This Article Full Text (PDF) Other Versions of this Article: AAC.00776-07v1 52/1/244    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Griffith, D. C. Articles by Dudley, M. N. Search for Related Content PubMed PubMed Citation Articles by Griffith, D. C. Articles by Dudley, M. N.

 Previous Article  |  Next Article 

Antimicrob. Agents Chemother. doi:10.1128/AAC.00776-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Pharmacodynamics of RWJ-54428 against Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecalis in the Neutropenic Mouse Thigh Infection Model

Microcide Pharmaceuticals, Inc. Mountain View, CA 94043

^* To whom correspondence should be addressed. Email: dgriffith{at}mpexpharma.com.

	Abstract

RWJ-54428 (also known as MC-02,479) is a new cephalosporin with promising activity against gram-positive bacteria. The pharmacodynamics of RWJ-54428 were studied in a neutropenic mouse thigh infection model against S. aureus, S. pneumoniae, and E. faecalis. The RWJ-54428 MICs ranged between 0.25 and 1 mg/L. Mice with ca. 10⁶ CFU/thigh at initiation of therapy were treated with intraperitoneal doses of the RWJ-54428 at doses from 3 – 1200 mg/kg/day (in 2, 3, 4, 6 or 12 divided doses) for 24h. Maximal reduction in bacterial counts in thigh tissues at 24h for methicillin-resistant S. aureus (MRSA), penicillin-resistant S. pneumoniae (PRSP), and E. faecalis strains were -2.8, -3.8, and -1.7 log₁₀ cfu/thigh, respectively. The percent of 24h that unbound serum RWJ-54428 concentrations exceeded the MIC (fT_>MIC) was the PK-PD parameter that best described the efficacy of RWJ-54428. The fT_>MIC for a bacteriostatic effect (no net change in CFU/thigh over 24h) ranged from 14–20% for staphylococci and streptococci; for maximal reductions in CFU/thigh, the fT_>MIC ranged from 22–36% in these strains. For E. faecalis, the ranges of fT_>MIC for a static and maximal effect were 30 – 46 and 55 - 60, respectively. These data show RWJ-54428 results in marked antibacterial effects in vivo, with PK-PD parameters for efficacy comparable to penicillins and carbapenems active against staphylococci and pneumococci.