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Title: Bacteriophage therapy and the mutant selection window

Authors: B.J. Cairns and R.J.H. Payne.

Reference: Antimicrobial Agents and Chemotherapy 52(12): 4344-4350.

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Abstract:

We use kinetic models to investigate how to design antimicrobial phage therapies to minimise emergence of resistant bacteria. We do this by modifying the 'mutant selection window' hypothesis in a way that accounts for the ongoing self-replication of the phage. We show that components of combination phage therapies need to be appropriately matched if treatment is to avoid the emergence of resistant bacteria. Matching of components is more easily achieved when phage dosages are high enough that ongoing phage replication is not needed for the clearance of the bacteria. Theoretical predictions such as ours need to be tested experimentally if applications of phage therapy are to avoid the problems of widespread resistance that have beset chemical antibiotics.

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

Acknowledgement. This work was funded by the BBSRC and UK Food Standards Agency, grant BB/C504578/1. RJHP is supported by a Royal Society University Research Fellowship. We thank Andrew Timms, Ian Connerton and Vincent Jansen for helpful discussions on phage biology and modelling, and two anonymous referees for their helpful suggestions.


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Cancer Epidemiology Unit, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, U.K.