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

Kathy N. Williams, Steven J. Brickner, Charles K. Stover, Tong Zhu, Adam Ogden, Rokeya Tasneen, Sandeep Tyagi, Jacques H. Grosset, Eric L. Nuermberger

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)371-376
Number of pages6
JournalAmerican journal of respiratory and critical care medicine
Volume180
Issue number4
DOIs
StatePublished - Aug 15 2009

Keywords

  • Antagonism
  • Linezolid
  • Oxazolidinone
  • Pharmacokinetics
  • Tuberculosis treatment

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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