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 HIV Status
HIV-Infected Patients
- 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/day for 8 weeks 2, 3
- Maintenance: Fluconazole 200 mg/day lifelong or until immune reconstitution with CD4 >200 cells/mm³ for at least 6 months 4, 3
- Antiretroviral therapy should be initiated 2-10 weeks after starting antifungal treatment to reduce risk of immune reconstitution inflammatory syndrome 1
HIV-Negative/Immunocompetent Patients
- Standard approach: Amphotericin B (0.7-1.0 mg/kg/day) plus flucytosine (100 mg/kg/day) for 6 weeks 2
- Alternative approach: Amphotericin B (0.5-1.0 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks, followed by fluconazole (400 mg/day) for 8-10 weeks 2
- Optional maintenance: Fluconazole (200 mg/day) for 6-12 months 2
Immunocompromised Non-HIV Patients
- Induction and consolidation: Similar to HIV regimen with amphotericin B (0.7-1.0 mg/kg/day) for 2 weeks, followed by fluconazole (400-800 mg/day) for 8-10 weeks 2
- Maintenance: Fluconazole (200 mg/day) for 6-12 months 2
- For patients on chronic steroids, reduction of prednisone to ≤10 mg/day if possible 2
Alternative Regimens for Special Situations
Renal Impairment
- Liposomal amphotericin B (AmBisome) 3-4 mg/kg/day can be substituted for conventional amphotericin B 1, 5
- Experience with lipid formulations is limited in non-HIV patients, but AmBisome 4 mg/kg is the best substitute 2
When Flucytosine is Unavailable
- Amphotericin B plus fluconazole (800 mg/day) is recommended, though less effective 1
- Initial therapy with fluconazole alone is discouraged, even in "low-risk" patients 2
Recent Evidence on Single-Dose Liposomal Amphotericin B
- A 2022 study showed that a single high dose of liposomal amphotericin B (10 mg/kg) on day 1 plus 14 days of flucytosine and fluconazole was noninferior to standard treatment in HIV patients 6
Monitoring and Management
Cerebrospinal Fluid (CSF) Monitoring
- Lumbar puncture should be performed after 2 weeks of treatment to assess CSF sterilization 2, 1
- Patients with positive cultures at 2 weeks may require longer induction therapy 2
Intracranial Pressure Management
- Monitor for increased intracranial pressure, which is present in up to 75% of patients 2
- Daily therapeutic lumbar punctures until normalization if opening pressure >200 mm H₂O 2, 1
- Consider CSF shunting for patients who cannot tolerate repeated lumbar punctures 2
Drug Level Monitoring
- For patients receiving flucytosine, monitor serum levels (target: 30-80 μg/mL) 2, 1
- Adjust flucytosine dose based on renal function 1
- Monitor complete blood counts regularly due to bone marrow suppression risk with flucytosine 1
Common Pitfalls and Caveats
- Failure to test for HIV in patients with cryptococcal meningitis 1
- Inadequate management of increased intracranial pressure, which contributes significantly to mortality 1
- Premature initiation of antiretroviral therapy in HIV patients (should wait 2-10 weeks) 1
- Relying solely on cryptococcal antigen titers to guide treatment decisions 1, 4
- Initial therapy with fluconazole alone, which yields unsatisfactory outcomes 2
- Failure to monitor for drug toxicities, especially with amphotericin B and flucytosine 1
Efficacy Considerations
- Higher dose amphotericin B (1 mg/kg/day) plus flucytosine is more rapidly fungicidal than standard dose (0.7 mg/kg/day) 7
- Combination therapy of amphotericin B and flucytosine will sterilize CSF within 2 weeks in 60-90% of patients 2
- Fluconazole is superior to itraconazole for maintenance therapy, with significantly lower relapse rates (2-3%) 4