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 g/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.Endocarditis has many underlying causes, including complications from intravenous drug use, prosthetic valves, and nosocomial bacteremia, leading to extended hospital stays and high mortality rates (19). Streptococci, staphylococci, and enterococci are considered the three leading causes of infective endocarditis (3, 6). It is recognized as a difficult infection to treat and presents a therapeutic challenge, especially when caused by methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. (3).Treatment of resistant strains is limited, involving removal of the vegetation or associated device, constant infusion of effective antibiotics, and synergistic combinations of two or more antibacterial agents (8). Several investigational antibiotics may prove efficacious in the treatment of infective endocarditis. The fluoroquinolones, everninomicin, modified glycopeptides (LY 333328), linezolid, and quinupristin-dalfopristin have demonstrated good in vitro activities, and some are under investigation in animal models of infection (4,

A series of novel aminomethyl tetrahydrofuranyl (THF)-1β-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight against Escherichia coli and 0.9 mg/kg against Staphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs withl-amino acids demonstrated improved efficacy after oral administration, while the d forms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of <1 mg/kg against infections caused by S. aureus, E. coli,Enterobacter cloacae, or penicillin-susceptibleStreptococcus pneumoniae were obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious against Morganella morganii,Serratia marcescens, penicillin-resistant S. pneumoniae, extended-spectrum β-lactamase-producingKlebsiella pneumoniae, and E. coli infections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to >32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.