Understanding Bacteriophage Therapy as a Density-dependent Kinetic Process

Abstract

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.

Pharmacodynamics of non-replicating viruses, bacteriocins and lysins

“…Their model focused on the maintenance of phage populations, which thus do not admit nonreplicating phages. Payne & Jansen (2001) generated the result in our model 1 as a contrast to the effect produced by a replicating phage and thus did not explore it. Wodarz developed a model of viral treatment of tumour cells (Wodarz 2001(Wodarz , 2003; one version of that model considered a non-replicating virus (Wodarz 2003), but that model did not address how much virus was needed, and there was no viral loss when infecting cells.…”

Phages as Therapeutic Tools to Control Major Foodborne Pathogens: Campylobacter and Salmonella

“…The practical applicability of this approach may be compromised by the minimum density of host cells that are suggested to be required for phage replication (Payne et al, 2000;Payne & Jansen, 2001). Nevertheless it was demonstrated that phages can be effective biocontrol agents when the population of host cells is as low as 46 CFU/cm 2 (Greer, 1988).…”

Bacteriophage Infection Dynamics: Multiple Host Binding Sites

“…Ignoring bacterial growth (a m = 0) and viral replication (L = 0), the simulation shows viral attachment to bacteria (total bound virus) during the first few hours after introduction of phage at 100-to-one phage-host ratio. Such phage to host ratios are appropriate for so-called "passive phage therapy" which relies on first generation phage to overwhelm bacteria [22,23]. Note that increasing levels of bound virus mean decreasing numbers of free virus which mean fewer new infections.…”

“…However, as multidrug resistant bacteria have become an enormous public health problem, there is a renewed interest in phage therapy [17,20,22,23,4,30].…”

“…In a recent paper [25], one of us introduced a model accounting for multiple adsorption of phage to host. The aim of this work was to use this much more complicated model, Figure 1: Bacterium with multiple adsorbed phage which tracks "host + n-phage" complexes, together with time-scale arguments to obtain a simplified low-dimensional model comparable to traditional models, such as Campbell's and others [1,21,8,22,23,4,24], but with the effects of multiple adsorption taken into account by a modification of mass-action adsorption kinetics. However, the time-scale arguments in [25] are less than convincing.…”