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Antimicrobial Agents and Chemotherapy, April 2009, p. 1314-1319, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01182-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Promising Antituberculosis Activity of the Oxazolidinone PNU-100480 Relative to That of Linezolid in a Murine Model{triangledown}

K. N. Williams,1 C. K. Stover,2 T. Zhu,3 R. Tasneen,1 S. Tyagi,1 J. H. Grosset,1 and E. Nuermberger1*

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland,1 Pfizer Inc., Kalamazoo, Michigan 49009,2 Pfizer Inc., Groton, Connecticut 063403

Received 4 September 2008/ Returned for modification 29 September 2008/ Accepted 5 December 2008

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-log10-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.

* Corresponding author. Mailing address: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD 21231. Phone: (410) 502-0580. Fax: (410) 614-8173. E-mail: enuermb{at}jhmi.edu

{triangledown} Published ahead of print on 15 December 2008.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1314-1319, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01182-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Williams, K. N., Brickner, S. J., Stover, C. K., Zhu, T., Ogden, A., Tasneen, R., Tyagi, S., Grosset, J. H., Nuermberger, E. L. (2009). Addition of PNU-100480 to First-Line Drugs Shortens the Time Needed to Cure Murine Tuberculosis. Am. J. Respir. Crit. Care Med. 180: 371-376 [Abstract] [Full Text]  
  • Dorman, S. E., Johnson, J. L., Goldberg, S., Muzanye, G., Padayatchi, N., Bozeman, L., Heilig, C. M., Bernardo, J., Choudhri, S., Grosset, J. H., Guy, E., Guyadeen, P., Leus, M. C., Maltas, G., Menzies, D., Nuermberger, E. L., Villarino, M., Vernon, A., Chaisson, R. E., the Tuberculosis Trials Consortium, (2009). Substitution of Moxifloxacin for Isoniazid during Intensive Phase Treatment of Pulmonary Tuberculosis. Am. J. Respir. Crit. Care Med. 180: 273-280 [Abstract] [Full Text]  


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