Cryptococcosis medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.

The standard regimen of treatment in non-AIDS patients is 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.

The standard regimen of treatment in non-AIDS patients is 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.

• 1. Cryptococcus neoformans

• 1.1 Meningoencephalitis in HIV infected patients^[1]

• 1.1.1 Induction and consolidation

• Preferred regimen: (Amphotericin B deoxycholate 0.7-1.0 mg/kg IV q24h for 2 weeks AND Flucytosine 100 mg/kg/day PO/IV q6h for 2 weeks) THEN Fluconazole 400 mg (6 mg/kg) PO qd for ≥ 8 weeks
• Preferred regimen (renally impaired): (Liposomal AmB 3-4 mg/kg IV q24h AND Flucytosine 100 mg/kg/day PO/IV q6h for 2 weeks) THEN Fluconazole 400 mg (6 mg/kg) PO qd for ≥ 8 weeks
• Preferred regimen (renally impaired): (Amphotericin B lipid complex (ABLC) 5 mg/kg IV q24h AND Flucytosine 100 mg/kg/day PO/IV q6h for 2 weeks) THEN Fluconazole 400 mg (6 mg/kg) PO qd for ≥ 8 weeks
• Alternative regimen (1): Amphotericin B deoxycholate 0.7-1.0 mg/kg IV q24h OR Liposomal AmB 3-4 mg/kg IV q24h OR Amphotericin B lipid complex 5 mg/kg IV q24h for 4-6 weeks
• Alternative regimen (2): (Amphotericin B deoxycholate 0.7 mg/kg IV q24h AND Fluconazole 800 mg PO qd for 2 weeks) THEN Fluconazole 800 mg PO qd for ≥ 8 weeks
• Alternative regimen (3): Fluconazole 800-1200 mg PO qd AND Flucytosine 100 mg/kg/day PO qid for 6 weeks
• Alternative regimen (4): Fluconazole PO 800-2000 mg PO qd for 10-12 weeks

• 1.1.2 Maintenance and prophylactic therapy

• Preferred regimen: Fluconazole 200 mg PO qd AND HAART 2-10 weeks after initiation of antifungal therapy
• Alternative regimen (1): Itraconazole 200 mg PO bid
• Alternative regimen (2): Amphotericin B deoxycholate 1 mg/kg IV qw
• Note (1): Consider discontinuing therapy if CD4 count is higher than 100 cells/uL AND undetectable OR very low HIV RNA level for > 3 months
• Note (2): Consider reinstitution of maintenance therapy if CD4 count <100 cells/uL

• 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 amphotericin B deoxycholate, consider changing to liposomal AmB 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 400 mg PO qd for 6-12 months

• Severe pneumonia, 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 400 mg 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 the patient has 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 (renally impaired): 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 6-18 months

• Pulmonary disease: Very large or multiple cryptococcomas

• Preferred regimen: Administer flucytosine AND Amphotericin B 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