What are the recommended fluconazole doses for different Candida infections and cryptococcal meningitis, and how should they be adjusted for renal impairment, hepatic disease, and pediatric patients?

Fluconazole Dosing Guidelines

Standard Dosing by Indication

For most Candida infections and cryptococcal disease, fluconazole dosing ranges from 200-800 mg daily depending on infection severity and site, with specific adjustments required for renal impairment but not for hepatic disease in most cases. 1, 2

Candida Infections

Oropharyngeal Candidiasis:

• Loading dose: 200 mg on Day 1 1, 2
• Maintenance: 100 mg daily for minimum 14 days 1, 2
• Pediatric: 6 mg/kg loading dose, then 3 mg/kg daily 2

Esophageal Candidiasis:

• Loading dose: 200-400 mg on Day 1 1, 2
• Maintenance: 100-200 mg daily for minimum 3 weeks and at least 2 weeks after symptom resolution 1, 2
• Pediatric: 6 mg/kg loading dose, then 3 mg/kg daily (up to 12 mg/kg/day based on response) 2

Candidemia and Invasive Candidiasis:

• Standard dose: 400-800 mg (6-12 mg/kg) daily 1
• Continue for 2 weeks after documented blood culture clearance and symptom resolution 1
• Pediatric: 6-12 mg/kg/day 2

Candida Cystitis:

• 200 mg (3 mg/kg) daily for 2 weeks for fluconazole-susceptible species 1

Candida Pyelonephritis:

• 200-400 mg (3-6 mg/kg) daily for 2 weeks 1

Asymptomatic Candiduria in High-Risk Patients:

• 200-400 mg (3-6 mg/kg) daily for several days before and after urologic procedures 1

Cryptococcal Infections

Cryptococcal Meningitis (Non-HIV, Immunocompetent):

• After initial amphotericin B induction (2 weeks): Consolidation with 400 mg daily for 8-10 weeks 1
• Maintenance: 200 mg daily for 6-12 months 1

Cryptococcal Meningitis (Transplant Recipients):

• Consolidation phase: 400-800 mg (6-12 mg/kg) daily for 8 weeks after induction 1
• Maintenance: 200-400 mg daily for 6-12 months 1
• Pediatric: 12 mg/kg loading dose, then 6 mg/kg daily (up to 12 mg/kg daily based on response) 2
• Suppression in pediatric AIDS: 6 mg/kg daily 2

Cryptococcal Meningitis Suppression (AIDS):

• 200 mg daily indefinitely 2

Coccidioidomycosis

Coccidioidal Meningitis:

• 400-1200 mg daily is recommended, with no role for doses below 400 mg daily in adults without substantial renal impairment 1, 3
• For treatment failure: Increase to higher doses within this range as first option 1
• Lifelong therapy required 1

Extrapulmonary Soft Tissue Coccidioidomycosis:

• 400 mg daily or equivalent itraconazole 1

Bone and Joint Coccidioidomycosis:

• Azole therapy (fluconazole preferred) for at least 1-2 years 1

Transplant Recipients with Coccidioidomycosis:

• 400 mg daily for clinically stable patients with normal renal function 1

Prophylaxis

Bone Marrow Transplant:

• 400 mg once daily starting several days before anticipated neutropenia, continuing for 7 days after neutrophil count >1000 cells/mm³ 2

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Renal Dose Adjustments

The critical threshold for fluconazole dose reduction is creatinine clearance ≤50 mL/min, NOT 60 mL/min. 3

Dosing Algorithm by Renal Function

CrCl >50 mL/min:

• No adjustment needed; use standard dosing based on indication 3, 2

CrCl ≤50 mL/min (not on dialysis):

• Administer full loading dose on Day 1, then reduce maintenance dose to 50% starting Day 2 3, 2
• Example: For 400 mg standard dose → 400 mg Day 1, then 200 mg daily 3
• Example: For 200 mg standard dose → 200 mg Day 1, then 100 mg daily 3

Hemodialysis:

• Administer 100% of recommended dose after each hemodialysis session 3, 2
• On non-dialysis days: Use the 50% reduced dose according to CrCl 3
• Rationale: Approximately 38-50% of fluconazole is removed during a 3-hour hemodialysis session 4

Continuous Ambulatory Peritoneal Dialysis (CAPD):

• 50 mg intraperitoneally or 100 mg orally 5
• Alternative: 150 mg in 2L dialysis solution every 2 days 6

Pharmacokinetic Rationale

• Fluconazole is cleared primarily by renal excretion as unchanged drug (>90% excreted unchanged in urine) 3, 7
• Renal clearance decreases proportionally with declining CrCl, leading to drug accumulation without dose adjustment 3
• Elimination half-life is approximately 30 hours in normal renal function but prolonged significantly in renal impairment 3, 6

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Hepatic Impairment

No dose adjustment is required for fluconazole in hepatic impairment (unlike voriconazole, which requires 50% dose reduction) 8. However, monitor for hepatotoxicity, as fluconazole can cause hepatic injury 1.

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Pediatric Dosing Considerations

Age-Based Adjustments

Premature Neonates (Gestational Age 26-29 Weeks):

• First 2 weeks of life: Same mg/kg dose as older children but administered every 72 hours 2
• After 2 weeks: Dose once daily 2

Children and Adolescents:

• Fluconazole is rapidly cleared in children, requiring higher mg/kg doses than adults 1, 2
• Use the following dose equivalency: 2
  • 3 mg/kg pediatric ≈ 100 mg adult
  • 6 mg/kg pediatric ≈ 200 mg adult
  • 12 mg/kg pediatric ≈ 400 mg adult
• Maximum absolute dose: 600 mg/day 2

Renal Impairment in Pediatrics

Dosage reduction in children with renal insufficiency should parallel adult recommendations 2:

• Estimate CrCl using: K × height (cm) / serum creatinine (mg/100 mL) 2
  • K = 0.55 for children >1 year
  • K = 0.45 for infants
• Apply same 50% dose reduction for CrCl ≤50 mL/min after loading dose 2

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Important Drug Interactions and Monitoring

CYP450 Interactions

Fluconazole inhibits CYP3A4 and CYP2C9, requiring careful evaluation of concomitant medications: 3, 4

• Warfarin: Reduce dose by 50% and monitor INR closely 8
• Cyclosporine/Tacrolimus: Significant dose reductions required with therapeutic drug monitoring 4, 8
• Phenytoin: Monitor for increased anticonvulsant levels and toxicity 4
• Oral hypoglycemics: Monitor blood glucose 3
• Antiretroviral drugs: Careful evaluation necessary 3

Monitoring Parameters

• Renal function: Monitor regularly, as changes necessitate dose adjustments 3, 4
• Hepatic function: Monitor for hepatotoxicity, especially with prolonged therapy 1
• Drug levels: Not routinely required for fluconazole (unlike voriconazole) 1
• If using flucytosine concurrently: Monitor flucytosine levels (target 40-60 µg/mL), particularly in renal impairment 3

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Critical Clinical Pearls

Common Pitfalls to Avoid

1. Do not reduce fluconazole dose at CrCl 60 mL/min — the threshold is ≤50 mL/min 3
2. Always give full loading dose on Day 1, even in renal impairment; only reduce maintenance dosing 3, 2
3. Do not use fluconazole for urinary tract infections in severe renal impairment without dose adjustment, despite excellent urinary excretion, as accumulation causes toxicity 9
4. Fluconazole is NOT suitable for CNS aspergillosis — voriconazole is preferred 8
5. For coccidioidal meningitis, never use <400 mg daily in adults without substantial renal impairment 1, 3

Administration Considerations

• Can be taken with or without food — absorption not affected 2, 7
• Oral bioavailability is excellent (>90%), allowing easy IV-to-oral transition 1, 8
• Once-daily dosing is appropriate due to long half-life (30 hours) 3, 7
• Tissue persistence: Fluconazole remains detectable in tissues for up to 6 months after discontinuation 3

Special Populations

Transplant Recipients:

• Use same dosing as non-transplant patients for most infections 1
• Monitor closely for drug interactions with immunosuppressants 4
• Consider sequential reduction of immunosuppressants, lowering corticosteroids first 1

Neutropenic Patients:

• Manage as invasive candidiasis with 400-800 mg daily 1

Neonates with Low Birth Weight:

• Treat as invasive candidiasis; use age-appropriate dosing every 72 hours initially 1, 2