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