Efficacy of linezolid in treatment of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus

Abstract

The efficacies of orally (p.o.) dosed linezolid and intravenously (i.v.) dosed vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in rabbits with experimental aortic-valve endocarditis were investigated. After endocarditis was established with a recent clinical MRSA isolate, rabbits were dosed for 5 days with linezolid (p.o., three times a day) at either 25, 50, or 75 mg/kg of body weight or vancomycin (i.v., twice a day) at 25 mg/kg. The 25-mg/kg linezolid group had a high mortality rate and bacterial counts in the valve vegetations that were not different from those of the controls. Linezolid dosed p.o. at 50 and 75 mg/kg and i.v. vancomycin produced statistically significant reductions in bacterial counts compared to those of the untreated controls. The reduced bacterial counts and culture-negative valve rates for the animals treated with linezolid at 75 mg/kg were similar to those for the vancomycin-treated animals. Concentrations of linezolid in plasma were determined at several points in the dosing regimen. These results suggest that the efficacy of linezolid in this infection model is related to trough levels in plasma that remain above the MIC for this microorganism. At the ineffective dose of linezolid (25 mg/kg) the concentration at sacrifice was 0.045 times the MIC, whereas the concentrations of linezolid in plasma in the 50- and 75-mg/kg groups were 2 and 5 times the MIC at sacrifice, respectively. The results from this experimental model suggest that the oxazolidinone linezolid may be effective for the treatment of serious staphylococcal infections when resistance to other antimicrobials is present.

FIG. 1

Bacterial vegetation counts versus trough (day 5) linezolid concentrations in plasma. The trough linezolid concentrations in plasma and valve vegetation bacterial counts were determined after 5 days of treatment. The symbols represent animals treated with linezolid in doses of 25 mg/kg (circles), 50 mg/kg (triangles), and 75 mg/kg (squares). The closed symbols represent culture-positive vegetations, and the open symbols represent culture-negative valvular vegetations (bacterial counts below the limit of detection [LOD]). The linezolid MIC for this strain of MRSA is 2 μg/ml, and the LOD is 2.9 to 3.2 log₁₀ CFU/g.