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

Antimicrob Agents Chemother. 1996 Jun;40(6):1508-13. doi: 10.1128/AAC.40.6.1508.

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.

Publication types

  • Comparative Study

MeSH terms

  • Acetamides / administration & dosage
  • Acetamides / 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
  • Oxazoles / therapeutic use*
  • Oxazolidinones*
  • Staphylococcus aureus / drug effects
  • Vancomycin / therapeutic use

Substances

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