Quantitative Models of In Vitro Bacteriophage–Host Dynamics and Their Application to Phage Therapy

Phage therapy is the use of bacteriophages as antimicrobial agents for the control of pathogenic and other problem bacteria. It has previously been argued that successful application of phage therapy requires a good understanding of the non-linear kinetics of phage–bacteria interactions. Here we combine experimental and modelling approaches to make a detailed examination of such kinetics for the important food-borne pathogen Campylobacter jejuni and a suitable virulent phage in an in vitro system. Phage-insensitive populations of C. jejuni arise readily, and as far as we are aware this is the first phage therapy study to test, against in vitro data, models for phage–bacteria interactions incorporating phage-insensitive or resistant bacteria. We find that even an apparently simplistic model fits the data surprisingly well, and we confirm that the so-called inundation and proliferation thresholds are likely to be of considerable practical importance to phage therapy. We fit the model to time series data in order to estimate thresholds and rate constants directly. A comparison of the fit for each culture reveals density-dependent features of phage infectivity that are worthy of further investigation. Our results illustrate how insight from empirical studies can be greatly enhanced by the use of kinetic models: such combined studies of in vitro systems are likely to be an essential precursor to building a meaningful picture of the kinetic properties of in vivo phage therapy.Author Summary: Phage therapy is an antimicrobial treatment based on specific viruses which are natural predators of bacteria. This approach is being promoted as a possible alternative treatment for use against antibiotic-resistant strains of bacteria. Despite its long history and many potential benefits, adoption of phage therapy has been retarded by a variety of factors, including a poor understanding of the therapeutic consequences of the phage–bacteria relationship. In our work we bring together theory and data by testing kinetic models of phage–bacteria interactions against data for an important agent of human food poisoning, Campylobacter jejuni. Our model explicitly allows for resistant bacteria because these have not been properly accounted for in previous phage therapy theory but will be relevant to practical applications. The excellent fit of our model to the data confirms the value of such combined approaches and supports an interpretative viewpoint based on critical density-dependent thresholds that are not part of standard pharmacology. We also find that phage activity appears to be dose-dependent, and we speculate on possible causes for this. Our work illustrates how mathematical models can considerably enhance insights from empirical studies, as an important step in advancing the understanding of phage therapy.