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: Agnès Lefort, Matthieu Lafaurie, Laurent Massias, Yolande Petegnief, Azzam Saleh-Mghir, Claudette Muller-Serieys, Dominique Le Guludec, Bruno Fantin
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 47 Issue 1 Pg. 216-22 (Jan 2003) ISSN: 0066-4804 [Print] United States
• PMID: 12499194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tigecycline
• Minocycline

Topics

• Animals
• Area Under Curve
• Autoradiography
• Endocarditis (drug therapy, metabolism)
• Enterococcus faecalis (drug effects, genetics)
• Enterococcus faecium (drug effects, genetics)
• Half-Life
• Metabolic Clearance Rate
• Microbial Sensitivity Tests
• Minocycline (analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• Rabbits
• Tigecycline
• Tissue Distribution