Fluconazole
Fluconazole
Generic Name
Fluconazole
Mechanism
- Inhibits ergosterol synthesis: Fluconazole competitively blocks the fungal cytochrome P450 14α‑demethylase enzyme.
- Disrupts cell membrane integrity: Lack of ergosterol leads to increased membrane permeability and impaired cell growth.
- Selective toxicity: The drug preferentially targets fungal cells, sparing mammalian cells due to differences in sterol composition.
Pharmacokinetics
- Absorption: Oral bioavailability >90 %; reaches peak serum concentrations in 1–2 h.
- Distribution: Widely distributes; volume of distribution ≈0.6 L/kg. Penetrates CSF (~30–50 % of plasma), and accumulates in epithelial cells of the eye, kidney, and liver.
- Metabolism: Predominantly hepatic via CYP2C19, CYP3A4, and CYP2C9; minimal glucuronidation.
- Excretion: Renal elimination constitutes ~70–80 % of dose; half‑life 30–70 h (shorter in renal impairment).
- Drug interactions: Strong inhibitors of CYP2C19 (e.g., *ketoconazole*) or CYP3A4 (e.g., *clarithromycin*) increase fluconazole exposure; conversely, rifampin reduces plasma levels.
Indications
- Systemic candidiasis (e.g., candidemia, esophageal candidiasis).
- Cryptococcal meningitis (initial induction and suppressive therapy).
- Ocular cryptococcosis and endophthalmitis.
- Prophylaxis in neutropenic patients or those undergoing organ transplantation.
- Vulvovaginal candidiasis (oral 400 mg loading + 200 mg daily for 1–2 weeks).
- Fungal otitis media (1 g oral loading dose).
Contraindications
- Severe hepatic impairment (use only if benefits outweigh risks).
- Known hypersensitivity to fluconazole or other azoles.
- Pregnancy (Category C): Use only if clearly needed; counsel regarding potential fetal risk.
- Concurrent use with drugs that prolong QT interval (e.g., *amiodarone*), due to rare risk of torsades de pointes.
- Drug interactions: Avoid co‑administration with drugs metabolized by CYP2C19/CYP3A4 without dose adjustment.
Dosing
| Indication & Population | Dose / Route | Duration | Notes |
| Systemic candidiasis | 200–400 mg PO daily (200 mg for mild, 400 mg for severe) | 14–21 days (adjust per response) | Loading dose not required |
| Cryptococcal meningitis | 400 mg PO IM/IV daily | 8 weeks induction; 400 mg PO weekly suppressive | Loading dose of 800 mg if IV; monitor lumbar puncture CSF opening pressure |
| Ophthalmic cryptococcosis | 400 mg PO daily | 12 weeks | Add intravitreal amphotericin if severe |
| Neutropenic prophylaxis | 400 mg PO daily | Until neutrophil recovery | 2–4 weeks or until immune recovery |
| Vulvovaginal candidiasis | 400 mg PO loading then 200 mg daily | 1–2 weeks | Adequate for widespread mucosal disease |
| Fungal otitis media | 1 g PO single dose | 1 dose | If recurrent, repeat every 3–4 weeks |
• IV formulation (fluconazole 50 mg/mL): same mg/kg dosing, with 200–400 mg daily for severe infections.
• Pediatric dosing: weight‑based 10 mg/kg (max 400 mg)/day for systemic candidiasis; 8 mg/kg (max 200 mg)/day for cryptococcal meningitis (loading 8 mg/kg).
Adverse Effects
- Common (≤10 %)
- GI upset (nausea, vomiting, diarrhea)
- Headache, dizziness
- Mild transaminitis (↑AST/ALT)
- Rash (maculopapular)
- Serious (≤1 %)
- Severe hepatotoxicity → jaundice, elevated bilirubin, cholestatic patterns
- Stevens-Johnson syndrome / TEN
- QT interval prolongation → arrhythmias
- Anaphylactoid reactions (rare, typically with IV access)
- Drug‑induced lupus-like syndrome (extremely uncommon)
- Drug‑drug interactions
- Strong CYP2C19/3A4 inhibitors: ↑fluconazole toxicity
- Drugs with narrow therapeutic index (e.g., *warfarin*, *clopidogrel*): monitor INR
- Potassium‑soluble salts: risk of hypokalemia (if used long‑term)
Monitoring
- Baseline: LFTs, CBC, serum creatinine, electrolytes, QT interval.
- During therapy (especially >4 weeks):
- LFTs every 1–2 weeks → if AST/ALT >3× ULN, discontinue.
- Serum creatinine & eGFR for dose adjustment.
- Electrolytes + ECG if QT‑prolonging drugs co‑administered.
- Special populations:
- Renal impairment: Reduce dose (200 mg daily for CrCl 30–60 mL/min; 100 mg daily for CrCl <30 mL/min).
- Hepatic impairment: Use lowest effective dose, monitor LFTs closely.
Clinical Pearls
1. “Fluconazole‑first” rule – For most *Candida* infections, fluconazole remains the first‑line choice due to its excellent safety profile, minimal drug interactions, and oral bioavailability.
2. CSF penetration matters – In cryptococcal meningitis, a loading dose of 800 mg IV (if awaiting conversion) may shorten time to therapeutic CSF levels, especially in patients with high intracranial pressure.
3. Avoid in pregnancy only if benefit outweighs risk. The drug does cross the placenta; zero‑risk alternatives (e.g., topical azoles for superficial infection) should be considered when possible.
4. Beware of drug‑drug “syndromes.” Fluconazole can displace other agents from protein binding (e.g., *clozapine*, *cisapride*) and increase their plasma levels.
5. Monitoring isn’t always required – For short courses (≤2 weeks) in uncomplicated mucosal candidiasis, routine LFT checks can be omitted; but for >4 weeks or in liver disease, serial LFTs are mandatory.
6. Kidneys, not liver, are the main excretion route → fluconazole is often preferred over amphotericin B in patients with hepatic insufficiency but may still require dose adjustment in renal failure.
7. Cost‑effective prophylaxis – In neutropenic patients, 400 mg daily for 2–4 weeks is proven effective and inexpensive compared with posaconazole or itraconazole ISMN-based formulations.
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• Key take‑away: Fluconazole offers broad, potent antifungal activity with convenient oral dosing. By anticipating interactions, adjusting for organ dysfunction, and monitoring hepatic and renal parameters appropriately, clinicians can safely employ fluconazole as a mainstay therapy across a spectrum of fungal infections.