cephalosporin hypersensitivity
DESCRIPTION
Cephalosporin hypersensitivity Presented bySirapassorn Sornphiphatphong, MD. August1, 2014TRANSCRIPT
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
Kelkar PS, Li JT-C. N Engl J Med 2001;345:804-9
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
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
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
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
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142
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
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
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
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142
Identical/similar R1-side chains
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142
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
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142
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
Kelkar PS, Li JT-C. N Engl J Med 2001;345:804-9
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
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
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
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
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
Skin testing: timing? Retesting?
• Similar percentages were
obtained for both groups
and for all investigated
drugs
Markovic. Pediatr Allergy Immunol 2005: 16: 341–347
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
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
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
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
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142
Dickson SD et al. Clinic Rev Allerg Immunol (2013) 45:131–142