In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections.
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.
Ford
C W
CW
Pharmacia & Upjohn Inc., Kalamazoo, Michigan 49001, USA.
Hamel
J C
JC
Wilson
D M
DM
Moerman
J K
JK
Stapert
D
D
Yancey
R J
RJ
Hutchinson
D K
DK
Barbachyn
M R
MR
Brickner
S J
SJ
D000081:Acetamides / Q000008:administration & dosage / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D004359:Drug Therapy, Combination / Q000627:therapeutic use; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D000069349:Linezolid; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D010080:Oxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D023303:Oxazolidinones; D013211:Staphylococcus aureus / Q000187:drug effects; D014640:Vancomycin / Q000627:therapeutic use
D000081:Acetamides; D000900:Anti-Bacterial Agents; D010080:Oxazoles; D023303:Oxazolidinones; D014640:Vancomycin; C098011:eperezolid; D000069349:Linezolid