What is the recommended treatment regimen for cryptococcal meningitis, including induction, consolidation, and maintenance phases, and how should it be modified for pregnancy or non‑central nervous system disease?

Cryptococcus Treatment

For cryptococcal meningitis, treat with amphotericin B deoxycholate 0.7–1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally (divided into 4 doses) for at least 2 weeks, followed by fluconazole 400 mg daily for 8 weeks, then fluconazole 200 mg daily for 6–12 months. 1, 2

Induction Therapy (Initial 2 Weeks Minimum)

Standard regimen for all patients:

• 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 1, 2
• This combination achieves CSF sterilization in 60–90% of patients within 2 weeks and is superior to amphotericin B monotherapy 3, 4
• The addition of flucytosine significantly reduces relapse risk without increasing immediate mortality 1, 4

For patients with renal dysfunction or transplant recipients:

• Liposomal amphotericin B 3–4 mg/kg/day IV or amphotericin B lipid complex (ABLC) 5 mg/kg/day IV plus flucytosine 100 mg/kg/day for ≥2 weeks 1, 2
• Lipid formulations are strongly preferred in transplant recipients to avoid compounding nephrotoxicity from calcineurin inhibitors 2, 5

Duration modifications for non-HIV, non-transplant patients:

• Extend induction to 4 weeks when no neurological complications exist and CSF cultures are sterile at 2 weeks 2
• Extend to 6 weeks if complications develop or CSF remains culture-positive at 2 weeks 2, 5

Alternative Induction Regimens (Listed by Preference)

When flucytosine is unavailable:

• Amphotericin B deoxycholate 0.7 mg/kg/day IV plus fluconazole 800 mg/day orally for 2 weeks 1, 2
• This is less effective than amphotericin B plus flucytosine but acceptable when combination therapy cannot be given 5

When amphotericin B cannot be used:

• Fluconazole 1200 mg/day plus flucytosine 100 mg/kg/day for 2 weeks (inferior to amphotericin-based regimens) 1, 2

Amphotericin B monotherapy (when combination impossible):

• Continue any amphotericin B formulation for 4–6 weeks 1, 2

Fluconazole monotherapy (last resort only):

• 800–2000 mg/day for 10–12 weeks (≥1200 mg/day strongly preferred) 1
• Never use fluconazole monotherapy as initial therapy—pilot studies showed unsatisfactory results 3

Consolidation Therapy (8 Weeks)

• Fluconazole 400–800 mg/day orally for 8 weeks after completing induction 1, 2, 3
• Use the higher dose (800 mg/day) when only 2 weeks of induction was given, flucytosine was omitted, or in non-HIV/non-transplant patients 2

Maintenance (Suppressive) Therapy

Standard maintenance:

• Fluconazole 200 mg/day orally for 6–12 months minimum 1, 2, 5
• Transplant recipients may require 200–400 mg/day (higher doses often needed) 1, 2

Discontinuation criteria in HIV-infected patients:

• Stop after ≥12 months of total antifungal therapy and CD4 >100 cells/µL for ≥3 months and undetectable HIV RNA 1, 2, 3
• Restart maintenance if CD4 falls below 100 cells/µL 1, 2

Special Populations and Modifications

HIV-Infected Patients

Timing of antiretroviral therapy (ART):

• Start ART 2–10 weeks after beginning antifungal treatment to reduce immune reconstitution inflammatory syndrome (IRIS) risk 1, 2, 3, 5

Pregnancy

• Amphotericin B (any formulation) is the only safe option during pregnancy—azoles are teratogenic 2
• Use amphotericin B deoxycholate or lipid formulation monotherapy for 4–6 weeks, then consider suppressive therapy after delivery 2

Non-CNS Cryptococcal Disease

Pulmonary cryptococcosis without CNS involvement:

• Mild disease in immunocompetent patients: Fluconazole 400 mg/day for 6–12 months 1
• Severe pulmonary or disseminated disease: Treat as meningitis with full induction, consolidation, and maintenance phases 1, 2
• Always perform lumbar puncture in immunosuppressed patients with pulmonary cryptococcosis to exclude CNS involvement 5

Pediatric Patients

• Amphotericin B 0.5–1.5 mg/kg/day plus flucytosine for induction 1
• Fluconazole 5–6 mg/kg/dose twice daily (10–12 mg/kg/day total) for consolidation, then lower dose for maintenance 1
• Children have more rapid fluconazole clearance than adults, requiring higher weight-based doses 1

Critical Management Considerations

Intracranial Pressure Management

• Measure opening pressure at every initial lumbar puncture—elevated pressure (>25 cm H₂O) occurs in up to 75% of patients and is associated with 93% of early deaths 3, 5
• When opening pressure >25 cm H₂O with symptoms, perform therapeutic lumbar puncture to lower pressure by ≥50% or to ≤20 cm H₂O 5
• Repeat daily until pressures stabilize for 1–2 days 5
• Consider temporary lumbar drain or ventriculostomy if daily taps fail to control pressure 5
• Never use acetazolamide—it causes excess acidosis, hypokalemia, and adverse effects without benefit 1

Monitoring and Toxicity Prevention

Amphotericin B toxicity mitigation:

• Provide routine IV saline hydration and preemptive electrolyte replacement to minimize hypokalemia and nephrotoxicity 6
• Monitor hemoglobin (expect mean drop of 1.5 g/dL by day 7,2.3 g/dL by day 14), serum creatinine, and potassium 6
• Grade III/IV anemia occurs in 33% of patients and is a risk factor for 10-week mortality (adjusted OR 2.2) 6
• Nephrotoxicity (creatinine >220 µmol/L) occurs in 9.5% and is a strong mortality risk factor (adjusted OR 4.5) 6

Flucytosine monitoring:

• Monitor complete blood counts regularly for bone marrow suppression 2
• Target serum levels 30–80 µg/mL and adjust dose based on renal function 2
• The addition of flucytosine causes slight increase in anemia but does not increase neutropenia 6

CSF sterilization assessment:

• Perform lumbar puncture at 2 weeks to document CSF sterility and guide induction duration 2, 5

Common Pitfalls to Avoid

1. Failing to test for HIV in all patients with cryptococcal meningitis 2, 5
2. Inadequate intracranial pressure management—this is a pivotal determinant of outcome 5
3. Premature ART initiation in HIV patients (must wait 2–10 weeks) 1, 2
4. Using fluconazole monotherapy as initial treatment—this is associated with poor outcomes 3
5. Failing to distinguish IRIS from treatment failure when symptoms worsen during or after therapy 2, 5
6. Relying on cryptococcal antigen titers to guide treatment decisions—titers do not correlate with treatment response 2
7. Using deoxycholate amphotericin B in transplant recipients without considering lipid formulations first 2, 5

Corticosteroid Use

Generally contraindicated except:

• Cryptococcomas with mass effect and surrounding edema: Prednisone 0.5–1.0 mg/kg/day for 2–6 weeks with taper 5
• ARDS in the setting of IRIS: Use per ARDS protocols 5