Amphotericin B Penetrates into the Central Nervous System through Focal Disruption of the Blood-Brain Barrier in Experimental Hematogenous Candida Meningoencephalitis

Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeation and low cerebrospinal fluid (CSF) concentrations but is effective in the treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. ABSTRACT Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeation and low cerebrospinal fluid (CSF) concentrations but is effective in the treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro blood-brain barrier (BBB) model was serially infected with Candida albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml was then provided, and the vascular and CNS compartments were sampled 4 h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB at 1 mg/kg of body weight or LAMB at 5 mg/kg and were euthanized after 1, 3, 6, and 24 h. Evans blue dye solution (2%, 2 ml/kg) administered intravenously (i.v.) at 1 h prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using ultraperformance liquid chromatography. For selected rabbits, magnetic resonance imaging (MRI) scans performed on days 1 to 7 postinoculation were acquired before and after i.v. bolus administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) at 15-min intervals through 2 h postinjection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24 h of exposure (P = 0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35 ± 0.59 and 3.14 ± 0.89 times higher, respectively, than those in normal tissue (P ≤ 0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with a disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low cerebrospinal fluid concentrations.