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A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro.

Clewe, O; Aulin, L; Hu, Y; Coates, AR; Simonsson, US (2015) A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro. Journal of Antimicrobial Chemotherapy, 71 (4). pp. 964-974. ISSN 1460-2091 https://doi.org/10.1093/jac/dkv416
SGUL Authors: Coates, Anthony Robert Milnes Hu, Yanmin

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Abstract

OBJECTIVES: Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states. METHODS: The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships. RESULTS: The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively. CONCLUSIONS: The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.

Item Type: Article
Additional Information: © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
Keywords: Microbiology, 1115 Pharmacology And Pharmaceutical Sciences, 0605 Microbiology, 1108 Medical Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Journal of Antimicrobial Chemotherapy
ISSN: 1460-2091
Language: eng
Dates:
DateEvent
24 December 2015Published
Publisher License: Creative Commons: Attribution-Noncommercial 4.0
Projects:
Project IDFunderFunder ID
521-2011-344Swedish Research Council Formashttp://dx.doi.org/10.13039/501100001862
115337Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
PubMed ID: 26702921
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107825
Publisher's version: https://doi.org/10.1093/jac/dkv416

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