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Β-lactam Antibiotic Hypersensitivity & Cross-
ReactivityNathan Hare MD
11/03/09
Outline
• Drug Allergy• Allergy Testing• Structures• Penicillins• Cephalosporins• Carbapenems• Monobactams
http://www.3dchem.com/moremolecules.asp?ID=250&othername=Penicillin-g#
Adverse Drug Reactions
• Immune Mediated = “Allergy”
– Immediate: likely IgE-mediated– Delayed: likely T-cell -mediated
IgE-mediated Allergic Reactions
Y Y
YYY
Allergen
Histamine
Mast Cell
IgE
Symptoms
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
Allergy Skin Testing
Y Y
YYY
Allergen
Histamine
Mast Cell
IgE
Positive Skin test-wheal-flare-itching
Measuring Specific IgE levels
Allergen
Y
SpecificIgE
YIgGAnti-IgE
FluorescentTag
Β-Lactam Antibiotics
Penicillins
Zhao Z et. al. Clin Exp Allergy. 2002 Nov;32(11):1644-50
Drug Hapten Immune Response
Gruchalla RS and Pirmohamed M. N Engl J Med. Feb 9;346(6):601-609
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
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
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
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 NOWSchafer JA et. al. Pharmacotherapy 2007;27(4):542-545
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
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
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
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
Cross-Reactivity among Penicillin drugs
• Virtually Complete
Cephalosporin structure
Penicillins
Cephalosporins
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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):804-09Romano A. et. al. J Allergy Clin Immunol. 2000;106(6):1177-83.
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
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
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
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.
Empedrad R et. al. J Allergy Clin Immunol. 2003 Sep;112(3):629-30.
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
Penicillin and Cephalosporin Cross-reactivity
Penicillins
Cephalosporins
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.
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
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
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.
•Romano A. et. al. Ann Intern Med. 2004;141(1):16-22.
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.
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
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.
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.
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.
Carbapenem Structure
•Prescott WA et. al. Pharmacotherapy 2007:27(1):137-142
Imipenem
Meropenem
Ertapenem
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
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.
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
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
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 reactionRomano A et. al. Ann Intern Med. 2007;146:266-269
Aztreonam
The diagnosis and management of anaphylaxis: An updated practice parameter. J Allergy Clin Immunol. 2005 Mar; (3 Suppl 2): S483-523.
Skin test2 ml/ml
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.
Review
• Carbapenem cross-reactivity– Not likely
• Monobactam cross-reactivity– Not likely
Thank you. Questions?
Windsor, VTN Hare