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Sunday, July 27, 2025

Fluconazole


Fluconazole is a systemic triazole antifungal agent used for the treatment and prevention of fungal infections caused by yeasts and other fungi, particularly Candida and Cryptococcus species. It is widely employed in both immunocompetent and immunocompromised patients, including those undergoing chemotherapy, transplantation, or long-term antibiotic therapy. Fluconazole’s excellent oral bioavailability and relatively low toxicity profile make it a first-line agent in many clinical scenarios.

Pharmacological Classification

  • Therapeutic Class: Antifungal agent

  • Pharmacologic Class: Triazole derivative

  • ATC Code: J02AC01

  • Formulations: Oral tablets, oral suspension, intravenous injection

  • Route: Oral or IV

Mechanism of Action

Fluconazole acts by inhibiting the fungal cytochrome P450 enzyme 14α-demethylase, which is responsible for converting lanosterol to ergosterol—a key component of the fungal cell membrane. Inhibition leads to depletion of ergosterol, accumulation of toxic 14α-methylated sterols, and ultimately disruption of membrane integrity and fungal cell death.

It exhibits fungistatic activity against Candida species and Cryptococcus neoformans, though at high concentrations or in certain infections it may be fungicidal.

Spectrum of Activity

Sensitive Fungi

  • Candida albicans (most strains)

  • Candida tropicalis, Candida parapsilosis

  • Cryptococcus neoformans

  • Coccidioides immitis

  • Histoplasma capsulatum

  • Blastomyces dermatitidis

  • Dermatophytes (e.g., Trichophyton, Epidermophyton)

Resistance Concerns

  • Candida glabrata and Candida krusei show reduced or intrinsic resistance

  • Long-term or repeated fluconazole exposure may promote azole resistance

Therapeutic Indications

Treatment

  • Oropharyngeal candidiasis

  • Esophageal candidiasis

  • Vaginal candidiasis

  • Candidemia and invasive candidiasis

  • Cryptococcal meningitis

  • Dermatophytosis and tinea infections (off-label in some cases)

  • Fungal urinary tract infections

  • Systemic fungal infections in immunocompromised hosts

Prophylaxis

  • Candidiasis prophylaxis in neutropenic patients (e.g., chemotherapy or stem cell transplant recipients)

  • Cryptococcosis prophylaxis in HIV/AIDS patients with CD4 counts <200 cells/mm³

Dosage and Administration

Adults

  • Vaginal candidiasis: 150 mg orally as a single dose

  • Oropharyngeal candidiasis: 200 mg on day 1, then 100 mg daily for 7–14 days

  • Esophageal candidiasis: 200 mg on day 1, then 100–400 mg daily for 14–21 days

  • Systemic candidiasis: 400 mg daily (after 800 mg loading dose)

  • Cryptococcal meningitis: 400 mg on day 1, then 200–400 mg daily for 6–8 weeks; maintenance in HIV: 200 mg daily

  • Onychomycosis (off-label): 150–300 mg once weekly

Children

  • Dose is weight-based: typically 3–12 mg/kg/day depending on severity and site of infection

  • Maximum dose usually does not exceed adult dosing limits

Renal Impairment

  • Dose adjustment required when creatinine clearance <50 mL/min

  • Loading dose usually unchanged, followed by reduced maintenance

Route

  • Oral (tablets/suspension) and IV are interchangeable due to high bioavailability (>90%)

  • Can be taken with or without food

Pharmacokinetics

  • Absorption: Excellent oral bioavailability (90%)

  • Distribution: Wide tissue penetration including CSF, urine, and saliva

  • Protein Binding: Low (~11–12%)

  • Half-life: 20–50 hours (longer in neonates and renal impairment)

  • Metabolism: Minimal hepatic metabolism

  • Excretion: Primarily renal (80% excreted unchanged in urine)

Contraindications

  • Known hypersensitivity to fluconazole or other azoles

  • Concomitant use with terfenadine (≥400 mg/day fluconazole) or cisapride, pimozide, quinidine due to risk of QT prolongation and torsades de pointes

  • Caution with congenital long QT syndrome, severe renal dysfunction (unless dose adjusted)

Warnings and Precautions

  • Hepatotoxicity: Ranging from mild elevations in liver enzymes to rare cases of hepatic failure

  • QT prolongation: Use with caution in patients with cardiac risk factors

  • Superinfection: Prolonged use may lead to overgrowth of non-susceptible fungi or bacteria

  • Anaphylactic reactions: Rare but serious allergic reactions reported

  • Use in pregnancy: Avoid high doses or prolonged use in pregnancy; possible risk of congenital anomalies with chronic use

Adverse Effects

Common (1–10%)

  • Nausea, vomiting, abdominal pain

  • Headache

  • Diarrhea

  • Elevated liver enzymes

  • Rash

Uncommon to Rare (<1%)

  • Hepatitis, hepatic failure

  • QT prolongation

  • Seizures

  • Anaphylaxis

  • Stevens-Johnson syndrome (rare)

  • Alopecia (with long-term use)

Drug Interactions

Enzyme Inhibition

Fluconazole inhibits CYP2C9, CYP2C19, and CYP3A4, leading to increased plasma concentrations of many co-administered drugs:

  • Warfarin: ↑ bleeding risk – monitor INR

  • Phenytoin: ↑ phenytoin toxicity – monitor levels

  • Sulfonylureas (e.g., glipizide): ↑ risk of hypoglycemia

  • Benzodiazepines (e.g., midazolam): ↑ sedation

  • Statins (e.g., simvastatin, atorvastatin): ↑ myopathy risk

  • Methadone: Potential for QT prolongation

  • Oral contraceptives: Generally not significantly affected, but monitor for decreased efficacy in some cases

  • Cyclosporine, tacrolimus: ↑ nephrotoxicity – monitor levels

  • Theophylline: Delayed clearance

Drugs That Prolong QT

  • Risk of additive QT prolongation when combined with amiodarone, cisapride, quinidine, haloperidol, macrolides

Pregnancy and Lactation

Pregnancy

  • Avoid prolonged use or high doses in pregnancy (especially in the first trimester)

  • Single-dose (150 mg) use for vaginal candidiasis is generally considered low risk

  • Animal studies show teratogenic effects at high doses; some human reports of skeletal and craniofacial anomalies

Lactation

  • Excreted in breast milk but considered compatible by WHO and LactMed

  • Use with caution; monitor infant for GI upset or candidiasis

Use in Special Populations

Elderly

  • No specific dosage adjustment unless renal impairment is present

Pediatrics

  • Effective in neonatal and pediatric fungal infections

  • Dosing must be weight-adjusted and renal function assessed

Renal Impairment

  • Dose reduction required for maintenance therapy

  • Hemodialysis patients should receive supplemental dosing post-session

Patient Counseling Points

  • Take with or without food

  • Complete the full course even if symptoms improve early

  • Report signs of liver dysfunction: dark urine, jaundice, fatigue

  • Notify prescriber about other medications due to potential interactions

  • Avoid alcohol during extended treatment

  • Women with recurrent vaginal thrush should not self-treat repeatedly without evaluation

Clinical Practice Highlights

  • 150 mg single dose is gold standard for uncomplicated vaginal candidiasis

  • Preferred oral agent for cryptococcal meningitis maintenance in HIV/AIDS

  • Effective in candidemia when fluconazole-susceptible Candida is confirmed

  • IV form used in hospitalized or critically ill patients unable to take oral agents

  • Often replaced by echinocandins (e.g., caspofungin) or amphotericin B in resistant infections or C. glabrata/C. krusei




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