Cryptococcosis medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Medical Therapy

The standard regimen of treatment in non-AIDS patients intravenous Amphotericin B combined with oral flucytosine.

AIDS patients often have a reduced response to Amphotericin B and flucytosine, therefore after initial treatment as above, oral fluconazole can be used.

Antimicrobial Regimen

• Cryptococcus

• 1. Cryptococcus neoformans

• 1.1. Cryptococcus neoformans meningitis in HIV infected patients

• 1.1.1. Induction and consolidation

• Preferred regimen : (Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction) OR Liposomal AmB 3-4mg/kg IV qd OR Amphotericin B lipid complex (ABLC) 5mg/kg IV qd) PLUS Flucytosine 100mg/kg/day PO or IV qid for at least 2 weeks followed by Fluconazole 400mg (6mg/kg) PO qd for at least 8 weeks.
• Alternative regimen (1): Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd OR Liposomal AmB 3-4 mg/kg IV qd OR AmB lipid complex 5mg/kg IV qd for 4-6 weeks
• Alternative regimen (2): Amphotericin B deoxycholate 0.7 mg/kg IV qd AND Fluconazole 800mg PO qd for 2 weeks, followed by Fluconazole 800mg PO qd for at least 8 weeks
• Alternative regimen (3): Fluconazole (>800 mg PO qd, 1200mg PO qd is favored) AND Flucytosine 100mg/kg/day PO qid for 6 weeks
• Alternative regimen (4): Fluconazole PO 800-2000mg qd for 10-12 weeks

• 1.1.2. Maintenance and prophylactic therapy

• Preferred regimen for : Initiate HAART 2-10 weeks after commencing initial antifungal therapy AND Fluconazole 200mg PO qd
• Alternative regimen : Itraconazole 200mg PO bid - monitor drug-level OR Amphotericin B deoxycholate (1 mg/kg) per week IV (should be used in azole-intolerant patients).
• Note (1): Consider discontinuing supressive therapy if CD4 count is higher than 100 cells/uL AND undetectable OR very low HIV RNA level for more than 3 months. Consider reinstitution of maintenance therapy if CD4 count <100 cels/uL.
• Note (2): Do not use acetazolamide OR mannitol OR corticosteroids to treat increased intracranial pressure, instead it should be used lombar puncture in the absence of focal neurologic signs or impaired mentation (which, if present, patient must be submitted to CT or MRI scan first).

• 1.2. Cerebral cryptococcomas

• Preferred regimen for induction and consolidation: (Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction) OR Liposomal AmB 3-4mg/kg IV qd OR Amphotericin B lipid complex (ABLC) 5mg/kg IV qd) PLUS Flucytosine 100mg/kg/day PO or IV qid for at least 2 weeks followed by Fluconazole 400mg (6mg/kg) PO qd for at least 8 weeks
• Note: Consider surgery if lesions are larger than 3cm, accessible lesions with mass effect or lesions that are enlarging and not explained by IRIS.

• 1.3. Cryptococcus neoformans meningitis in HIV negative patients

• Preferred regimen: Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd PLUS Flucytosine 100mg/kg/day PO or IV qid for at least 4 weeks (which may be extended to 6 weeks if there is any neurological complication) followed by Fluconazole 400mg PO qd for 8 weeks. If there's toxicity to AmBd, consider changing to LFAmB in the second 2 weeks.
• Note (1): After induction and consolidation therapy, start Fluconazole 200mg (3mg/kg) PO qd for 6-12 months.
• Note (2): If Flucytosine is not given, consider lengthening the induction therapy for at least 2 weeks.

• 1.4. Cryptococcus neoformans pulmonary disease - immunosupressed

• Mild-moderate symptoms, without severe immunosupression and absence of diffuse pulmonary infiltrates:

• Preferred regimen: Fluconazole 400mg PO qd for 6-12 months

• Severe pneumonia or disseminated disease or CNS infection:

• Preferred regimen: treat like CNS cryptococcosis.

• Note (1): In HIV- infected patients, treatment should be stopped after 1 year if CD4 count is >100 and a cryptococcal antigen titer is <1:512 and not increasing.
• Note (2): Consider corticosteroid if ARDS is present in a context which it might be attributed to IRIS.

• 1.5 Cryptococcus neoformans pulmonary disease - non-immunosupressed

• Mild-moderate symptoms, without severe immunosupression and absence of diffuse pulmonary infiltrates:

• Preferred regimen: Fluconazole 400mg PO qd for 6-12 months
• Alternative regimen: if Fluconazole is unavailable or contraindicated, Itraconazole 200mg PO bid, Voriconazole 200 mg PO bid, and Posaconazole 400mg PO bid

• If there's severe pneumonia, disseminated disease or CNS infection:

• Preferred regimen: treat like CNS cryptococcosis for 6-12 months.

• 1.6 Cryptococcus neoformans non-lung, non-CNS infection

• Cryptococcemia or disseminated cryptococcic disease (involvement of at least 2 noncontiguous sites or cryptococcal antigen titer >1:512):

• Preferred regimen: treat like CNS infection.

• If infection occurs at a single site and no immunosupressive risk factors

• Preferred regimen: Fluconazole 400mg PO qd for 6-12 months

• 1.7. Cryptococcosis in Children

• Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 1.0 mg/kg qd IV PLUS Flucytosine 100mg/kg PO or IV qid for 2 weeks followed by Fluconazole 10-12mg/kg PO qd for 8 weeks
• Alternative regimen: patients with renal dysfunction: change Amphotericin B deoxycholate by Liposomal AmB 5mg/kg IV qd or Amphotericin B lipid complex (ABLC) 5mg/kg IV qd
• Preferred regimen for maintenance: Fluconazole 6mg/kg PO qd. Discontinuation of maintenance therapy is poorly studied and should be individualized.

• Cryptococcal pneumonia:

• Preferred regimen Fluconazole 6-12mg/kg PO qd for 6-12 months

• 1.8. Cryptococcosis in Pregnant Women

• Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction - Liposomal AmB 3-4mg/kg IV qd OR Amphotericin B lipid complex (ABLC) 5mg/kg IV qd. Consider using Flucytosine in relationship to benefit risk basis, since it is a Category C drug for pregnancy. Start Fluconazole after delivery. Avoid use during first trimester and consider use in the last 2 trimesters with the need for continuous antifungal therapy during pregnancy.
• Note: If pulmonary cryptococcosis: perform close follow-up and administer fluconazole after delivery.

• 2. Cryptococcus gatti

• Disseminated cryptococcosis or CNS disease:

• Preferred regimen: treatment is the same as C. neoformans.

• Pulmonary disease: single and small cryptococcoma:

• Preferred regimen: Fluconazole 400mg per day PO for 6-18months

• Pulmonary disease: Very large or multiple cryptococcomas:

• Preferred regimen: administer Flucytosine AND AmB deocycholate for 4-6 weeks, followed by fluconazole for 6-18 months.
• Note: Surgery should be considered if there is compression of vital structures OR failure to reduce the size of the cryptococcoma after 4 weeks of therapy