What is the recommended treatment for chronic cryptococcosis?

Treatment of Chronic Cryptococcosis

For chronic cryptococcosis, the optimal treatment depends critically on disease location and host immune status, with CNS involvement requiring aggressive combination therapy of amphotericin B plus flucytosine for induction, while isolated pulmonary or non-CNS disease in immunocompetent patients can be managed with fluconazole monotherapy.

Initial Diagnostic Evaluation

Before initiating treatment, comprehensive assessment is mandatory to determine disease extent:

• Perform lumbar puncture in all patients to rule out CNS involvement, even if neurologically asymptomatic 1, 2
• Obtain serum cryptococcal antigen testing, as positive results indicate deep tissue invasion and high likelihood of dissemination 1, 2
• Order blood cultures to assess for cryptococcemia 2
• Obtain chest imaging (X-ray or CT) to evaluate pulmonary involvement 2

Treatment Algorithm Based on Disease Site and Severity

CNS Disease (Cryptococcal Meningitis/Meningoencephalitis)

Non-HIV, Non-Transplant Patients

Induction Phase (First-Line):

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally (divided into 4 doses) for at least 4 weeks 1
• For patients without neurological complications, no significant underlying disease, and negative CSF culture at 2 weeks: 4 weeks total induction is sufficient 1
• For patients with neurological complications: extend induction to 6 weeks 1
• Lipid formulations of amphotericin B (liposomal amphotericin B 3-4 mg/kg/day or ABLC 5 mg/kg/day) should be substituted in patients with renal dysfunction 1

Alternative Induction (if flucytosine unavailable):

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV alone for at least 6 weeks 1

Consolidation Phase:

• Fluconazole 400-800 mg/day orally for 8 weeks 1
• Higher dose (800 mg/day) recommended if 2-week induction regimen was used 1

Maintenance Phase:

• Fluconazole 200 mg/day orally for 6-12 months 1

HIV-Positive Patients

Induction Phase:

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally for at least 2 weeks 1
• Lipid formulations (liposomal amphotericin B 3-4 mg/kg/day or ABLC 5 mg/kg/day) preferred to reduce nephrotoxicity 1
• Recent evidence supports single-dose liposomal amphotericin B 10 mg/kg plus 14 days of flucytosine and fluconazole as noninferior with fewer adverse events 3

Consolidation Phase:

• Fluconazole 400 mg/day orally for minimum 8 weeks 1

Maintenance/Suppressive Therapy:

• Fluconazole 200 mg/day orally indefinitely 1
• Consider discontinuation after CD4 count >100 cells/μL and undetectable HIV RNA for ≥3 months (minimum 12 months antifungal therapy completed) 1
• Reinstitute if CD4 count decreases to <100 cells/μL 1

Antiretroviral Therapy Timing:

• Initiate HAART 2-10 weeks after starting antifungal treatment to reduce IRIS risk 1

Organ Transplant Recipients

Induction Phase:

• Liposomal amphotericin B 3-4 mg/kg/day or ABLC 5 mg/kg/day plus flucytosine 100 mg/kg/day for at least 2 weeks 1
• Amphotericin B deoxycholate should be avoided due to nephrotoxicity risk in this population 1
• If flucytosine not included, extend induction to 4-6 weeks 1

Consolidation Phase:

• Fluconazole 400-800 mg/day orally for 8 weeks 1

Maintenance Phase:

• Fluconazole 200-400 mg/day orally for 6-12 months 1

Immunosuppression Management:

• Sequential reduction of immunosuppressants, lowering corticosteroid dose first 1
• Reduce prednisone to ≤10 mg/day if possible 1

Cerebral Cryptococcomas

Extended Therapy Required:

• Induction: Amphotericin B (deoxycholate 0.7-1.0 mg/kg/day or lipid formulation 3-4 mg/kg/day) plus flucytosine 100 mg/kg/day for at least 6 weeks 1
• Consolidation and maintenance: Fluconazole 400-800 mg/day for 6-18 months 1, 2

Adjunctive Measures:

• Corticosteroids for mass effect and surrounding edema 1
• Surgical debulking for large (≥3 cm), accessible lesions with mass effect 1
• Surgery also indicated for enlarging lesions not explained by IRIS 1

Pulmonary and Non-CNS Cryptococcosis

Mild-to-Moderate Disease in Immunocompetent Patients

• Fluconazole 400 mg/day orally for 6-12 months 1
• Itraconazole 200-400 mg/day orally for 6-12 months is an alternative if fluconazole not tolerated 1

Severe Pulmonary Disease or Immunosuppressed Patients

• Treat as CNS disease with full induction, consolidation, and maintenance regimen 1
• This applies to severe symptoms, diffuse pulmonary infiltrates, or any immunocompromised host 1

Cryptococcemia

• Treat as CNS disease regardless of CNS symptoms 1
• Lumbar puncture mandatory to rule out meningitis 1

Isolated Non-CNS, Non-Pulmonary Disease

• For single site infection without immunosuppression and CNS ruled out: Fluconazole 400 mg/day for 6-12 months 1

Asymptomatic Cryptococcal Antigenemia

• Perform lumbar puncture and blood cultures 1, 4
• If positive, treat as symptomatic meningoencephalitis/disseminated disease 1
• If CNS and blood cultures negative: Fluconazole 400 mg/day until immune reconstitution 1, 4

Critical Management Considerations

Monitoring During Therapy

• Repeat lumbar puncture at 2 weeks to assess CSF sterilization 1
• Patients with positive culture at 2 weeks require longer induction therapy 1
• Monitor renal function, electrolytes, and bone marrow function with amphotericin B 2
• Monitor flucytosine blood levels; peak serum levels should not exceed 75 μg/mL 2

Elevated Intracranial Pressure Management

• Serial therapeutic lumbar punctures are the primary intervention 2, 5
• Drain CSF to reduce opening pressure by 50% or to <20 cm H₂O 5
• Daily lumbar punctures until pressure normalizes 5
• Consider CSF shunting for hydrocephalus or persistent elevated ICP 2

Treatment Failure

Defined as lack of clinical improvement after 2 weeks of appropriate therapy or relapse after initial response 2:

• Switch to amphotericin B with or without flucytosine 2
• Consider higher doses of liposomal amphotericin B (4-6 mg/kg/day) 2
• For cryptococcomas not responding, consider surgical intervention 1

Common Pitfalls to Avoid

• Never use fluconazole monotherapy for initial treatment of CNS disease - it is inferior to amphotericin B-based regimens and associated with treatment failure 1
• Do not rely on cryptococcal antigen titers to guide treatment decisions; clinical and mycological response are paramount 1
• Do not start HAART immediately in HIV patients with CM - delay 2-10 weeks to prevent IRIS 1
• Do not use amphotericin B deoxycholate as first-line in transplant recipients due to high nephrotoxicity risk 1
• Do not treat isolated pulmonary disease in immunocompromised patients with fluconazole alone - these patients require CNS-level therapy 1

Renal Dose Adjustments for Fluconazole

For patients with creatinine clearance ≤50 mL/min receiving multiple doses 6:

• Give initial loading dose (50-400 mg based on indication)
• Reduce maintenance dose to 50% of recommended dose
• For hemodialysis patients: give 100% dose after each dialysis session