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Quinolone
Hypersensitivity
Sirinoot Palapinyo,RPh
Case
• ผู้ป่วยหญิงไทย อายุ 43 ปี
• CC: เหนื่อย อ่อนแรงด้านซ้าย 7 วันก่อนมาโรงพยาบาล
• Underlying disease
• SLE with second...
Case
• Septic work up -> UTIs
• Med : Ciprofloxacin 400 mg IV once daily
• หลังจากได้รับยาไป 3 วัน เริ่มมีผื่น generalized ...
Case
• จากประวัติการรักษาพบว่าผู้ป่วยเคยได้รับยา Ciprofloxacin 4 ครั้ง
• 5/1/55 : Ciprofloxacin (500) 1x2 pc นาน 15 วัน 

• ...
Introduction
Introduction
• History of ADR to antibiotics -> receive alternative
antibiotics which are sometimes less effective,
often ...
Quinolone
• One of the largest classes of antimicrobial agents
used worldwide
• The development of the quinolones
• 1962 w...
http://www.antimicrobe.org/new/d17.asp#t1
Quinolone
• 4 groups, based on chemical structure and
antibacterial activity.
• First generation : Pipemidic acid
• Second...
Anaphylaxis and anaphylactoid
(Type 1 hypersensitivity reactions)
• Urticaria, angioedema and anaphylactic shock were the
...
Anaphylaxis and anaphylactoid
(Type 1 hypersensitivity reactions)
• In Europe
• Moxifloxacin was associated with the highes...
Anaphylaxis and anaphylactoid
(Type 1 hypersensitivity reactions)
• Incidence of anaphylaxis reactions to quinolones is
on...
http://www.antimicrobe.org/new/d17.asp#t1
Anaphylaxis and anaphylactoid
(Type 1 hypersensitivity reactions)
• The diagnosis of immediate hypersensitivity
reactions ...
• Retrospective analysis of clinic cases
• 71 patients with reactions to a quinolone over a
period of 5 years
• 12 with no...
J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398
Results
• 34 patients were diagnosed with quinolone hypersensitivity:
• 21 diagnosed by means of positive skin tests
• 7 d...
Discussion
• Skin prick test useful before DPT
• Size of wheal : diameter of 4 mm in the prick test
and 6 mm in the ID tes...
Anaphylaxis and anaphylactoid
(Type 1 hypersensitivity reactions)
• The European Network for Drug Allergy of the
European ...
Anaphylaxis and anaphylactoid
(Type 1 hypersensitivity reactions)
• In vitro specific IgE to quinolones
• Sepharose radioim...
• “In vitro evaluation of IgE-mediated hypersensitivity reactions
to quinolones” in Allergy 2011
• Evaluated 38 patients w...
• “In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones” in
Allergy 2011
• Results:
• Sepharose-RI...
Immune-mediated severe
cutaneous hypersensitivity
reactions
Immune-mediated severe cutaneous
hypersensitivity reactions
• Immune-mediated ADRs : Rare
• Stevens–Johnson syndrome (SJS)...
Immune-mediated severe cutaneous
hypersensitivity reactions
• Study in Europe
• HSR to fluoroquinolone (OR 3.09, 95% CI 1.1...
Immune-mediated severe cutaneous
hypersensitivity reactions
• Cutaneous ADRs were the predominant type of
ADRs (0.5-3.0%)
...
Immune-mediated severe cutaneous
hypersensitivity reactions
• Retrospective study
• Voluntary reports (≥18 years of age) o...
Immune-mediated severe cutaneous
hypersensitivity reactions
• Prevalence of ADRs from FQ was 0.13%
• Rate of cutaneous ADR...
Immune-mediated severe cutaneous
hypersensitivity reactions
• SJS/TEN developed during 1–19 days after oral FQ
• 8.6% invo...
Immune-mediated severe cutaneous
hypersensitivity reactions
• FQs were associated with a high risk of SJS/TEN in
the EuroS...
Immune-mediated severe cutaneous
hypersensitivity reactions
• Immune-mediated ADRs
• Suspected mechanism
• Quinolones are ...
Nature Reviews Drug Discovery 4, 59-69 (January 2005)
http://www.antimicrobe.org/new/d17.asp#t1
Mechanisms and cross-reactivity
• In vivo : patch test
• In vitro : lymphocyte proliferation test (LTT)
• Investigated thr...
T cell-mediated hypersensitivity to
quinolones: mechanisms and cross-reactivity
• The use of 8 different quinolones as ant...
In Vitro (Ex Vivo)
• Lymphocyte Transformation Testing (LTT)
• Lymphocytes isolated from peripheral blood mononuclear cell...
In Vitro (Ex Vivo)
• ELISpot and Intracellular Cytokine Staining
• Similar to LTT, the enzyme-linked immunospot (ELISpot)
...
Take home message
• Most common: Immediate type
• Skin testing (Sensitivity ~50% ) is not reliable because
high number of false-positive res...
Quinolone CYP 450
Metabolte
Conjugation
Sulfation
Detoxification
Quinolone CYP 450
Metabolte
IgE mediated
Anaphylaxis
Conjugation
Sulfation
Detoxification
Quinolone CYP 450
Metabolte
Conjugation
Sulfation
Detoxification
T-cell HSR
Cytotoxicity
Quinolone CYP 450
Metabolte
Conjugation
Sulfation
Detoxification
T-cell HSR
Th2
cytokin
Th1
Hapten
Hapten&pro
hapten
Pi-con...
Quinolone CYP 450
Metabolte
Conjugation
Sulfation
Detoxification
Th2
cytokin
Th1
Hepatotoxicity
Renal toxicity
Dermatotoxic...
“Thank you”
Quinolone hypersensitivity: case demonstration (in Thai) and review
Quinolone hypersensitivity: case demonstration (in Thai) and review
Quinolone hypersensitivity: case demonstration (in Thai) and review
Quinolone hypersensitivity: case demonstration (in Thai) and review
Quinolone hypersensitivity: case demonstration (in Thai) and review
Quinolone hypersensitivity: case demonstration (in Thai) and review
Quinolone hypersensitivity: case demonstration (in Thai) and review
Quinolone hypersensitivity: case demonstration (in Thai) and review
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Quinolone hypersensitivity: case demonstration (in Thai) and review

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Quinolone hypersensitivity: case demonstration (in Thai) and review

Presented by Sirinoot Palapinyo, RPh,

June12, 2015

Published in: Health & Medicine
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Quinolone hypersensitivity: case demonstration (in Thai) and review

  1. 1. Quinolone Hypersensitivity Sirinoot Palapinyo,RPh
  2. 2. Case • ผู้ป่วยหญิงไทย อายุ 43 ปี • CC: เหนื่อย อ่อนแรงด้านซ้าย 7 วันก่อนมาโรงพยาบาล • 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 : ไม่ทราบอาการ
  3. 3. Case • Septic work up -> UTIs • Med : Ciprofloxacin 400 mg IV once daily • หลังจากได้รับยาไป 3 วัน เริ่มมีผื่น generalized MP rash ขึ้นบริเวณแขน ฝ่ามือ ขา หน้าท้อง และหลัง (2/6/58) • No mucosal involvement, No internal organ involvement • Culprit drug : Ciprofloxacin
  4. 4. Case • จากประวัติการรักษาพบว่าผู้ป่วยเคยได้รับยา Ciprofloxacin 4 ครั้ง • 5/1/55 : Ciprofloxacin (500) 1x2 pc นาน 15 วัน 
 • 29/3/55 : Ciprofloxacin (500) 1x2 pc นาน 10 วัน 
 • 1/8/56 : Ciprofloxacin (500) 1x2 pc นาน 7 วัน
 • เคยได้รับยา Levofloxacin ทั้งรูปแบบฉีดและรับประทานรวมกัน 11 ครั้ง โดยไม่พบอาการไม่พึงประสงค์จากยา
  5. 5. Introduction
  6. 6. Introduction • History of ADR to antibiotics -> receive alternative antibiotics which are sometimes less effective, often more toxic, and usually more expensive. • Beta lactams & sulfa are most common -> 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. 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. 8. http://www.antimicrobe.org/new/d17.asp#t1
  9. 9. Quinolone • 4 groups, based on chemical structure and antibacterial activity. • First generation : Pipemidic acid • Second generation : Ciprofloxacin, Norfloxacin and Ofloxain. • Third generation : Levofloxacin • Fourth generation : Moxifloxacin Fluoroquinolone Safety and Tolerability, CID 2005:41 (Suppl 2)
  10. 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) • Moxifloxacin [4.3, 95% confidence interval (CI) 3.5–5.3] • Ciprofloxacin (5.4, 95% CI 4.4–6.5) • Levofloxacin (8.7, 95% CI 7.4–10.0) Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015)
  11. 11. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) • In Europe • Moxifloxacin was associated with the highest incidence of anaphylactic shock (57.1%), • Levofloxacin (35.7%) • Ciprofloxacin (7.1%)
  12. 12. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) • Incidence of anaphylaxis reactions to quinolones is on the rise • Estimated at 1.8–2.3 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. 13. http://www.antimicrobe.org/new/d17.asp#t1
  14. 14. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) • The diagnosis of immediate hypersensitivity reactions is often difficult • 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. 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 -> ID -> DPT J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398
  16. 16. J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398
  17. 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 -> negative DPT • 50% positive skin prick test -> positive DPT J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398
  18. 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. 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 confirm drug hypersensitivity • Drug provocation test (DPT), which is not free of risk J Investig Allergol Clin Immunol 2007; Vol. 17(6): 393-398
  20. 20. Anaphylaxis and anaphylactoid (Type 1 hypersensitivity reactions) • In vitro specific 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 specific 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 specific IgE to quinolones, JACI 2004
  21. 21. • “In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones” in Allergy 2011 • Evaluated 38 patients with confirmed 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 : Ciprofloxacin, Moxifloxacin & Levofloxacin - J Investig Allergol Clin Immunol. 2010;20(7):607-11. - Allergy 2011; 66: 247–254.
  22. 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 ciprofloxacin • 7 (18.4%) were positive to moxifloxacin • 7 (18.4%) were positive to levofloxacin. • 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. • Specific IgE was demonstrated by Sepharose-RIA and inhibition assay. - J Investig Allergol Clin Immunol. 2010;20(7):607-11. - Allergy 2011; 66: 247–254.
  23. 23. Immune-mediated severe cutaneous hypersensitivity reactions
  24. 24. Immune-mediated severe cutaneous hypersensitivity reactions • Immune-mediated ADRs : Rare • Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), fixed 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. 25. Immune-mediated severe cutaneous hypersensitivity reactions • Study in Europe • HSR to fluoroquinolone (OR 3.09, 95% CI 1.16–8.24, p = 0.024) • Common HSR manifestations were cutaneous (urticarial or exanthema) • Moxifloxacin was the most commonly incriminated drug • Moxifloxacin carries a higher risk of HSRs compared to levofloxacin and ciprofloxacin :141.3 vs. 40.8 and 26.3 emergency department visits/100,000 prescriptions Curr Opin Allergy Clin Immunol 2011;11:285–91.
  26. 26. Immune-mediated severe cutaneous hypersensitivity reactions • Cutaneous ADRs were the predominant type of ADRs (0.5-3.0%) • Ciprofloxacin : 34.9% of all reported ADRs • Moxifloxacin : 13.5% • Levofloxacin : 19.9% Curr Opin Allergy Clin Immunol 2011;11:285–91.
  27. 27. Immune-mediated severe cutaneous hypersensitivity reactions • Retrospective study • Voluntary reports (≥18 years of age) of any adverse events associated with fluoroquinolone • Reported from January 2004 to December 2008 • From the Adverse Drug Reaction Center, Siriraj Hospital, Thailand • Among 166,736 patients treated with FQ -> 155 enrolled Dermatitis, Vol 22, No 3 (May/June), 2011: pp 155–160
  28. 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 • Ciprofloxacinwas 0.37% • Moxifloxacin 0.1% • Levofloxacin 0.06% Dermatitis, Vol 22, No 3 (May/June), 2011: pp 155–160
  29. 29. Immune-mediated severe cutaneous hypersensitivity reactions • SJS/TEN developed during 1–19 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 155–160
  30. 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 1.8–27) • FQs were identified 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 first 2 months of treatment Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015)
  31. 31. Immune-mediated severe cutaneous hypersensitivity reactions • Immune-mediated ADRs • Suspected mechanism • Quinolones are suspected of causing HSR by both the hapten and the p–i concepts • Quinolone- induced toxicity • Parent compound of quinolones (chemically not reactive) -> directly bind to the MHC-peptide/T cell receptors and stimulate T cells by pharmaceutical interaction (p–i)
  32. 32. Nature Reviews Drug Discovery 4, 59-69 (January 2005)
  33. 33. http://www.antimicrobe.org/new/d17.asp#t1
  34. 34. Mechanisms and cross-reactivity • In vivo : patch test • In vitro : lymphocyte proliferation test (LTT) • Investigated through the generation and analysis (flow cytometry and proliferation assays) of quinolone-specific T cell clones (TCC). • Results : • The LTT confirmed 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-specific 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, 59–69
  35. 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-fixed Ag-presenting cells (APC) could present the drug and washing quinolone-pulsed APC removed the drug, abrogating the reactivity of quinolone-specific TCC. Clinical and Experimental Allergy,2006; 36, 59–69
  36. 36. In Vitro (Ex Vivo) • Lymphocyte Transformation Testing (LTT) • Lymphocytes isolated from peripheral blood mononuclear cells (PBMCs) of a patient with a specific delayed HSR • Cultured with pharmacologic concentrations of the culprit drug • After 5–7 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-specific T-cell sensitisation. • Most quinolone hypersensitivity study reported this technique
  37. 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. 38. Take home message
  39. 39. • Most common: Immediate type • Skin testing (Sensitivity ~50% ) is not reliable because high number of false-positive results • Specific IgE & 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. 40. Quinolone CYP 450 Metabolte Conjugation Sulfation Detoxification
  41. 41. Quinolone CYP 450 Metabolte IgE mediated Anaphylaxis Conjugation Sulfation Detoxification
  42. 42. Quinolone CYP 450 Metabolte Conjugation Sulfation Detoxification T-cell HSR Cytotoxicity
  43. 43. Quinolone CYP 450 Metabolte Conjugation Sulfation Detoxification T-cell HSR Th2 cytokin Th1 Hapten Hapten&pro hapten Pi-concept
  44. 44. Quinolone CYP 450 Metabolte Conjugation Sulfation Detoxification Th2 cytokin Th1 Hepatotoxicity Renal toxicity Dermatotoxicity Cytotoxic T-cell HSR
  45. 45. “Thank you”

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