In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections.

Abstract

The Upjohn oxazolidinones, U-100592 and U-100766, are orally bioavailable synthetic antimicrobial agents with spectra of activity against antibiotic-susceptible and -resistant gram-positive pathogens. In several mouse models of methicillin-resistant Staphylococcus aureus infection, U-100592 and U-100766 yielded oral 50% effective doses (ED50) ranging from 1.9 to 8.0 mg/kg of body weight, which compared favorably with vancomycin subcutaneous ED50 values of 1.1 to 4.4 mg/kg. Similarly, both compounds were active versus a Staphylococcus epidermidis experimental systemic infection. U-100592 and U-100766 effectively cured an Enterococcus faecalis systemic infection, with ED50 values of 1.3 and 10.0 mg/kg, and versus a vancomycin-resistant Enterococcus faecium infection in immunocompromised mice, both drugs effected cures at 12.5 and 24.0 mg/kg. Both compounds were exceptionally active in vivo against penicillin- and cephalosporin-resistant Streptococcus pneumoniae, with ED50 values ranging from 1.2 to 11.7 mg/kg in systemic infection models. In soft tissue infection models with S. aureus and E. faecalis, both compounds exhibited acceptable curative activities in the range of 11.0 to 39.0 mg/kg. U-100766 was also very active versus the Bacteroides fragilis soft tissue infection model (ED50 = 46.3 mg/kg). In combination-therapy studies, both U-100592 and U-100766 were indifferent or additive in vivo against a monomicrobic S. aureus infection in combination with other antibiotics active against gram-positive bacteria and combined as readily as vancomycin with gentamicin in the treatment of a polymicrobic S. aureus-Escherichia coli infection. U-100592 and U-100766 are potent oxazolidinones active against antibiotic-susceptible and -resistant gram-positive pathogens in experimental systemic and soft tissue infections.

• Authors: C W Ford, J C Hamel, D M Wilson, J K Moerman, D Stapert, R J Yancey Jr, D K Hutchinson, M R Barbachyn, S J Brickner
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 40 Issue 6 Pg. 1508-13 (Jun 1996) ISSN: 0066-4804 [Print] United States
• PMID: 8726028 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Acetamides
• Anti-Bacterial Agents
• Oxazoles
• Oxazolidinones
• Vancomycin
• eperezolid
• Linezolid

Topics

• Acetamides (administration & dosage, therapeutic use)
• Administration, Oral
• Animals
• Anti-Bacterial Agents (therapeutic use)
• Bacterial Infections (drug therapy)
• Drug Therapy, Combination (therapeutic use)
• Female
• Gram-Negative Bacteria (drug effects)
• Gram-Positive Bacteria (drug effects)
• Injections, Intravenous
• Injections, Subcutaneous
• Linezolid
• Methicillin Resistance
• Mice
• Microbial Sensitivity Tests
• Oxazoles (administration & dosage, therapeutic use)
• Oxazolidinones
• Staphylococcus aureus (drug effects)
• Vancomycin (therapeutic use)