What is the treatment for cryptococcal meningitis, particularly in patients with HIV (Human Immunodeficiency Virus) infection?

Treatment of Cryptococcal Meningitis

Induction Therapy for HIV-Infected Patients

The optimal induction regimen is 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, followed by fluconazole consolidation therapy. 1, 2

Standard Induction Regimen (Strongest Evidence)

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally for 2 weeks is the preferred regimen with the highest level of evidence (A-I) 1
• This combination achieves the fastest fungal clearance from cerebrospinal fluid compared to other regimens 3
• At 2 weeks, CSF cultures become negative in 60% of patients receiving this combination versus 51% with amphotericin B alone 4

Alternative Induction Regimens When Standard Therapy Cannot Be Used

For patients with renal dysfunction or at high risk for nephrotoxicity:

• Liposomal amphotericin B (3-4 mg/kg/day IV) or amphotericin B lipid complex (5 mg/kg/day IV) plus flucytosine (100 mg/kg/day) for at least 2 weeks 1
• Lipid formulations should be substituted for amphotericin B deoxycholate in transplant recipients due to nephrotoxicity concerns 1

For patients who cannot tolerate flucytosine:

• Amphotericin B deoxycholate (0.7-1.0 mg/kg/day) or liposomal amphotericin B (3-4 mg/kg/day) alone for 4-6 weeks 1
• Amphotericin B deoxycholate (0.7 mg/kg/day) plus fluconazole (800 mg/day) for 2 weeks, followed by fluconazole (800 mg/day) for minimum 8 weeks (B-I evidence) 1

All-oral regimen when amphotericin B is unavailable or IV therapy cannot be safely administered:

• Fluconazole (≥1200 mg/day orally) plus flucytosine (100 mg/kg/day) for 2 weeks showed 10-week mortality of 35.1%, which was non-inferior to 2-week amphotericin B regimens 5
• This regimen is particularly relevant for resource-limited settings 6, 5

Shortened Duration Regimen (Recent High-Quality Evidence)

One week of amphotericin B plus flucytosine followed by fluconazole on days 8-14 is superior to standard 2-week regimens in resource-limited settings:

• This shortened regimen demonstrated lower 10-week mortality compared to 2 weeks of amphotericin B plus flucytosine (RR 0.62,95% CI 0.42-0.93) 6
• It also showed lower 10-week mortality compared to 2 weeks of amphotericin B plus fluconazole (RR 0.58,95% CI 0.39-0.86) 6
• The 1-week regimen had similar fungal clearance but lower risk of severe anemia (RR 0.31,95% CI 0.16-0.60) compared to 2-week amphotericin B plus flucytosine 6
• In network meta-analysis, this regimen ranked highest (SUCRA 88%) for 10-week mortality outcomes 6

Consolidation Therapy

After completing induction therapy, all patients should receive fluconazole 400 mg daily for 8 weeks. 1, 2

• This consolidation phase is critical and inadequate treatment is associated with relapse 7
• Fluconazole 400 mg daily has the strongest evidence (A-I) for consolidation 1
• Itraconazole 400 mg daily is an inferior alternative (C-I evidence) for patients unable to tolerate fluconazole 1, 7

Maintenance (Suppressive) Therapy

Following consolidation, patients require fluconazole 200 mg daily for at least 1 year as maintenance therapy. 1, 2

Duration of Maintenance Therapy

• Continue fluconazole 200 mg daily indefinitely until immune reconstitution occurs 1
• Maintenance therapy can be discontinued when: CD4 count rises above 100 cells/μL AND HIV viral load is undetectable or very low for ≥3 months AND patient has completed minimum 12 months of antifungal therapy 1
• Reinstitute maintenance therapy if CD4 count decreases to <100 cells/μL 1

Alternative Maintenance Regimens (Inferior)

• Itraconazole 400 mg daily (C-I evidence) 1
• Amphotericin B deoxycholate 1 mg/kg weekly (C-I evidence) 1

Timing of Antiretroviral Therapy in HIV-Infected Patients

Initiate highly active antiretroviral therapy (HAART) 2-10 weeks after starting antifungal treatment, not immediately. 1, 2

• Premature initiation of antiretroviral therapy increases risk of immune reconstitution inflammatory syndrome (IRIS) 2, 7
• The 2-10 week delay allows for initial fungal clearance and reduces IRIS risk 1

Management of Increased Intracranial Pressure

Aggressive management of elevated intracranial pressure is mandatory and failure to do so is associated with death. 1, 2

• Elevated intracranial pressure was associated with death in 13 of 14 patients in one major trial 4
• Perform lumbar puncture at baseline and monitor opening pressure 2, 7
• For symptomatic increased intracranial pressure: perform serial therapeutic lumbar punctures with drainage of sufficient CSF to reduce opening pressure by 50% or to <20 cm H2O 1
• Repeat lumbar punctures daily until pressure normalizes 1
• Consider temporary lumbar drain or ventriculoperitoneal shunt for refractory cases 1

Monitoring During Treatment

Microbiologic Monitoring

• Perform lumbar puncture at 2 weeks to document CSF sterilization 1, 2, 7
• Patients with positive CSF culture at 2 weeks require longer induction therapy 1
• Serial quantitative CSF cultures provide the most accurate assessment of treatment response 3
• Do not rely on cryptococcal antigen titers to guide treatment decisions—clinical response and CSF cultures are what matter 1, 2, 7

Laboratory Monitoring for Drug Toxicity

For amphotericin B therapy:

• Monitor serum creatinine, electrolytes (especially potassium and magnesium), and complete blood counts regularly 1, 2, 7
• Saline loading reduces amphotericin B nephrotoxicity 8
• Only 3% of patients require discontinuation due to toxicity in the first 2 weeks 1

For flucytosine therapy:

• Monitor serum flucytosine levels (target: 30-80 μg/mL) 2
• Monitor complete blood counts for bone marrow suppression 2
• Adjust dose based on renal function 2

For itraconazole therapy:

• Monitor serum drug levels and adjust for therapeutic range 7

Treatment in Special Populations

Transplant Recipients and Non-HIV Immunocompromised Hosts

For CNS disease in transplant recipients, use liposomal amphotericin B (3-4 mg/kg/day) or ABLC (5 mg/kg/day) plus flucytosine for at least 2 weeks, followed by fluconazole 400-800 mg daily for 8 weeks, then fluconazole 200-400 mg daily for 6-12 months. 1

• Amphotericin B deoxycholate should be avoided in transplant recipients due to nephrotoxicity risk 1
• If induction does not include flucytosine, consider lipid formulation amphotericin B for 4-6 weeks 1
• Reduce immunosuppression in stepwise fashion, lowering corticosteroids first 1

Immunocompetent Hosts with CNS Disease

Standard therapy is amphotericin B 0.7-1 mg/kg/day plus flucytosine 100 mg/kg/day for 6-10 weeks. 1

• Alternative: amphotericin B plus flucytosine for 2 weeks, followed by fluconazole 400 mg daily for minimum 10 weeks 1
• Fluconazole consolidation may continue for 6-12 months depending on clinical status 1

Pediatric Patients

For children with cryptococcal meningitis, use amphotericin B plus flucytosine for induction, followed by fluconazole 12 mg/kg on first day, then 6 mg/kg daily. 2, 9

• Recommended duration is 10-12 weeks after CSF becomes culture negative 9
• For suppression of relapse in children with AIDS, use fluconazole 6 mg/kg daily 9
• Neonates (gestational age 26-29 weeks) should receive same mg/kg dose but every 72 hours for first 2 weeks of life 9

Common Pitfalls and How to Avoid Them

Critical Errors to Avoid

Failure to test for HIV: All patients with cryptococcal meningitis should be tested for HIV infection 1, 2

Inadequate management of intracranial pressure: This is a leading cause of early mortality—monitor opening pressure at every lumbar puncture and treat aggressively 1, 2, 7

Premature initiation of antiretroviral therapy: Wait 2-10 weeks after starting antifungal treatment to reduce IRIS risk 2, 7

Relying on cryptococcal antigen titers: Treatment decisions should be based on clinical response and CSF cultures, not antigen titers 1, 2, 7

Inadequate consolidation therapy: Shortened consolidation increases relapse risk—complete the full 8-week course 7

Using voriconazole: There is no evidence supporting voriconazole efficacy for cryptococcal meningitis—do not use it 7

Failure to monitor for drug toxicities: Regular monitoring of renal function, electrolytes, and blood counts is essential, particularly with amphotericin B and flucytosine 2, 7

Distinguishing Treatment Failure from IRIS

If symptoms worsen during or after treatment, carefully distinguish between treatment failure and immune reconstitution inflammatory syndrome. 1, 2, 7

• Treatment failure: persistent positive CSF cultures, inadequate drug levels, drug resistance, or non-adherence 1
• IRIS: worsening symptoms despite negative cultures and adequate antifungal therapy, typically occurring after HAART initiation 1
• Perform repeat lumbar puncture with quantitative cultures to differentiate 1