Effective treatment of multidrug-resistant enterococcal experimental endocarditis with combinations of cell wall-active agents.

The efficacy of treatment with a combination of ampicillin, imipenem, and vancomycin was compared with that of two-drug combinations or monotherapy in a model of experimental endocarditis using a strain of Enterococcus faecium with high-level resistance to vancomycin and moderate intrinsic resistance to ampicillin and imipenem. In vitro time-kill synergy studies demonstrated bactericidal synergistic activity only for the triple combination. In vivo, monotherapy with vancomycin was not effective. Treatment with either ampicillin or imipenem alone or in combination with vancomycin resulted in <4 log10 reduction in colony-forming units (cfu) per gram of vegetation. The combination of ampicillin with imipenem was highly active (an additional 5 log10 reduction in cfu per gram of vegetation compared with the most active single agent), but efficacy was not increased by the addition of vancomycin to ampicillin and imipenem. Therapy with the combination of ampicillin and imipenem may be effective for some strains of multidrug-resistant enterococcal infections.