What is the treatment for cryptococcal meningitis?

Treatment of Cryptococcal Meningitis

The optimal treatment for cryptococcal meningitis is induction therapy with amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) for at least 2 weeks, followed by consolidation with fluconazole (400 mg/day) for 8-10 weeks, then maintenance therapy with fluconazole (200 mg/day). 1, 2

Induction Therapy (First 2 Weeks)

Preferred regimen:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally (divided into 4 doses) for 2 weeks 1, 2
• This combination achieves CSF sterilization in 60-90% of patients within 2 weeks 1
• The addition of flucytosine significantly improves CSF sterilization rates and reduces relapse risk 1, 3

Alternative induction regimens (in order of preference):

• Liposomal amphotericin B (AmBisome) 3-4 mg/kg/day IV plus flucytosine 100 mg/kg/day for 2 weeks for patients with renal dysfunction or at risk for nephrotoxicity 1, 2
• A recent high-quality trial demonstrated that single-dose liposomal amphotericin B 10 mg/kg plus 14 days of flucytosine (100 mg/kg/day) and fluconazole (1200 mg/day) was noninferior to standard therapy in HIV-positive patients, with fewer adverse events 4
• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day alone for 4-6 weeks when flucytosine is unavailable 1, 2
• Amphotericin B deoxycholate 0.7 mg/kg/day plus fluconazole 800 mg/day for 2 weeks when flucytosine is unavailable 1
• Fluconazole ≥1200 mg/day plus flucytosine 100 mg/kg/day for 6 weeks when amphotericin B cannot be used 1, 2

Do not use fluconazole monotherapy for initial induction, even in "low-risk" patients, as outcomes are unsatisfactory 1

Consolidation Therapy (Weeks 3-10)

• Fluconazole 400 mg/day orally for 8-10 weeks after completing induction therapy 1, 2
• Itraconazole 200 mg twice daily is an acceptable but less effective alternative for patients unable to tolerate fluconazole 1

Maintenance/Suppressive Therapy

For HIV-infected patients:

• Fluconazole 200 mg/day orally for at least 12 months 1, 2, 5
• Consider discontinuing suppressive therapy only if CD4 count >100 cells/μL and undetectable HIV RNA sustained for ≥3 months after completing at least 12 months of antifungal therapy 1
• Reinstitute maintenance if CD4 count decreases to <100 cells/μL 1

For immunocompromised non-HIV patients (transplant recipients, chronic immunosuppression):

• Fluconazole 200 mg/day for 6-12 months 1, 5
• These patients require more prolonged therapy due to higher failure rates (15-20%) with shorter courses 1

For immunocompetent patients:

• Optional fluconazole 200 mg/day for 6-12 months 1

Antiretroviral Therapy Timing (HIV Patients)

• Initiate or optimize antiretroviral therapy 2-10 weeks after starting antifungal treatment 1, 2
• Earlier initiation risks immune reconstitution inflammatory syndrome (IRIS) 2

Critical Monitoring and Management

Flucytosine monitoring:

• Measure serum flucytosine levels 2 hours post-dose, targeting 30-80 μg/mL 1, 2, 5
• Monitor complete blood counts regularly for bone marrow suppression 2
• Adjust dose based on renal function 1

Intracranial pressure management:

• Always measure opening pressure during lumbar puncture 1
• Elevated intracranial pressure (>200 mm H₂O) occurs in up to 75% of patients and is a major cause of death 1
• Perform daily therapeutic lumbar punctures for symptomatic elevated intracranial pressure 1, 2
• Consider CSF shunting if daily lumbar punctures are not tolerated or ineffective 1

CSF sterilization assessment:

• Perform lumbar puncture at 2 weeks to assess CSF sterilization 1, 2
• Patients with positive cultures at 2 weeks may require longer induction therapy 1

Common Pitfalls to Avoid

• Failing to test for HIV in all patients with cryptococcal meningitis 2, 5
• Inadequate management of elevated intracranial pressure, which accounts for 93% of deaths in the first 2 weeks and 40% of deaths in weeks 3-10 1, 2
• Premature initiation of antiretroviral therapy in HIV patients (should wait 2-10 weeks to reduce IRIS risk) 2
• Failure to monitor for drug toxicities, particularly nephrotoxicity with amphotericin B and myelosuppression with flucytosine 2
• Using cryptococcal antigen titers alone to guide treatment decisions, as titers do not reliably correlate with treatment response 2, 5
• Distinguishing treatment failure from IRIS when symptoms worsen during or after treatment 2

Special Populations

Patients with renal disease:

• Substitute lipid formulations of amphotericin B (liposomal amphotericin B 3-4 mg/kg/day or amphotericin B lipid complex 5 mg/kg/day) for amphotericin B deoxycholate 1

Patients on chronic corticosteroids:

• Reduce prednisone dose to ≤10 mg/day if possible to improve antifungal therapy outcomes 1