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Antimicrobial Agents and Chemotherapy, January 2003, p. 216-222, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.216-222.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Activity and Diffusion of Tigecycline (GAR-936) in Experimental Enterococcal Endocarditis

Agnès Lefort,1,2 Matthieu Lafaurie,1,2 Laurent Massias,3 Yolande Petegnief,2,4 Azzam Saleh-Mghir,1,2 Claudette Muller-Serieys,5 Dominique Le Guludec,2,4 and Bruno Fantin1,2*

Service de Pharmacie Clinique et des Biomatériaux,3 Service de Biophysique et de Médecine Nucléaire,4 Service de Microbiologie, Hôpital Bichat,5 Institut National de la Santé et de la Recherche Médicale, EMI-U 9933,1 Université Paris VII, Paris, France2

Received 21 March 2002/ Returned for modification 17 August 2002/ Accepted 6 October 2002

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 [14C]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.

* Corresponding author. Mailing address: Service de Médecine Interne, Hôpital Beaujon, 100, boulevard du Général Leclerc, 92118 Clichy Cedex, France. Phone: (33) (1) 40 87 58 90. Fax: (33) (1) 40 87 10 81. E-mail: bruno.fantin{at}bjn.ap-hop-paris.fr.

Antimicrobial Agents and Chemotherapy, January 2003, p. 216-222, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.216-222.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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