What is the recommended treatment for cryptococcal meningitis?

Treatment of Cryptococcal Meningitis

The recommended treatment for cryptococcal meningitis is induction therapy with amphotericin B deoxycholate (0.7-1.0 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks, followed by fluconazole (400 mg/day) for 8-10 weeks as consolidation therapy, and then fluconazole (200 mg/day) for maintenance. 1

Treatment Regimens Based on Immune Status

HIV-Associated Cryptococcal Meningitis

• Induction: Amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) for 2 weeks 2, 1
• Consolidation: Fluconazole 400 mg daily for 8 weeks 2, 1
• Maintenance: Fluconazole 200 mg daily for at least 1 year or until immune reconstitution 1, 3
• Antiretroviral therapy should be initiated 2-10 weeks after starting antifungal treatment to reduce risk of IRIS 1

Non-HIV Immunocompromised Patients

• Induction: Amphotericin B (0.7-1.0 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks 2
• Consolidation: Fluconazole (400-800 mg/day) for 8-10 weeks 2
• Maintenance: Fluconazole (200 mg/day) for 6-12 months 2

Immunocompetent Patients

• Option 1: Amphotericin B plus flucytosine for 6 weeks (most effective) 2
• Option 2: Amphotericin B (0.5-1 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks, followed by fluconazole (400 mg/day) for 8-10 weeks 2

Alternative Regimens

• For patients with renal impairment: Liposomal amphotericin B (AmBisome) 4 mg/kg/day can be substituted for conventional amphotericin B 2, 1
• When flucytosine is unavailable: Amphotericin B plus fluconazole (400-800 mg/day) 1
• When amphotericin B cannot be used: Fluconazole (1200 mg daily) plus flucytosine (100 mg/kg/day) for 2 weeks 1
• For patients unable to tolerate fluconazole: Itraconazole (200 mg twice daily) may be substituted 2

Recent Evidence on Treatment Duration

• The most recent evidence supports shorter courses of amphotericin B (1 week) when combined with flucytosine 4
• A 2022 study demonstrated that a single high dose of liposomal amphotericin B (10 mg/kg) plus 14 days of flucytosine and fluconazole was noninferior to the standard 7-day amphotericin B deoxycholate regimen 5

Monitoring and Management

• Lumbar puncture should be performed after 2 weeks of treatment to assess CSF sterilization 2
• Patients with positive CSF cultures at 2 weeks require longer induction therapy 2
• Monitor for increased intracranial pressure and manage aggressively with repeated lumbar punctures 2, 1
• For patients receiving flucytosine, monitor serum levels (target: 30-80 μg/mL) and adjust dose based on renal function 2, 1
• Regular monitoring of renal function, electrolytes, and complete blood counts is essential during amphotericin B therapy 1, 3

Evidence Supporting Combination Therapy

• Combination therapy with amphotericin B plus flucytosine is associated with improved survival compared to amphotericin B alone 4
• The addition of flucytosine to amphotericin B significantly increases the rate of CSF sterilization 4, 6
• A meta-analysis showed a 44% reduction in mortality at 2 weeks with amphotericin B plus flucytosine compared to other regimens 7

Common Pitfalls and Caveats

• Initial therapy with fluconazole alone, even among "low risk" patients, is discouraged due to unsatisfactory outcomes 2
• Treatment decisions should not be based solely on cryptococcal antigen titers in either serum or CSF 2, 1
• Inadequate management of increased intracranial pressure is associated with high mortality 2, 1
• Premature initiation of antiretroviral therapy in HIV patients can lead to immune reconstitution inflammatory syndrome (IRIS) 1
• Failure to monitor for drug toxicities, especially with amphotericin B and flucytosine, can lead to serious adverse events 1

Dosing in Special Populations

• For children: Amphotericin B plus flucytosine for induction, followed by fluconazole (12 mg/kg on first day, then 6 mg/kg daily) 8
• For patients with renal impairment: Dose adjustment is required for fluconazole based on creatinine clearance 8
• For patients on hemodialysis: 100% of the recommended fluconazole dose should be given after each hemodialysis 8