Oral linezolid as an adequate therapy of experimental endocarditis by methicillin-resistant Staphylococcus aureus

Abstract number: 1134_04_94

Tsaganos T., Sabracos L., Adamis T., Skiadas I., Mouktaroudi M., Giamarellou H., Giamarellos-Bourboulis E.J.

Objective:  

Linezolid is a new antimicrobial agent with excellent oral bioavailability and well documented in vitro activity against gram positive cocci when resistance to other antistaphylococcal agents is present. Little is known on its potential use in endocarditis. The efficacy of oral linezolid on experimental endocarditis by MRSA was studied.

Methods:  

Left sided endocarditis was induced by the insertion of a catheter in the aortic valves of 19 white male rabbits. Twenty-four hours after catheter insertion, animals were challenged by a 7log₁₀ inoculum of an MRSA clinical isolate, with MIC of linezolid equal to 4 mg/ml. Eleven animals were administered linezolid at a dose of 75mg/kg q8h per os for five days. Eight served as controls. Blood samples were drawn 16, 32, 48, 72, 96 and 120h post therapy, immediately before drug administration, for the determination of trough levels. At the end of treatment animals were sacrificed and valves were quantitavely cultured. Concentration of linezolid was determined by an HPLC method with UV detection.

Results:  

Mean ± survival was 133.27 ± 10.23 hours and 66.00 ± 13.75 hours animals treated with linezolid and controls respectively. Mean log₁₀ (±SE) bacterial counts of valves was 3.9 ± 0.86 CFU/g and 7.93 ± 1.21 CFU/g (p 0.019) for animals treated with linezolid and controls respectively. Mean ± SE trough linezolid concentrations were 5.22 ± 1.96 mg/l at 16 h, 5.52 ± 1.57 mg/l at 32 h, 8.29 ± 1.62 mg/ml at 48 h, 17.94 ±8.65 mg/l at 72 h, 27.58 ± 8.67 mg/l at 96 h and 8.78 ±1.36 mg/l at the end of therapy.

Conclusion:  

Therapy of experimental endocarditis by MRSA with oral linezolid results in increased survival and in lower bacterial counts of valve vegetations. Trough blood concentrations of linezolid are above the MIC of the MRSA isolate even reaching 7 times the MIC at the 4th day of therapy. The results are promising for the therapy of serious staphylococcal infections when resistance to other antistaphylococcal agents is present.