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: Jamese J Hilliard, Jeffrey Fernandez, John Melton, Mark J Macielag, Raul Goldschmidt, Karen Bush, Darren Abbanat
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 53 Issue 5 Pg. 2028-33 (May 2009) ISSN: 1098-6596 [Electronic] United States
• PMID: 19273686 (Publication Type: Journal Article)

Chemical References

• Acetamides
• Anti-Bacterial Agents
• Oxazolidinones
• RWJ-416457
• Vancomycin
• Linezolid

Topics

• Acetamides (administration & dosage, therapeutic use)
• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Disease Models, Animal
• Female
• Humans
• Linezolid
• Methicillin-Resistant Staphylococcus aureus (drug effects)
• Mice
• Oxazolidinones (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Pneumococcal Infections (drug therapy, microbiology, mortality)
• Staphylococcal Infections (drug therapy, microbiology, mortality)
• Staphylococcal Skin Infections (drug therapy, microbiology, mortality)
• Staphylococcus aureus (drug effects)
• Streptococcus pneumoniae (drug effects)
• Treatment Outcome
• Vancomycin (administration & dosage, therapeutic use)