Therapeutic efficacy of GAR-936, a novel glycylcycline, in a rat model of experimental endocarditis.
GAR-936, a novel glycylcycline, was investigated with a rat model of experimental endocarditis. It was compared with vancomycin against both vancomycin-susceptible and -resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus. GAR-936 exhibited the lowest MICs (</=0.12 microgram/ml) in vitro against each of the isolates tested. Endocarditis was established by placement of a catheter across the aortic valve, followed by intravenous injection of 10(6) CFU of bacteria 48 h later. Treatment with GAR-936 or vancomycin was initiated 24 to 36 h after bacterial infection and administered subcutaneously twice a day for 3 days at ascending doses. GAR-936 reduced bacterial vegetation titers by >2 log(10) CFU, compared to those in untreated controls, for both vancomycin-susceptible and -resistant (VanA and VanB) E. faecalis strains and >4 log(10) CFU for a methicillin-resistant S. aureus isolate. The glycylcycline was more efficacious at a lower administered dose in the rat model of endocarditis than was vancomycin. The efficacy of GAR-936 in this model was apparently not enhanced by a factor in rat serum, as was observed for vancomycin with a time-kill curve. The results of this study demonstrate the therapeutic potential of GAR-936 for the treatment of enterococcal and staphylococcal infections and warrant further investigation.
Murphy
T M
TM
Infectious Disease Research Section, Antimicrobial Chemotherapy, Wyeth-Ayerst Research, Pearl River, New York 10965, USA. murphytm@war.wyeth.com
Deitz
J M
JM
Petersen
P J
PJ
Mikels
S M
SM
Weiss
W J
WJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000378:metabolism; D013293:Enterococcus faecalis / Q000187:drug effects; D008297:Male; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D000078304:Tigecycline
D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline