What are the recommended amphotericin B (including liposomal formulation) and fluconazole dosing regimens for an adult with cryptococcal meningitis during induction, consolidation, and maintenance, and how should the doses be adjusted in renal or hepatic impairment?

Cryptococcal Meningitis Treatment Dosing

For HIV-infected adults with cryptococcal meningitis, use amphotericin B deoxycholate 0.7–1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally (divided into 4 doses) for at least 2 weeks, followed by fluconazole 400 mg daily for 8 weeks, then fluconazole 200 mg daily for maintenance. 1

Induction Therapy Dosing

Standard Regimen (Preferred)

• Amphotericin B deoxycholate: 0.7–1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally divided into 4 doses for minimum 2 weeks in HIV-infected patients (strongest evidence, A-I rating) 2, 1
• Non-HIV, non-transplant patients: Same amphotericin B + flucytosine combination but extend to 4 weeks minimum 1
• This combination provides superior early fungicidal activity and reduces mortality compared to amphotericin B alone 3

Lipid Formulations (For Renal Dysfunction or Transplant Recipients)

• Liposomal amphotericin B: 3–4 mg/kg/day IV plus flucytosine 100 mg/kg/day for 2 weeks 1, 4
• Amphotericin B lipid complex (ABLC): 5 mg/kg/day IV plus flucytosine for 2 weeks 1
• Transplant recipients should receive lipid formulations rather than deoxycholate due to concurrent nephrotoxic calcineurin inhibitors 2, 1
• Liposomal amphotericin B at 3 mg/kg/day causes significantly less nephrotoxicity than deoxycholate while maintaining equal efficacy 5

Alternative Regimens When Flucytosine Unavailable

• Amphotericin B deoxycholate 0.7 mg/kg/day IV plus fluconazole 800 mg/day orally for 2 weeks 2, 1
• Amphotericin B monotherapy (any formulation) for 4–6 weeks if combination therapy impossible 1
• Liposomal amphotericin B 6 mg/kg/day IV for 4–6 weeks in refractory cases or high fungal burden 1, 4

Alternative When Amphotericin B Contraindicated

• Fluconazole 1200 mg/day plus flucytosine 100 mg/kg/day for 2 weeks (inferior to amphotericin-based regimens) 1

Consolidation Therapy Dosing

• Fluconazole 400–800 mg daily orally for 8 weeks after completing induction 2, 1
• Use the higher dose (800 mg/day) when only 2-week induction was given, flucytosine was omitted, or in non-HIV/non-transplant patients 1

Maintenance (Suppressive) Therapy Dosing

• Fluconazole 200 mg daily orally for 6–12 months minimum 2, 1
• Transplant recipients: May require 200–400 mg daily (higher doses often needed) 2, 1
• HIV patients: Continue until CD4 > 100 cells/µL for ≥3 months AND undetectable HIV RNA AND completed ≥12 months total antifungal therapy 1
• Restart maintenance if CD4 falls below 100 cells/µL 1

Pediatric Dosing

• Induction: Amphotericin B 0.5–1.5 mg/kg/day IV (doses up to 1.5 mg/kg/day well tolerated) plus flucytosine 25 mg/kg four times daily for minimum 2 weeks 2
• Liposomal amphotericin B in children: 2 mg/kg/day effective; doses up to 7.5 mg/kg/day used for refractory cases 2
• Consolidation: Fluconazole 5–6 mg/kg twice daily (total 10–12 mg/kg/day) for 8 weeks 2, 1
• Maintenance: Lower dose fluconazole for life-long suppression 2
• Children clear fluconazole more rapidly than adults, requiring higher weight-based dosing 2, 1

Dose Adjustments in Renal Impairment

• Switch to lipid formulations (liposomal amphotericin B 3–4 mg/kg/day or ABLC 5 mg/kg/day) rather than adjusting deoxycholate dose 1
• Flucytosine: Monitor serum levels (target 30–80 µg/mL, some sources cite 40–60 µg/mL) and adjust dose based on renal function to prevent bone marrow suppression 2, 1
• Avoid flucytosine entirely in severe renal impairment 2
• Fluconazole dose adjustment not typically required for consolidation/maintenance phases, but monitor in severe renal dysfunction

Dose Adjustments in Hepatic Impairment

• Amphotericin B formulations: No dose adjustment required; not hepatically metabolized 2
• Fluconazole: Use with caution; monitor for asymptomatic transaminase elevations and rare hepatitis 2
• Flucytosine: No specific hepatic dose adjustment, but monitor liver function tests 2
• Azoles inhibit cytochrome P-450 hepatic enzymes, creating significant drug interaction potential with antiretrovirals and immunosuppressants 2

Critical Monitoring Requirements

• Flucytosine therapy: Monitor complete blood counts regularly for bone marrow suppression (anemia, leukopenia, thrombocytopenia) and serum drug levels 2, 1
• Amphotericin B therapy: Monitor serum creatinine, potassium, and magnesium throughout treatment 1, 4
• Serial lumbar punctures at 2 weeks to document CSF sterilization and guide induction duration 1
• Grade III/IV anemia and nephrotoxicity during amphotericin therapy are independent risk factors for 10-week mortality 6

Common Pitfalls to Avoid

• Do not start antiretroviral therapy immediately in HIV patients—delay ART for 2–10 weeks after starting antifungal treatment to reduce immune reconstitution inflammatory syndrome (IRIS) risk 1, 4
• Do not use amphotericin B deoxycholate in transplant recipients unless lipid formulations have been considered, due to additive nephrotoxicity with calcineurin inhibitors 1
• Do not use liposomal amphotericin B monotherapy for only 2 weeks without flucytosine unless extending to 4–6 weeks 4
• Do not use acetazolamide for elevated intracranial pressure—it causes metabolic acidosis and offers no benefit 2, 1
• Do not rely on cryptococcal antigen titers to guide treatment duration; use clinical response and CSF sterilization 1, 4
• Do not use voriconazole for cryptococcal meningitis—no evidence supports its efficacy 7
• Preemptive intravenous saline hydration and electrolyte replacement during amphotericin therapy minimizes hypokalemia and nephrotoxicity 6