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Promising antituberculosis activity of the oxazolidinone PNU-100480 relative to that of linezolid in a murine model.

Abstract
Oxazolidinone antibiotics have activity against Mycobacterium tuberculosis. Linezolid, the only marketed oxazolidinone, has been used off-label in combination regimens to treat multidrug-resistant tuberculosis, but its precise contribution to the efficacy of such combinations is unclear. Another oxazolidinone, PNU-100480, has been demonstrated to have more potent activity in vitro and in a murine model of tuberculosis. In this study, we compared the pharmacokinetics and the antituberculosis activities of these two oxazolidinones over a range of doses and found that linezolid has limited activity at clinically relevant doses in the murine model compared to that of PNU-100480, which has potent bactericidal activity, even at lower drug exposures. These findings were unexpected, given the similar in vitro activities of PNU-100480, its major metabolites, and linezolid. Moreover, the incorporation of PNU-100480 dramatically improved the bactericidal activities of regimens containing current first-line antituberculosis drugs and moxifloxacin. For example, the addition of PNU-100480 (100 mg/kg of body weight/day) to the standard daily regimen of rifampin (rifampicin), isoniazid, and pyrazinamide resulted in an additional 2.0-log(10)-unit reduction in lung CFU counts during the first 2 months of treatment. The combination of PNU-100480, moxifloxacin, and pyrazinamide, which does not contain either rifampin or isoniazid, was also more active than rifampin, isoniazid, and pyrazinamide. These results suggest that PNU-100480 may have the potential to significantly shorten the duration of therapy for drug-susceptible as well as multidrug-resistant tuberculosis.
AuthorsK N Williams, C K Stover, T Zhu, R Tasneen, S Tyagi, J H Grosset, E Nuermberger
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 53 Issue 4 Pg. 1314-9 (Apr 2009) ISSN: 1098-6596 [Electronic] United States
PMID19075058 (Publication Type: Journal Article)
Chemical References
  • Acetamides
  • Antitubercular Agents
  • Oxazolidinones
  • Linezolid
Topics
  • Acetamides (pharmacokinetics, pharmacology, therapeutic use)
  • Animals
  • Antitubercular Agents (pharmacokinetics, pharmacology, therapeutic use)
  • Colony Count, Microbial
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Female
  • Linezolid
  • Lung (microbiology)
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis (drug effects)
  • Oxazolidinones (pharmacokinetics, pharmacology, therapeutic use)
  • Tuberculosis (drug therapy, microbiology)

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