Affiliation:
1. Institut National de la Santé et de la Recherche Médicale, EMI-U 9933
2. Université Paris VII, Paris, France
3. Service de Pharmacie Clinique et des Biomatériaux
4. Service de Biophysique et de Médecine Nucléaire
5. Service de Microbiologie, Hôpital Bichat
Abstract
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 μg/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 μg/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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
61 articles.
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