Fungal meningitis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Rim Halaby

Overview

Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose antifungals. In addition, frequent lumbar punctures are recommended in order to relieve the increased intracranial pressure.

Medical Therapy

• The treatment of fungal meningitis, such as cryptococcal meningitis, is a long course of high dose antifungals. The most commonly administered antifungals are amphotericin B and flucytosine. Other antifungals that can be used are miconazole and fluconazole.
• Increased intracranial pressure is a common finding in fungal meningitis. Therefore, it is recommended to do frequent, ideally daily, lumbar punctures to relieve the intracranial pressure.

Antimicrobial Regimens

Pathogen-directed antimicrobial therapy

The pathogen specific antifungal therapy for fungal meningitis is shown in the table below:

ANTIFUNGAL THERAPY IN FUNGAL MENINGITIS
Type of fungal meningitis	Preferred therapy	Alternate therapy
Cryptococcus	HIV-infection (Induction/consolidation): Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 25 mg/kg PO QID for at least 2 weeks THEN fluconazole 400 mg/day PO/IV (6 mg/kg/day); Lipid formulations of amphotericin B may be substituted for Amphotericin B deoxycholate if necessary: liposomal amphotericin B 3-4 mg/kg/day IV and amphotericin B lipid complex 5 mg/kg/day IV. (Maintenance): Fluconazole 200 mg/day Solid organ transplant: Lipid formulations of amphotericin B (liposomal amphotericin B 3-4 mg/kg/day IV or amphotericin B lipid complex 5 mg/kg/day IV) plus flucytosine 25 mg/kg PO QID for at least 2 weeks THEN fluconazole 400-800 mg/day PO/IV (6-12 mg/kg/day) for 8 weeks THEN fluconazole 200-400 mg/day for 6-12 months Non-HIV, non-organ transplant: Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 25 mg/kg QID for at least 4 weeks THEN fluconazole 200 mg/day (3 mg/kg) for 6-12 months	HIV-infection (Induction/consolidation): Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV or lipid formulations of amphotericin B (liposomal Amphotericin B 3-4 mg/kg/day IV and amphotericin B lipid complex 5 mg/kg/day IV) monotherapy for 4-6 weeks; Amphotericin B deoxycholate 0.7 mg/kg/day IV plus fluconazole 800 mg/day PO/IV for 2 weeks THEN fluconazole 800 mg/day for a minimum of 8 weeks; fluconazole (≥800 mg/day) PO/IV plus flucytosine 25 mg/kg PO QID for 6 weeks (Maintenance): Itraconazole 200 mg PO BID Solid organ transplant: If flucytosine not used, then consider extension of induction with lipid formulations of amphotericin B for at least 4-6 weeks. Non-HIV, non-organ transplant: Lipid formulations of amphotericin B (liposomal amphotericin B 3-4 mg/kg/day IV or amphotericin B lipid complex 5 mg/kg/day IV) can be substituted in those unable to tolerate Amphotericin B deoxycholate; if flucytosine not used, then consider extension of Amphotericin B deoxycholate or lipid formulations of amphotericin B induction for at least 2 additional weeks.
Aspergillus	Voriconazole 6 mg/kg IV q12h on day 1 THEN 4 mg/kg q12h; further conversion to oral therapy may be considered. Typical oral dosing is 200 mg q12h but is dependent on therapeutic drug monitoring. Total duration of therapy has not been defined. Multiple factors must be considered, including extent of disease, response to therapy, and underlying immune status of the host.	Liposomal amphotericin B 3-5 mg/kg/day IV, amphotericin B lipid complex 5 mg/kg/day IV, itraconazole 200 mg PO BID, or posaconazole 200 mg PO q6h. Combination therapy with voriconazole and an echinocandin such as caspofungin 70 mg IV on day 1 and 50 mg/day IV thereafter may be considered.
Candida	Lipid formulations of Amphotericin B 3-5 mg/kg/day +/− Flucytosine 25 mg/kg QID for ∼3 weeks THEN Fluconazole 400-800 mg/day PO/IV (6-12 mg/kg/day) Treatment continued until clinical signs and symptoms resolved and CNS and radiographic abnormalities have normalized.	Fluconazole 400-800 mg/day PO/IV (6-12 mg/kg/day)
Blastomyces	Lipid formulations of Amphotericin B 5 mg/kg/day for 4-6 weeks THEN Fluconazole 800 mg/day PO/IV Treatment for at least 12 months and until resolution of CSF abnormalities	Alternative azole considerations include itraconazole 200 mg PO BID to TID and voriconazole 200-400 mg PO BID.
Coccidioides	Fluconazole 400 mg/day PO/IV. Some use higher doses of Fluconazole, up to 1,000 mg/day up-front. Azole therapy is typically continued indefinitely.	Itraconazole 200 mg PO BID to TID The addition of Intrathecal amphotericin B deoxycholate to azole therapy may be considered in those not responding to azoles. Intrathecal amphotericin B deoxycholate. dosing ranges from 0.1 to 1.5 mg per dose given daily to weekly.
tfExserohilum	Voriconazole 6 mg/kg IV every 12h with assessment of voriconazole trough concentrations on day 5 of therapy with adjustment to achieve trough of 2-5 mcg/ml. IV therapy should be initiated in most cases with transition to PO therapy once improving and clinically stable. Total duration of therapy is unknown and will depend on extent of infection, response to therapy, and underlying immune status of the host. Minimum duration of 3-6 months.	The addition of liposomal amphotericin B 5-6 mg/kg/day IV should be considered in patients with severe disease and/or not responding appropriately to voriconazole monotherapy. Doses of liposomal amphotericin B up to 7.5 mg/kg/day IV may be considered in patients who continue to do poorly.
Histoplasma	Liposomal amphotericin B 5 mg/kg/day IV for 4-6 weeks THEN itraconazole 200 mg BID to TID for at least 1 year and until resolution of CSF abnormalities including Histoplasma antigen levels.	Amphotericin B deoxycholate 0.7-1.0 mg/kg/day is an alternative to liposomal amphotericin B in patients at low risk of nephrotoxicity.
KEY: IV, intravenous; PO, per os, oral administration; BID, twice daily; TID, three times daily; QID, four times daily;