DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria

DRUG ALLERGY TO ANTIBIOTICS: DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEWGENERAL REVIEW

Ricardo Cardona Villa, Ricardo Cardona Villa, M.D.M.D.

MSc in Immunology - AllergistMSc in Immunology - Allergist

Chief of Clinical Allergology ServiceChief of Clinical Allergology Service

IPS Universitaria - Clínica León XIIIIPS Universitaria - Clínica León XIII

Medical School Medical School

Universidad de AntioquiaUniversidad de Antioquia

Carder K.R. Hypersensitivity reactions in neonates and infants. Dermatologic Therapy, Vol. 18, 2005, 160–175

Urticarial plaques Urticarial plaques associated with associated with

cephalexincephalexin

Photograph courtesy of Peter Friedmann, University

of Southampton, United Kingdom.

Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9.

Urticaria associated with Urticaria associated with ampicillin allergyampicillin allergy

Photograph courtesy of Peter Friedmann, Universityof Southampton, United Kingdom.


Maculopapular rash Maculopapular rash associated with associated with

flucloxacillin allergyflucloxacillin allergy

McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423

Exanthematous Exanthematous drug eruption drug eruption

caused by caused by amoxicillinamoxicillin


Acute generalized exanthematous pustulosis

from amoxicillin


Leukocytoclastic vasculitis


Toxic epidermal necrolysisToxic epidermal necrolysis

Allergic contact dermatitis Allergic contact dermatitis to topical antibioticsto 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.

Type A reactions

Type B reactions that are uncommonType 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

ADRs have been classified byADRs have been classified byRawlins and Thompson in four types:Rawlins and Thompson in four types:

Allergic reactions are, by definition, immunologically mediated.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.

Pathogenic FeaturesPathogenic Features

The reaction is not an expectedis 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 Several criteria characterize an allergic reactionan allergic reaction


A period of sensitization precedessensitization precedes the reaction.





A period of sensitization precedessensitization precedes the reaction.

The reaction may occur at a dose much lowerdose much lower than that required for a pharmacologic effect.






The clinical symptoms are characteristic of an are characteristic of an allergic reactionallergic reaction


Resolution occurs within an expected interval,within an expected interval, usually days, after discontinuation of the offending agent



The clinical symptoms are characteristic of anare characteristic of an allergic reactionallergic reaction


Resolution occurs within an expected interval,within an expected interval, usually days, after discontinuation of the

offending agent

Chemical cross-reactivity may occurmay occur

Classification ofClassification ofallergic reactions to drugsallergic reactions to drugs

Gell and Coombs classification (1960):

The physiological The physiological mechanismsmechanisms

(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.)

Levine classification (1966):

The time taken for The time taken for symptoms to appearsymptoms to appearImmediately: Less than an hour

Fast: 6-48 hours later.

Delayed: 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)

http://www.monografias.com/trabajos59/fabula-lanzador-redes/Image23883.gif

Is a fishing net adequate for our purposes ?Is a fishing net adequate for our purposes ?

My personal opinion is that, My personal opinion is that,

like our fisherman here like our fisherman here

Our fishing net is

not big enough to

catch all drug

allergies

My personal opinion is that, My personal opinion is that,

like our fisherman herelike our fisherman here

AND

Our fishing net allows

too many of them to

escape

We need to discover new knowledge or create a

new system that captures everything.

OR MAYBE...OR MAYBE...

Middleton’s. allergy: Principles and Practices. Seventh edition. 2009

Multivalency theory Multivalency theory of haptenic drug allergyof haptenic drug allergy

Gerber B.O. And and Pichler W.J. Cellular mechanisms of T cell mediated drug hypersensitivity. Current Opinion in Immunology 2004, 16:732–737

A schematic comparison A schematic comparison of the p-i concept with the hapten modelof the p-i concept with the hapten model

The World Allergy Organization has recommended the use of the adjectives immediateimmediate and delayeddelayed

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 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)

Werner J. Pichler, MD Immune mechanism of drug hypersensitivity Immunol Allergy Clin N Am 24 (2004) 373–397

Schematic representation of overlapping Schematic representation of overlapping immune functionsimmune functions

Pichler, W.J. Immune mechanism of drug hypersensitivity. Immunol Allergy Clin N Am 24 (2004) 373– 397

Revised Gell and Coombs classification Revised Gell and Coombs classification of drug reactionsof drug reactions

Scheme adapted from Janeway CA, Travers P, Walport M, Shlochik M. Immunobiology. New York: Garland Publishing; 2001

Th17Th 9

T Cell T Reg

Th2

Th1

Th17

Th9

Th1Th1

Th2Th2

Th9Th9

Th17Th17

TregTreg

TT

Cell TCell T

type IVa

macrophage

type IVd

neutrophils

type IVb

eosinophils

INF INF γγ, TNF, TNFαα

(Th1 cells)(Th1 cells)

CXCL 8, GM-SCFCXCL 8, GM-SCF

(T cell)(T cell)

Perforin/Granzyme B Perforin/Granzyme B (CTL)(CTL)

IL 5, IL4/IL13 IL 5, IL4/IL13


type IVc

CD4 and CD8

Cytotoxic T cell

Th1Th1

Th2Th2

Th9Th9

Th17Th17

TregTreg

TT

Cell TCell T

type IVa

macrophage

type IVd

neutrophils

type IVb

eosinophils

type I

type IVb

eosinophils

cell B




(T cell)(T cell)




IL 5, IL4/IL13

type IVc

CD4 and CD8

Cytotoxic T cell

Th1Th1

Th2Th2

Th9Th9

Th17Th17

TregTreg

TT

Cell TCell T

IgE

Th1Th1

Th2Th2

Th9Th9

Th17Th17

TregTreg

TT

Cell TCell T

IgE

type IVa

macrophage

type IVd

neutrophils

type IVb

eosinophils

type IVa

macrophage

type II

type III

cell B

type I

type IVb

eosinophils

cell B

C, O2

IgG

IgG




(T cell)(T cell)




IL 5, IL4/IL13

type IVc

CD4 and CD8

Cytotoxic T cell

Th1Th1

Th2Th2

Th9Th9

Th17Th17

TregTreg

TT

Cell TCell T

IgE

IL 17

type IVa

macrophage

type IVd

neutrophils

type IVb

eosinophils

type IVa

macrophage

type II

type III

cell B

type I

type IVb

eosinophils

type IVd

neutrophilscell B

C, O2

IgG

IgG




(T cell)(T cell)




IL 5, IL4/IL13

type IVc

CD4 and CD8

Cytotoxic T cell

Th1Th1

Th2Th2

Th9Th9

Th17Th17

TregTreg

TT

Cell TCell TIL 17

IgE

type IVa

macrophage

type IVd

neutrophils

type IVb

eosinophils

type IVa

macrophage

type II

type III

cell B

type I

type IVb

eosinophils

type IVd

neutrophils

Pre Th

cell B

C, O2

IgG

IgG

Th1

Th2




(T cell)(T cell)


IL 10, TGF β

IL 12 β



IL 5, IL4/IL13

type IVc

CD4 and CD8

Cytotoxic T cell

Th1Th1

Th2Th2

Th9Th9

Th17Th17

TregTreg

TT

Cell TCell T

IgE

?

IL 17

type IVa

macrophage

type IVd

neutrophils

type IVb

eosinophils

type IVa

macrophage

type II

type III

cell B

type I

type IVb

eosinophilstype IVb

eosinophils

type IVd

neutrophils

Pre Th

cell B

C, O2

IgG

IgG

Th1

Th2




(T cell)(T cell)


IL 10, TGF β

IL 12 β



IL 5, IL4/IL13

type IVc

CD4 and CD8

Cytotoxic T cell

Th1Th1

Th2Th2

Th9Th9

Th17Th17

TregTreg

TT

Cell TCell T

IgE

?

IL 17

type IVa

macrophage

type IVd

neutrophils

type IVb

eosinophils

type IVa

macrophage

type II

type III

cell B

type I

type IVb

eosinophilstype IVb

eosinophils

type IVd

neutrophils

Pre Th

cell B

C, O2

IgG

IgG

Th1

Th2




(T cell)(T cell)


IL 10, TGF β

IL 12 β



IL 5, IL4/IL13

type IVc

CD4 and CD8

Cytotoxic T cell

The mechanisms The mechanisms underlyingunderlying

antibiotic allergyantibiotic allergy have have not been clearly not been clearly

elucidatedelucidated..

..Some people believe that ..Some people believe that everything they see is true; everything they see is true;

like “the world is flat”...like “the world is flat”...

Areas of UncertaintyAreas of Uncertainty

Indications for ‘skin prick test’ Indications for ‘skin prick test’ and ‘intradermal 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’ No indications for ‘skin prick test’ and ‘intradermal test’and ‘intradermal test’

Drug-induced autoimmune diseases:Drug-induced autoimmune diseases:

Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus erythematosus.



Drug-induced autoimmune diseases:Drug-induced autoimmune diseases:

Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus erythematosus.

Severe vasculitis syndromesSevere vasculitis syndromes



Severe exfoliative skin reactions: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.


SPT and IDT with the major and minor SPT and IDT with the major and minor determinates of determinates of penicillinpenicillin


Medical history taking is

critical in the evaluationevaluation of

antibiotic allergy and

in distinguishingdistinguishing

allergic reactions from other

adverse reactions


Clinical assessmentClinical assessment

Ancient Greek painting in a vase, showing a physician (iatros) bleeding a patient

http://en.wikipedia.org/wiki/File:Iatros.jpg

Skin Testing:Skin Testing:

Skin testing is the basic diagnostic toolthe basic diagnostic tool, although in patients with a history of severe reactions, in vitro

tests may be the recommended choice.

Diagnosis testsDiagnosis 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

Skin testing is highly accurate for the identification

of penicillin allergy.of penicillin allergy.

Other Testing:Other Testing:

The measurement of IL-2, IL-5, IL-13 or IFN-gammaIL-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


Hausmann O.V et al. The basophil activation test in immediate-type drug allergy. Immunol Allergy Clin N Am 29 (2009) 555–566

The basophil activation test as a funtional a funtional in vitro in vitro testtest

in immediate-type drug allergy.


Drug-specific T cells, which are involved in some hypersensitivity reactions, may be detected with the use of in vitro lymphocyte transformation testslymphocyte transformation tests



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


Drug provocation test.Drug provocation test. The ENDA document stated that the DPT was, at that time, the best tool to to confirmconfirm 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.


Clinical History of reaction

Delayed (> 1 hour)

(Urticaria, AE, rash)

Skin test(*)

Specific IgE (CAP)

Any Positive Both negative

Late with intradermal or

epicutaneous with drug envolved

Negative

Immediate (< 1hour)

(urticaria, AE, Anaphylaxis)

Positive

PEC(**)AllergyPEC(**)Allergy

Negative

Positive

Positive

Reaction

Negative

Tolerance

Allergy

Allergy

Skin test +

PEC (**)(^^)

Yes

Reaction over two

Years ago

No

No Allergy Allergy

No AllergyAllergy

Both NegativeAny positive

Complete curse of

the treatment

Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento.Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press)

No Allergy

Delayed (> 1 hour)

(Urticaria, AE, rash)

Skin test(*)

Specific IgE (CAP)

Any Positive Both negative

Late with intradermal or

epicutaneous with drug envolved

Negative

Immediate (< 1hour)

(urticaria, AE, Anaphylaxis)

Positive

PEC(**)AllergyPEC(**)Allergy

Negative

Positive

Positive

Reaction

Negative

Tolerance

Allergy

Allergy

Skin test +

PEC (**)(^^)

Yes

Reaction over two

Years ago

No

No Allergy Allergy

No AllergyAllergy

Both NegativeAny positive

Complete curse of

the treatment

Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento.Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press)

No Allergy

Clinical History of reaction

Volcheck G.W. Clinical evaluation and manegement of drug hypersensitivity.Immunol Allergy Clin N Am 24(2004) 357-371

Identification Identification and futureand future

management ofmanagement of the most common the most common

drug reactionsdrug reactions

Aberer W. And Kranke B. ProvocationTests in Drug Hypersensitivity. Immunol Allergy Clin N Am 29 (2009) 567–584

Autoimmune diseases:Autoimmune diseases:Bullous pemphigoid, Pemphigus vulgaris,

Systemic lupus erythematosus

Drug Provocation Test: Drug Provocation Test: ContraindicationsContraindications

Severe exfoliative skin reactions: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

Severe vasculitis syndromeSevere vasculitis syndrome

Drug Provocation Test: Contraindications

Specific organ manifestations:Specific organ manifestations:Blood cytopenia, hepatitis, nephritis,

pneumonitis

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

Culprit drugCulprit drug DiseaseDisease HLAHLA EthnicityEthnicity

Carbamazepine SJS/TEN HLA-B 1502 Han-Chinese

Allopurinol SJS/TEN/HSS HLA-B 5801 Han-Chinese

Abacavir HSS HLA-B 5701 Caucasians

Genetic susceptibility toGenetic susceptibility to drug hypersensitivity drug hypersensitivity

“Drug allergy and

hypersensitivity have been recognized for decades,

but there are still large gapslarge gaps in our knowledge”

Bousquet P-J., Demoly P. & Romano A. Drug allergy and hypersensitivity: still a hot topic. Allergy 2009: 64: 179–182

Summary

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DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria