In vivo efficacy of continuous infusion versus intermittent dosing of linezolid compared to vancomycin in a methicillin-resistant Staphylococcus aureus rabbit endocarditis model.
Linezolid is the first drug issued from the oxazolidinones, a novel class of antimicrobial agents with potent activity against gram-positive pathogens. A rabbit endocarditis model was used to compare the in vivo activities of different linezolid regimens mimicking intermittent dosing of 10 mg/kg of body weight every 12 h for 5 days or continuous (constant-rate) infusion of a daily dose of 20 mg/kg (for 5 days) or 40 mg/kg (for 3 and 5 days) and the activities of intermittent dosing and continuous infusion of vancomycin (for 5 days). The in vivo activities of these regimens were tested against three strains of methicillin-resistant Staphylococcus aureus. A human-like pharmacokinetic simulation was used for linezolid in order to improve the extrapolation of the results to human therapy. All linezolid regimens significantly reduced the numbers of S. aureus cells in aortic valve vegetations compared to the numbers in the control groups. Linezolid intermittent dosing had an in vivo bacteriostatic effect. Switching from intermittent dosing to continuous infusion (at the same dose) led to in vivo bactericidal activity, with a decrease of at least 3 log(10) CFU/g of vegetation compared to the counts for the controls. After 5 days of treatment, continuous infusion of linezolid (corresponding to a daily dose of 40 mg/kg in humans) seemed to be at least as effective as vancomycin against the three strains. No resistant variant was isolated from the vegetations during any of the treatments. These data suggest that continuous infusion of linezolid could be an appropriate alternative to the use of glycopeptides for the treatment of severe methicillin-resistant S. aureus infections.
Jacqueline
Cédric
C
Laboratoire d'Antibiologie (UPRES EA-1156), Faculté de Médecine, 44035 Nantes, Cedex 01, France.
Batard
Eric
E
Perez
Lucia
L
Boutoille
David
D
Hamel
Antoine
A
Caillon
Jocelyne
J
Kergueris
Marie-France
MF
Potel
Gilles
G
Bugnon
Denis
D
D000081:Acetamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004697:Endocarditis, Bacterial / Q000188:drug therapy*; D005260:Female; D006207:Half-Life; D007262:Infusions, Intravenous; D000069349:Linezolid; D016106:Methicillin Resistance; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000472:pathogenicity; D014640:Vancomycin / Q000008:administration & dosage / Q000627:therapeutic use*
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D014640:Vancomycin; D000069349:Linezolid