What is the treatment for Cryptococcal Meningitis?

Treatment for Cryptococcal Meningitis

The optimal 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 consolidation (400 mg daily for 8 weeks) and maintenance therapy (200 mg daily for at least 1 year). 1, 2

Induction Therapy (First 2 Weeks)

For HIV-infected patients:

• 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
• Higher doses of amphotericin B (1 mg/kg/day) achieve significantly faster fungal clearance (-0.56 vs -0.45 log CFU/mL/day) compared to standard dosing (0.7 mg/kg/day), with manageable and reversible toxicities 3
• This combination sterilizes CSF in 60-90% of patients within 2 weeks and reduces mortality to <10% 1
• The addition of flucytosine to amphotericin B significantly improves survival (hazard ratio 0.61 for death by 70 days) and increases fungal clearance rates 4

For HIV-negative immunocompetent patients:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day plus flucytosine 100 mg/kg/day for at least 4 weeks (can extend to 6 weeks for complete treatment) 1
• A shorter 2-week induction followed by fluconazole consolidation is acceptable only for low-risk patients (early diagnosis, no severe immunosuppression, excellent clinical response) 1

For transplant recipients and immunosuppressed patients:

• Liposomal amphotericin B 3-4 mg/kg/day or ABLC 5 mg/kg/day plus flucytosine 100 mg/kg/day for 2 weeks minimum 1, 5
• Lipid formulations are preferred over amphotericin B deoxycholate to minimize nephrotoxicity, especially in patients with pre-existing chronic kidney disease or those on calcineurin inhibitors 1, 5

Alternative induction regimens when flucytosine is unavailable:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day plus fluconazole 400-800 mg/day for 4-6 weeks 1, 2
• This combination is inferior to amphotericin B plus flucytosine and should only be used when flucytosine cannot be obtained 1, 2

Novel regimen with strong recent evidence:

• Single-dose liposomal amphotericin B 10 mg/kg on day 1 plus flucytosine 100 mg/kg/day plus fluconazole 1200 mg/day for 14 days was noninferior to WHO-recommended treatment (mortality 24.8% vs 28.7%) with fewer grade 3-4 adverse events (50.0% vs 62.3%) 6
• This represents the most recent high-quality evidence (2022, NEJM) and offers a practical alternative in resource-limited settings where daily amphotericin B administration is challenging 6

Consolidation Therapy (Weeks 3-10)

Fluconazole 400 mg daily for 8 weeks after completing induction therapy 1, 2, 7

• Higher doses (800 mg daily) may be used if only a 2-week induction regimen was completed 1
• Itraconazole 400 mg daily is an acceptable but less effective alternative for fluconazole-intolerant patients 1
• Perform lumbar puncture at 2 weeks to confirm CSF sterilization; patients with positive cultures require longer induction therapy 1, 2

Maintenance/Suppressive Therapy

For HIV-infected patients:

• Fluconazole 200 mg daily for at least 1 year 1, 2, 7
• Continue until CD4 count ≥100 cells/μL with undetectable viral load for ≥3 months on antiretroviral therapy 1
• Initiate antiretroviral therapy 2-10 weeks after starting antifungal treatment to reduce risk of immune reconstitution inflammatory syndrome (IRIS) 1, 2

For HIV-negative immunocompetent patients:

• Fluconazole 200 mg daily for 6-12 months 1

For transplant recipients:

• Fluconazole 200-400 mg daily for 6-12 months with sequential reduction of immunosuppression 1, 5

Management of Elevated Intracranial Pressure

Critical intervention that directly impacts mortality:

• 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 within the first 2 weeks 1
• Perform daily therapeutic lumbar punctures to remove CSF and reduce pressure until opening pressure normalizes 1, 2
• Remove sufficient CSF to reduce opening pressure by 50% or to <200 mm H₂O 1
• Consider CSF shunting for patients who cannot tolerate daily lumbar punctures or whose symptoms persist despite aggressive drainage 1, 2

Monitoring and Dose Adjustments

Flucytosine monitoring:

• Measure serum flucytosine levels 2 hours post-dose, targeting 30-80 μg/mL 1, 2
• Monitor complete blood counts regularly for bone marrow suppression (neutropenia more common with combination therapy) 2, 4
• Adjust dose based on renal function using 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 5, 7
• Patients on hemodialysis should receive 100% of recommended dose after each dialysis session 7

Common Pitfalls to Avoid

• Never use fluconazole monotherapy for initial treatment, even in "low-risk" patients—this approach has unsatisfactory outcomes and is strongly discouraged 1
• Do not start antiretroviral therapy immediately in HIV-infected patients; wait 2-10 weeks to reduce IRIS risk 1, 2
• Do not rely on cryptococcal antigen titers alone to guide treatment decisions or assess response 2
• Always test for HIV in patients presenting with cryptococcal meningitis 2
• Do not neglect intracranial pressure management—this is a leading cause of early mortality despite microbiologic response 1, 2
• Monitor for drug toxicities aggressively, particularly nephrotoxicity with amphotericin B and myelosuppression with flucytosine 2

Special Populations

Pediatric patients:

• Amphotericin B plus flucytosine for induction, followed by fluconazole 12 mg/kg on day 1, then 6 mg/kg daily 2, 7
• Treatment duration mirrors adult recommendations: 10-12 weeks after CSF becomes culture-negative 7