What is the treatment for disseminated cryptococcosis in a patient, potentially with HIV/AIDS (Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome) and impaired renal function?

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 with fluconazole (400 mg daily) for 8 weeks, then maintenance therapy with fluconazole (200-400 mg daily) for 6-12 months. 1, 2

Initial Evaluation

Before initiating treatment, several critical assessments must be completed:

• Perform lumbar puncture in all patients to rule out CNS involvement, even if neurologically asymptomatic, as Cryptococcus has strong CNS tropism 1, 2, 3
• Measure opening pressure during lumbar puncture if CNS disease is present, as elevated intracranial pressure (>25 cm H₂O) significantly impacts mortality 1, 2
• Obtain blood cultures and serum cryptococcal antigen testing to assess for fungemia and quantify fungal burden 2
• Perform chest imaging to evaluate pulmonary involvement 2
• Test for HIV infection in all patients with disseminated cryptococcosis 1

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, 2
• For patients with renal dysfunction or receiving nephrotoxic immunosuppressants, substitute liposomal amphotericin B (3-4 mg/kg/day) or ABLC (5 mg/kg/day) plus flucytosine 1
• For flucytosine-intolerant patients, use amphotericin B alone for 4-6 weeks 1

Consolidation Phase (8 weeks):

• Fluconazole 400 mg daily orally 1, 2
• Higher doses (400-800 mg daily) may be used in transplant recipients 1

Maintenance Phase (6-12 months):

• Fluconazole 200-400 mg daily 1, 2
• Duration depends on immune status and clinical response 1

Moderate Disease (Single non-CNS site, no cryptococcemia, antigen titer <1:512)

• Fluconazole 400 mg daily for 6-12 months if CNS disease is definitively ruled out 1, 2
• This applies only to patients without immunosuppressive risk factors, negative blood cultures, and confirmed negative CSF studies 1

High Fungal Burden Disease (Cryptococcemia, dissemination to ≥2 sites, or antigen titer ≥1:512)

• Treat as CNS disease regardless of meningeal involvement 1, 2
• Use full induction, consolidation, and maintenance regimen as outlined above 1

Special Population Considerations

HIV-Infected Patients

• Delay antiretroviral therapy (ART) initiation until 2-10 weeks after starting antifungal treatment to reduce risk of immune reconstitution inflammatory syndrome (IRIS) 1, 4
• Consider discontinuing maintenance therapy after CD4 count >100 cells/μL and undetectable viral load for ≥3 months, with minimum 1 year of antifungal therapy 1
• Reinstitute maintenance therapy if CD4 count decreases to <100 cells/μL 1

Transplant Recipients

• Prefer liposomal amphotericin B (3-4 mg/kg/day) or ABLC (5 mg/kg/day) plus flucytosine for 2 weeks due to concurrent nephrotoxic calcineurin inhibitors 1
• Sequential or step-wise reduction of immunosuppressants should be considered, lowering corticosteroid dose first 1
• Consolidation therapy with fluconazole 400-800 mg daily for 6 months to 1 year 1
• Maintenance therapy with fluconazole 200-400 mg daily 1

Patients with Impaired Renal Function

• Use lipid formulations of amphotericin B (liposomal amphotericin B 3-4 mg/kg/day or ABLC 5 mg/kg/day) instead of amphotericin B deoxycholate 1
• Adjust fluconazole dosing based on creatinine clearance: for CrCl ≤50 mL/min without dialysis, reduce dose to 50% of normal 5
• For hemodialysis patients, give 100% of recommended dose after each dialysis session 5
• Adjust flucytosine dose based on renal function to prevent bone marrow toxicity 1

Critical Management Considerations

Intracranial Pressure Management (for CNS disease)

• Measure opening pressure at baseline and with any clinical deterioration 1, 2, 4
• If opening pressure >25 cm H₂O with symptoms, perform therapeutic lumbar puncture to reduce pressure by 50% or to 20 cm H₂O 1, 2
• Repeat daily lumbar punctures until intracranial pressure and symptoms stabilize for 1-2 days 1
• Consider temporary percutaneous lumbar drains or ventriculostomy for patients requiring daily lumbar punctures 1
• Permanent ventriculoperitoneal shunts should only be placed with appropriate antifungal therapy when conservative measures fail 1
• Avoid mannitol, acetazolamide, and corticosteroids for intracranial pressure control (unless treating IRIS) 1

Monitoring During Treatment

• Monitor renal function, electrolytes, and complete blood count in patients receiving amphotericin B 2
• Check flucytosine peak serum levels (target 30-80 μg/mL, keep <75 μg/mL) to prevent bone marrow toxicity 1, 4
• Perform serial lumbar punctures to document CSF sterilization 4
• Monitor for drug toxicities, especially nephrotoxicity with amphotericin B and bone marrow suppression with flucytosine 4

Alternative Regimens (when primary regimens unavailable)

• Amphotericin B deoxycholate (0.7 mg/kg/day) plus fluconazole (800 mg daily) for 2 weeks, followed by fluconazole 800 mg daily for minimum 8 weeks 1
• Fluconazole (≥1200 mg daily) plus flucytosine (100 mg/kg/day) for 6 weeks 1, 4
• Fluconazole monotherapy (800-2000 mg daily, preferably ≥1200 mg daily) for 10-12 weeks 1
• Itraconazole (200 mg twice daily) for 10-12 weeks, though this is discouraged 1

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 2
• Distinguish between treatment failure and IRIS, as management differs significantly 1, 4

Common Pitfalls to Avoid

• Failing to perform lumbar puncture in all patients with disseminated disease, even without neurological symptoms 4, 3
• Inadequate management of elevated intracranial pressure, which is a critical determinant of outcome 1, 4
• Premature initiation of ART in HIV patients (must wait 2-10 weeks) 4
• Using mannitol, acetazolamide, or corticosteroids to control intracranial pressure 1
• Relying solely on cryptococcal antigen titers to guide treatment decisions 4
• Failing to monitor for drug toxicities, particularly nephrotoxicity and bone marrow suppression 4
• Not distinguishing between treatment failure and IRIS when symptoms worsen during therapy 1, 4