There is a need for new agents, or combinations of agents, for the treatment of infections caused by vancomycin- and gentamicin-resistant Enterococcus faecium (VGREF) that may be resistant to all available antimicrobial agents. The early in-vitro activity of quinupristin/dalfopristin (30:70)--an injectable streptogramin--encouraged us to test this agent against VGREF. By broth dilution, the MICs of quinupristin/dalfopristin against 38 isolates of VGREF ranged from 0.06 mg/L to 2.0 mg/L (mode 0.12 mg/L). The addition of 0.5 mg/L of ciprofloxacin significantly reduced the modal MIC of quinupristin/dalfopristin to 0.015 mg/L (P = 5.75 x 10(-8)). Although the addition of 8.0 mg/L of teicoplanin or 4 mg/L of tetracycline did not significantly reduce the modal MIC, the lowest concentration of the MIC range was reduced from 0.06 to 0.015 mg/L. In broth, quinupristin/dalfopristin had slow bactericidal activity against the four strains tested over 48 h, with a 1-2 log10 cfu/mL reduction after 24 h in > 1 mg/L of quinupristin/dalfopristin for two strains and > 8 mg/L for the two other strains. A mixture of quinupristin/dalfopristin in a 70:30 ratio was more bactericidal: against one of the four strains 4-32 mg/L of the combination produced a further 0.5-1.0 log10 reduction in cfu/mL after 24 h and there was a reduction of 6.0 log10 cfu/mL after 48 h for another. By ultracentrifugation, the binding of 32 mg/L quinupristin/dalfopristin to human plasma protein was 90%, and in plasma broth, 32 mg/L of quinupristin/dalfopristin maintained bacteriostatic but not bactericidal activity. There is some useful synergy with ciprofloxacin and tetracycline, and the activity of quinupristin/dalfopristin may be enhanced against some strains by reversing the concentrations of its two components, quinupristin and dalfopristin, as that may occur in vivo.