title: 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.
authors.affiliation: Department of Medicine, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Williams
authors.forename: C K
authors.initials: CK
authors.lastname: Stover
authors.forename: T
authors.initials: T
authors.lastname: Zhu
authors.forename: R
authors.initials: R
authors.lastname: Tasneen
authors.forename: S
authors.initials: S
authors.lastname: Tyagi
authors.forename: J H
authors.initials: JH
authors.lastname: Grosset
authors.forename: E
authors.initials: E
authors.lastname: Nuermberger
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D000069349:Linezolid; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D023303:Oxazolidinones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; D000069349:Linezolid