FLUCONAZOLE Pascalis Vergidis, MD, MSc Infectious Diseases Consultant Manchester University NHS Foundation Trust

Learning Objectives To understand the mechanism of action of fluconazole To be aware of fluconazole resistance and cross resistance to other antifungal drugs To be familiar with the pharmacokinetics and pharmacodynamics of fluconazole To be aware of the various indications of fluconazole prophylaxis and therapy To be aware of the different doses of fluconazole and their use in adults and children To know adverse reactions related to fluconazole

Structure Fluconazole is a first-generation synthetic triazole Molecular weight: 306.3 g/mol

Structure Voriconazole and fluconazole are structurally similar

Mechanism of Action Preferentially binds fungal cytochrome P450-dependent lanosterol C-14-α demethylase Inhibits the conversion of lanosterol to ergosterol – major constituent of fungal cell membrane Resulting in the accumulation of fungal 14 alpha-methyl sterols, the loss of normal fungal sterols, and fungistatic activity. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Fungicidal to Cryptococcus spp in a dose-dependent pattern Accumulation of methylated ergosterol precursors. Increased membrane permeability and fungal growth arrest

Squalene monooxygenase Mechanism of Action Acetyl-CoA Squalene Squalene -2,3 oxide Lanosterol C-14 α demethylase Squalene monooxygenase Azoles Ergosterol

Spectrum of activity Yeast Dimorphic Dermatophytes Candida spp. (except C. krusei) Cryptococcus spp. Dimorphic Blastomyces dermatitidis, Coccidioides spp., Histoplasma spp. Dermatophytes Microsporum spp, Epidermophyton spp and Trichophyton spp. Moulds: No activity (Aspergillus spp, Fusarium spp, Scedosporium spp ) Mucorales: No activity

Spectrum of activity Fungi Fluconazole Itraconazole Voriconazole Posaconazole Candida albicans +++ Candida glabrata +/- + Candida krusei - Cryptococcus spp ++ Aspergillus fumigatus Aspergillus terreus Blastomyces spp Coccidioides spp Histoplasma spp Sporothrix spp Fusarium spp Scedosporium spp Mucorales

Drug Resistance Primary/intrinsic resistance Acquired resistance C. krusei, C. glabrata-high MIC Acquired resistance 7% Candida species (U.S) 9-14% fluconazole-resistant C. glabrata Lack of source control Suboptimal treatment dose, duration Immunosuppression

Mechanism of azole resistance Four major mechanisms Decreased drug concentration. The development of active efflux pumps results in decreased drug concentrations at the site of action. Target site alteration. Prevents binding of azoles to the enzymatic site. Up-regulation of target enzyme. Target enzyme up-regulation can be achieved through gene amplification, increased transcription rate, or decreased degradation of the gene product. Development of bypass pathways. Replacement of ergosterol with the latter product leads to functional membranes and negates the action of azoles on the ergosterol biosynthetic pathway. More than 1 mechanism can be functioning in any given fungal strain with additive effects The predominant mechanism of azole resistance described for C. albicans are: (1) Increased expression of ATP-dependent efflux pumps (CDR1, CDR2) (2) Point mutations in ERG11, the gene encoding the azole target 14-a-demethylase.

Molecular mechanism of azole resistance Mutations in genes that encodes 14α-demethylase. Cyp51a ERG11 Upregulation of efflux pumps Cyp51b

Pharmacokinetics Bioavailability: >90% (oral), no acid effect. Linear pharmacokinetics Distribution: Effectively penetrates brain parenchyma/CSF, eye, skin tissue. Achieves concentrations in saliva, urine, vaginal secretions Protein binding: 11-12% Metabolism: Liver 10-11% ; zero order kinetics Half-life: 20-50 hours ; ~30 hours Excretion: Urine (61-88%); sweat

Pharmacokinetic profile Triazole Solubility Absorption Food effect Bioavailability T1/2 (h) Excretion Fluconazole High - >90% 20-50 Renal Itraconazole Low Erratic ++ 55% 24-42 Hepatic Voriconazole 96% 6 Posaconazole

Target therapeutic range Drug Therapeutic range (mcg/mL) Toxic level CYPs inhibited Rationale for TDM 5-flucytosine >25 >100 n/a Clearance in renal disease Fluconazole 4-20 not established 2C19, 3A4 Select patients only Itraconazole >0.5 (localized) >1.0 (systemic) 3A4 Variable absorption Voriconazole 1.0 -5.5 >6.0 2C9, 3A4 Nonlinear kinetics

Formulations Oral Parenteral Capsules/Tablets: 50mg, 100mg, 150mg, 200mg Oral suspension : 50mg/5mL [35mL bottle] Parenteral 2mg/mL; 100-mL bottle

Clinical Indications Targeted therapy Pre-emptive treatment Vaginal candidiasis Candidal balanitis Mucosal candidiasis Tinea pedis, corporis, cruris, pityriasis versicolor and dermal candidiasis Invasive candidal infection (candidaemia & disseminated candidiasis) Cryptococcal infection(including meningitis) Pre-emptive treatment Cryptococcal antigenaemia Primary prophylaxis Immunocompromised patients (HSCT, pre-term babies etc.) Secondary prophylaxis Cryptococcal meningitis

Dose Targeted therapy Vaginal candidiasis Candidal balanitis Mucosal candidiasis Tinea pedis, corporis, cruris, pityriasis versicolor and dermal candidiasis Invasive candidal infection (candidaemia & disseminated candidiasis) Cryptococcal infection(including meningitis) Uncomplicated Adult & Child >16 years: 150mg single dose, by mouth Recurrent vulvovaginal candidiasis Adult & Child >16 years: 150mg 3 doses, 72hourly, then 150mg , every week , 6 months

Dose Targeted therapy Adult: 50-100mg, PO, daily, 7-14 days Vaginal candidiasis Candidal balanitis Mucosal candidiasis Tinea pedis, corporis, cruris, pityriasis versicolor and dermal candidiasis Invasive candidal infection (candidaemia & disseminated candidiasis) Cryptococcal infection(including meningitis) Adult: 50-100mg, PO, daily, 7-14 days 14-30 days if associated with dentures Child: 3-6mg/kg, day 1, PO or IV Then 3mg/kg daily, 7-14 days

Dose Targeted therapy Adult & Child: 50mg , PO, Daily; 2-4 week Vaginal candidiasis Candidal balanitis Mucosal candidiasis Tinea pedis, corporis, cruris, pityriasis versicolor and dermal candidiasis Invasive candidal infection (candidaemia & disseminated candidiasis) Cryptococcal infection(including meningitis) Adult & Child: 50mg , PO, Daily; 2-4 week Up to 6 weeks, tinea pedis Maximum duration, 6 weeks

Dose Targeted therapy Adult: 800mg day 1, then 400mg daily , 2-8 weeks Vaginal candidiasis Candidal balanitis Mucosal candidiasis Tinea pedis, corporis, cruris, pityriasis versicolor and dermal candidiasis Invasive candidal infection (candidaemia & disseminated candidiasis) Adult: 800mg day 1, then 400mg daily , 2-8 weeks Child: 6-12mg/kg, Daily, PO or IV (Max 800mg daily)

Dose Targeted therapy Induction: 1200mg daily, IV or PO, 2 weeks Cryptococcal infection (including meningitis) Induction: 1200mg daily, IV or PO, 2 weeks Consolidation: 400-800mg daily, PO, 2-8 weeks Maintenance: 200mg , OD, PO, long-term Until immune reconstitution

Dose Pre-emptive treatment Induction: 800mg daily,PO, 2 weeks Cryptococcal antigenaemia Induction: 800mg daily,PO, 2 weeks Consolidation: 400mg daily, PO, 8 weeks Maintenance: 200mg daily, PO, long-term Until immune reconstitution

Dose Primary prophylaxis Adult: 50mg-400mg daily, PO or IV Immunocompromised patients Adult: 50mg-400mg daily, PO or IV 400mg for high risk patients (e.g. HSCT) Start treatment before anticipated onset of neutropenia Continue for 7 days after normal neutrophil count has been attained Child: 3-12mg/kg , daily, PO or IV: Max 400mg

Dose Secondary prophylaxis Maintenance : 200mg PO daily ; long-term Cryptococcal meningitis Maintenance : 200mg PO daily ; long-term Until immune reconstitution

Renal impairment Decrease dosage by 50% for CrCl <50 cc/min Fluconazole is removed by hemofiltration. It should be administered after hemodialysis

Hepatic impairment Fluconazole is not extensively metabolised in the liver Dose adjustments not necessary for patients with hepatic failure Toxicity with related drugs

Pregnancy & Breastfeeding Multiple congenital abnormalities Avoid in pregnancy Breast-feeding Present in breastmilk Compatible with breastfeeding

Common Adverse Reactions Nausea Abdominal discomfort Diarrhoea Headache Elevated liver enzymes

Less frequent Side Effects GI Dyspepsia Vomiting Taste disturbance CNS Dizziness Seizures Liver Hepatitis Pruritus Cardiac QT prolongation Torsades de pointes Skin Alopecia Skin rash Toxic epidermal necrolysis Stevens Johnson syndrome Blood Leukopenia Thrombocytopenia Systemic/metabolic Hyperlipidaemia Hypokalaemia Hypersensitivity reactions Anaphylaxis

Summary Inhibits the conversion of lanosterol to ergosterol Active against Candida spp, Cryptococcus spp, dimorphic fungi, dermatophytes Resistance: Increased expression of efflux pumps, point mutations in ERG11 Excellent oral bioavailability. Administered PO or IV Hepatic adverse reactions