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

2. 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

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

4. Structure
Voriconazole and fluconazole are structurally similar

5. 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

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

7. 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

8. 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

9. 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

10. 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.

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

12. 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: %
Metabolism: Liver 10-11% ; zero order kinetics
Half-life: hours ; ~30 hours
Excretion: Urine (61-88%); sweat

13. 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

14. 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
>6.0
2C9, 3A4
Nonlinear
kinetics

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

16. 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

17. 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: mg single dose, by mouth
Recurrent vulvovaginal candidiasis
Adult & Child >16 years: mg 3 doses, 72hourly, then
150mg , every week , 6 months

18. 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: mg, 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

19. 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

20. 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: mg/kg, Daily, PO or IV (Max 800mg daily)

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

22. 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

23. 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

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

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

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

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

28. Common Adverse Reactions
Nausea
Abdominal discomfort
Diarrhoea
Headache
Elevated liver enzymes

29. Less frequent Side EffectsGI
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

30. 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