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.