Killing of susceptible strains of enterococci requires the synergistic action of penicillin, ampi- cillin, or vancomycin in combination with either gentamicin or streptomycin. Enterococci are relatively impermeable to aminogly- cosides. High concentrations of aminoglycosides in the extracellular environment are required to achieve sufficient concentrations of the drug at the site of the ribosomal target within the bacterial cell for bactericidal activity. These con- centrations are higher than can be achieved safely in patients; however, cell wall active agents such as penicillin, ampicillin, and vancomycin raise the permeability of the enterococcal cell so that a bactericidal effect can be achieved by relatively low concentrations of an aminoglycoside. If an enterococcal strain is resistant to the cell wall active agent or high concentrations of an aminoglycoside (500 g/mL gentamicin or 1000 g/mL streptomycin), then the combination of an aminoglycoside and the cell wall active agent will not result in bactericidal activity in vitro or in vivo (ie, in experimental IE models), nor will it predictably produce a microbiological cure in human enterococcal IE. Recommendations 1. Enterococci should be tested routinely in vitro for susceptibility to penicillin and vancomycin (MIC determination) and for high-level resistance to gen- tamicin to predict synergistic interactions (Class I; Level of Evidence A). 2. In vitro susceptibility to daptomycin and linezolid should be obtained for strains that are resistant to -lactams, vancomycin, or aminoglycosides (Class I; Level of Evidence C). Table 11. 