What is the recommended treatment for cryptococcal fungemia?

Treatment of Cryptococcal Fungemia

For cryptococcal fungemia, treat as disseminated cryptococcosis with the same aggressive induction regimen as cryptococcal meningitis: amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) for at least 2 weeks, followed by fluconazole consolidation therapy. 1

Critical First Step: Rule Out CNS Disease

• Perform lumbar puncture immediately to exclude cryptococcal meningitis, as fungemia frequently heralds disseminated disease with CNS involvement 1
• Blood cultures should be obtained to confirm fungemia 1
• Test all patients for HIV infection, as this fundamentally alters treatment duration and monitoring 1

Induction Therapy (First 2 Weeks)

Standard regimen:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally for at least 2 weeks 1
• This combination achieves superior fungal clearance and improved survival compared to amphotericin B alone (hazard ratio 0.61 for death by 70 days; P=0.04) 2
• The combination demonstrates significantly faster yeast clearance (-0.42 log10 CFU/mL/day vs -0.31 log10 CFU/mL/day with monotherapy; P<0.001) 2

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 (ABLC) 5 mg/kg/day IV plus flucytosine 100 mg/kg/day 1
• Recent data confirm daily liposomal amphotericin B 3 mg/kg with flucytosine achieves similar fungal clearance (mean EFA 0.495 log10 CFU/mL/day) and 10-week mortality (28.2%) as amphotericin B deoxycholate 3
• Lipid formulations cause significantly fewer grade 3-4 adverse events (50% vs 62.3%) 4

Alternative if flucytosine unavailable:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV alone for 4-6 weeks 1
• Amphotericin B plus fluconazole 800 mg/day is inferior and should only be used when flucytosine is truly unavailable 1, 2

Consolidation Therapy (Weeks 3-10)

• Fluconazole 400 mg daily orally for 8 weeks after completing induction 1, 5, 6
• Higher doses (800 mg daily) may be considered if only 2 weeks of induction therapy was given 1

Maintenance/Suppressive Therapy

HIV-infected patients:

• Fluconazole 200 mg daily for minimum 12 months 1, 7, 8
• Continue until CD4 count >100 cells/μL with undetectable or very low HIV RNA for ≥3 months on antiretroviral therapy 1, 7
• Delay antiretroviral therapy initiation for 2-10 weeks after starting antifungals to reduce immune reconstitution inflammatory syndrome (IRIS) risk 1, 5, 6

Transplant recipients:

• Fluconazole 200-400 mg daily for 6-12 months 1, 7
• Attempt to reduce immunosuppression if medically feasible 1

Immunocompetent patients:

• Fluconazole 200 mg daily for 6-12 months 1, 7
• Shorter duration acceptable if no ongoing immunosuppression 1

Critical Monitoring Requirements

Flucytosine monitoring:

• Target serum levels 30-80 μg/mL (some sources cite 40-60 mg/mL) 5, 6
• Adjust dose based on renal function 5, 8
• Monitor complete blood counts regularly for bone marrow suppression 6

Amphotericin B monitoring:

• Monitor serum electrolytes (potassium, magnesium), renal function, and complete blood counts at least twice weekly 1
• Nephrotoxicity, hypokalemia, and anemia are most common toxicities 1

Mycological monitoring:

• Repeat blood cultures at 2 weeks to document clearance 1
• If cultures remain positive at 2 weeks, extend induction therapy 1

Common Pitfalls to Avoid

• Do not use fluconazole monotherapy for initial treatment of fungemia, even in "low-risk" patients—this approach yields unsatisfactory outcomes 1
• Do not rely on cryptococcal antigen titers to guide treatment decisions or determine cure 1
• Do not give flucytosine for less than 14 days during induction—this is independently associated with treatment failure (OR 3.30; P=0.030) 9
• Do not assume isolated fungemia—CNS involvement must be actively excluded with lumbar puncture 1
• Do not start antiretroviral therapy immediately in HIV patients—wait 2-10 weeks to reduce IRIS risk 1, 5, 6

Special Populations

Transplant recipients:

• Prefer lipid formulations of amphotericin B due to concurrent nephrotoxic calcineurin inhibitors 1
• Liposomal amphotericin B 3-4 mg/kg/day or ABLC 5 mg/kg/day plus flucytosine for at least 2 weeks 1
• Consider higher dose liposomal amphotericin B (6 mg/kg/day) if flucytosine not used or in high fungal burden 1

Patients with severe renal disease:

• Lipid formulations mandatory to avoid further renal injury 1
• Adjust flucytosine dosing based on creatinine clearance 8