kelkar PS and Li JTC. N Engl J Med. Sept. 13, 2001; 345(11):804-09
Romano 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 testing
The diagnosis and management of anaphylaxis: An updated practice
parameter. 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 allergy
Kelkar 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):1644-50
El-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 Parameter
The diagnosis and management of anaphylaxis: An updated practice
parameter. J Allergy Clin Immunol. 2005 Mar; (3 Suppl 2): S483-523.

38. 2nd and 3rd Generation
Cephalosporins
• Less likely to cross-react
Pichichero 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 penicillins
Antunez 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 practice
parameter. 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 reaction
Romano 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/ml
The diagnosis and management of anaphylaxis: An updated practice
parameter. 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 drugs
The diagnosis and management of anaphylaxis: An updated practice
parameter. 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