Cryptococcosis medical therapy

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

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 Regimens

• Cryptococcosis

• 1. Cryptococcus neoformans

• 1.1. Cryptococcus neoformans meningoencephalitis in HIV infected patients

• 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 AmB 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 800mg 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 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