Fungal Meningitis Treatment
Immediate Treatment Approach by Pathogen
For cryptococcal meningitis, initiate induction therapy with amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally) for 2 weeks, followed by fluconazole consolidation therapy. 1, 2
This combination represents the highest level of evidence (A-I) and has been shown to improve survival compared to amphotericin B alone, with a hazard ratio of 0.61 for death by 70 days 3. The addition of flucytosine significantly increases yeast clearance from CSF (-0.42 log10 CFU/mL/day vs. -0.31 with amphotericin B alone, P<0.001) 3.
Cryptococcal Meningitis: Standard Regimen
Induction Phase (First 2 Weeks)
- Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally for 2 weeks 1, 2
- This combination is superior to amphotericin B alone and represents A-I level evidence for HIV-infected patients 1
- Fewer deaths occur with combination therapy (15 deaths by day 14) compared to amphotericin B alone (25 deaths by day 14) 3
Alternative Induction Regimens When Standard Therapy Cannot Be Used
For patients with renal impairment:
- Liposomal amphotericin B (3-4 mg/kg/day) or ABLC (5 mg/kg/day) plus flucytosine (100 mg/kg/day) 1, 2
- This is particularly important for transplant recipients who often have baseline renal dysfunction and concurrent nephrotoxic medications 1
When flucytosine is unavailable:
- Amphotericin B alone for 4-6 weeks 1, 2
- OR amphotericin B plus high-dose fluconazole (400-800 mg daily) for 2 weeks 1
- Note: Flucytosine is unavailable in Africa and most of Asia, making these alternatives clinically relevant 4
When amphotericin B cannot be used:
- Fluconazole (1200 mg daily) plus flucytosine (100 mg/kg/day) for 2 weeks 2
Important caveat: Amphotericin B plus fluconazole showed no significant survival benefit compared to amphotericin B alone (hazard ratio 0.71, P=0.13), making this a less desirable alternative 3
Consolidation Phase (Weeks 3-10)
- Fluconazole 400 mg daily for 8 weeks after completing induction therapy 1, 2, 5
- Treatment duration should be 10-12 weeks after CSF becomes culture negative 5
Maintenance Phase (Long-term Suppression)
- Fluconazole 200 mg daily for at least 1 year 6, 1, 2
- This prevents relapse, which occurred in 18% of patients receiving amphotericin B weekly versus only 2% receiving fluconazole maintenance 6
- For HIV patients with immune reconstitution (CD4 >100 cells/μL and undetectable HIV RNA for ≥3 months), consider discontinuing after minimum 12 months of antifungal therapy 6
Candida Meningitis
Initiate liposomal amphotericin B plus flucytosine for at least 2 weeks, with total treatment duration of 4-10 weeks depending on response. 1
Treatment Details
- The preponderance of clinical experience is with amphotericin B, often combined with flucytosine (B-III evidence) 6
- High-dose fluconazole (400-800 mg daily) can be used as follow-up or long-term suppressive therapy 6, 1
- Therapy should be administered for a minimum of 4 weeks after resolution of all signs and symptoms 6
- Critical step: Remove all prosthetic devices (e.g., neurosurgical devices, peritoneal dialysis catheters) 6
Histoplasma Meningitis
Begin induction therapy with amphotericin B 0.7-1.0 mg/kg/day to complete a total dose of 35 mg/kg over 3-4 months. 1
Treatment Details
- Follow with consolidation/maintenance therapy using fluconazole 800 mg daily for 9-12 months after completing amphotericin B 1
- This prolonged consolidation reduces relapse risk 1
Critical Monitoring and Management
Flucytosine Monitoring
- Monitor serum levels targeting 30-80 μg/mL (or 40-60 mg/mL) 6, 1, 2
- Adjust dose based on renal function 1, 2
- Monitor complete blood counts regularly due to bone marrow suppression risk 2
Intracranial Pressure Management
- Measure opening pressure at baseline lumbar puncture 1
- Perform therapeutic lumbar punctures to reduce pressure by 50% or to ≤20 cm H₂O 1
- Aggressive management of elevated intracranial pressure is critical—inadequate management is a common pitfall 2
CSF and Laboratory Monitoring
- Perform serial lumbar punctures to document CSF sterilization 1, 2
- Monitor serum electrolytes and renal function for amphotericin B nephrotoxicity 1
- Do not rely solely on cryptococcal antigen titers to guide treatment decisions 2
Special Populations
HIV-Infected Patients
- Delay antiretroviral therapy initiation for 2-10 weeks after starting antifungal treatment 1, 2
- This reduces risk of immune reconstitution inflammatory syndrome (IRIS) 1, 2
- Distinguish between treatment failure and IRIS if symptoms worsen during or after treatment 2
- Always test for HIV in patients presenting with cryptococcal meningitis—failure to do so is a common pitfall 2
Pediatric Patients
- Amphotericin B 0.7-1.0 mg/kg/day plus flucytosine for induction 1
- Fluconazole 12 mg/kg on first day, then 6 mg/kg daily for consolidation 1, 5
- For premature newborns (gestational age 26-29 weeks), administer the same mg/kg dose but every 72 hours for the first two weeks of life 5
Renal Impairment
- For creatinine clearance ≤50 mL/min (no dialysis): reduce fluconazole dose to 50% of recommended dose 5
- For hemodialysis patients: give 100% of recommended dose after each hemodialysis session 5
- Consider liposomal amphotericin B formulations to reduce nephrotoxicity 1, 2
Immunocompetent Patients
- May not require prolonged maintenance therapy if immunosuppression can be reduced 1
Common Pitfalls to Avoid
- Premature initiation of antiretroviral therapy in HIV patients—wait 2-10 weeks to reduce IRIS risk 2
- Inadequate management of increased intracranial pressure—this directly impacts mortality 1, 2
- Failure to monitor for drug toxicities, especially amphotericin B nephrotoxicity and flucytosine bone marrow suppression 2
- Failure to test for HIV in patients with cryptococcal meningitis 2
- Inadequate treatment duration—may lead to recurrence of active infection 5
- Using fluconazole monotherapy for induction in resource-limited settings is associated with significantly increased mortality rates 4