What is the recommended treatment for cryptococcal meningitis?

Treatment of Cryptococcal Meningitis

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

Induction Phase (First 2 Weeks)

Combination therapy is superior to monotherapy and saves lives. The addition of flucytosine to amphotericin B achieves CSF sterilization in 60-90% of patients within 2 weeks and significantly reduces mortality compared to amphotericin B alone 1, 3, 4. In a landmark trial, amphotericin B plus flucytosine reduced 70-day mortality with a hazard ratio of 0.61 (95% CI 0.39-0.97) compared to amphotericin B monotherapy 4.

Standard 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
• Higher-dose amphotericin B (1 mg/kg/day) achieves faster fungal clearance (-0.56 vs -0.45 log CFU/mL/day) without significantly increased toxicity 5

Alternative for Renal Dysfunction

• Liposomal amphotericin B (AmBisome) 3-4 mg/kg/day IV or amphotericin B lipid complex (ABLC) 5 mg/kg/day IV plus flucytosine for patients with renal impairment 1, 2
• A single high dose of liposomal amphotericin B (10 mg/kg) combined with 14 days of flucytosine and fluconazole demonstrated noninferiority to standard therapy with fewer adverse events in HIV-positive patients 6

When Flucytosine is Unavailable

• Amphotericin B 0.7-1.0 mg/kg/day for 4-6 weeks alone 1, 2
• Do NOT use fluconazole monotherapy for initial treatment—this approach yields unsatisfactory outcomes and is strongly discouraged even in "low-risk" patients 1, 2, 7

Consolidation Phase (Weeks 3-10)

After successful 2-week induction with documented clinical improvement:

• Fluconazole 400 mg daily orally for 8-10 weeks 1, 2, 8
• Perform lumbar puncture at 2 weeks to document CSF sterilization; patients with positive cultures may require extended induction therapy 1
• Itraconazole 200 mg twice daily is an acceptable but less effective alternative for fluconazole-intolerant patients 1

Maintenance/Suppressive Therapy

HIV-Infected Patients

• Fluconazole 200 mg daily for at least 12 months after completing consolidation 1, 2, 8
• Maintenance therapy prevents relapse (2% with fluconazole vs 37% with placebo) 1
• Antiretroviral therapy should be initiated 2-10 weeks after starting antifungal treatment to reduce IRIS risk 2

Immunosuppressed Non-HIV Patients (Transplant Recipients)

• Fluconazole 200-400 mg daily for 6-12 months 1, 7
• Consider reducing immunosuppression (e.g., prednisone to ≤10 mg/day if possible) 1

Immunocompetent Patients

• Fluconazole 200 mg daily for 6-12 months is optional 1, 2, 7
• Some immunocompetent patients may be successfully treated with 6 weeks of amphotericin B plus flucytosine without extended maintenance 1

Critical Management of Elevated Intracranial Pressure

Elevated intracranial pressure (opening pressure >200 mm H₂O) occurs in up to 75% of patients and is the leading cause of early death. 1, 2

• Always measure opening pressure when performing lumbar puncture in the lateral decubitus position 1, 2
• Elevated intracranial pressure was associated with 93% of deaths in the first 2 weeks and 40% of deaths in weeks 3-10 in one major trial 1

Management Algorithm

• Perform daily therapeutic lumbar punctures removing sufficient CSF to reduce opening pressure by 50% or to <200 mm H₂O 1, 2
• If daily lumbar punctures fail to control symptoms or are no longer tolerated, place a temporary lumbar drain or ventriculoperitoneal shunt 1, 2
• Acetazolamide and corticosteroids are NOT recommended for managing elevated intracranial pressure in cryptococcal meningitis 1

Essential Monitoring Requirements

Flucytosine Monitoring

• Target serum levels: 30-80 μg/mL (measured 2 hours post-dose) 1, 2, 7
• Monitor complete blood counts at least twice weekly for bone marrow suppression (neutropenia, thrombocytopenia) 2, 3, 4
• Adjust dose based on renal function using a nomogram or serum level monitoring 1

Amphotericin B Monitoring

• Monitor serum creatinine, electrolytes (especially potassium and magnesium), and complete blood counts at least twice weekly 2, 7
• Nephrotoxicity and electrolyte abnormalities are common but typically reverse after switching to fluconazole 5

CSF Follow-up

• Repeat lumbar puncture at 2 weeks to document CSF sterilization 1, 2
• Do NOT rely on cryptococcal antigen titers to guide treatment decisions or determine cure—they remain elevated despite successful therapy 2, 7

Population-Specific Considerations

HIV-Infected Patients

• Test all patients with cryptococcal meningitis for HIV—this fundamentally alters treatment duration and monitoring 2, 7
• Mortality without treatment approaches 100%; with optimal therapy, 2-week mortality is 5-6% and 10-week mortality is 24-29% 1, 3, 6
• Delay ART initiation for 2-10 weeks to minimize IRIS risk 2

Transplant Recipients

• Prefer lipid formulations of amphotericin B due to concurrent nephrotoxic calcineurin inhibitors 7
• Require more prolonged therapy similar to HIV patients due to ongoing immunosuppression 1

Patients with Renal Disease

• Lipid formulations are mandatory to avoid further renal injury 1, 7
• Adjust flucytosine dosing based on creatinine clearance 8

Common Pitfalls to Avoid

• Never use fluconazole monotherapy for initial treatment, even in apparently low-risk patients—this is associated with treatment failure 1, 2, 7
• Never fail to measure and aggressively manage elevated intracranial pressure—this is the primary cause of early death 1, 2
• Never start ART immediately in HIV patients—wait 2-10 weeks to reduce IRIS risk 2
• Never assume isolated disease—always perform lumbar puncture to exclude CNS involvement in patients with cryptococcal fungemia 7
• Never rely on cryptococcal antigen titers to determine treatment response or cure 2, 7
• Never neglect monitoring for drug toxicities, particularly bone marrow suppression with flucytosine and nephrotoxicity with amphotericin B 2, 3, 4, 5