The increased prevalence of multidrug resistant bacterial pathogens, such as enterococci resistant to vancomycin (VRE), motivated us to enhance the therapeutic efficacy of bacterial viruses or bacteriophages (phages). The therapeutic application of phages as antibacterial agents has been impeded by several factors: the failure to recognize the relatively narrow host range of phages; the presence of toxins in unpurified phage preparations; and a lack of appreciation for the capacity of mammalian host defense systems, particularly the organs of the reticuloendothelial system (RES), to remove phage particles from the circulatory system. In our studies involving bacteremic mice, the problem of the narrow host range of phage was dealt with by using selected bacterial strains and virulent phage specific for them. Toxin levels were diminished by purifying phage preparations. To reduce phage elimination by the host defense system, we developed a serial passage technique in mice to select for phage mutants able to remain in the circulatory system for longer periods of time. By this approach we have isolated long-circulating mutants of phage for a number of different species of bacteria. We demonstrated that these long-circulating phage mutants have greater capability as antibacterial agents than the corresponding parental strain in animals infected with lethal doses of bacteria. In these efforts we recently isolated bacteriophages with activity against enterococci resistant to vancomycin (VRE). The emergence of VRE poses a problem for patients with immune deficiency related illnesses (including those who have been immune suppressed for organ transplantation). From a clinical point of view, there are currently no therapeutic agents commercially available with established efficacy for patients infected by VRE. We have used these phage to rescue mice infected with lethal doses of VRE. Preliminary studies have demonstrated a dose response to the phage titers used and we have found that we can rescue animals late in the infectious cycle.