Studies of bacteriophage as therapeutic agents have had mixed and unpredictable outcomes. We argue that interpretation of these apparently paradoxical results requires appreciation of various density-dependent threshold e!ects. We use a mathematical model to delineate di!erent categories of outcome, including therapy by simple inundation, by active biocontrol, and by delayed active biocontrol. Counter-intuitively, there are situations in which earlier inoculation can be less e$cacious, and simultaneous inoculation with antibiotics can be detrimental. Predictions of therapeutic responses are made using formulae dependent on biologically meaningful parameters; experimental measurement of the parameters will be a prerequisite of application of the model to particular study systems. Such modelling can point to which aspects of phage biology might most fruitfully be engineered so as to enhance the viability of bacteriophage therapy.

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The specter of antibiotic-resistant bacteria has provoked renewed interest in the possible use of bacteriophages to control bacterial infections. We argue that clinical application of phage therapy has been held back by a failure to appreciate the extent to which the pharmacokinetics of self-replicating agents differ from those of normal drugs. For self-replicating pharmaceutical agents, treatment outcome depends critically on various density-dependent thresholds, often with apparently paradoxical consequences. An ability to predict these thresholds and associated critical time points is a necessity if phage therapy is to become clinically practicable.