To truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis.
As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments.
In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid.
On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic.
Relapse results were inconclusive due to the low rate of relapse in all test groups.
In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment.
Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated.
The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone.
2011-11-14
Eng.
Antimicrobial agents and chemotherapy
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2011 Dec;55(12):5485-92
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