fluconazole

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fluconazole antifungal clinical pharmacology

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Fluconazole

Drug Class & Mechanism

Fluconazole is a fluorinated bis-triazole antifungal agent. Like all azoles, it inhibits 14-α-demethylase (CYP51), a fungal cytochrome P450 enzyme required for converting lanosterol to ergosterol. Depletion of ergosterol disrupts fungal cell membrane integrity and permeability, resulting in fungistatic (and at high concentrations, fungicidal) activity.

Katzung's Basic and Clinical Pharmacology, 16e
Lippincott Illustrated Reviews: Pharmacology

Spectrum of Activity

Organism	Susceptibility
Candida albicans, C. parapsilosis	Susceptible
Candida krusei	Intrinsically resistant
Candida glabrata	~30% resistant
Cryptococcus neoformans	Susceptible
Coccidioides immitis (meningitis)	Susceptible
Aspergillus spp.	No activity
Mucorales (mucormycosis)	No activity
Dimorphic fungi (histoplasma, sporothrix)	Minimal/no activity

Fluconazole is the least active of all triazoles and has the narrowest spectrum, primarily covering yeasts. - Lippincott Illustrated Reviews: Pharmacology, p. 1090

Pharmacokinetics (ADME)

Parameter	Details
Oral bioavailability	~90-100% - nearly complete; NOT affected by food or gastric pH
Peak plasma conc.	4-8 μg/mL after 100 mg doses
Protein binding	~11-12% (very low)
Volume of distribution	Widely distributes into body fluids
CSF penetration	Excellent - 50-90% of simultaneous plasma levels
Elimination	>90% renal excretion, mostly unchanged
Half-life	25-30 hours

Key distinguishing features vs. other azoles:

Highest oral bioavailability (unlike ketoconazole or itraconazole)
Best CSF penetration of all azoles
Least effect on hepatic microsomal enzymes - widest therapeutic index
Available in both oral and IV formulations (IV and oral are bioequivalent)
Goodman & Gilman's The Pharmacological Basis of Therapeutics; Katzung's, 16e

Therapeutic Uses & Dosing (Adults)

Indication	Dose
Oropharyngeal candidiasis	200 mg load, then 100-200 mg/day x 7-14 days
Esophageal candidiasis	400 mg load, then 200-400 mg/day
Vulvovaginal candidiasis	Single dose 150 mg PO
Systemic/invasive candidiasis	800 mg load, then 400-800 mg/day
Cryptococcal meningitis (consolidation)	400 mg/day x 8 weeks after AmB + 5-FC induction; then 200 mg/day indefinitely (AIDS)
Coccidioidal meningitis	Drug of choice - good CSF penetration avoids intrathecal AmB
BMT prophylaxis	400 mg/day
HIV - cryptococcal suppression	200-400 mg/day

Goodman & Gilman's, Harriet Lane Handbook 23e

Role in candidemia: Acceptable alternative to echinocandins (first-line) in select, non-neutropenic patients with susceptible isolates; recommended as step-down therapy once the patient stabilizes and blood cultures clear. - Goodman & Gilman's

Renal Dose Adjustments

CrCl (mL/min)	Dosing Interval
>40	Q24h (normal)
21-40	Q48h
10-20	Q72h
Hemodialysis	100-200 mg after each session

Adverse Effects

Common (2-4%): Nausea, vomiting, headache, skin rash, abdominal pain, diarrhea
Reversible alopecia with prolonged therapy at ≥400 mg/day
Hepatotoxicity: Rare - hepatitis, cholestasis; fatal hepatic failure reported rarely
Stevens-Johnson syndrome / TEN / DRESS: Rare exfoliative skin disorders
QT prolongation: Contraindicated with other QT-prolonging drugs metabolized via CYP3A4 (e.g., erythromycin)
Hematologic: Neutropenia, agranulocytosis, thrombocytopenia (rare)
Adrenal insufficiency: Reversible, reported
Harriet Lane Handbook 23e; Goodman & Gilman's

Drug Interactions

Fluconazole inhibits CYP2C9 and CYP3A4 (weaker than other azoles but clinically significant):

Drug	Effect
Warfarin	Increased anticoagulation - monitor INR closely
Phenytoin	Elevated phenytoin levels
Cyclosporine / Tacrolimus	Increased immunosuppressant levels
Statins (HMG-CoA reductase inhibitors)	Risk of myopathy/rhabdomyolysis - consider dose reduction
Oral hypoglycemics	Elevated levels - hypoglycemia risk
Rifampin	Increases fluconazole metabolism (decreases fluconazole levels)
Midazolam, benzodiazepines	Prolonged sedation
AZT (zidovudine)	Increased AZT levels

Use in Pregnancy

Pregnancy category C for single 150 mg dose (vaginal candidiasis)
Pregnancy category D for all other indications (high-dose use)
Associated with skeletal and cardiac deformities (including tetralogy of Fallot) in infants born to mothers on high-dose therapy
A 2024 systematic review and meta-analysis (PMID 39658659) confirmed increased risk of congenital malformations and miscarriages with first-trimester use - fluconazole should be avoided in pregnancy

Resistance

C. krusei: intrinsically resistant
C. glabrata: ~30% acquired resistance
Candida auris: typically resistant to all azoles - treat with echinocandins
A 2026 systematic review (PMID 41612235) documents rising global prevalence of fluconazole resistance in non-albicans Candida species - a clinically important trend

Key Comparisons vs. Other Azoles

Feature	Fluconazole	Voriconazole	Itraconazole
Spectrum	Narrow (yeasts)	Broad (+ Aspergillus)	Broad
Oral bioavailability	~100%	~96%	Variable (food-dependent)
CSF penetration	Excellent	Good	Poor
CYP inhibition	Moderate (2C9, 3A4)	Strong (3A4, 2C9)	Strong (3A4)
Aspergillus coverage	No	Yes	Limited
Therapeutic index	Widest of azoles	Narrower	Narrower

Sources: Katzung's Basic and Clinical Pharmacology 16e; Goodman & Gilman's Pharmacological Basis of Therapeutics; Lippincott Illustrated Reviews: Pharmacology; Harriet Lane Handbook 23e; Goldman-Cecil Medicine; Red Book 2021

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