Transcript Antibiotic Allergy: General review

DRUG ALLERGY TO ANTIBIOTICS:
GENERAL REVIEW
Ricardo Cardona Villa, M.D.
MSc in Immunology - Allergist
Chief of Clinical Allergology Service
IPS Universitaria - Clínica León XIII
Medical School
Universidad de Antioquia
Urticarial plaques
associated with
cephalexin
Carder K.R. Hypersensitivity reactions in neonates and infants. Dermatologic Therapy, Vol. 18, 2005, 160–175
Urticaria associated with
ampicillin allergy
Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9.
Photograph courtesy of Peter Friedmann, University
of Southampton, United Kingdom.
Maculopapular rash
associated with
flucloxacillin allergy
Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9.
Photograph courtesy of Peter Friedmann, University
of Southampton, United Kingdom.
Exanthematous
drug eruption
caused by
amoxicillin
McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions.
Immunol Allergy Clin N Am 24 (2004) 399– 423
Acute generalized
exanthematous pustulosis
from amoxicillin
McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions.
Immunol Allergy Clin N Am 24 (2004) 399– 423
Leukocytoclastic
vasculitis
McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions.
Immunol Allergy Clin N Am 24 (2004) 399– 423
Toxic epidermal necrolysis
McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions.
Immunol Allergy Clin N Am 24 (2004) 399– 423
Allergic contact dermatitis
to topical antibiotics
Kathryn A. Gehrig k.A. and Warshaw E.M. Allergic contact dermatitis to topical antibiotics:
Epidemiology, responsible allergens, and management. J Am Acad Dermatol 2008;58:1-21.
ADRs have been classified by
Rawlins and Thompson in four types:
 Type A reactions
 Type B reactions that are uncommon
(approximately 10% to 15%),
not predictable, and occur only
in susceptible individuals
 Others: type C and type D reactions.
Rawlins M, Thompson W. Mechanisms of adverse drug reactions. In: Davies D, editor. Textbook of adverse drug reactions. New York: Oxford Press; 1991. p. 18–45.
Schnyder B. Approach to the Patient with Drug Allergy. Immunol Allergy Clin N Am 29 (2009) 405–418
Pathogenic Features
Allergic reactions are, by definition,
immunologically mediated.
A single drug may initiate multiple immune
responses, and multiple antigenic determinants
may be formed from a single drug.
Park BK, Pirmohamed M, Kitteringham NR. Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res Toxicol
1998;11:969-88.
Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ. Direct, MHCdependent presentation of the drug sulfamethoxazole to human alpha/beta T cell clones. J Clin
Invest 1997;100:136-41.
Several criteria characterize
an allergic reaction

The reaction is not an expected pharmacologic
effect.
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Several criteria characterize
an allergic reaction

The reaction is not an expected pharmacologic
effect.

A period of sensitization precedes the reaction.
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Several criteria characterize
an allergic reaction

The reaction is not an expected pharmacologic
effect.

A period of sensitization precedes the reaction.

The reaction may occur at a dose much lower than
that required for a pharmacologic effect.
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Several criteria characterize
an allergic reaction
The clinical symptoms are characteristic of an
allergic reaction
Resolution occurs within an expected interval,
usually days, after discontinuation of the
offending agent
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Several criteria characterize
an allergic reaction
The clinical symptoms are characteristic of an
allergic reaction
Resolution occurs within an expected interval,
usually days, after discontinuation of the
offending agent
Chemical cross-reactivity may occur
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Classification of
allergic reactions to drugs
Gell and Coombs
classification (1960):
The physiological
mechanisms
Levine classification
(1966):
The time taken for
symptoms to appear
Immediately:
Fast:
Delayed:
(Gell P. and Coombs R. Clinical aspects of immunology Blalckwell Scient
Publ Oxford; 1964).
(Coombs PRA, Gell PGH. Classification of allergic reactions responsible
for clinical hypersensitivity and disease. In: Gell RRA, editor.
Clinical aspects of immunology. Oxford: Oxford University Press;
1968. p. 575–96.)
Less than an hour
6-48 hours later.
After 48 hours.
(Immunologic mechanisms of penicillin allergy. A haptenic model system for the
study of allergic diseasess of man. NEJM 1966; 275: 1115-25)
Is a fishing net adequate for our purposes ?
http://www.monografias.com/trabajos59/fabula-lanzador-redes/Image23883.gif
My personal opinion is
that, like our fisherman
here
Our fishing net
is not big
enough to catch
all drug allergies
My personal opinion is
that, like our fisherman
here
AND
Our fishing net allows
too many of them to
escape
OR MAYBE...
We need to discover new knowledge or
create a new system that captures
everything.
Multivalency theory
of haptenic drug allergy
Middleton’s. allergy: Principles and Practices. Seventh edition. 2009
A schematic comparison
of the p-i concept with the hapten model
Gerber B.O. And and Pichler W.J. Cellular mechanisms of T cell mediated drug hypersensitivity.
Current Opinion in Immunology 2004, 16:732–737
The World Allergy Organization has recommended
the use of the adjectives immediate and delayed
referring to the onset of the symptoms,
as helpful in distinguishing whether the probable
immunologic mechanism is antibody mediated or
T-lymphocyte-mediated.
Johansson S.G., Bieber T., Dahl R., et al: Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization
October 2003. J Allergy Clin Immunol 2004; 113:832-836.
Gell and Coombs classification
Ricardo Cardona V. y Carlos Serrano ,Alergia: Abordaje Clínico, Diagnóstico y Tratamiento.
Cap. 1, Aspectos Básicos de la Alergia y Reacciones de Hipersensibilidad. Ed. Panamericana (en prensa)
Schematic representation of overlapping
immune functions
Werner J. Pichler, MD Immune mechanism of drug hypersensitivity Immunol Allergy Clin N Am 24 (2004) 373–397
Revised Gell and Coombs classification
of drug reactions
Th17
Th2
T Cell
Th1
Th9
Th
9
T Reg
Th17
Pichler, W.J. Immune mechanism of drug hypersensitivity. Immunol Allergy Clin N Am 24 (2004) 373– 397
Scheme adapted from Janeway CA, Travers P, Walport M, Shlochik M. Immunobiology. New York: Garland Publishing; 2001
T
Th1
Treg
Cell T
Th2
Th17
Th9
type IVb
type IVa
macrophage
eosinophils
IL 5, IL4/IL13
type IVd
neutrophils
(Th2 cells)
INF γ, TNFα
(Th1 cells)
CXCL 8, GM-SCF
type IVc
CD4 and CD8
(T cell)
Cytotoxic T cell
Perforin/Granzyme B
(CTL)
T
Th1
Treg
Cell T
Th2
Th17
Th9
type IVb
type IVa
macrophage
eosinophils
IL 5, IL4/IL13
type IVd
neutrophils
(Th2 cells)
INF γ, TNFα
(Th1 cells)
CXCL 8, GM-SCF
type IVc
CD4 and CD8
(T cell)
Cytotoxic T cell
Perforin/Granzyme B
(CTL)
T
Th1
Treg
Cell T
IL 5, IL4/IL13
cell B
Th2
Th17
IgE
Th9
type I
type IVb
eosinophils
type IVb
type IVa
macrophage
eosinophils
IL 5, IL4/IL13
type IVd
neutrophils
(Th2 cells)
INF γ, TNFα
(Th1 cells)
CXCL 8, GM-SCF
type IVc
CD4 and CD8
(T cell)
Cytotoxic T cell
Perforin/Granzyme B
(CTL)
type II
T
IgG
cell B
type IVa
Th1
Treg
macrophage
IgG
type III
Cell T
IL 5, IL4/IL13
cell B
C, O2
Th2
Th17
IgE
Th9
type I
type IVb
eosinophils
type IVb
type IVa
macrophage
eosinophils
IL 5, IL4/IL13
type IVd
neutrophils
(Th2 cells)
INF γ, TNFα
(Th1 cells)
CXCL 8, GM-SCF
type IVc
CD4 and CD8
(T cell)
Cytotoxic T cell
Perforin/Granzyme B
(CTL)
type II
T
IgG
cell B
type IVa
Th1
Treg
macrophage
IgG
type III
Cell T
IL 5, IL4/IL13
cell B
C, O2
IL 17
Th2
Th17
IgE
Th9
type I
type IVb
eosinophils
type IVd
neutrophils
type IVb
type IVa
macrophage
eosinophils
IL 5, IL4/IL13
type IVd
neutrophils
(Th2 cells)
INF γ, TNFα
(Th1 cells)
CXCL 8, GM-SCF
type IVc
CD4 and CD8
(T cell)
Cytotoxic T cell
Perforin/Granzyme B
(CTL)
type II
Th1
T
IL 10, TGF β
IgG
cell B
IL 12 β
type IVa
Th1
Treg
Pre Th
macrophage
IgG
type III
Th2
Cell T
IL 5, IL4/IL13
cell B
C, O2
IL 17
Th2
Th17
IgE
Th9
type I
type IVb
eosinophils
type IVd
neutrophils
type IVb
eosinophils
type IVa
macrophage
IL 5, IL4/IL13
type IVd
neutrophils
(Th2 cells)
INF γ, TNFα
(Th1 cells)
CXCL 8, GM-SCF
type IVc
CD4 and CD8
(T cell)
Cytotoxic T cell
Perforin/Granzyme B
(CTL)
type II
Th1
T
IL 10, TGF β
IgG
cell B
IL 12 β
type IVa
Th1
Treg
Pre Th
macrophage
IgG
type III
Th2
Cell T
IL 5, IL4/IL13
cell B
C, O2
IgE
IL 17
Th2
Th17
?
Th9
type I
type IVb
eosinophils
type IVb
eosinophils
type IVd
neutrophils
type IVb
eosinophils
type IVa
macrophage
IL 5, IL4/IL13
type IVd
neutrophils
(Th2 cells)
INF γ, TNFα
(Th1 cells)
CXCL 8, GM-SCF
type IVc
CD4 and CD8
(T cell)
Cytotoxic T cell
Perforin/Granzyme B
(CTL)
type II
Th1
T
IL 10, TGF β
IgG
cell B
IL 12 β
type IVa
Th1
Treg
Pre Th
macrophage
IgG
Th2
Cell T
type III
IL 5, IL4/IL13
cell B
C, O2
IgE
IL 17
Th2
Th17
?
Th9
type I
type IVb
eosinophils
type IVb
eosinophils
type IVd
neutrophils
Areas of Uncertainty
The mechanisms
underlying
antibiotic allergy
have not been
clearly elucidated.
..Some people believe that
everything they see is true;
like “the world is flat”...
Indications for ‘skin prick test’
and ‘intradermal test’
Erythematous eruption/flushing
Bronchospasm/asthma
Conjunctivitis
Anaphylaxis
Angioedema
Urticaria
Rhinitis
Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516
No indications for ‘skin prick test’
and ‘intradermal test’
Drug-induced autoimmune diseases:
Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus
erythematosus.
Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516
No indications for ‘skin prick test’
and ‘intradermal test’
Drug-induced autoimmune diseases:
Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus
erythematosus.
Severe vasculitis syndromes
Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516
No indications for ‘skin prick test’
and ‘intradermal test’
Severe exfoliative skin reactions:
Acute generalized exanthematic pustulosis, drug reaction
with eosinophilia and systemic symptoms or drug
hypersensitivity syndrome, exfoliative dermatitis,
multilocalized bullous fixed drug eruption,
Stevens-Johnson syndrome, toxic epidermal necrolysis.
Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516
SPT and IDT with the major and minor
determinates of penicillin
Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516
Clinical assessment
Medical history taking is
critical in the evaluation of
antibiotic allergy and
in distinguishing
allergic reactions from other
adverse reactions
Ancient Greek painting in a vase,
showing a physician (iatros) bleeding a patient
Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9.
Diagnosis tests
Skin Testing:

Skin testing is the basic diagnostic tool, although in
patients with a history of severe reactions, in vitro
tests may be the recommended choice.
Skin
testing is highly accurate for the identification
of penicillin allergy.
Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009.
64, 183-193
Diagnosis tests
Other Testing:
The measurement of IL-2, IL-5, IL-13 or IFN-gamma or
a combination there of might be a useful in vitro tool for
detection of T-cell sensitization to drugs
Lochmatter P., Beeler A., Kawabata T.T., Gerber B.O., Pichler W. J. Drug-specific in vitro release of IL-2, IL-5, IL-13
and IFN-gamma in patients with delayed-type drug hypersensitivity . Allergy 2009: 64: 1269–1278
The basophil activation test as a funtional in vitro test
in immediate-type drug allergy.
Hausmann O.V et al. The basophil activation test in immediate-type drug allergy. Immunol Allergy Clin N Am 29 (2009) 555–566
Diagnosis tests
Other Testing:
Drug-specific T cells, which are involved in some
hypersensitivity reactions, may be detected with the
use of in vitro lymphocyte transformation tests
Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009. 64, 183-193
Bernstein I.L., James T., Li J.T., Bernstein D.I.,Hamilton R., et al, Allergy Diagnostic Testing: An Updated Practice Parameter.
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY. VOLUME 100, MARCH, 2008: S1-S148
Diagnosis tests
Other Testing:
Drug provocation test. The ENDA document stated
that the DPT was, at that time, the best tool to
confirm a causal relationship between drug
administration and non-immediate adverse reactions.
Romano A, Blanca M, Torres MJ, Bircher A, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 2004;59:1153-1160
Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams.
Allergy 2009. 64, 183-193
.
Clinical History of reaction
Immediate (< 1hour)
(urticaria, AE, Anaphylaxis)
Delayed (> 1 hour)
(Urticaria, AE, rash)
Skin test(*)
Specific IgE (CAP)
Late with intradermal or
epicutaneous with drug envolved
Any Positive
Both negative
Allergy
PEC(**)
Positive
Negative
Allergy
Reaction over two
Years ago
Yes
Positive
Negative
Allergy
PEC(**)
No
Skin test +
PEC (**)(^^)
Any positive
Allergy
Both Negative
Positive
Negative
Allergy
Complete curse of
the treatment
Tolerance
Reaction
No Allergy
Allergy
No Allergy
No Allergy
Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento.
Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press)
Clinical History of reaction
Immediate (< 1hour)
(urticaria, AE, Anaphylaxis)
Delayed (> 1 hour)
(Urticaria, AE, rash)
Skin test(*)
Specific IgE (CAP)
Late with intradermal or
epicutaneous with drug envolved
Any Positive
Both negative
Allergy
PEC(**)
Positive
Negative
Allergy
Reaction over two
Years ago
Yes
Positive
Negative
Allergy
PEC(**)
No
Skin test +
PEC (**)(^^)
Any positive
Allergy
Both Negative
Positive
Negative
Allergy
Complete curse of
the treatment
Tolerance
Reaction
No Allergy
Allergy
No Allergy
No Allergy
Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento.
Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press)
Identification
and future
management of
the most common
drug reactions
Volcheck G.W. Clinical evaluation and manegement of drug hypersensitivity.Immunol Allergy Clin N Am 24(2004) 357-371
Drug Provocation Test:
Contraindications
Autoimmune diseases:
Bullous pemphigoid, Pemphigus vulgaris,
Systemic lupus erythematosus
Severe exfoliative skin reactions:
AGEP, DRESS/Drug-induced hypersensitivity
syndrome, Exfoliative dermatitis, SJS,
Toxic epidermal necrolysis
Aberer W. And Kranke B. ProvocationTests in Drug Hypersensitivity.
Immunol Allergy Clin N Am 29 (2009) 567–584
Drug Provocation Test:
Contraindications
Severe vasculitis syndrome
Specific organ manifestations:
Blood cytopenia, hepatitis, nephritis,
pneumonitis
Aberer W. And Kranke B. ProvocationTests in Drug Hypersensitivity.
Immunol Allergy Clin N Am 29 (2009) 567–584
Genetic susceptibility to
drug hypersensitivity
Culprit drug
Disease
HLA
Ethnicity
Carbamazepine SJS/TEN
HLA-B 1502
Han-Chinese
Allopurinol
SJS/TEN/HSS
HLA-B 5801
Han-Chinese
Abacavir
HSS
HLA-B 5701
Caucasians
Midlleton´s Allergy Principles and practice 7 edition.
Werner J Pichler, Andreas Beeler. Pharmacological Interaction of Drugs
with Immune Receptors: The p-I Concept Allergology International Vol 55, No1, 2006
Summary
“Drug allergy and
hypersensitivity have been recognized for decades,
but there are still large gaps in our knowledge”
Bousquet P-J., Demoly P. & Romano A. Drug allergy and hypersensitivity: still a hot topic. Allergy 2009: 64: 179–182
Thanks !!