Quinolone hypersensitivity: case demonstration (in Thai) and review

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<p> 1. Quinolone Hypersensitivity Sirinoot Palapinyo,RPh 2. Case 43 CC: 7 Underlying disease SLE with secondary APS with Hx of DVT Lt.leg Suspected renal vasculitis Moderate pulmonary hypertension OA knee Hypertension Allergy : Cotrimoxazole : MP rash Ceftriaxone : anaphylaxis Cefditoren : 3. Case Septic work up -&gt; UTIs Med : Ciprooxacin 400 mg IV once daily 3 generalized MP rash (2/6/58) No mucosal involvement, No internal organ involvement Culprit drug : Ciprooxacin 4. Case Ciprooxacin 4 5/1/55 : Ciprooxacin (500) 1x2 pc 15 29/3/55 : Ciprooxacin (500) 1x2 pc 10 1/8/56 : Ciprooxacin (500) 1x2 pc 7 Levooxacin 11 5. Introduction 6. Introduction History of ADR to antibiotics -&gt; receive alternative antibiotics which are sometimes less effective, often more toxic, and usually more expensive. Beta lactams &amp; sulfa are most common -&gt; lots of study Quinolones are the third most common class of drugs associated with hypersensitivity syndrome reactions (HSRs) Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015) 7. Quinolone One of the largest classes of antimicrobial agents used worldwide The development of the quinolones 1962 with the discovery of nalidixic acid, the prototype 4-quinolone antibiotic Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015) 8. http://www.antimicrobe.org/new/d17.asp#t1 9. Quinolone 4 groups, based on chemical structure and antibacterial activity. First generation : Pipemidic acid Second generation : Ciprooxacin, Noroxacin and Ooxain. Third generation : Levooxacin Fourth generation : Moxioxacin Fluoroquinolone Safety and Tolerability, CID 2005:41 (Suppl 2) 10. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) Urticaria, angioedema and anaphylactic shock were the most common immediate ADRs associated with quinolone Incidence of serious allergic reactions (Per 10,000 ; Siriraj) Moxioxacin [4.3, 95% condence interval (CI) 3.55.3] Ciprooxacin (5.4, 95% CI 4.46.5) Levooxacin (8.7, 95% CI 7.410.0) Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015) 11. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) In Europe Moxioxacin was associated with the highest incidence of anaphylactic shock (57.1%), Levooxacin (35.7%) Ciprooxacin (7.1%) 12. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) Incidence of anaphylaxis reactions to quinolones is on the rise Estimated at 1.82.3 per 10,000,000 days of treatment Mechanism is not well understood IgE-molecule seems to induce a covalent binding between the substitute at position 7 of the quinolone-molecule and a unknown soluble protein Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015) 13. http://www.antimicrobe.org/new/d17.asp#t1 14. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) The diagnosis of immediate hypersensitivity reactions is often difcult Skin testing is not reliable Vs some authors consider skin testing useful A high number of false-positive results FQs induce direct histamine release Sensitivity for skin test : ~50% Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015) 15. Retrospective analysis of clinic cases 71 patients with reactions to a quinolone over a period of 5 years 12 with no history of allergy Skin prick test -&gt; ID -&gt; DPT J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398 16. J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398 17. Results 34 patients were diagnosed with quinolone hypersensitivity: 21 diagnosed by means of positive skin tests 7 diagnosed by means of challenge tests (5 with positive skin tests and 2 with negative skin tests) 6 patients by means of a suggestive clinical history despite having negative skin tests 94% negative skin prick test -&gt; negative DPT 50% positive skin prick test -&gt; positive DPT J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398 18. Discussion Skin prick test useful before DPT Size of wheal : diameter of 4 mm in the prick test and 6 mm in the ID test was the usual size in false positive patients Wheal sizes were usually greater in true positives J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398 19. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) The European Network for Drug Allergy of the European Academy of Allergology and Clinical Immunology recommends the use of drug provocation test (DPT) to conrm drug hypersensitivity Drug provocation test (DPT), which is not free of risk J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398 20. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) In vitro specic IgE to quinolones Sepharose radioimmunoassay (Sepharose-RIA) Sensitivity of 54.5% In vitro tests detecting only free serum IgE but not cell-bound Level of the specic serum IgE does not correlate with the severity Considering only the patients tested within 8 months of the ADRs Cross-reactivity: common core structure of quinolones predisposes Basophil activation test (BAT) Detection of specic IgE to quinolones, JACI 2004 21. In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones in Allergy 2011 Evaluated 38 patients with conrmed immediate allergic reactions to quinolones. Those with anaphylaxis were considered allergic by clinical history, once other possible causes were ruled out Those with urticaria by drug provocation. Sepharose-radioimmunoassay (RIA) and basophil activation test (BAT) Culprit drug : Ciprooxacin, Moxioxacin &amp; Levooxacin - J Investig Allergol Clin Immunol. 2010;20(7):607-11. - Allergy 2011; 66: 247254. 22. In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones in Allergy 2011 Results: Sepharose-RIA was positive in 12 cases (31.57%) 8 (21%) were positive to ciprooxacin 7 (18.4%) were positive to moxioxacin 7 (18.4%) were positive to levooxacin. BAT was positive in 27 (71.05%). Sepharose-RIA and BAT were repeated in positive cases 1 year later, detecting a decrease in all cases, with four becoming negative. Conclusion: BAT is a useful method for diagnosing patients. Specic IgE was demonstrated by Sepharose-RIA and inhibition assay. - J Investig Allergol Clin Immunol. 2010;20(7):607-11. - Allergy 2011; 66: 247254. 23. Immune-mediated severe cutaneous hypersensitivity reactions 24. Immune-mediated severe cutaneous hypersensitivity reactions Immune-mediated ADRs : Rare StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN), xed drug eruption (FDE), cutaneous vasculitis, maculopapular exanthema, serum sickness-like disease, and acute generalized exanthematous pustulosis (AGEP) Hemolytic uremic syndrome, hemolytic anemia, thrombocytopenia, leukopenia or pancytopenia, acute interstitial nephritis, pacute pancreatitis, hotosensitization, acute hepatitis and acute cholestatic jaundice and eosinophilic meningitis Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015) 25. Immune-mediated severe cutaneous hypersensitivity reactions Study in Europe HSR to uoroquinolone (OR 3.09, 95% CI 1.168.24, p = 0.024) Common HSR manifestations were cutaneous (urticarial or exanthema) Moxioxacin was the most commonly incriminated drug Moxioxacin carries a higher risk of HSRs compared to levooxacin and ciprooxacin :141.3 vs. 40.8 and 26.3 emergency department visits/100,000 prescriptions Curr Opin Allergy Clin Immunol 2011;11:28591. 26. Immune-mediated severe cutaneous hypersensitivity reactions Cutaneous ADRs were the predominant type of ADRs (0.5-3.0%) Ciprooxacin : 34.9% of all reported ADRs Moxioxacin : 13.5% Levooxacin : 19.9% Curr Opin Allergy Clin Immunol 2011;11:28591. 27. Immune-mediated severe cutaneous hypersensitivity reactions Retrospective study Voluntary reports (18 years of age) of any adverse events associated with uoroquinolone Reported from January 2004 to December 2008 From the Adverse Drug Reaction Center, Siriraj Hospital, Thailand Among 166,736 patients treated with FQ -&gt; 155 enrolled Dermatitis, Vol 22, No 3 (May/June), 2011: pp 155160 28. Immune-mediated severe cutaneous hypersensitivity reactions Prevalence of ADRs from FQ was 0.13% Rate of cutaneous ADRs was 0.09% [0.04-0.37] Maculopapular rash (39.7%) Cutaneous ADRs Ciprooxacinwas 0.37% Moxioxacin 0.1% Levooxacin 0.06% Dermatitis, Vol 22, No 3 (May/June), 2011: pp 155160 29. Immune-mediated severe cutaneous hypersensitivity reactions SJS/TEN developed during 119 days after oral FQ 8.6% involved a previous history of FQ hypersensitivity 15.4% had cross-reactivity potential Dermatitis, Vol 22, No 3 (May/June), 2011: pp 155160 30. Immune-mediated severe cutaneous hypersensitivity reactions FQs were associated with a high risk of SJS/TEN in the EuroSCAR study (OR 6.9, 95% CI 1.827) FQs were identied as one of classes of drugs associated with SJS/TEN in a large sample of patients in a multinational cohort. SJS/TEN associated with FQs was found to occur exclusively in the rst 2 months of treatment Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015) 31. Immune-mediated severe cutaneous hypersensitivity reactions Immune-mediated ADRs Suspected mechanism Quinolones are suspected of causing HSR by both the hapten and the pi concepts Quinolone- induced toxicity Parent compound of quinolones (chemically not reactive) -&gt; directly bind to the MHC-peptide/T cell receptors and stimulate T cells by pharmaceutical interaction (pi) 32. Nature Reviews Drug Discovery 4, 59-69 (January 2005) 33. http://www.antimicrobe.org/new/d17.asp#t1 34. Mechanisms and cross-reactivity In vivo : patch test In vitro : lymphocyte proliferation test (LTT) Investigated through the generation and analysis (ow cytometry and proliferation assays) of quinolone-specic T cell clones (TCC). Results : The LTT conrmed the involvement of T cells because peripheral blood mononuclear cells (PBMC) mounted an enhanced in vitro proliferative response to CPFX and/or NRFX or MXFX in all patients. Patch tests were positive after 24 and 48 h in three out of the six patients. From two patients, CPFX- and MXFX-specic CD41/CD81 T cell receptor (TCR) ab1 TCC were generated to investigate the nature of the drug-T cell interaction as well as the cross-reactivity with other quinolones. Clinical and Experimental Allergy,2006; 36, 5969 35. T cell-mediated hypersensitivity to quinolones: mechanisms and cross-reactivity The use of 8 different quinolones as antigens (Ag) revealed three patterns of cross-reactivity: Clones exclusively reacting with the eliciting drug Clones with a limited cross-reactivity Clones showing a broad cross-reactivity The TCC recognized quinolones directly without need of processing and without covalent association with the major histocompatability complex (MHC)peptide complex Glutaraldehyde-xed Ag-presenting cells (APC) could present the drug and washing quinolone-pulsed APC removed the drug, abrogating the reactivity of quinolone-specic TCC. Clinical and Experimental Allergy,2006; 36, 5969 36. In Vitro (Ex Vivo) Lymphocyte Transformation Testing (LTT) Lymphocytes isolated from peripheral blood mononuclear cells (PBMCs) of a patient with a specic delayed HSR Cultured with pharmacologic concentrations of the culprit drug After 57 days the amount of incorporated 3H-thymidine is determined and the result is expressed as a stimulation index. Enhanced proliferative responses in the presence of a drug are interpreted as drug-specic T-cell sensitisation. Most quinolone hypersensitivity study reported this technique 37. In Vitro (Ex Vivo) ELISpot and Intracellular Cytokine Staining Similar to LTT, the enzyme-linked immunospot (ELISpot) assay and intracellular cytokine staining (ICS) have been used in the research Both ELISpot and ICS are ex vivo assays that are used to measure the production and release of a target cytokine(s) by a population of T-cells in relation to exposure to pharmacological concentrations of the suspected drug or drug metabolite Only 2 study showed ELISpot technique (Immediate type) 38. Take home message 39. Most common: Immediate type Skin testing (Sensitivity ~50% ) is not reliable because high number of false-positive results Specic IgE &amp; Basophil activation test : useful Standard for Dx: Drug provocation test Cross-reactivity: common core structure of quinolones predisposes (15-40%) Non immediate type Lab assay 40. Quinolone CYP 450 Metabolte Conjugation Sulfation Detoxication 41. Quinolone CYP 450 Metabolte IgE mediated Anaphylaxis Conjugation Sulfation Detoxication 42. Quinolone CYP 450 Metabolte Conjugation Sulfation Detoxication T-cell HSR Cytotoxicity 43. Quinolone CYP 450 Metabolte Conjugation Sulfation Detoxication T-cell HSR Th2 cytokin Th1 Hapten Hapten&amp;pro hapten Pi-concept 44. Quinolone CYP 450 Metabolte Conjugation Sulfation Detoxication Th2 cytokin Th1 Hepatotoxicity Renal toxicity Dermatotoxicity Cytotoxic T-cell HSR 45. Thank you </p>

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