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

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

2019-05-01T17:34:11Z

2019-05-01T17:34:11Z

2019-02

2019-05-01T17:34:09Z

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.).

AAC.01739-18

0066-4804

1098-6596

https://hdl.handle.net/10161/18492

eng

American Society for Microbiology

Antimicrobial Agents and Chemotherapy

10.1128/AAC.01739-18

PK-PD

Penicillium

Talaromyces

amphotericin

antifungal

pharmacodynamics

population pharmacokinetics

talaromycosis

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

Journal article

Le, Thuy|0000-0002-3393-6580

Perfect, John|0000-0002-6606-9460|0000-0003-3465-5518

e01739

18

2

School of Medicine

Duke

Medicine, Infectious Diseases

Medicine

Clinical Science Departments

Molecular Genetics and Microbiology

Basic Science Departments

Published

63