Dynamics of success and failure in phage and antibiotic therapy in experimental infections

We develop quantitative microbiological procedures that (1) explore the in vivo processes responsible for the efficacy of phage and antibiotic treatment protocols in experimental infections (the Resistance Competition Assay, or RCA), and (2) survey the therapeutic potential of phages in vitro (the Phage Replication Assay or PRA). We illustrate the application and utility of these methods in a repetition of Smith and Huggins' experiments, using the E. coli K1 mouse thigh infection model, and applying treatments of phages or streptomycin.1) The Smith and Huggins phage and antibiotic therapy results are quantitatively and qualitatively robust. (2) Our RCA values reflect the microbiological efficacies of the different phages and of streptomycin in preventing mortality, and reflect the decline in their efficacy with a delay in treatment. These results show specifically that bacteria become refractory to treatment over the term of infection. (3) The K1-specific and non-specific phages had similar replication rates on bacteria grown in broth (based on the PRA), but the K1-specific phage had markedly greater replication rates in mouse serum.Mounting concerns about drug-resistant pathogenic bacteria [1-3] have rekindled interest in alternative treatments of bacterial infections. Prominent among these alternatives is phage therapy, the use of bacteriophages to kill or otherwise control the bacterial populations in infected hosts. The use of bacteriophage for the treatment of bacterial infections is an old idea [4] that not only caught the imagination of at least one novelist [5] it was practiced with sporadic successes worldwide in the 1920s and 1930s. However, following the development of antibiotics in the 1940s, the use of phages to treat and prevent infections disappeared from so-called Western Medicine, but it did survive in the former Soviet Union. A rekindled interest in phage therapy over the past decade has inspired historical reviews, increased our awareness of a su