The purpose of this study was to determine the penetration of minocycline and vancomycin into cardiac vegetations and to determine their efficacy in a rabbit model of endocarditis caused by oxacillin-resistant Staphylococcus aureus. Animals were randomized into three groups: control (no antibiotic), minocycline (6 mg/kg given intravenously every 8 h), and vancomycin (50 mg/kg given intravenously every 8 h). Penetration of the antibiotics into aortic valve vegetations was determined by using the tissue/serum area under the concentration-time curve ratio. The reductions in the bacterial density of the vegetations caused by both vancomycin (4.8 +/- 1.2 CFU/g) and minocycline (5.3 +/- 1.6 CFU/g) were significantly different from that of controls (8.7 +/- 1.8 CFU/g). Although the penetration of minocycline was twice that of vancomycin, they were equally effective in reducing the bacterial density of the vegetations, since the concentrations of both agents in tissue remained above their MICs for oxacillin-resistant S. aureus. For organisms for which the MICs are higher, however, these penetration differences may result in treatment differences.