SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

Investigation of elimination rate, persistent subpopulation removal and relapse rates of Mycobacterium tuberculosis by combinations of first-line drugs in a modified Cornell mouse model.

Hu, Y; Pertinez, H; Ortega-Muro, F; Alameda-Martin, L; Liu, Y; Schipani, A; Davies, G; Coates, A (2016) Investigation of elimination rate, persistent subpopulation removal and relapse rates of Mycobacterium tuberculosis by combinations of first-line drugs in a modified Cornell mouse model. Antimicrobial Agents and Chemotherapy, 60 (8). pp. 4778-4785. ISSN 1098-6596 https://doi.org/10.1128/AAC.02548-15
SGUL Authors: Coates, Anthony Robert Milnes Hu, Yanmin

[img]
Preview
PDF Accepted Version
Available under License Creative Commons Attribution.

Download (1MB) | Preview

Abstract

Currently, the most effective tuberculosis control method resides in case-finding and 6 months chemotherapy. There is a need to improve our understanding about drug interactions, combination activities and the ability to remove persistent bacteria in the current regimens, particularly in relation to relapse. We aimed to investigate the therapeutic effects of three main components, rifampicin (RMP), isoniazid (INH), and pyrazinamide (PZA), in current drug regimens using a modified version of the Cornell mouse model. We evaluated the post-treatment levels of persistent Mycobacterium tuberculosis in the organs of mice using culture filtrate derived from M. tuberculosis strain H37Rv. When RMP was combined with INH, PZA or INH-PZA, significant additive activities were observed compared to each of the single drug treatments. However, the combination of INH and PZA showed a less significant additive effect than either of the drugs used on their own. Apparent culture negativity of mouse organs was achieved at 14 weeks of treatment with RMP-INH, RMP-PZA and RMP-INH-PZA but not with INH-PZA, when conventional tests, namely culture on solid agar and in liquid broth indicated that the organs were bacteria negative. The relapse rates for RMP-containing regimens were not significantly different to a 100% relapse rate at the numbers of mice examined in this study. In parallel, we examined the organs for the presence of culture filtrate-dependent persistent bacilli after 14 weeks of treatment. Culture filtrate treatment of the organs revealed persistent M. tuberculosis Modelling of mycobacterial elimination rates and evaluation of culture-filtrate dependent organisms showed promise as surrogate methods for efficient factorial evaluation of drug combinations in tuberculosis in mouse models and should be further evaluated against relapse. The presence of culture filtrate-dependent persistent M. tuberculosis is the likely cause of disease relapse in this modified Cornell mouse model.

Item Type: Article
Additional Information: Copyright © 2016 Hu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
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: Antimicrobial Agents and Chemotherapy
ISSN: 1098-6596
Language: ENG
Dates:
DateEvent
23 May 2016Published
20 May 2016Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FP7/2007-201Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
PubMed ID: 27216065
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107940
Publisher's version: https://doi.org/10.1128/AAC.02548-15

Actions (login required)

Edit Item Edit Item