Addition of PNU-100480 to first-line drugs shortens the time needed to cure murine tuberculosis.

Abstract

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.

• Authors: Kathy N Williams, Steven J Brickner, Charles K Stover, Tong Zhu, Adam Ogden, Rokeya Tasneen, Sandeep Tyagi, Jacques H Grosset, Eric L Nuermberger
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 180 Issue 4 Pg. 371-6 (Aug 15 2009) ISSN: 1535-4970 [Electronic] United States
• PMID: 19520903 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Antitubercular Agents
• Oxazolidinones
• PNU-100480
• Linezolid

Topics

• Acetamides (administration & dosage, adverse effects, pharmacokinetics)
• Animals
• Antitubercular Agents (administration & dosage, adverse effects, pharmacokinetics)
• Colony-Forming Units Assay
• Disease Models, Animal
• Drug Administration Schedule
• Drug Synergism
• Drug Therapy, Combination
• Female
• Linezolid
• Lung (pathology)
• Mice
• Mice, Inbred BALB C
• Oxazolidinones (administration & dosage, adverse effects, pharmacokinetics)
• Time Factors
• Treatment Outcome
• Tuberculosis, Pulmonary (drug therapy, pathology)