Treatment of Cryptococcal Meningitis
The recommended treatment for cryptococcal meningitis is 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 as induction therapy, followed by fluconazole (400 mg/day) for a minimum of 8 weeks as consolidation therapy. 1
Induction Therapy (First 2 Weeks)
Primary 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 is associated with mortality <10% 1
- The addition of flucytosine to amphotericin B does not improve immediate outcomes but significantly decreases relapse risk 1
For patients with renal dysfunction or at risk for nephrotoxicity:
- Liposomal amphotericin B (AmBisome) 3-4 mg/kg/day IV plus flucytosine 100 mg/kg/day for at least 2 weeks 1, 2
- Alternatively, amphotericin B lipid complex (ABLC) 5 mg/kg/day IV plus flucytosine 1
- Liposomal amphotericin B can be safely administered at 6 mg/kg/day for high fungal burden disease or treatment failure 1
Consolidation Therapy (Weeks 3-10)
- Fluconazole 400 mg (6 mg/kg) daily orally for a minimum of 8 weeks 1, 3
- Continue until 10-12 weeks after CSF becomes culture-negative 3
- Perform lumbar puncture after 2 weeks of induction to assess CSF sterilization status 1
Maintenance/Suppressive Therapy
For HIV-infected patients:
- Fluconazole 200 mg daily for at least 1 year 1, 2
- Consider discontinuing suppressive therapy if CD4 count >100 cells/μL and HIV RNA undetectable for ≥3 months (after minimum 12 months of antifungal therapy) 1
- Reinstitute maintenance if CD4 count decreases to <100 cells/μL 1
For HIV-negative immunocompromised patients (transplant recipients, chronic immunosuppression):
- Fluconazole 200 mg daily for 6-12 months 1
For immunocompetent patients:
- Optional fluconazole 200 mg daily for 6-12 months 1
Alternative Regimens (When Standard Therapy Cannot Be Used)
Listed in order of preference:
Amphotericin B deoxycholate alone (0.7-1.0 mg/kg/day IV) or liposomal amphotericin B (3-4 mg/kg/day IV) or ABLC (5 mg/kg/day IV) for 4-6 weeks 1
Amphotericin B deoxycholate (0.7 mg/kg/day IV) plus fluconazole (800 mg/day orally) for 2 weeks, followed by fluconazole (800 mg/day) for minimum 8 weeks 1
Fluconazole (≥800 mg/day orally; 1200 mg/day preferred) plus flucytosine (100 mg/kg/day orally) for 6 weeks 1, 2
- This regimen is only for patients who cannot receive amphotericin B 2
Fluconazole alone (800-2000 mg/day orally) for 10-12 weeks; dosage ≥1200 mg/day encouraged 1
- This is discouraged even in "low risk" patients and should only be used when no other options exist 1
Itraconazole 200 mg twice daily for 10-12 weeks is discouraged 1
Critical Management of Increased Intracranial Pressure
- Measure opening pressure at every lumbar puncture 1
- Elevated intracranial pressure (>200 mm H₂O) occurs in up to 75% of patients and is a major cause of death 1
- Primary intervention: repeated daily lumbar punctures to reduce symptomatic elevated pressure 1, 2
- 93% of deaths within first 2 weeks and 40% of deaths in weeks 3-10 are associated with increased intracranial pressure 1
- Consider CSF shunting if daily lumbar punctures are no longer tolerated or symptoms not relieved 1
Monitoring Requirements
For flucytosine therapy:
- Monitor serum flucytosine levels 2 hours post-dose; optimal levels 30-80 mg/mL (or 30-80 μg/mL) 1, 2
- Adjust dose based on renal function using nomogram or serum level monitoring 1
- Monitor complete blood counts regularly for bone marrow suppression 2
For amphotericin B therapy:
- Monitor serum electrolytes, renal function, and bone marrow function carefully 1
- Common toxicities include nausea, vomiting, chills, fever, rigors, renal injury, hypokalemia, hypomagnesemia, renal tubular acidosis, and anemia 1
- Only 3% of patients require discontinuation within first 2 weeks due to toxicity 1
Serial assessments:
- Perform lumbar puncture after 2 weeks to document CSF sterilization 1, 2
- Patients with positive culture at 2 weeks may require longer induction therapy 1
- Blood cultures should be obtained to confirm clearance of cryptococcemia 4
Special Populations
HIV-infected patients:
- Initiate antiretroviral therapy (HAART) 2-10 weeks after starting antifungal treatment 1, 2
- Premature initiation of antiretroviral therapy increases risk of immune reconstitution inflammatory syndrome (IRIS) 2
- Distinguish between treatment failure and IRIS if symptoms worsen during or after treatment 2
Immunocompromised non-HIV patients (transplant recipients):
- Require more prolonged therapy due to 15-20% failure rates with 6-week regimens 1
- Follow induction-consolidation-suppression strategy similar to HIV patients 1
- For patients on chronic prednisone, reduce to ≤10 mg/day if possible to improve outcomes 1
Pediatric patients:
- Amphotericin B 0.7-1.0 mg/kg/day plus flucytosine 100 mg/kg/day for induction 2
- Fluconazole 12 mg/kg on first day, then 6 mg/kg daily for consolidation 2, 3
- For cryptococcal meningitis treatment: 12 mg/kg on first day, then 6-12 mg/kg once daily based on response 3
- For suppression in children with AIDS: 6 mg/kg once daily 3
Critical Pitfalls to Avoid
- Never rely solely on cryptococcal antigen titers (serum or CSF) to guide treatment decisions 1, 2
- Always test for HIV in patients presenting with cryptococcal meningitis 2
- Never start with fluconazole monotherapy, even in apparently "low-risk" patients 1
- Do not initiate antiretroviral therapy too early in HIV patients (wait 2-10 weeks) 2
- Always measure and aggressively manage increased intracranial pressure 1, 2
- Do not fail to monitor for amphotericin B and flucytosine toxicities 2
- Always perform lumbar puncture to rule out CNS involvement in any patient with cryptococcemia 4
Salvage Therapy
For refractory cases where systemic therapy has failed: