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Title: Quantitative models of in vitro bacteriophage-host dynamics and their application to phage therapy

Authors: B.J. Cairns, A.R. Timms, V.A.A. Jansen, I.F. Connerton and R.J.H. Payne.

Reference: PLoS Pathogens 2009 5(1): e1000253.

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Abstract:

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.

Keywords. Mutant selection window, phage therapy, combination therapy, antimicrobial resistance, pharmacokinetics/pharmacodynamics.

Acknowledgement. This work was supported by the Biotechnology and Biological Sciences Research Council and the United Kingdom Food Standards Agency through a Government Partnerships Award. RJHP is supported by a Royal Society University Research Fellowship.


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