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 experi mental endocarditis. It was compared with vancomycin against both vancomyci n-susceptible and -resistant Enterococcus faecalis and methicillin-resistan t Staphylococcus aureus. GAR-936 exhibited the lowest MICs (less than or eq ual to0.12 mug/ml) in vitro against each of the isolates tested. Endocardit is was established by placement of a catheter across the aortic valve, foll owed by intravenous injection of 10(6) CFU of bacteria 48 h later. Treatmen t with GAR-936 or vancomycin was initiated 24 to 36 h after bacterial infec tion and administered subcutaneously twice a day for 3 days at ascending do ses. GAR-936 reduced bacterial vegetation titers by >2 log(10) CFU, compare d to those in untreated controls, for both vancomycin-susceptible and -resi stant (VanA and VanB) E. faecalis strains and >4 log,, CFU for a methicilli n-resistant S. aureus isolate. The glycylcycline was more efficacious at a lower administered dose in the rat model of endocarditis than was vancomyci n. The efficacy of GAR-936 in this model was apparently not enhanced by a f actor 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.