Table 3.

Treatment recommendations (IDSA, ESCMID, and ECMM) for fungal CNS infections

Fungal CNS infection	First-line therapy		References R*
	Adults	Children
Cryptococcal meningoencephalitis	Initial therapy (for the non–HIV-infected and non-transplant patients): AmBd (0.7–1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day) ≥ 4 weeks AmBd (0.7–1.0 mg/kg/day IV) ≥ 6 weeks—for flucytosine-intolerant patients L-AmB (3–4 mg/kg/day) or ABLC (5 mg/kg/day IV) combined with flucytosine ≥ 4 weeks—for AmBd-intolerant patients Consolidation therapy: fluconazole (400–800 mg /day) ≥ 8 weeks Maintenance therapy: fluconazole (200 mg/day) for 6–12 months	Initial therapy: AmBd (1 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) for 2 weeks L-AmB (5 mg/kg/day) or ABLC (5 mg/kg/day) for AmBb-intolerant patients Consolidation therapy: fluconazole (10–12 mg/kg /day orally) for 8 weeks Maintenance therapy: fluconazole (6 mg/kg/day orally) for 6–12 months	[125] IDSA
Cerebral cryptococcomas	Initial therapy: AmBd (0.7–1 mg/kg/day IV), or L-AmB (3–4 mg/kg/day IV), or ABLC (5 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) ≥ 6 weeks Consolidation and maintenance therapy: fluconazole (400–800 mg/day orally) for 6–18 months Adjunctive therapies Corticosteroids for mass effect and surrounding edema Surgery: for large (≥ 3 cm lesion), accessible lesions with mass	No recommendation	[125] IDSA
Candidiasis	Initial therapy: L-AmB (5 mg/kg/day), with or without oral flucytosine (25 mg/kg 4 times daily) for several weeks Step-down therapy: fluconazole, 400–800 mg (6–12 mg/kg) daily. Therapy should continue until all signs and symptoms and CSF and radiological abnormalities have resolved	Initial therapy for the neonatal patients: AmBd (1 mg/kg/day IV) or L-AmB (5 mg/kg/day IV) for several weeks Step-down therapy: fluconazole (12 mg/kg/day). Therapy should continue until all signs, symptoms, and CSF and radiological abnormalities, have resolved	[37] IDSA
Aspergillosis	Voriconazole: loading dose, 6 mg/kg IV every 12 h for 1 day, maintenance dose 4 mg/kg IV every 12 h L-AmB (3–5 mg/kg/day IV) for intolerant or refractory to voriconazole Therapy should continue until all signs and symptoms and CSF and radiological abnormalities have resolved	Voriconazole: loading dose, 9 mg/kg IV every 12 h for 1 day; maintenance dose, 8 mg/kg IV every 12 h L-AmB (3–5 mg/kg/day IV) for intolerant or refractory to voriconazole Treatment duration is determined on a case-by-case basis	[111] IDSA
Mucormycosis	L-AmB (10 mg/kg/day IV), initial 28 days The duration of antifungal treatment should be determined on an individual basis, usually continues for at least 6–8 weeks	L-AmB (5–10 mg/kg/day IV). Treatment duration is determined on a case-by-case basis	[110] ESCMID and ECMM
Hyalohyphomycosis Fusarium species and Scedosporium apiospermum infection	Voriconazole: loading dose (6 mg/kg IV every 12 h for 1 day) maintenance dose (4 mg/kg IV every 12 h) for long-term	Voriconazole: 4 mg/kg IV every 12 h (13–18 years old) and 8 mg/kg IV every 12 h (2–12 years old)	[129] ESCMID and ECMM
Histoplasmosis	Initial therapy: L-AmB (5.0 mg/kg/day for a total of 175 mg/kg given over 4–6 weeks) Step-down therapy: itraconazole (200 mg 2 or 3 times daily) for at least 1 year and until resolution of CSF abnormalities, including Histoplasma antigen levels	Initial therapy: AmBd (1 mg/kg/day IV) for 2 weeks Step-down therapy: itraconazole (5.0–10.0 mg/kg/day in 2 divided doses), not to exceed 400 mg daily; for at least 1 year	[126] IDSA
Blastomycosis	Initial therapy: L-AmB (5 mg/kg/day) over 4–6 weeks Step-down therapy: fluconazole (800 mg/day), itraconazole (200 mg 2 or 3 times per day), or voriconazole (200–400 mg twice per day) for at least 12 months and until resolution of CSF abnormalities	Initial therapy: AmBd (0.7–1.0 mg/kg/ day), or L-AmB (3–5 mg/kg/day) Step-down therapy: oral itraconazole, 10 mg/kg/ day (up to 400 mg/day) for a total of 12 months	[127] IDSA
Coccidioidal meningitis	Fluconazole (400–1200 mg /day orally) for patients with normal renal function and without substantial renal impairment; lifelong treatment In patients who clinically fail initial therapy with fluconazole, higher doses are a first option, and second—change of therapy to another orally administered azole, or to initiate intrathecal AmBd therapy	Fluconazole (12 mg/kg/day IV) or ABLC (3–5 mg/kg/day IV), lifelong treatment	[29, 128] IDSA
Cerebral phaeohyphomycosis	No strong recommendation for antifungal treatment When surgery (complete excision) is not possible voriconazole (400 mg) or posaconazole (800 mg) or combination therapy including a triazole plus an echinocandin plus flucytosine are proposed	No recommendation	[130] ESCMID and ECMM

AmBd Amphotericin B deoxycholate, L-AmB Liposomal amphotericin B, ABLC Amphotericin B lipid complex, IV intravenous, R* recommendation,