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

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.

Investigation of Elimination Rate, Persistent Subpopulation Removal, and Relapse Rates of Mycobacterium tuberculosis by Using Combinations of First-Line Drugs in a Modified Cornell Mouse Model.

Currently, the most effective tuberculosis control method involves case finding and 6 months of chemotherapy. There is a need to improve our understanding about drug interactions, combination activities, and the ability to remove persistent bacteria using the current regimens, particularly in relation to relapse. We aimed to investigate the therapeutic effects of three main components, rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA), in current drug regimens using a modified version of the Cornell mouse model.

High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo.

Although high-dose rifampicin holds promise for improving tuberculosis control by potentially shortening treatment duration, these effects attributed to eradication of persistent bacteria are unclear. The presence of persistent Mycobacterium tuberculosis was examined using resuscitation promoting factors (RPFs) in both in vitro hypoxia and in vivo murine tuberculosis models before and after treatment with incremental doses of rifampicin. Pharmacokinetic parameters and dose-dependent profile of rifampicin in the murine model were determined.