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Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria.

Liu, Y; Pertinez, H; Ortega-Muro, F; Alameda-Martin, L; Harrison, T; Davies, G; Coates, A; Hu, Y (2018) Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria. J Antimicrob Chemother, 73 (3). pp. 724-731. ISSN 1460-2091 https://doi.org/10.1093/jac/dkx467
SGUL Authors: Coates, Anthony Robert Milnes Hu, Yanmin

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Abstract

Objectives: Although high-dose rifampicin holds promise for improving tuberculosis disease control by eradication of persistent bacteria, the optimal dose of rifampicin that kills persistent bacteria and shortens the treatment duration is unknown. Methods: The Cornell mouse model was used to test the efficacy of rifampicin at elevated doses combined with isoniazid and pyrazinamide to kill actively growing and persistent bacilli and to measure relapse rate. Persistent bacteria were evaluated using Mycobacterium tuberculosis culture supernatant containing resuscitation-promoting factors. Pharmacokinetic parameters and dose-dependent activity for cultivable and persistent bacilli were determined. Results: Increasing doses of rifampicin in combination with isoniazid and pyrazinamide resulted in dose-dependent faster bacterial clearance. Evaluated both on solid media and in culture filtrate containing resuscitation-promoting factors, a regimen containing a standard dose of rifampicin at 10 mg/kg over 14 weeks failed to achieve organ sterility. In contrast, higher doses of rifampicin achieved organ sterility in a much shorter time of 8-11 weeks. Disease relapse, which occurred in 86% of mice treated with the standard regimen for 14 weeks, was completely prevented by rifampicin doses of ≥ 30 mg/kg. Conclusions: In the treatment of murine tuberculosis, a rifampicin dose of 30 mg/kg was sufficient to eradicate persistent M. tuberculosis, allowing shorter treatment duration without disease relapse.

Item Type: Article
Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record Yingjun Liu, Henry Pertinez, Fatima Ortega-Muro, Laura Alameda-Martin, Thomas Harrison, Geraint Davies, Anthony Coates, Yanmin Hu; Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria, Journal of Antimicrobial Chemotherapy, Volume 73, Issue 3, 1 March 2018, Pages 724–731 is available online at: https://doi.org/10.1093/jac/dkx467
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: J Antimicrob Chemother
ISSN: 1460-2091
Language: eng
Dates:
DateEvent
March 2018Published
12 December 2017Published Online
8 November 2017Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
MR/P011144/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 29244108
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109574
Publisher's version: https://doi.org/10.1093/jac/dkx467

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