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Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffei.

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Date
2019-02
Authors
Le, Thuy
Ly, Vo Trieu
Thu, Nguyen Thi Mai
Nguyen, Ashley
Thanh, Nguyen Tat
Chau, Nguyen Van Vinh
Thwaites, Guy
Perfect, John
Kolamunnage-Dona, Ruwanthi
Hope, William
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Abstract
Amphotericin B deoxycholate (DAmB) is a first-line agent for the initial treatment of talaromycosis. However, little is known about the population pharmacokinetics and pharmacodynamics of DAmB for talaromycosis. Pharmacokinetic data were obtained from 78 patients; among them, 55 patients had serial fungal CFU counts in blood also available for analysis. A population pharmacokinetic-pharmacodynamic model was fitted to the data. The relationships between the area under the concentration-time curve (AUC)/MIC and the time to blood culture sterilization and the time to death were investigated. There was only modest pharmacokinetic variability in the average AUC, with a mean ± standard deviation of 11.51 ± 3.39 mg·h/liter. The maximal rate of drug-induced kill was 0.133 log10 CFU/ml/h, and the plasma concentration of the DAmB that induced the half-maximal rate of kill was 0.02 mg/liter. Fifty percent of patients sterilized their bloodstreams by 83.16 h (range, 13 to 264 h). A higher initial fungal burden was associated with a longer time to sterilization (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.36 to 0.70; P < 0.001). There was a weak relationship between AUC/MIC and the time to sterilization, although this did not reach statistical significance (HR, 1.03; 95% CI, 1.00 to 1.06, P = 0.091). Furthermore, there was no relationship between the AUC/MIC and time to death (HR, 0.97; 95% CI, 0.88 to 1.08; P = 0.607) or early fungicidal activity {slope = log[(0.500 - 0.003·(AUC/MIC)]; P = 0.319} adjusted for the initial fungal burden. The population pharmacokinetics of DAmB are surprisingly consistent. The time to sterilization of the bloodstream may be a useful pharmacodynamic endpoint for future studies. (This study has been registered at the ISRCTN registry under no. ISRCTN59144167.).
Type
Journal article
Subject
PK-PD
Penicillium
Talaromyces
amphotericin
antifungal
pharmacodynamics
population pharmacokinetics
talaromycosis
Permalink
https://hdl.handle.net/10161/18492
Published Version (Please cite this version)
10.1128/AAC.01739-18
Publication Info
Le, Thuy; Ly, Vo Trieu; Thu, Nguyen Thi Mai; Nguyen, Ashley; Thanh, Nguyen Tat; Chau, Nguyen Van Vinh; ... Hope, William (2019). Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffei. Antimicrobial Agents and Chemotherapy, 63(2). pp. e01739-18. 10.1128/AAC.01739-18. Retrieved from https://hdl.handle.net/10161/18492.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Le

Thuy Le

Associate Professor of Medicine
Perfect

John Robert Perfect

James B. Duke Distinguished Professor of Medicine
Research in my laboratory focuses around several aspects of medical mycology. We are investigating antifungal agents (new and old) in animal models of candida and cryptococcal infections. We have examined clinical correlation of in vitro antifungal susceptibility testing and with in vivo outcome. Our basic science project examines the molecular pathogenesis of cryptococcal infections. We have developed a molecular foundation for C. neoformans, including transformation systems, gene disr
Alphabetical list of authors with Scholars@Duke profiles.
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