Patterns of cross-reactivity
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1 Patterns of cross-reactivity Werner J. Pichler, MD Division Allergology, RIA, Inselspital, University of Bern, CH 3010 Bern Switzerland ADR-AC GmbH Adverse Drug Reactions Analysis and Consulting Holligenstr 91, CH-3008-Bern, Switzerland
2 D.H Endocarditis (due to Enterococcus faecalis, blood culture positive ) Valvulopathie (aortal stenosis, sick-sinus-syndrome, pace maker implantation 2004) Breast cancer and mastectomy 1997 and 2003 Hypothyreosis (substituted) Renale insufficiency (clearance 40ml/min). Multiple ulcerationen on digits of both feets
3 D.H Therapy of endocarditis: scheduled for 6 weeks: b-lactams or Vancomycin and Garamycin Amoxicillin & clavulanic acid i.v Amoxicllin i.v. Exanthem 1.5. (itchy)
4
5 What now? D.H Acute situation 1. Severity of exanthem? 2. Type of exanthem/of immune reaction (immediate/delayed) 3. Stop of amoxicillin; other therapy Advice for future 1.Can one use cephalosporin in future? 2.Can one use other penicillins (i.e. piperacillin, flucloxacillin?) 3.Can one use monobactam or carbapenem?
6 D.H Severity of exanthem? 2. Type of exanthem/of immune reaction (immediate/delayed) 3. Stop of amoxicillin, continue with vancomycin (kidney!). alternative? 4. Desensibilisation? : no bullae oder mucosal involvement ALAT/ASAT/gGT/AP constant No eosinophilia, no increase of creatinine 2:
7 What now? D.H Acute situation 1. Severity of exanthem? 2. Type of exanthem/of immune reaction (immediate/delayed) 3. Stop of amoxicillin; other therapy Advice for future 1.Can one use cephalosporin in future? 2.Can one use other penicillins (i.e. piperacillin, flucloxacillin?) 3.Can one use monobactam or carbapenem?
8 Core structure and side-chain Side chain Core-structure (Cephem)
9 Cross-reactivity b-lactam Antibiotika
10 IgE: 4-11% in penicillin/amoxicillin allergic patients with cephalosporins Cefadroxil and Amoxicillin: same side chain T cells: < 1% between penicillins and cephalsoporins, but frequent in between penicillins, cephalsosporins... Check the structure: Google: amoxicillin / picture...
11 Cephadroxil Amoxicillin Cross-reactivity based on identical side chain
12 Patterns of cross-reactivity Differentiate between IgE and T-cell reactions: antibodies and T-cells recognize different parts of the same molecule Cross-reactivity of IgE appears to be more common, as minor determinants might be responsible Cross-reactivity of T-cells is often less severe
13 IgE or T-cell cross-reactivity Amoxicillin and Cefadroxil? Same core structure T & IgE cefadroxil amoxicillin Same side chain Seldom IgE, even more rarely T
14 T cells and antibodies recognize different parts of the molecule (albumin)
15 T cells and antibodies recognize different parts of the molecule (albumin) TCR: peptide + drug + HLA Ab: Drug + albumin
16 Patterns of cross-reactivity Differentiate between IgE and T-cell reactions: antibodies and T-cells recognize different parts of the same molecule Cross-reactivity of IgE appears to be more common, as minor determinants might be responsible Cross-reactivity of T-cells is often less severe: only part of reactive T-cells is crossreactive; the same for IgE, but very few IgE may already cause symptoms
17 Cross reactivity Patient with anaphylactic shock after Kefzol Can you give him Augmentin? Can you give him Ciproxin? Can you give him Zinazef? Patient witht maculopapular exanthem after Amoxillin Can you give him Augmentin? Can you give him Ciproxin? Can you give him Zinazef?
18 Cross-reactivity Patient with allergy to ciproxin (urticaria) can you give him Norfloxazin? can you give him Augmentin? Patient with allergy to ciproxin (exanthem with hepatitis) can you give him Norfloxazin? can you give him Augmentin?
19 2 Flare up reactions
20 symptoms symptoms symptoms Multiple drug hypersensitivity, flare up reactions, cross-reactivity Multiple drug hypersensitivity A) Independent reactions to chemically not related compounds drug x drug y x Skin and LTT ++ to x and y Multiple Drug Hypersensitivity s.s. t I B) Flare up reactions drug x drug y Skin and LTT a) ++ to x only b) ++ to both drugs Frequent, try to make an interval t C) crossreactivity drug x drug x l Skin and LTT ++ to x and x l Look to the chemical structure (e.g. google-pictures) t
21 Dangerous symptoms: 19 year old female, coeliac disease, DM I with neuropathy Tegretol (Carbamazepine; 2x200mg); later Neurontine (Gabapentin 3x300mg) after 10 weeks treatment with Gabapentine
22 atypival lymphocytes (= activated CD8+ T-cells) in the blood at massive immune reactions (e.g. generalised drug allergy, acute EBV und HIV-infection, acute Still syndrom...)
23 Flare up Reactions Drug hypersensitivity causes a massive immune stimulation Immune stimulations are risk factors for drug hypersensitivity reactions Addition of a new drug (antibiotic) into an ongoing drug hypersensitivity may lead to flare up reactions, resulting in aggravation of clinical symptoms
24 Flare up Reactions (?) The allergy is directed against the first antibiotic (e.g. clamoxyl), The second drug stimulates preactivated T cells Examples: Staph. aureus in artificial knee joints Therapy with Clamoxyl : severe exanthema on day 10; Addition of rimactan and vibramycin 2 days after stopping clamoxyl aggravates the exanthema Is it an allergy to rimactan or vibramycin as well? Or are the clamoxyl activated T cells also reacting with rimactan as well (?)
25 Take home message Cross-reactivity and flare up reactions Cross-reactivity occurs mainly in the same chemical group Cross-reactivity is mainly a problem with acute reactions, it is overestimated in delayed reactions (DD flare up reactions). Delayed reactions to penicillins like amoxicillin (exanthem) are NO contraindicationds for cephalosporins (and vice versa) Massive immune stimulations like severe drug allergies can lead to flare up reactions
26 Thank you very much...
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