title: In vivo activity of the pyrrolopyrazolyl-substituted oxazolidinone RWJ-416457.
abstract: 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 log(10) at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log(10) (MSSA) and 2 log(10) (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 (fAUC(24)) 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 fAUC(24)/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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, 1000 Route 202, Raritan, NJ 08869, USA. jhilliar@its.jnj.com
authors.forename: Jamese J
authors.initials: JJ
authors.lastname: Hilliard
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fernandez
authors.forename: John
authors.initials: J
authors.lastname: Melton
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Macielag
authors.forename: Raul
authors.initials: R
authors.lastname: Goldschmidt
authors.forename: Karen
authors.initials: K
authors.lastname: Bush
authors.forename: Darren
authors.initials: D
authors.lastname: Abbanat
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D016896:Treatment Outcome; D014640:Vancomycin / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; C518323:RWJ-416457; D014640:Vancomycin; D000069349:Linezolid