What is the recommended treatment for Cryptococcus meningitis?

Treatment of Cryptococcal Meningitis

The recommended treatment for cryptococcal meningitis is amphotericin B deoxycholate (0.7-1.0 mg/kg/day) plus flucytosine (100 mg/kg/day in 4 divided doses) for 2 weeks (induction phase), followed by fluconazole 400 mg daily for 8 weeks (consolidation phase), and then fluconazole 200 mg daily for maintenance therapy. 1

Treatment Algorithm

Induction Phase (First 2 weeks)

• First-line regimen:

  • Amphotericin B deoxycholate (AmBd) 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day (divided into 4 doses) 1
  • Duration: 2 weeks

• Alternative for patients with renal impairment:

  • Liposomal amphotericin B 3-4 mg/kg/day IV or amphotericin B lipid complex (ABLC) 5 mg/kg/day IV plus flucytosine 1, 2

• If flucytosine is unavailable or contraindicated:

  • AmBd or liposomal AmB alone for 4-6 weeks 1
  • OR AmBd plus high-dose fluconazole 800 mg daily 1

Consolidation Phase (8 weeks)

• Fluconazole 400 mg daily (can increase to 800 mg daily if shorter induction regimen was used) 1, 2
• Duration: 8 weeks or until CSF cultures are sterile 1

Maintenance Phase

• Fluconazole 200 mg daily 1
• Duration:
  • HIV patients: At least 1 year; consider discontinuing when CD4 >100 cells/μL and viral load undetectable for >3 months 1
  • Non-HIV immunocompromised patients: 6-12 months 1, 2
  • Immunocompetent patients: 6-12 months 1

Evidence for Treatment Recommendations

The combination of amphotericin B plus flucytosine has demonstrated superior efficacy compared to amphotericin B alone in randomized controlled trials 3. This combination increases survival and enhances the rate of yeast clearance from cerebrospinal fluid 3. A meta-analysis showed that mortality at 2 weeks was 44% lower with amphotericin B plus flucytosine compared to other regimens 4.

Higher doses of amphotericin B (1 mg/kg/day) combined with flucytosine have shown more rapid fungicidal activity than standard doses (0.7 mg/kg/day) 5, though this must be balanced against potential toxicity.

Recent evidence suggests that a single high dose of liposomal amphotericin B (10 mg/kg) combined with flucytosine and fluconazole may be non-inferior to the standard 7-day amphotericin B deoxycholate regimen 6, but this approach is not yet incorporated into major guidelines.

Management of Elevated Intracranial Pressure

Elevated intracranial pressure (ICP) is common in cryptococcal meningitis and associated with increased mortality 1:

• Measure opening pressure during initial lumbar puncture 1
• If CSF pressure >25 cm H₂O and symptoms of increased ICP:
  • Perform daily lumbar punctures to reduce pressure by 50% or to normal levels (<20 cm H₂O) 1
  • Continue daily lumbar punctures until pressure and symptoms stabilize for at least 2 days 1
• Consider temporary percutaneous lumbar drains or ventriculostomy for patients requiring daily lumbar punctures 1
• Permanent ventriculoperitoneal shunts should be placed only after appropriate antifungal therapy when conservative measures fail 1
• Avoid mannitol, acetazolamide, and corticosteroids (unless treating IRIS) for ICP control 1

Monitoring Treatment

• Perform follow-up lumbar puncture after 2 weeks of treatment to assess CSF sterilization 1
• Patients with positive cultures at 2 weeks may require longer induction therapy 1
• Monitor renal function, electrolytes, and complete blood count regularly 2
• When using flucytosine, monitor for bone marrow toxicity (anemia, leukopenia, thrombocytopenia) 1
• Target flucytosine levels should be between 40-60 μg/mL, particularly in patients with renal impairment 1, 2

Important Considerations and Pitfalls

• Flucytosine toxicity: Can cause bone marrow suppression; avoid in severe renal impairment or adjust dose and monitor levels 1
• Drug interactions: Azoles (fluconazole) have substantial drug interactions, particularly with antiretroviral medications, requiring careful evaluation 1
• Distinguishing relapse from IRIS: Relapse of symptoms during or after treatment needs careful evaluation to determine if it represents treatment failure or immune reconstitution inflammatory syndrome 1
• Initial therapy with fluconazole alone is discouraged, even among "low risk" patients 1
• Test for HIV in all patients with cryptococcal meningitis 1

By following this treatment algorithm and monitoring protocol, clinicians can optimize outcomes for patients with this life-threatening infection.