What is the treatment for cryptococcus 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 orally) for 8 weeks, then maintenance therapy with fluconazole (200 mg/day) for at least 1 year in HIV patients. 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 at least 2 weeks 1, 2
• This combination achieves CSF sterilization in 60-90% of patients within 2 weeks and reduces mortality to <10% 1
• The addition of flucytosine decreases relapse risk, though it doesn't improve immediate survival 1

Alternative induction regimens (in order of preference):

• Liposomal amphotericin B (3-4 mg/kg/day IV) or amphotericin B lipid complex (5 mg/kg/day IV) plus flucytosine for 2 weeks - use this in patients with pre-existing renal dysfunction or at high risk for nephrotoxicity 1, 3, 4

• Single-dose liposomal amphotericin B (10 mg/kg IV on day 1) plus flucytosine (100 mg/kg/day) and fluconazole (1200 mg/day) for 14 days - this newer regimen showed noninferiority to standard therapy with fewer adverse events (24.8% vs 28.7% mortality at 10 weeks) and is particularly attractive for resource-limited settings 5

• Amphotericin B deoxycholate alone (0.7-1.0 mg/kg/day) for 4-6 weeks - only if flucytosine is unavailable or not tolerated 1, 2

• Amphotericin B (0.7 mg/kg/day) plus fluconazole (800 mg/day) for 2 weeks - less effective than amphotericin B plus flucytosine 1

• Fluconazole (≥1200 mg/day) plus flucytosine (100 mg/kg/day) for 6 weeks - only when amphotericin B cannot be used 1, 2

Never use fluconazole monotherapy for initial induction therapy, even in "low-risk" patients, as this yields unsatisfactory outcomes 1

Consolidation Therapy (Weeks 3-10)

• Fluconazole 400 mg/day orally for 8 weeks after completing induction therapy 1, 2, 6
• Higher doses (400-800 mg/day) may be used based on clinical response 1
• Perform lumbar puncture at week 2 to assess CSF sterilization; patients with positive cultures may require longer induction therapy 1

Maintenance/Suppressive Therapy

For HIV-infected patients:

• Fluconazole 200 mg/day for at least 1 year 1, 2, 6
• Continue indefinitely until immune reconstitution occurs (CD4 count >100-200 cells/µL sustained for ≥3 months on antiretroviral therapy) 1

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

• Fluconazole 200 mg/day for 6-12 months 1, 3
• Longer duration needed compared to immunocompetent hosts due to 15-20% failure rates with shorter courses 1

For immunocompetent patients:

• Fluconazole 200 mg/day for 6-12 months is optional 1

Critical Management of Elevated Intracranial Pressure

This is a life-threatening complication that requires aggressive intervention:

• Always measure opening pressure during lumbar puncture 1, 2
• Elevated intracranial pressure (>200 mm H₂O) occurs in up to 75% of patients and accounts for 93% of deaths in the first 2 weeks 1

Management approach:

• Perform daily therapeutic lumbar punctures to reduce symptomatic elevated intracranial pressure until normalization 1, 2, 7
• Remove sufficient CSF to reduce opening pressure by 50% or to <200 mm H₂O 1
• Consider CSF shunting if daily lumbar punctures are no longer tolerated or symptoms persist despite repeated drainage 1, 2

Antiretroviral Therapy Timing in HIV Patients

Delay initiation of antiretroviral therapy (ART) for 4-6 weeks after starting antifungal treatment to prevent immune reconstitution inflammatory syndrome (IRIS), which is common in cryptococcal meningitis 1, 2, 7

• The 2010 IDSA guidelines recommend initiating ART 2-10 weeks after antifungal therapy begins 1
• More recent evidence supports the 4-6 week delay to minimize IRIS risk 7

Monitoring and Dose Adjustments

Flucytosine monitoring:

• Monitor serum flucytosine levels 2 hours post-dose, targeting 30-80 µg/mL 1, 2
• Check complete blood counts regularly due to bone marrow suppression risk 2
• Adjust dose based on renal function using a nomogram or serum levels 1

Fluconazole dose adjustment in renal impairment:

• For creatinine clearance <50 mL/min, reduce maintenance dose by 50% after loading dose 3, 6

Amphotericin B considerations:

• Monitor renal function, electrolytes (especially potassium and magnesium), and complete blood counts 1
• Lipid formulations cause less nephrotoxicity than deoxycholate formulation 1, 3, 4

Population-Specific Considerations

HIV-infected patients (CD4 <50 cells/µL):

• Follow standard induction-consolidation-maintenance approach as outlined above 1, 2
• Mortality remains high (24-29% at 10 weeks even with optimal therapy) 5

Non-HIV immunocompromised patients:

• Use same induction regimen but require more prolonged consolidation and maintenance therapy (6-12 months minimum) 1, 3

Immunocompetent patients:

• May use abbreviated regimen: amphotericin B plus flucytosine for 2 weeks, then fluconazole 400 mg/day for 8-10 weeks 1
• Optional maintenance with fluconazole 200 mg/day for 6-12 months 1

Common Pitfalls to Avoid

• Failing to test for HIV in all patients presenting with cryptococcal meningitis 2
• Inadequate management of elevated intracranial pressure - this kills patients despite microbiologic response 1, 2
• Starting ART too early in HIV patients (before 4-6 weeks) increases IRIS risk 2, 7
• Using fluconazole monotherapy for induction - this is associated with poor outcomes 1
• Failing to monitor for drug toxicities, particularly nephrotoxicity with amphotericin B and myelosuppression with flucytosine 2
• Relying on cryptococcal antigen titers to guide treatment decisions rather than clinical and mycological response 2
• Not performing follow-up lumbar puncture at week 2 to document CSF sterilization 1, 2