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Antimicrobial Agents and Chemotherapy, January 1999, p. 115-120, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Activity and Diffusion of LY333328 in Experimental Endocarditis Due to Vancomycin-Resistant Enterococcus faecalis

Azzam Saleh-Mghir,1 Agnès Lefort,1 Yolande Petegnief,2 Sophie Dautrey,3 Jean-Marie Vallois,1 Dominique Le Guludec,2 Claude Carbon,1 and Bruno Fantin1,*

Institut National pour la Santé et la Recherche Médicale, CRI 4 U 002D, and Université Paris 7,1 Service de Biophysique et de Médecine Nucléaire, Hôpital Bichat, and Université Paris 7,2 and Service de Pharmacie Clinique et des Biomatériaux, Hôpital Bichat,3 Paris, France

Received 15 April 1998/Returned for modification 22 July 1998/Accepted 6 October 1998

The activity of LY333328 against Enterococcus faecalis JH2-2, which is susceptible to glycopeptides, and against its transconjugants E. faecalis BM4281 and BM4316, with VanB and VanA phenotypes, respectively, was investigated. LY333328 was active in vitro against the three strains, for which MICs were 2 µg/ml on agar and 0.25 µg/ml in broth. LY333328 was bactericidal in broth against E. faecalis JH2-2 and BM4281 at a concentration of 8 µg/ml and against BM4316 at a concentration of 30 µg/ml. The protein binding of LY333328 to rabbit serum was >99%, and the bactericidal activity of LY333328 in broth was reduced when it was tested in the presence of 90% rabbit serum. Autoradiographic studies performed in rabbits with enterococcal endocarditis showed that 14[C]LY333328 was distributed heterogeneously throughout cardiac vegetations. In rabbits with aortic endocarditis, a regimen of 20 mg of LY333328 per kg of body weight administered intramuscularly twice a day for 5 days after a loading dose of 40 mg/kg was active against the three strains in vivo (P < 0.01), whereas vancomycin was not active against the VanB-type strain and teicoplanin was not active against the VanA-type strain. We conclude that the activity of LY333328 is not significantly modified by acquired resistance to glycopeptides in E. faecalis either in vitro or in experimental endocarditis.

* Corresponding author. Mailing address: Unité de Médecine Interne, 100 boulevard du Général Leclerc, 92118 Clichy Cedex 18, France. Phone: 33 1 40 87 58 90. Fax: 33 1 40 87 54 95. E-mail: bruno.fantin{at}bjn.ap-hop-paris.fr.

Antimicrobial Agents and Chemotherapy, January 1999, p. 115-120, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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