What is the appropriate induction, consolidation, and maintenance therapy for cryptococcal meningitis in an adult patient with HIV/AIDS or other immunosuppression?

Cryptococcal Meningitis Treatment

Treatment Algorithm by Patient Population

For HIV-infected patients, use amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) for 2 weeks as induction therapy, followed by fluconazole consolidation and maintenance. 1, 2

Induction Therapy

HIV/AIDS Patients:

• Preferred regimen: Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV + flucytosine 100 mg/kg/day orally (divided into 4 doses) for at least 2 weeks 1, 2
• This combination has the strongest evidence (A-I rating) and provides superior early fungicidal activity compared to other regimens 1, 2
• Alternative if renal dysfunction present: Liposomal amphotericin B 3-4 mg/kg/day IV or ABLC 5 mg/kg/day IV + flucytosine for at least 2 weeks 1, 3, 2
• If flucytosine unavailable: Amphotericin B deoxycholate 0.7 mg/kg/day + fluconazole 800 mg/day for 2 weeks 1, 2
• If amphotericin B cannot be used: Fluconazole 1200 mg/day + flucytosine 100 mg/kg/day for 2 weeks (though inferior to amphotericin-based regimens) 1, 2

Non-HIV, Non-Transplant Patients:

• Preferred regimen: Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV + flucytosine 100 mg/kg/day orally for at least 4 weeks 1
• The 4-week duration is reserved for patients without neurological complications and with negative CSF cultures at 2 weeks 1
• If neurological complications present or CSF remains positive: Extend induction to 6 weeks total; consider switching to lipid formulation amphotericin B for the final 4 weeks to reduce toxicity 1
• If amphotericin B intolerant: Liposomal amphotericin B 3-4 mg/kg/day or ABLC 5 mg/kg/day + flucytosine 1
• If flucytosine unavailable or interrupted: Extend amphotericin B monotherapy by at least 2 additional weeks 1
• Low-risk patients only (early diagnosis, no underlying immunosuppression, excellent clinical response): May use 2-week induction with amphotericin B + flucytosine, but must follow with fluconazole 800 mg/day for consolidation 1

Transplant Recipients:

• Preferred regimen: Liposomal amphotericin B 3-4 mg/kg/day or ABLC 5 mg/kg/day + flucytosine 100 mg/kg/day for 2 weeks 1, 3
• Lipid formulations are strongly preferred over deoxycholate due to calcineurin inhibitor nephrotoxicity 1, 3
• Alternative if needed: Liposomal amphotericin B 6 mg/kg/day or ABLC 5 mg/kg/day monotherapy for 4-6 weeks 1

Consolidation Therapy

All patient populations:

• Fluconazole 400-800 mg/day orally for 8 weeks following induction 1, 3, 2
• Use the higher dose (800 mg/day) if: (1) only 2-week induction was given, (2) flucytosine was not used during induction, or (3) patient is non-HIV/non-transplant 1
• If fluconazole cannot be used: Itraconazole 400 mg/day is an inferior alternative (C-I evidence), or continue amphotericin B with close monitoring 4
• Do NOT use voriconazole for cryptococcal meningitis—there is no evidence supporting its efficacy 4

Maintenance Therapy

All patient populations:

• Fluconazole 200 mg/day orally for 6-12 months 1, 3, 2
• For transplant recipients: Fluconazole 200-400 mg/day (higher dose may be needed) 1

HIV patients specifically:

• Continue maintenance therapy for at least 1 year total 2
• May discontinue suppressive therapy if: CD4 count >100 cells/μL sustained for ≥3 months AND undetectable/very low HIV RNA level AND completed minimum 12 months antifungal therapy 1
• Reinstitute maintenance if CD4 count drops below 100 cells/μL 1
• Initiate antiretroviral therapy 2-10 weeks after starting antifungal treatment, not earlier (to reduce IRIS risk) 1, 2

Critical Management Considerations

Flucytosine is essential for optimal outcomes but must be combined with amphotericin B to prevent rapid resistance development 3, 5. The combination provides superior early fungicidal activity and reduces 2-week mortality by 44% compared to amphotericin B + fluconazole 6. Recent evidence from Africa demonstrates that 1 week of amphotericin B + flucytosine followed by fluconazole is highly effective with lower toxicity than 2-week amphotericin regimens 7.

Monitor flucytosine levels: Target serum concentration 30-80 μg/mL; adjust dose based on renal function 2

Serial lumbar punctures are mandatory to document CSF sterilization regardless of chosen regimen 2, 4. Perform LP at 2 weeks to guide duration of induction therapy 1.

Intracranial pressure management is critical: Monitor opening pressure at each LP and manage aggressively if elevated (>25 cm H2O requires therapeutic LPs) 2, 4

Renal function monitoring: Check serum creatinine, potassium, and magnesium at least twice weekly during amphotericin B therapy 4. In patients with chronic kidney disease (CrCl <50 mL/min), reduce fluconazole maintenance dose by 50% after loading dose 3.

Hematologic monitoring: Check complete blood counts regularly due to bone marrow suppression risk with flucytosine 2

Common Pitfalls to Avoid

Do not fail to test for HIV in any patient presenting with cryptococcal meningitis 2

Do not start antiretroviral therapy too early in HIV patients—wait 2-10 weeks after antifungal initiation to reduce IRIS risk 1, 2

Do not rely on cryptococcal antigen titers to guide treatment decisions; clinical response and CSF culture sterilization are what matter 2, 4

Do not inadequately manage increased intracranial pressure—this is a major cause of morbidity and mortality 2

Do not undertreat the consolidation phase—inadequate consolidation is associated with relapse 4

Do not use voriconazole for cryptococcal meningitis treatment 4

Do not use amphotericin B deoxycholate in transplant recipients without considering lipid formulations first due to compounded nephrotoxicity with calcineurin inhibitors 1, 3