Background: Tuberculosis (TB) is a leading cause of mortality worldwide. Efforts to control TB are hampered by the lengthy, cumbersome treatment regimens for active TB, latent TB infection (LTBI), and infection with multidrug-resistant TB (MDR-TB). The new antibiotic moxifloxacin (MXF) has potent activity against Mycobacterium tuberculosis (including MDR-TB) in vitro and in experimental murine models of TB, suggesting great potential to improve current therapy of TB. Objectives and Methods: The objectives of this K08 proposal are four-fold. Objective I is to use a murine model simulating active TB in humans to define the potential of MXF-containing regimens to shorten the duration of therapy needed to cure TB or to permit more intermittent drug administration. Mice will be treated for varying durations and dosing frequencies with combinations of first-line agents and MXF. Outcomes will include CFU counts and relapse rates after therapy. Regimens that effectively sterilize mouse lungs in < 4 months or are effective with once-weekly or more intermittent administration will be sought. Objective 2 is to improve upon a murine model of LTBI using strategies to increase TB-specific immunity and to employ it to develop new MXF-containing regimens for the treatment of LTBI, including LTBI with MDR-TB. Mice vaccinated with M. bovis BCG or another vaccine will be infected with a low dose of M. tuberculosis. After immune control of infection, treatment with daily and intermittent regimens containing MXF and other first-line or experimental agents will be given. Test regimens will be compared to standard regimens for LTBI for their ability to sterilize mouse lungs. Objective 3 is to utilize an in vitro pharmacodynamic (PD) system to determine basic PD parameters for first-line anti-TB agents and MXF that correlate with bactericidal activity, post-antibiotic effects and selection of drug-resistant mutants. Actively growing M. tuberculosis will be exposed to MXF and first-line anti-TB drugs using a flow-controlled methodology that can simulate human pharmacokinetics or give fractionated doses. Outcomes will include change in CFU counts, delay in re-growth after drug exposure and prevention of resistant mutant selection. Relevance: Results of these studies will help to define optimal treatment regimens for TB that can be used to design new clinical trials or, in some cases, directly applied to clinical practice.
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