Published ahead of print on June 11, 2009, doi:10.1164/rccm.200904-0611OC
© 2009 American Thoracic Society doi: 10.1164/rccm.200904-0611OC
Addition of PNU-100480 to First-Line Drugs Shortens the Time Needed to Cure Murine Tuberculosis 1 Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; 2 Pfizer Inc., Groton, Connecticut; and 3 Pfizer Inc., Kalamazoo, Michigan Correspondence and requests for reprints should be addressed to Eric L. Nuermberger, M.D., 1550 Orleans Street, Baltimore, MD 21231. E-mail: enuermb{at}jhmi.edu Rationale: We recently reported strong bactericidal activity of the oxazolidinone PNU-100480 and its ability to increase the initial bactericidal effect of various combinations of first-line tuberculosis drugs and moxifloxacin in a murine model. Objectives: To investigate whether the addition of PNU-100480 to the standard first-line regimen of rifampin, isoniazid, and pyrazinamide could shorten the duration of treatment necessary to prevent relapse after treatment discontinuation. Methods: Following aerosol infection with Mycobacterium tuberculosis H37Rv and a 13-day incubation period, control mice were treated with the first-line regimen while test mice received the same regimen with PNU-100480 or linezolid added for the first 2 or 4 months. Efficacy was assessed on the basis of quantitative cultures of lung homogenates performed monthly during treatment and 3 months after completion of 3, 4, 5, or 6 months of treatment to determine the relapse rate. Measurements and Main Results: After 2 months of treatment, mice receiving PNU-100480 in addition to the first-line regimen had lung CFU counts two orders of magnitude lower than control mice receiving the first-line regimen alone. Relapse rates after 4 months of treatment were 90, 35, and 5% when PNU-100480 was added to the first-line regimen for 0, 2, and 4 months, respectively. When the total treatment duration was 3 months, relapse rates were 85 and 35 to 45% when mice received PNU-100480 for 2 and 3 months, respectively; all control mice remained culture positive at the time of treatment completion with 17 to 72 CFU per lung. Addition of linezolid to the first-line regimen had an antagonistic effect resulting in higher CFU counts and failure to render mice culture-negative in 4 months of treatment. Conclusions: Together with previous findings, these results confirm that PNU-100480, which is now in Phase I clinical testing, has sterilizing activity in the murine model and suggest that it may be capable of shortening treatment duration for drug-susceptible as well as drug-resistant tuberculosis in humans.
Key Words: tuberculosis treatment • oxazolidinone • pharmacokinetics • linezolid • antagonism
This article has been cited by other articles:
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
