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Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis.

Lestner, J; McEntee, L; Johnson, A; Livermore, J; Whalley, S; Schwartz, J; Perfect, JR; Harrison, T; Hope, W (2017) Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis. Antimicrob Agents Chemother, 61 (6). ee00090-17. ISSN 1098-6596 https://doi.org/10.1128/AAC.00090-17
SGUL Authors: Harrison, Thomas Stephen

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Abstract

Cryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. Induction regimens are usually administered for 2-weeks. The shortest effective period of induction therapy with liposomal amphotericin B (LAmB) is unknown. The pharmacodynamics of LAmB were studied in murine and rabbit models of cryptococcal meningoencephalitis. The concentrations of LAmB in plasma and brain of mice were measured using HPLC. Histopathological changes were determined. The penetration of LAmB into the brain was determined by immunohistochemistry using an antibody directed to amphotericin B. A dose-dependent decline in fungal burden was observed in the brain of mice with near-maximal efficacy achieved with LAmB 10-20 mg/kg/day. The terminal elimination half-life in brain was 133 hours. The pharmacodynamics of a single dose of 20 mg/kg was the same as 20 mg/kg/day administered for 2 weeks. Changes in quantitative counts were reflected by histopathological changes in the brain. Three doses of LAmB 5 mg/kg/day in rabbits were required to achieve fungicidal activity in cerebrospinal fluid (cumulative AUC 2500 mg.h/L). Amphotericin B was visible in the intra- and perivascular spaces, leptomeninges and choroid plexus. The prolonged mean residence time of amphotericin B in the brain suggest abbreviated induction regimens of LAmB are possible for cryptococcal meningoencephalitis.

Item Type: Article
Additional Information: © 2017 Lestner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Microbiology, 0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Antimicrob Agents Chemother
ISSN: 1098-6596
Language: eng
Dates:
DateEvent
4 March 2017Accepted
20 March 2017Published Online
June 2017Published
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDMedical Research Councilhttp://dx.doi.org/10.13039/501100000265
UNSPECIFIEDDepartment for International Developmenthttp://dx.doi.org/10.13039/501100000278
PubMed ID: 28320715
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/108775
Publisher's version: https://doi.org/10.1128/AAC.00090-17

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