What is the treatment of choice for cryptococcal (fungal infection) meningitis?

Treatment of Cryptococcal Meningitis

The treatment of choice for cryptococcal meningitis is combination induction therapy with 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, 2

Induction Therapy (First 2 Weeks)

First-line regimen:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV PLUS flucytosine 100 mg/kg/day orally (divided into 4 doses) for 2 weeks 1, 2
• This combination achieves CSF sterilization in 60-90% of patients within 2 weeks and has the strongest evidence (AI rating) 1
• A recent high-quality trial demonstrated that single-dose liposomal amphotericin B (10 mg/kg) combined with 14 days of flucytosine and fluconazole was noninferior to standard therapy with fewer adverse events, representing an important alternative 3

For patients with renal impairment or transplant recipients:

• Liposomal amphotericin B (L-AmB) 3-6 mg/kg/day IV PLUS flucytosine 100 mg/kg/day for 2 weeks 1, 2
• Lipid formulations are preferable due to reduced nephrotoxicity, especially critical in transplant patients on concurrent nephrotoxic immunosuppressants 1

When flucytosine is unavailable or not tolerated:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day alone for 4-6 weeks 1, 2
• OR Amphotericin B 0.7-1.0 mg/kg/day PLUS high-dose fluconazole 800 mg/day for 2 weeks 1, 2
• Note: Fluconazole plus flucytosine without amphotericin yields unsatisfactory outcomes and should be avoided 1

Consolidation Therapy (Weeks 3-10)

• Fluconazole 400 mg daily for 8 weeks 1, 2
• For immunosuppressed patients (transplant recipients), consider higher doses of 400-800 mg daily 1

Maintenance Therapy

• Fluconazole 200 mg daily for at least 1 year 1, 2
• For HIV-infected patients: Continue until CD4 count >100 cells/μL and undetectable viral load for >3 months 1
• For transplant recipients: Continue for 6-12 months 1
• Fluconazole is superior to both itraconazole and weekly amphotericin B for maintenance, with relapse rates of only 2-3% 1, 4

Critical Management of Intracranial Pressure

Elevated intracranial pressure (ICP) is the most critical determinant of outcome and must be aggressively managed: 1, 2

• Measure opening pressure at baseline lumbar puncture 1
• If CSF pressure >25 cm H₂O with symptoms: perform therapeutic lumbar punctures to reduce pressure by 50% or to ≤20 cm H₂O 1
• If persistently elevated >25 cm H₂O: repeat daily lumbar punctures until stabilized for 1-2 days 1
• Consider temporary percutaneous lumbar drain or ventriculostomy for patients requiring daily LPs 1
• AVOID acetazolamide and corticosteroids for ICP management (unless treating IRIS) 1
• AVOID mannitol—no proven benefit 1

Monitoring Requirements

During flucytosine therapy:

• Monitor serum flucytosine levels 2 hours post-dose; target 30-80 mg/mL 1, 2, 4
• Monitor complete blood counts regularly for bone marrow suppression 2
• Adjust dose based on renal function 1, 4

During amphotericin B therapy:

• Monitor serum creatinine, electrolytes (especially potassium and magnesium), and complete blood counts 1
• Expect nephrotoxicity, hypokalemia, hypomagnesemia, and anemia 1

General monitoring:

• Perform lumbar puncture at 2 weeks to assess CSF sterilization 1, 2
• Patients with positive cultures at 2 weeks require longer induction therapy 1
• Do NOT base treatment decisions on cryptococcal antigen titers alone 1, 4

Special Populations

HIV-infected patients:

• Delay antiretroviral therapy (ART) initiation for 2-10 weeks after starting antifungal treatment to reduce IRIS risk 2
• Always test HIV status in patients presenting with cryptococcal meningitis 2

Immunocompetent patients:

• May be successfully treated with 6 weeks of amphotericin B plus flucytosine 1
• Alternative: 2 weeks induction followed by 8-10 weeks fluconazole consolidation 1

Transplant recipients and immunosuppressed patients:

• Require prolonged therapy with induction-consolidation-maintenance strategy 1
• Stepwise reduction of immunosuppression, lowering corticosteroids first 1
• Reduce prednisone to ≤10 mg/day if possible 1

Common Pitfalls to Avoid

• Failure to test for HIV in all cryptococcal meningitis patients 2
• Inadequate management of elevated intracranial pressure—this is the leading cause of preventable death 1, 2
• Premature ART initiation in HIV patients (must wait 2-10 weeks) 2
• Using fluconazole monotherapy for induction—this is inadequate and discouraged 1
• Failure to monitor for amphotericin B and flucytosine toxicities 2
• Relying on antigen titers to guide treatment decisions 1, 2