We compared ciprofloxacin, rifampin, and gentamicin treatments, alone and in combination, for 5 days in the therapy of experimental aortic valve endocarditis in rats caused by a clinical isolate of vancomycin-resistant Enterococcusfaecium. The MICs and MBCs of vancomycin, ciprofloxacin, rifampin, and gentamicin were 250 and >1,000, 3.1 and 6.3, 0.098 and 1.6, and 12.5 and >50 Fg/ml, respectively. Infected rats were sacrificed after completing 5 days of therapy. Additional rats within each treatment group were followed for 5 days beyond the last dose of antibiotic therapy. Although survivals in the different groups were not significantly different after 5 days of therapy, survival was significantly better 5 days beyond the last dose of antibiotic therapy in rats treated with rifampin-containing regimens. The combination of ciprofioxacin and gentamicin was bactericidal in vitro and in vegetations from rats with enterococcal endocarditis. Rifampin alone was similarly bactericidal in vivo, but it was not signifcantly better than rifampin in combination with other antibiotics. Subpopulations resistant to rifampin, but not ciprofloxacin, were detected in the inoculum and in most vegetations during therapy. However, the combination of ciprofloxacin plus both gentamicin and rifampin reduced both the rifampin-susceptible and -resistant population in vegetations of 9 of 10 animals below the level of detection after 5 days of therapy. Nevertheless, a residual enterococcal population apparently remained in numbers of <2 log10 CFU/g after 5 days of therapy, which resulted in relapse. Perhaps a longer course of therapy would have eliminated this residual population and improved efficacy.An aminoglycoside in combination with either penicillin or vancomycin has been the standard regimen for the treatment of serious enterococcal infections such as endocarditis (2). Recently, high-level penicillin resistance (MIC, > 100 Fg/ml) has been described in Enterococcus faecium (3, 21) and t-lactamase production has been described in Enterococcus faecalis (6, 13). High-level aminoglycoside resistance (MIC, >1,000 ,ug/ml) has been described in both species. Vancomycin-resistant enterococci have continued to be reported (8,10,17) with increasing frequency as a cause of nosocomial infections since they were first described by Uttley et al. in 1988 (19). Consequently, treatment of serious enterococcal infections has become problematic. We identified a nosocomial outbreak caused by a vancomycin-resistant E. faecium isolate that was also resistant to penicillin and streptomycin; in vitro data suggested that ciprofloxacin in combination with rifampin and gentamicin was active against this isolate (11). Bacteremic infections in several patients responded clinically and bacteriologically to this antibiotic combination. The purpose of the study described here was to determine the efficacies of ciprofloxacin, rifampin, and gentamicin, each alone and in combination, in a rat model of experimental endocarditis caused by this strain. We also evaluated...