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

• Published in: Antimicrobial agents and chemotherapy 2019-12, Vol.63 (12)
• Main Authors: Petraitis, Vidmantas, Petraitiene, Ruta, Valdez, Jessica M, Pyrgos, Vasilios, Lizak, Martin J, Klaunberg, Brenda A, Kalasauskas, Darius, Basevicius, Algidas, Bacher, John D, Benjamin, Jr, Daniel K, Hope, William W, Walsh, Thomas J
• Format: Article
• Language: English
• Subjects: Experimental Therapeutics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01626-19

Hematogenous meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeability and low cerebrospinal fluid (CSF) concentrations, but is effective in 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 BBB model was serially infected with Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml were then provided, vascular and CNS compartments were sampled 4h later. For correlation, rabbits with experimental HCME received a single dose of DAMB 1 mg/kg or LAMB 5 mg/kg, and were euthanized after 1, 3, 6 and 24h. Evans blue solution (2%) 2 ml/kg administered IV one hour prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using UPLC. For selected rabbits, MRI scans performed on days 1-7 postinoculation were acquired before and after IV bolus Gd-DTPA at 15min intervals through 2h post-injection. The greatest degree of penetration of DAMB and LAMB through the BBB occurred after 24h of exposure ( =0.0022). the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue ( ≤0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low CSF concentrations.