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JAC Advance Access published online on January 25, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm505
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Effects of EDP-420 on penicillin-resistant and quinolone- and penicillin-resistant pneumococci in the rabbit meningitis model

Armin Stucki1, Peter Gerber2, Fernando Acosta3, Marianne Cottagnoud3, Philippe Cottagnoud1,*, Lijiang Jiang4, Phong Nguyen4, Derek Wachtel4, Guoqiang Wang4 and Ly T. Phan4

1 Department of Internal Medicine, Inselspital, Bern, Switzerland 2 Clinic of Pneumology, Inselspital, Bern, Switzerland 3 Clinic of Internal Medicine, Spital Bern-Ziegler, Bern, Switzerland 4 Enanta Pharmaceuticals, Inc., Watertown, MA, USA

Received 12 July 2007; returned 20 November 2007; revised 23 September 2007; accepted 29 November 2007

* Corresponding author. Tel: +41-31-632-34-72; Fax: +41-31-632-38-47; E-mail: pcottagn{at}insel.ch

Objectives: To test the efficacy of EDP-420, a new ketolide, in experimental pneumococcal meningitis and to determine its penetration into the CSF.

Methods: The experimental rabbit model was used in this study and EDP-420 was tested against a penicillin-resistant and a penicillin- and quinolone-resistant mutant. EDP-420 was also tested against both strains in time-killing assays over 8 h in vitro.

Results: In experimental meningitis, EDP-420 produced a bactericidal activity comparable to the standard regimen based on a combination of vancomycin with ceftriaxone against a penicillin-resistant Streptococcus pneumoniae and a penicillin- and quinolone-resistant S. pneumoniae isolate. The penetration of EDP-420 into inflamed meninges was 38% after an iv injection of 10 mg/kg. The bactericidal activity of EDP-420 was also confirmed in in vitro time-killing assays.

Conclusions: EDP-420 is an efficacious alternative treatment in pneumococcal meningitis, especially when resistant strains are suspected.

Key Words: pneumococcal meningitis , ketolide , resistance


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