Therapeutic efficacy of GAR-936, a novel glycylcycline, in a rat model of experimental endocarditis

T. M. Murphy, J. M. Deitz, P. J. Petersen, S. M. Mikels, W. J. Weiss

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Abstract

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 μg/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 106 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 log10 CFU, compared to those in untreated controls, for both vancomycin-susceptible and -resistant (VanA and VanB) E. faecalis strains and >4 log10 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.

Original languageEnglish
Pages (from-to)3022-3027
Number of pages6
JournalAntimicrobial agents and chemotherapy
Volume44
Issue number11
DOIs
StatePublished - 9 Nov 2000

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