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Antimicrobial Agents and Chemotherapy, May 2009, p. 2028-2033, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.00833-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vivo Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457{triangledown}

Jamese J. Hilliard,* Jeffrey Fernandez, John Melton, Mark J. Macielag,{dagger} Raul Goldschmidt,{ddagger} Karen Bush,# and Darren Abbanat

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, New Jersey

Received 24 June 2008/ Returned for modification 6 January 2009/ Accepted 26 February 2009

RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against antibiotic-susceptible and -resistant gram-positive pathogens. Efficacies of RWJ-416457, linezolid, and vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in murine skin and systemic infections were compared, as were efficacies against Streptococcus pneumoniae in a lower respiratory infection. In staphylococcal systemic infections, RWJ-416457 was equipotent with to twofold more potent than linezolid, with 50% effective dose values ranging from 1.5 to 5 mg/kg of body weight/day. RWJ-416457 was two- to fourfold less potent than vancomycin against MSSA but up to fourfold more potent than vancomycin against CA-MRSA. In MSSA and CA-MRSA skin infections, RWJ-416457 demonstrated an efficacy similar to that of linezolid, reducing CFU/g skin approximately 1.0 log10 at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log10 (MSSA) and 2 log10 (CA-MRSA). In the pneumococcal model, RWJ-416457 was two- to fourfold more potent than linezolid. The free-drug area under the concentration-time curves at 24 h (fAUC24) were similar for RWJ-416457 and linezolid. The half-life of RWJ-416457 was up to threefold longer than that of linezolid for all routes of administration. The fAUC24/MIC ratio, the pharmacodynamic parameter considered predictive of oxazolidinone efficacy, was approximately twofold greater for RWJ-416457 than for linezolid. Since the fAUC values were similar for both compounds, the higher fAUC/MIC ratios of RWJ-416457 appear to result from its greater in vitro potency. These results demonstrate that RWJ-416457 is a promising new oxazolidinone with efficacy in S. aureus or S. pneumoniae mouse infection models.

* Corresponding author. Mailing address: Johnson & Johnson Pharmaceutical Research and Development, 1000 Route 202, Raritan, NJ 08869. Phone: (908) 704-4871. Fax: (908) 707-3501. E-mail: jhilliar{at}its.jnj.com

{triangledown} Published ahead of print on 9 March 2009.

{dagger} Present address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Cedarbrook Corporate Center, 8 Clarke Drive, Cranbury, NJ 08512.

{ddagger} Present address: Centocor, Inc., 145 King of Prussia Road, Radnor, PA 19087.

# Present address: Department of Biology, Indiana University, Bloomington, IN 47401.

Antimicrobial Agents and Chemotherapy, May 2009, p. 2028-2033, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.00833-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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