Quinolone hypersensitivity: case demonstration (in Thai) and review

Quinolone Hypersensitivity

Sirinoot Palapinyo,RPh

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

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

Case• จากประวัติการรักษาพบว่าผู้ป่วยเคยได้รับยา Ciprofloxacin 4 ครั้ง

• 5/1/55 : Ciprofloxacin (500) 1x2 pc นาน 15 วัน



• เคยได้รับยา Levofloxacin ทั้งรูปแบบฉีดและรับประทานรวมกัน 11 ครั้ง โดยไม่พบอาการไม่พึงประสงค์จากยา

Introduction

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)

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


http://www.antimicrobe.org/new/d17.asp#t1

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 : MoxifloxacinFluoroquinolone Safety and Tolerability, CID 2005:41 (Suppl 2)

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)



• In Europe

• Moxifloxacin was associated with the highest incidence of anaphylactic shock (57.1%),

• Levofloxacin (35.7%)

• Ciprofloxacin (7.1%)


• 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



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%


• 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


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


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



• 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


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

• “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.

• “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.

Immune-mediated severe cutaneous hypersensitivity

reactions

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



• 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.


• 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.


• 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


• 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


• 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


• 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



• 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)

Nature Reviews Drug Discovery 4, 59-69 (January 2005)


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

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

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

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)

Take home message

• 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

Quinolone CYP 450Metabolte

Conjugation Sulfation

Detoxification


IgE mediated

Anaphylaxis


Detoxification



Detoxification

T-cell HSR

Cytotoxicity



Detoxification

T-cell HSR

Th2 cytokin

Th1

Hapten

Hapten&pro hapten

Pi-concept



DetoxificationTh2

cytokin

Th1

Hepatotoxicity Renal toxicity

Dermatotoxicity

Cytotoxic

T-cell HSR

“Thank you”

Health & Medicine

Quinolone hypersensitivity: case demonstration (in Thai) and review