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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AI058993-01
Application #
6757621
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Laughon, Barbara E
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$116,910
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ahmad, Zahoor; Tyagi, Sandeep; Minkowski, Austin et al. (2013) Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis. Am J Respir Crit Care Med 188:97-102
Rosenthal, Ian M; Tasneen, Rokeya; Peloquin, Charles A et al. (2012) Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis. Antimicrob Agents Chemother 56:4331-40
Zhang, Tianyu; Zhang, Ming; Rosenthal, Ian M et al. (2009) Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection. Am J Respir Crit Care Med 180:1151-7
Nuermberger, Eric; Mitchison, Denis A (2009) Once-weekly treatment of tuberculosis with the diarylquinoline R207910: a real possibility. Am J Respir Crit Care Med 179:2-3
Tasneen, Rokeya; Tyagi, Sandeep; Williams, Kathy et al. (2008) Enhanced bactericidal activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of tuberculosis. Antimicrob Agents Chemother 52:3664-8
Nuermberger, Eric; Tyagi, Sandeep; Tasneen, Rokeya et al. (2008) Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother 52:1522-4
Rosenthal, Ian M; Zhang, Ming; Williams, Kathy N et al. (2007) Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. PLoS Med 4:e344
Rosenthal, Ian M; Williams, Kathy; Tyagi, Sandeep et al. (2006) Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. Am J Respir Crit Care Med 174:94-101
Nuermberger, Eric; Rosenthal, Ian; Tyagi, Sandeep et al. (2006) Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother 50:2621-5
Tyagi, Sandeep; Nuermberger, E; Yoshimatsu, T et al. (2005) Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents Chemother 49:2289-93

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