What is the recommended treatment regimen for an immunocompromised patient, such as one with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), diagnosed with Cryptococcal meningitis?

Treatment of Cryptococcal Meningitis in Immunocompromised Patients

For HIV-infected patients with cryptococcal meningitis, the optimal regimen is amphotericin B deoxycholate (0.7-1.0 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks as induction therapy, followed by fluconazole 400 mg daily for 8 weeks (consolidation), then fluconazole 200 mg daily for at least 1 year (maintenance). 1

Induction Therapy (First 2 Weeks)

Preferred regimen:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV PLUS flucytosine 100 mg/kg/day PO for 2 weeks 1, 2
• This combination achieves CSF sterilization in 60-90% of patients within 2 weeks and carries the strongest evidence (A-I rating) 1

Alternative induction regimens when standard therapy cannot be used:

• Liposomal amphotericin B (3-4 mg/kg/day) or ABLC (5 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks - preferred in patients with renal dysfunction or when nephrotoxicity is a concern 1, 3

• Single-dose liposomal amphotericin B (10 mg/kg) on day 1 plus flucytosine (100 mg/kg/day) and fluconazole (1200 mg/day) for 14 days - this novel regimen demonstrated noninferiority to standard therapy with 24.8% mortality at 10 weeks versus 28.7% with conventional treatment, and had fewer grade 3-4 adverse events (50.0% vs 62.3%) 4

• Amphotericin B deoxycholate alone for 4-6 weeks - only if flucytosine is unavailable or not tolerated 1

• Fluconazole (1200 mg/day) plus flucytosine (100 mg/kg/day) for 2 weeks - all-oral option when amphotericin B cannot be safely administered, though less effective 1, 2, 5

One-week shortened regimen:

• Amphotericin B deoxycholate (0.7-1.0 mg/kg/day) plus flucytosine (100 mg/kg/day) for 1 week, followed by fluconazole (400 mg/day) on days 8-14 showed superior outcomes in a large African study with 10-week mortality of approximately 38% compared to 62% with two-week AmBd/5FC, 58% with two-week AmBd/FLU, and 68% with two-week 5FC/FLU 1, 5
• This regimen also reduced grade 3-4 anemia risk (RR 0.31) compared to two weeks of amphotericin B and flucytosine 5

Consolidation Therapy (Weeks 3-10)

• Fluconazole 400 mg daily for 8 weeks after completing induction 1, 2, 6
• Higher doses (400-800 mg daily) may be used based on clinical response 1

Maintenance Therapy (Secondary Prophylaxis)

• Fluconazole 200 mg daily for at least 1 year 1, 2, 6
• Continue until CD4 count ≥100 cells/μL and undetectable viral load for ≥3 months on antiretroviral therapy, with minimum 1 year total antifungal therapy 1

Critical Management Considerations

Antiretroviral therapy timing:

• Delay ART initiation until 2-10 weeks after starting antifungal therapy to reduce risk of immune reconstitution inflammatory syndrome (IRIS) 1, 2, 7

Intracranial pressure management:

• Aggressively manage elevated intracranial pressure with serial therapeutic lumbar punctures - remove sufficient CSF to reduce opening pressure by 50% or to <20 cm H2O 1, 2
• Perform daily lumbar punctures if symptomatic elevated pressure persists 1
• Consider lumbar drain, ventriculostomy, or ventriculoperitoneal shunt for refractory cases 1, 7
• Do NOT use corticosteroids, mannitol, or acetazolamide - these are ineffective and potentially harmful 7

Monitoring requirements:

• Perform lumbar puncture at 2 weeks to document CSF sterilization 1
• Patients with positive CSF culture at 2 weeks require longer induction therapy (4-6 weeks total) 1, 8
• Monitor flucytosine levels - target 30-80 μg/mL measured 2 hours post-dose 1, 2
• Monitor complete blood counts regularly for flucytosine-associated bone marrow suppression 2
• Monitor renal function closely with amphotericin B therapy 1

Common Pitfalls to Avoid

Critical errors:

• Never use fluconazole monotherapy for initial induction - pilot studies showed unsatisfactory outcomes even in low-risk patients 1
• Never start ART within the first 2 weeks of antifungal therapy - early ART initiation increases IRIS risk and mortality 1, 7
• Never rely on cryptococcal antigen titers alone to guide treatment decisions 2
• Never assume symptom worsening during treatment is treatment failure - distinguish between inadequate fungal control versus IRIS, which requires different management 1, 2

Testing and diagnosis:

• Always test for HIV in any patient presenting with cryptococcal meningitis 1, 2
• Rule out CNS disease in all patients with disseminated cryptococcosis 1

Drug interactions:

• Exercise caution with concomitant fluconazole and nevirapine - monitor closely for nevirapine-associated hepatotoxicity 7
• Potential drug interactions between antiretrovirals and antifungals are generally minimal 7

Special Populations

Transplant recipients and other non-HIV immunocompromised patients:

• Liposomal amphotericin B (3-4 mg/kg/day) or ABLC (5 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks as induction 1, 3
• Followed by fluconazole 400-800 mg daily for 6 months to 1 year consolidation 1, 3
• Then fluconazole 200-400 mg daily for maintenance 1
• These patients require more prolonged therapy due to persistent immunosuppression 1

Renal impairment:

• Adjust fluconazole dosing: give 50% of recommended dose when creatinine clearance ≤50 mL/min (after loading dose) 6
• Prefer lipid formulations of amphotericin B over deoxycholate to minimize nephrotoxicity 1, 3