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  
• 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

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
Neuman MG, et al, Quinolones-induced
hypersensitivity reactions, Clin Biochem (2015)

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 : Moxifloxacin
Fluoroquinolone 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)
Neuman MG, et al, Quinolones-induced hypersensitivity reactions, Clin Biochem (2015)

• 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

• 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

• 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%

• 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

• 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)

• 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 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-concept

Quinolone CYP 450
Metabolte
Conjugation
Sulfation
Detoxiﬁcation
Th2
cytokin
Th1
Hepatotoxicity
Renal toxicity
Dermatotoxicity
Cytotoxic
T-cell HSR

Quinolone hypersensitivity: case demonstration (in Thai) and review

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