What is the treatment for cryptococcal meningitis, particularly in patients with HIV/AIDS (Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome)?

Treatment of Cryptococcal Meningitis

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

Induction Therapy (First 2 Weeks)

Preferred regimen:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg IV daily PLUS flucytosine 100 mg/kg orally in 4 divided doses daily for 2 weeks 1, 2
• This combination is superior to amphotericin B alone or fluconazole monotherapy, achieving faster CSF sterilization and lower mortality (6% vs. 14-25% in older studies) 1, 3
• The higher amphotericin B dose (1.0 mg/kg) is more fungicidal with manageable toxicity 1

Alternative induction regimens when standard therapy cannot be used:

For patients with renal concerns or chronic kidney disease:

• Liposomal amphotericin B 3-4 mg/kg IV daily OR amphotericin B lipid complex (ABLC) 5 mg/kg IV daily PLUS flucytosine 100 mg/kg orally daily for 2 weeks 1, 4
• Recent evidence shows single-dose liposomal amphotericin B (10 mg/kg) plus 14 days of flucytosine and fluconazole is noninferior to standard therapy with fewer adverse events 5

When flucytosine is unavailable (common in Africa and Asia):

• Amphotericin B 0.7-1.0 mg/kg IV daily PLUS fluconazole 800-1200 mg orally daily for 2 weeks 2, 6, 7
• One week of amphotericin B plus flucytosine showed 10-week mortality of only 24.2%, making it highly effective in resource-limited settings 7

When amphotericin B cannot be used:

• Fluconazole 1200 mg orally daily PLUS flucytosine 100 mg/kg orally daily for 2 weeks 2, 7
• This all-oral regimen showed 18.2% mortality at 2 weeks and 35.1% at 10 weeks, noninferior to 2 weeks of amphotericin B 7

For flucytosine-intolerant patients:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg IV daily OR liposomal amphotericin B 3-4 mg/kg IV daily for 4-6 weeks 1, 2

Consolidation Therapy (Weeks 3-10)

• Fluconazole 400 mg orally daily for 8 weeks after completing induction therapy 1, 2, 8
• Itraconazole 400 mg orally daily is an inferior alternative if fluconazole cannot be used, requiring serum drug level monitoring 1, 9
• Do NOT use voriconazole for consolidation—there is no evidence supporting its efficacy for cryptococcal meningitis 9, 6

Maintenance Therapy (Chronic Suppression)

• Fluconazole 200 mg orally daily for at least 1 year 1, 2, 8
• Continue until CD4 count ≥100 cells/μL and undetectable viral load for ≥3 months on antiretroviral therapy 1
• Without maintenance therapy, relapse rates reach 37% compared to 3% with fluconazole 1

Antiretroviral Therapy Timing

• Delay antiretroviral therapy initiation until 2-10 weeks after starting antifungal treatment 1, 2
• Premature initiation increases risk of immune reconstitution inflammatory syndrome (IRIS) 1, 2

Critical Management of Elevated Intracranial Pressure

• Measure CSF opening pressure at baseline in lateral recumbent position 1
• Perform serial lumbar punctures to aggressively manage symptomatic elevated intracranial pressure 1, 2, 9
• This is essential for reducing morbidity and mortality 1, 2

Monitoring Requirements

For flucytosine therapy:

• Monitor serum flucytosine levels (target: 30-80 μg/mL) and adjust dose based on levels or hematologic toxicity 1, 2
• Check complete blood counts regularly for bone marrow suppression 2
• Reduce dose by 50% if creatinine clearance <50 mL/min 4

For amphotericin B therapy:

• Monitor renal function, serum potassium, and magnesium closely 9
• Toxic side effects from amphotericin B are common 1

For all patients:

• Obtain serial quantitative CSF cultures to document sterilization 2, 9, 3
• Extend induction therapy beyond 2 weeks if CSF culture remains positive at 2 weeks, patient is comatose, clinically deteriorating, or has persistent symptomatic elevated intracranial pressure 1
• Consider 1-6 additional weeks of induction therapy in these circumstances 1

Diagnostic Considerations

• Test all patients with cryptococcal meningitis for HIV infection 1, 2
• Serum cryptococcal antigen is positive in >99% of cases, usually at titers ≥1:2048 1
• Perform CNS imaging before lumbar puncture due to potential for mass lesions 1

Common Pitfalls to Avoid

Do NOT:

• Rely on cryptococcal antigen titers to guide treatment decisions—clinical response and CSF cultures matter, not antigen levels 2, 9
• Use flucytosine as monotherapy—rapid resistance develops 1, 4
• Initiate antiretroviral therapy in the first 2 weeks of antifungal treatment 2
• Undertreat the consolidation phase—inadequate consolidation is associated with relapse 9
• Fail to distinguish between treatment failure and IRIS when symptoms worsen during therapy 1, 2

Special Populations

Transplant recipients:

• Use liposomal amphotericin B 3-4 mg/kg IV daily OR ABLC 5 mg/kg IV daily PLUS flucytosine 100 mg/kg orally daily for 2 weeks to avoid compounding nephrotoxicity 1, 4

Pediatric patients:

• Amphotericin B plus flucytosine for induction, followed by fluconazole 12 mg/kg on day 1, then 6 mg/kg daily 2, 8
• For cryptococcal meningitis: 12 mg/kg on first day, then 6 mg/kg once daily; may use 12 mg/kg daily based on response 8
• Treatment duration: 10-12 weeks after CSF becomes culture negative 8
• Maintenance: 6 mg/kg daily for children with AIDS 8