title: In vitro and in vivo synergistic activities of linezolid combined with subinhibitory concentrations of imipenem against methicillin-resistant Staphylococcus aureus.
abstract: 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.
authors.affiliation: Laboratoire d'Antibiologie, UER de Médecine, 1 rue Gaston Veil, 44035 Nantes, Cedex 01, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Jacqueline
authors.forename: Dominique
authors.initials: D
authors.lastname: Navas
authors.forename: Eric
authors.initials: E
authors.lastname: Batard
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Miegeville
authors.forename: Virginie
authors.initials: V
authors.lastname: Le Mabecque
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Kergueris
authors.forename: Denis
authors.initials: D
authors.lastname: Bugnon
authors.forename: Gilles
authors.initials: G
authors.lastname: Potel
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Caillon
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D015169:Colony Count, Microbial; D004357:Drug Synergism; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D015378:Imipenem / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000069349:Linezolid; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests / Q000379:methods; D023303:Oxazolidinones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D015378:Imipenem; D000069349:Linezolid