What is the treatment for disseminated cryptococcosis (fungal infection)?

Treatment of Disseminated Cryptococcosis

For disseminated cryptococcosis, initiate 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 consolidation therapy with fluconazole (400 mg daily) for 8 weeks, then maintenance therapy with fluconazole (200-400 mg daily) for 6-12 months. 1

Initial Evaluation

Before initiating treatment, perform a comprehensive workup to determine the extent of disease:

• Lumbar puncture is mandatory to rule out CNS involvement, even in neurologically asymptomatic patients, as Cryptococcus has strong CNS tropism 2, 3
• Obtain blood cultures and serum cryptococcal antigen testing to assess for fungemia 2
• Perform chest imaging to evaluate pulmonary involvement 2
• Measure opening pressure during lumbar puncture if CNS disease is present, as elevated intracranial pressure significantly impacts mortality 1, 4

Treatment Algorithm by Disease Severity

Severe Disseminated Disease (CNS involvement, cryptococcemia, or high fungal burden)

Induction Phase (2 weeks minimum):

• Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV PLUS flucytosine 100 mg/kg/day orally in 4 divided doses 1
• This combination is superior to amphotericin B alone, with significantly better fungal clearance and survival rates 5
• For transplant recipients or patients with renal insufficiency, substitute liposomal amphotericin B (3-4 mg/kg/day) or ABLC (5 mg/kg/day) 1
• Critical: Flucytosine must be given for the full 14 days; shorter courses are independently associated with treatment failure 5

Consolidation Phase (8 weeks):

• Fluconazole 400 mg daily orally 1, 2
• Begin after completing induction therapy and confirming CSF sterilization 2

Maintenance Phase (6-12 months):

• Fluconazole 200-400 mg daily orally 1
• Continue until immune reconstitution in HIV patients (CD4 >100 cells/μL for ≥3 months) 6

Moderate Disease (Cryptococcemia alone, high antigen titer ≥1:512, or single non-CNS site)

If CNS disease is definitively ruled out by negative CSF culture and cryptococcal antigen:

• Fluconazole 400 mg daily for 6-12 months 1, 2, 3
• However, treat as CNS disease if any doubt exists about CNS involvement 1, 3

Resource-Limited Settings

When flucytosine is unavailable (common scenario):

• Amphotericin B deoxycholate 0.7 mg/kg/day IV PLUS fluconazole 800 mg daily orally for 2 weeks 1
• Alternative: Amphotericin B deoxycholate 1 mg/kg/day IV alone for 2 weeks 1
• Follow with fluconazole 800 mg daily for 8 weeks consolidation, then 200-400 mg daily maintenance 1

When amphotericin B is unavailable:

• Fluconazole 1200 mg daily (preferred) or ≥800 mg daily for at least 10 weeks or until CSF culture negative 1
• Warning: Primary fluconazole therapy carries risk of drug resistance; obtain MIC testing 1

Critical Management Considerations

Intracranial Pressure Management (for CNS disease)

• Measure opening pressure at baseline and with any clinical deterioration 1, 4
• If opening pressure >25 cm H₂O with symptoms: perform therapeutic lumbar puncture to reduce pressure by 50% or to 20 cm H₂O 1
• Repeat daily lumbar punctures until pressure stabilizes for 2 consecutive days 1
• Consider lumbar drain or ventriculostomy for persistent elevation 1
• Do not use corticosteroids, mannitol, or acetazolamide—they are ineffective 4

Monitoring During Therapy

• Monitor renal function, electrolytes, and complete blood count in patients receiving amphotericin B 2
• Check flucytosine peak serum levels (target <75 μg/mL) to prevent bone marrow toxicity 2
• Repeat lumbar puncture at 2 weeks to confirm CSF sterilization 2
• Serial cryptococcal antigen titers to assess treatment response 3, 6

Special Populations

HIV-infected patients:

• Delay ART initiation until 2-10 weeks after starting antifungal therapy to reduce IRIS risk 6, 4
• Lifelong suppressive therapy may be needed until sustained immune reconstitution 2
• Can discontinue maintenance therapy after ≥12 months if CD4 >100 cells/μL and undetectable viral load for ≥3 months 1, 6

Transplant recipients:

• Prefer liposomal amphotericin B due to concurrent nephrotoxic immunosuppressants 1
• Consider sequential reduction of immunosuppression, starting with corticosteroids 6

Pregnant women:

• Use amphotericin B deoxycholate or liposomal amphotericin B with or without flucytosine (both category C) 1
• Avoid fluconazole in first trimester; use cautiously in second/third trimesters 1
• Monitor for IRIS in postpartum period 1

Children:

• Amphotericin B 1 mg/kg/day IV plus flucytosine 100 mg/kg/day orally for 2 weeks 1
• Consolidation: fluconazole 10-12 mg/kg/day for 8 weeks 1
• Maintenance: fluconazole 6 mg/kg/day 1

Common Pitfalls

• Failing to perform lumbar puncture in patients with positive serum cryptococcal antigen—CNS involvement dramatically changes treatment duration and monitoring 2, 3
• Inadequate duration of flucytosine (<14 days) is associated with treatment failure 5
• Starting ART too early in HIV patients increases IRIS risk; wait 5 weeks 6, 4
• Relying on imaging alone for cryptococcomas—lesions may persist or develop edema during effective therapy due to immune response 1
• Using fluconazole monotherapy for induction in severe disease—combination therapy with amphotericin B plus flucytosine is significantly superior 5

Treatment Failure

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

• Switch to or restart amphotericin B-based therapy 2
• Consider higher doses of liposomal amphotericin B (4-6 mg/kg/day) 2
• Obtain MIC testing for azole resistance 1
• For azole-resistant strains, use amphotericin B until all sites are sterile 1