What is the recommended treatment regimen for cryptococcal meningitis in an adult, including induction, consolidation, and maintenance phases?

Cryptococcal Meningitis Treatment

The gold standard treatment for cryptococcal meningitis is 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 and maintenance therapy. 1

Induction Phase: First-Line Regimens

HIV-Infected Adults

• Preferred regimen: Amphotericin B deoxycholate 0.7–1.0 mg/kg/day IV + flucytosine 100 mg/kg/day orally (divided into 4 doses) for ≥2 weeks (A-I evidence) 1, 2, 3
• This combination sterilizes cerebrospinal fluid in 60–90% of patients within 2 weeks and significantly reduces relapse risk 3
• For renal dysfunction: Substitute liposomal amphotericin B 3–4 mg/kg/day IV or amphotericin B lipid complex (ABLC) 5 mg/kg/day IV + flucytosine for ≥2 weeks 1, 2, 4

Non-HIV, Non-Transplant Patients

• Preferred regimen: Amphotericin B deoxycholate 0.7–1.0 mg/kg/day IV + flucytosine 100 mg/kg/day orally for ≥4 weeks 1, 2
• Duration criteria: 4-week induction is appropriate when there are no neurological complications AND cerebrospinal fluid cultures are sterile at 2 weeks 2
• If complications persist or CSF remains positive: Extend induction to 6 weeks total; consider switching to lipid amphotericin formulation for the final 4 weeks to reduce toxicity 2
• Low-risk patients only (early diagnosis, no immunosuppression, excellent clinical response): 2-week induction with amphotericin B + flucytosine is acceptable 2

Transplant Recipients

• Preferred regimen: Liposomal amphotericin B 3–4 mg/kg/day IV or ABLC 5 mg/kg/day IV + flucytosine 100 mg/kg/day for 2 weeks 1, 2, 4
• Critical rationale: Lipid formulations are strongly favored over deoxycholate because transplant recipients on calcineurin inhibitors face additive nephrotoxicity with amphotericin B deoxycholate 2, 4

Alternative Induction Regimens (When First-Line Unavailable)

Listed in descending order of preference:

When Flucytosine Is Unavailable

1. Amphotericin B deoxycholate 0.7 mg/kg/day IV + fluconazole 800 mg/day orally for 2 weeks (B-I evidence) 1, 2
2. Amphotericin B monotherapy (deoxycholate 0.7–1.0 mg/kg/day IV, liposomal 3–4 mg/kg/day IV, or ABLC 5 mg/kg/day IV) for 4–6 weeks (A-II evidence) 1, 2
3. Prolong amphotericin B monotherapy by ≥2 additional weeks beyond standard duration 2

When Amphotericin B Is Contraindicated

1. Fluconazole 1200 mg/day + flucytosine 100 mg/kg/day for 2 weeks (B-II evidence) 1, 2
   • This regimen is inferior to amphotericin-based therapy but acceptable when amphotericin cannot be used 2
2. Fluconazole monotherapy 800–2000 mg/day for 10–12 weeks (≥1200 mg/day encouraged) (B-II evidence) 1
   • Never use fluconazole monotherapy as initial treatment, even in "low-risk" patients—pilot studies showed unsatisfactory results 3

High-Dose Regimen for Refractory Cases

• Liposomal amphotericin B 6 mg/kg/day IV for 4–6 weeks for patients with high fungal burden, treatment failure, or severe disease 1, 4

Consolidation Phase (After Induction)

• All patient groups: Fluconazole 400–800 mg/day orally for 8 weeks after completing induction 1, 2, 3
• Use the higher dose (800 mg/day) when:
  • Only a 2-week induction was given 2
  • Flucytosine was omitted during induction 2
  • Patient is non-HIV/non-transplant 2
• Continue until cerebrospinal fluid cultures are sterile 3

Maintenance (Suppressive) Therapy

• General recommendation: Fluconazole 200 mg/day orally for 6–12 months minimum 1, 2, 4, 3
• Transplant recipients: Fluconazole 200–400 mg/day (higher doses may be required) 1, 2, 4

Stopping Maintenance in HIV-Infected Patients

• Criteria for discontinuation: After ≥12 months of antifungal therapy, CD4 count >100 cells/µL for ≥3 months, AND undetectable HIV RNA 1, 2, 4, 3
• Reinitiate maintenance therapy if CD4 falls below 100 cells/µL 1, 2

Antiretroviral Therapy Timing in HIV Patients

• Start ART 2–10 weeks after initiating antifungal treatment (B-III evidence) 1, 2, 4, 3, 5
• Rationale: Delaying ART reduces the risk of immune reconstitution inflammatory syndrome (IRIS), which can worsen outcomes 2, 4, 3, 5
• Any effective ART regimen is acceptable; drug interactions between antiretrovirals and antifungals are minimal 5
• Exception: Concomitant fluconazole and nevirapine requires caution—monitor closely for nevirapine-associated hepatotoxicity 5

Critical Management Considerations

Monitoring Requirements

• Perform lumbar puncture at 2 weeks to assess CSF sterility and guide induction duration 2, 4
• Serial lumbar punctures are essential to document CSF sterilization and manage elevated intracranial pressure 2, 4, 3
• Monitor serum creatinine, electrolytes (especially potassium and magnesium), and complete blood counts throughout amphotericin therapy 4
• If using flucytosine: Monitor serum levels (target 30–80 μg/mL) and adjust dose based on renal function 2, 4, 3
• Monitor complete blood counts regularly due to flucytosine-associated bone marrow suppression risk 2

Elevated Intracranial Pressure Management

• Always measure opening pressure during initial lumbar puncture (patient in lateral decubitus position) 3
• Elevated pressure (>25 cm H₂O) occurs in up to 75% of patients and is associated with 93% of deaths in the first 2 weeks 3
• Aggressive management is mandatory: Perform therapeutic lumbar punctures, consider lumbar drain insertion, ventriculostomy, or ventriculoperitoneal shunt 2, 5
• Do NOT use medical treatments such as corticosteroids, mannitol, or acetazolamide—they are ineffective 5

Common Pitfalls and How to Avoid Them

1. Failure to test for HIV in all patients with cryptococcal meningitis 2

   • Always perform HIV testing regardless of patient demographics

2. Inadequate management of elevated intracranial pressure 2, 4

   • Measure opening pressure at every lumbar puncture and perform aggressive therapeutic drainage when >25 cm H₂O

3. Premature initiation of ART in HIV patients 2, 4, 3

   • Wait 2–10 weeks after starting antifungals to minimize IRIS risk

4. Using liposomal amphotericin B monotherapy for only 2 weeks without flucytosine 4

   • If flucytosine is unavailable, extend amphotericin to 4–6 weeks

5. Relying on cryptococcal antigen titers to guide treatment decisions 2, 4

   • Use clinical response and CSF sterilization instead; antigen titers do not correlate with treatment success

6. Failure to monitor for drug toxicities 2

   • Amphotericin causes nephrotoxicity and electrolyte abnormalities; flucytosine causes bone marrow suppression

7. Using amphotericin B deoxycholate in transplant recipients 2, 4

   • Lipid formulations are strongly preferred due to additive nephrotoxicity with calcineurin inhibitors

8. Distinguishing treatment failure from IRIS 2

   • IRIS typically occurs 2–10 weeks after starting ART; treatment failure occurs earlier and requires antifungal adjustment

Resource-Limited Settings

When flucytosine is unavailable:

• Amphotericin B deoxycholate 1 mg/kg/day IV for 2 weeks OR amphotericin B 0.7 mg/kg/day IV + fluconazole 800 mg/day orally for 2 weeks, followed by fluconazole 800 mg/day for 8 weeks (A-I evidence) 1
• Maintenance: Fluconazole 200–400 mg/day until immune reconstitution 1

When amphotericin is unavailable but flucytosine is available:

• Fluconazole ≥800 mg/day (1200 mg/day favored) + flucytosine 100 mg/kg/day for 2–10 weeks, followed by fluconazole 200–400 mg/day maintenance 1

Recent evidence from Africa demonstrates that 1 week of amphotericin B plus flucytosine followed by 1 week of fluconazole is associated with the lowest 10-week mortality (24.2%) and is highly effective in resource-limited settings 6, 7