title: Activity and diffusion of tigecycline (GAR-936) in experimental enterococcal endocarditis.
abstract: The activity of tigecycline (GAR-936), a novel glycylcycline, was investigated in vitro and in experimental endocarditis due to the susceptible Enterococcus faecalis JH2-2 strain, its VanA type transconjugant BM4316, and a clinical VanA type strain, E. faecium HB217 resistant to tetracycline. MICs of GAR-936 were 0.06 micro g/ml for the three strains. In vitro pharmacodynamic studies demonstrated a bacteriostatic effect of GAR-936 that was not enhanced by increasing concentrations to more than 1 micro g/ml and a postantibiotic effect ranging from 1 to 4.5 h for concentrations of 1- to 20-fold the MIC. Intravenous injection of [(14)C]GAR-936 to five rabbits with enterococcal endocarditis sacrificed 30 min, 4 h, or 12 h after the end of the infusion evidenced a lower clearance of GAR-936 from aortic vegetations than from serum and a homogeneous diffusion of GAR-936 into the vegetations. In rabbits with endocarditis, GAR-936 (14 mg/kg of body weight twice a day [b.i.d.]) given intravenously for 5 days was bacteriostatic against both strains of E. faecalis. Against E. faecium HB217, bacterial counts in vegetations significantly decreased during therapy (P < 0.01), and the effect was similar with GAR-936 at 14 mg/kg b.i.d., 14 mg/kg once a day (o.d.), and 7 mg/kg o.d., which provided concentrations in serum constantly above the MIC. Mean serum elimination half-life ranged from 3.3 to 3.6 h. No GAR-936-resistant mutants were selected in vivo with any regimen. We concluded that the combination of prolonged half-life, significant postantibiotic effect, and good and homogeneous diffusion into the vegetations may account for the in vivo activity of GAR-936 against enterococci susceptible or resistant to glycopeptides and tetracyclines, even when using a o.d. regimen in rabbits.
authors.affiliation: Hôpital Bichat, Institut National de la Santé et de la Recherche Médicale, EMI-U 9933, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Lefort
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lafaurie
authors.forename: Laurent
authors.initials: L
authors.lastname: Massias
authors.forename: Yolande
authors.initials: Y
authors.lastname: Petegnief
authors.forename: Azzam
authors.initials: A
authors.lastname: Saleh-Mghir
authors.forename: Claudette
authors.initials: C
authors.lastname: Muller-Serieys
authors.forename: Dominique
authors.initials: D
authors.lastname: Le Guludec
authors.forename: Bruno
authors.initials: B
authors.lastname: Fantin
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001345:Autoradiography; D004696:Endocarditis / Q000188:drug therapy / Q000378:metabolism*; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000235:genetics; D016984:Enterococcus faecium / Q000187:drug effects* / Q000235:genetics; D006207:Half-Life; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D000078304:Tigecycline; D014018:Tissue Distribution
chemical_list: D000078304:Tigecycline; D008911:Minocycline