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Antimicrobial Agents and Chemotherapy, January 2005, p. 45-51, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.45-51.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Synergistic Activities of Linezolid Combined with Subinhibitory Concentrations of Imipenem against Methicillin-Resistant Staphylococcus aureus

Cédric Jacqueline, Dominique Navas, Eric Batard, Anne-Françoise Miegeville, Virginie Le Mabecque, Marie-France Kergueris, Denis Bugnon, Gilles Potel, and Jocelyne Caillon*

Laboratoire d'Antibiologie (UPRES EA 3826), UER de Médecine, Nantes, France

Received 26 July 2004/ Returned for modification 3 September 2004/ Accepted 27 September 2004

Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.

* Corresponding author. Mailing address: Laboratoire d'Antibiologie (UPRES EA 3826), UER de Médecine, 1 rue Gaston Veil, 44035 Nantes, Cedex 01, France. Phone and Fax: (33) 240-41-2854. E-mail: jcaillon{at}sante.univ-nantes.fr.

Antimicrobial Agents and Chemotherapy, January 2005, p. 45-51, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.45-51.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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