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JAC Advance Access published online on August 18, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh381
© 2004 by The British Society for Antimicrobial Chemotherapy
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Received March 24, 2004
Revised June 18, 2004
Accepted June 29, 2004

Original article

Comparison of in vivo intrinsic activity of cefepime and imipenem in a Pseudomonas aeruginosa rabbit endocarditis model: effect of combination with tobramycin simulating human serum pharmacokinetics

Dominique Navas 1, Jocelyne Caillon 1, Christele Gras-Le Guen 1, Cédric Jacqueline 1, Marie-France Kergueris 1, Denis Bugnon 1, Gilles Potel 1*

1 Laboratoire d'Antibiologie (UPRES EA-1156), UER de Médecine, 1 rue Gaston Veil, 44035 Nantes Cedex 01, France

* To whom correspondence should be addressed. E-mail: gpotel{at}sante.univ-nantes.fr.


  Abstract

Objectives: The purpose of this experimental study was first to compare the in vivo intrinsic activity of imipenem and cefepime administered as a continuous infusion and to determine their lowest effective serum steady-state concentration (LESSC). Secondly, we studied the effect of combining therapy with tobramycin.

Methods: In a Pseudomonas aeruginosa (ATCC 27853) rabbit endocarditis model, {beta}-lactam antibiotics were administered by continuous infusion over a 24 h treatment period at different doses until the LESSC was reached, i.e. able to achieve a 2-log drop of cfu/g of vegetations versus untreated animals. The effect of adding tobramycin (3 mg/kg once daily) was then studied.

Results: The LESSC was between 3x and 4x MIC of cefepime for P. aeruginosa and about 0.25xMIC of imipenem. Combination of tobramycin with each of the two {beta}-lactams did not result in any further significant killing.

Conclusion: The optimal Css/MIC ratio might differ from one molecule to another. The LESSC of imipenem is lower than that of cefepime, giving a better intrinsic activity in vivo, despite a higher MIC in vitro.

Keywords: continuous infusion; lowest effective serum concentration; amimal models.
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