Optimal treatment strategies for serious
infections caused by Staphylococcus aureus have not been fully characterized. The combination of a
beta-lactam plus an
aminoglycoside can act synergistically against S. aureus in vitro and in vivo. MiKasome, a new
liposome-encapsulated formulation of conventional
amikacin, significantly prolongs serum half-life (t1/2) and increases the area under the concentration-time curve (AUC) compared to free
amikacin. Microbiologic efficacy and left ventricular function, as assessed by echocardiography, were compared in animals administered either
oxacillin alone or
oxacillin in combination with conventional
amikacin or MiKasome in a rabbit model of experimental
endocarditis due to S. aureus. In vitro,
oxacillin, combined with either free
amikacin or MiKasome, prevented the bacterial regrowth observed with
aminoglycosides alone at 24 h of incubation. Rabbits with S. aureus
endocarditis were treated with either
oxacillin alone (50 mg/kg, given intramuscularly three times daily),
oxacillin plus daily
amikacin (27 mg/kg, given intravenously twice daily), or
oxacillin plus intermittent MiKasome (160 mg/kg, given intravenously, a single dose on days 1 and 4). The
oxacillin-alone dosage represents a subtherapeutic regimen against the infecting strain in the
endocarditis model (L. Hirano and A. S. Bayer, Antimicrob. Agents Chemother. 35:685-690, 1991), thus allowing recognition of any enhanced bactericidal effects between
oxacillin and either
aminoglycoside formulation. Treatment was administered for either 3 or 6 days, and animals were sacrificed after each of these time points or at 5 days after a 6-day treatment course (to evaluate for posttherapy relapse). Left ventricular function was analyzed by utilizing serial transthoracic echocardiography during treatment and posttherapy by measurement of left ventricular fractional shortening. At all sacrifice times, both combination regimens significantly reduced S. aureus vegetation counts versus control counts (P < 0.05). In contrast,
oxacillin alone did not significantly reduce S. aureus vegetation counts after 3 days of
therapy. Furthermore, at this time point, the two combinations were significantly more effective than
oxacillin alone (P < 0.05). All three regimens were effective in significantly decreasing bacterial counts in the myocardium during and after
therapy compared to controls (P < 0.05). In kidney and spleen
abscesses, all regimens significantly reduced bacterial counts during
therapy (P < 0.0001); however, only the combination regimens prevented bacteriologic relapse in these organs posttherapy. By echocardiographic analysis, both combination regimens yielded a significant physiological benefit by maintaining normal left ventricular function during treatment and posttherapy compared with
oxacillin alone (P < 0.001). These results suggest that the use of intermittent MiKasome (similar to daily conventional
amikacin) enhances the in vivo bactericidal effects of
oxacillin in a severe S. aureus
infection model and preserves selected physiological functions in target end organs.