Once- versus thrice-daily netilmicin combined with amoxicillin, penicillin, or vancomycin against Enterococcus faecalis in a pharmacodynamic in vitro model. Antimicrob. Agents Chemother

Several in vitro and in vivo studies as well as clinical trials have demonstrated that once-daily aminogly-coside regimens are as effective as or more effective than multiple daily dosings. However, the most favorable aminoglycoside dosing regimen for treating enterococcal endocarditis remains controversial. The same total dose of netilmicin was administered as once-daily (24-mg/ml peaks) and thrice-daily (8 mg/ml) regimens in a pharmacodynamic in vitro model simulating exposure of Enterococcus faecalis to human serum kinetics. Netilmicin was administered in combination with continuous infusions of amoxicillin, vancomycin, or peni-cillin against a bacterial biofilm adhering to glass beads. No significant differences in bacterial killing were found after 24 or 48 h between the once- and thrice-daily regimens. Additional experiments considering animal kinetics (half-life of netilmicin, 20 min) instead of human kinetics (half-life, 2.5 h) in the pharmacodynamic model also revealed similar results. The addition of netilmicin synergistically increased the activity of vanco-mycin (P < 0.05). In contrast, amoxicillin alone was as effective as the combination with netilmicin. Thus, it could not be established in this model that once-daily dosing of aminoglycosides is contraindicated for treating infections caused by E. faecalis. Enterococcal endocarditis requires the administration of a synergistic combination of a cell wall-active agent, usually