Dosing of Amphotericin B vs Liposomal Amphotericin B in Cryptococcal Meningitis
For cryptococcal meningitis, use amphotericin B deoxycholate at 0.7-1.0 mg/kg/day or liposomal amphotericin B at 3-6 mg/kg/day, both combined with flucytosine 100 mg/kg/day for at least 2 weeks of induction therapy. 1, 2
Standard Amphotericin B Deoxycholate Dosing
The recommended dose of amphotericin B deoxycholate is 0.7-1.0 mg/kg/day IV, combined with flucytosine 100 mg/kg/day orally (divided into 4 doses) for a minimum of 2 weeks. 3, 1, 2
- The higher dose of 1.0 mg/kg/day is more fungicidal than 0.7 mg/kg/day, with manageable toxicity and no difference in mortality at 2 and 10 weeks. 3
- This represents the gold standard with the highest level of evidence (A-I rating) for HIV-infected patients. 3, 1, 2
- After successful 2-week induction (defined as clinical improvement and negative CSF culture), transition to fluconazole 400 mg daily for 8 weeks of consolidation therapy. 3, 1, 2
Liposomal Amphotericin B Dosing
The recommended dose of liposomal amphotericin B is 3-6 mg/kg/day IV, with 4 mg/kg/day representing the optimal balance of efficacy and safety. 3, 1, 2
Evidence-Based Dose Selection:
3 mg/kg/day: Demonstrated equal efficacy to amphotericin B deoxycholate 0.7 mg/kg/day with significantly less nephrotoxicity (P = 0.004) and fewer infusion-related reactions (P < 0.001). 4
4 mg/kg/day: Achieved more rapid CSF sterilization than amphotericin B deoxycholate 0.7 mg/kg/day in a 3-week course, with significantly earlier CSF culture conversion (median 7-14 days vs >21 days, P < 0.05). 5, 3
6 mg/kg/day: An unpublished study showed improved outcomes compared to 3 mg/kg/day, though the 2010 comparative trial found similar mycological success rates (54% vs 64%) with no significant difference in clinical response or 10-week mortality. 3, 4
Based on this evidence, guidelines recommend 4-6 mg/kg/day for lipid formulations of amphotericin B (AII evidence). 3
When to Choose Liposomal Over Standard Formulation
Liposomal amphotericin B should be selected for patients with renal dysfunction during therapy or those at high risk for renal failure. 3, 1, 2
- Transplant recipients often have baseline renal dysfunction and concurrent nephrotoxic medications, making liposomal formulations (3-4 mg/kg/day) or ABLC (5 mg/kg/day) preferred. 1, 2
- Liposomal amphotericin B at 3 mg/kg/day causes significantly less nephrotoxicity than standard amphotericin B deoxycholate. 4
- Both formulations must be combined with flucytosine 100 mg/kg/day for optimal fungicidal activity. 1, 2
Alternative Dosing for Amphotericin B Lipid Complex (ABLC)
ABLC can be used at 5 mg/kg/day as an alternative lipid formulation, though data are more limited. 1, 2
- The CLEAR study used a mean dose of 4.4 mg/kg/day for treating cryptococcosis. 3
Novel Single-Dose Regimen (Resource-Limited Settings)
A single dose of liposomal amphotericin B at 10 mg/kg on day 1, combined with 14 days of flucytosine (100 mg/kg/day) and fluconazole (1200 mg/day), demonstrated noninferiority to standard WHO-recommended treatment. 6
- This regimen showed 24.8% mortality at 10 weeks versus 28.7% with standard amphotericin B deoxycholate (difference -3.9 percentage points, P<0.001 for noninferiority). 6
- Fewer grade 3-4 adverse events occurred with single-dose liposomal amphotericin B (50.0% vs 62.3%). 6
- This approach is primarily relevant for resource-limited settings in sub-Saharan Africa where daily amphotericin administration is challenging. 6
Critical Monitoring Requirements
Monitor renal function closely and adjust flucytosine dosing based on creatinine clearance. 3, 1, 2
- Target flucytosine serum levels of 30-80 μg/mL (or 40-60 mg/mL). 1, 2
- Monitor complete blood counts regularly due to bone marrow suppression risk with flucytosine. 1
- Perform serial lumbar punctures to document CSF sterilization after 2 weeks of induction therapy. 1, 2
- Measure opening pressure at baseline and manage elevated intracranial pressure aggressively, as 93% of deaths within the first 2 weeks are associated with increased ICP. 3
Common Pitfalls to Avoid
Do not use amphotericin B monotherapy without flucytosine unless flucytosine is absolutely unavailable or contraindicated. 3, 1
- The combination of amphotericin B plus flucytosine achieves significantly faster CSF sterilization than amphotericin B alone. 3
- If flucytosine is unavailable, extend amphotericin B monotherapy to 4-6 weeks or add high-dose fluconazole 400-800 mg daily. 1, 2
Do not initiate antiretroviral therapy immediately in HIV-infected patients. 1, 2
- Delay ART initiation for 2-10 weeks after starting antifungal treatment to reduce risk of immune reconstitution inflammatory syndrome (IRIS). 1, 2
Do not rely on cryptococcal antigen titers to guide treatment decisions. 1
- Clinical response and CSF culture results are the appropriate endpoints for assessing treatment success. 1