Defining Moxifloxacin as a First-line TB Drug

Summary

Principal Investigator: Eric Nuermberger
Abstract: 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.
Funding Period: 2004-06-01 - 2010-05-31
more information: NIH RePORT

Top Publications

  1. pmc Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis
    Eric Nuermberger
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Antimicrob Agents Chemother 50:2621-5. 2006
  2. pmc Potent twice-weekly rifapentine-containing regimens in murine tuberculosis
    Ian M Rosenthal
    Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Am J Respir Crit Care Med 174:94-101. 2006
  3. pmc Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model
    Ian M Rosenthal
    Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
    PLoS Med 4:e344. 2007
  4. pmc Enhanced bactericidal activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of tuberculosis
    Rokeya Tasneen
    Center for Tuberculosis Research, Johns Hopkins University, 1550 Orleans Street, Baltimore, MD 21231 1002, USA
    Antimicrob Agents Chemother 52:3664-8. 2008
  5. pmc Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and pyrazinamide in a murine model of tuberculosis
    Eric Nuermberger
    Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA
    Antimicrob Agents Chemother 52:1522-4. 2008
  6. pmc Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection
    Tianyu Zhang
    Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Am J Respir Crit Care Med 180:1151-7. 2009
  7. pmc Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis
    Ian M Rosenthal
    Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Antimicrob Agents Chemother 56:4331-40. 2012
  8. pmc Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis
    Zahoor Ahmad
    Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, India
    Am J Respir Crit Care Med 188:97-102. 2013

Detail Information

Publications8

  1. pmc Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis
    Eric Nuermberger
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Antimicrob Agents Chemother 50:2621-5. 2006
    ....
  2. pmc Potent twice-weekly rifapentine-containing regimens in murine tuberculosis
    Ian M Rosenthal
    Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Am J Respir Crit Care Med 174:94-101. 2006
    ..Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin...
  3. pmc Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model
    Ian M Rosenthal
    Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
    PLoS Med 4:e344. 2007
    ..Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens...
  4. pmc Enhanced bactericidal activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of tuberculosis
    Rokeya Tasneen
    Center for Tuberculosis Research, Johns Hopkins University, 1550 Orleans Street, Baltimore, MD 21231 1002, USA
    Antimicrob Agents Chemother 52:3664-8. 2008
    ....
  5. pmc Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and pyrazinamide in a murine model of tuberculosis
    Eric Nuermberger
    Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA
    Antimicrob Agents Chemother 52:1522-4. 2008
    ..If applicable to humans, regimens containing this combination may radically shorten the treatment of multidrug-resistant tuberculosis...
  6. pmc Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection
    Tianyu Zhang
    Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Am J Respir Crit Care Med 180:1151-7. 2009
    ....
  7. pmc Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis
    Ian M Rosenthal
    Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Antimicrob Agents Chemother 56:4331-40. 2012
    ..tuberculosis infection may better represent the pathology of human tuberculosis...
  8. pmc Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis
    Zahoor Ahmad
    Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, India
    Am J Respir Crit Care Med 188:97-102. 2013
    ..Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown...