cephalosporin hypersensitivity

Cephalosporin hypersensitivity

Overview

• Introduction

• Reactions

• Risk factors

• Chemical structure and classification

• Cross reactivity

• Diagnosis – Skin testing

– Specific IgE

– Basophil activation test

• Drug provocation testing

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

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



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



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


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


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

Chemical structure and classification

• 5 generations


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


Solensky R et al. Ann Allergy Asthma Immunol 2010; 105:259-73

Immunochemistry

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

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

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


Identical/similar R1-side chains


Identical/similar side chains

Romano A et al. J Allergy Clin Immunol 2000;106:1177-83

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

Side chain

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

Identical R2-Side chain


Diagnosis

• Clinical history

• Physical examination

• Evaluation of immediate reactions

– Skin prick testing

– Intradermal testing

– Serum specific IgE

• Drug provocation testing

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

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


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


Empedrad R et al (2003) J Allergy Clin Immunol 112(3):629–630


Romano et al. Pediatrics 2008; 122;521

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)


Empedrad R et al (2003) J Allergy Clin Immunol 112(3):629–630




Skin testing

• Sensitivity, specificity?

• Validation?

• Screening?

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

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


• 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)




• 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


• Similar percentages were

obtained for both groups

and for all investigated

drugs

Markovic. Pediatr Allergy Immunol 2005: 16: 341–347


• 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


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



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


Sanz Ml et al. Clin Exp Allergy 2002; 32:277-286 Torres MJ et al. Clin Exp Allergy 2004; 34:1768-1775

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

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


cephalosporin hypersensitivity

Health & Medicine

j allergy clin immunol

curr opin allergy clin

ann allergy asthma immunol

clin exp allergy

clinic rev allerg immunol

curr opon allergy clin

risk factorshistory

n engl j med