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.