Phage therapy: The peculiar kinetics of self-replicating pharmaceuticals

Payne, Robert J. H.; Jansen, Vincent

doi:10.1067/mcp.2000.109520

Cited by 191 publications

(197 citation statements)

References 15 publications

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“…It has also been observed that many phages that proliferate on a given host in vitro fail to do so in vivo (7). This fact, as well as concerns that lytic phage may facilitate the transfer of toxic genes from pathogenic bacteria to commensal flora, has encouraged the development of nonreplicating phage therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…The confirmation of this mathematical model also has implications for the use of phage as antimicrobial therapeutic agents. Payne et al (7,8) developed a mathematical model of lytic phage therapy treatment of bacterial infections in vivo in which they argue that administration of therapeutic phage must be carefully timed to coincide with a sufficiently dense bacterial population to support phage proliferation in order to be effective, similar to the replication threshold. Our results confirm that host cell density is essential to estimating what percentage of administered phage will find target cells within a given period of time and that progeny phage will be detectable sooner at higher initial cell densities.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, when host cell densities are very low, it has been observed that there is a longer delay before phage numbers increase over the numbers of input phage. This period has been explained as the time needed for the host cells to reach a "replication threshold" (16) or "proliferation threshold" (7,8) density. This density has been reported to be approximately 10 4 cells per ml for the multiple phage-host combinations tested (16) and has been said to have broad implications for the propagation of phages in natural environments and in terms of their use as antimicrobial therapies (7,8).…”

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confidence: 99%

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Overcoming the Phage Replication Threshold: a Mathematical Model with Implications for Phage Therapy

Kasman

Westwater

et al. 2002

J Virol

192

161

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Prior observations of phage-host systems in vitro have led to the conclusion that susceptible host cell populations must reach a critical density before phage replication can occur. Such a replication threshold density would have broad implications for the therapeutic use of phage. In this report, we demonstrate experimentally that no such replication threshold exists and explain the previous data used to support the existence of the threshold in terms of a classical model of the kinetics of colloidal particle interactions in solution. This result leads us to conclude that the frequently used measure of multiplicity of infection (MOI), computed as the ratio of the number of phage to the number of cells, is generally inappropriate for situations in which cell concentrations are less than 10 7 /ml. In its place, we propose an alternative measure, MOI actual , that takes into account the cell concentration and adsorption time. Properties of this function are elucidated that explain the demonstrated usefulness of MOI at high cell densities, as well as some unexpected consequences at low concentrations. In addition, the concept of MOI actual allows us to write simple formulas for computing practical quantities, such as the number of phage sufficient to infect 99.99% of host cells at arbitrary concentrations.It has long been observed that when bacteriophage are mixed with susceptible host bacteria, the number of phage in the culture supernatant does not increase until after an eclipse period of, generally, 30 to 40 min at 37°C has passed. This period of time is explained as the time the phage requires to inject its genome into the host, express its genes, and assemble progeny phage and release them into the environment. Additionally, when host cell densities are very low, it has been observed that there is a longer delay before phage numbers increase over the numbers of input phage. This period has been explained as the time needed for the host cells to reach a "replication threshold" (16) or "proliferation threshold" (7,8) density. This density has been reported to be approximately 10 4 cells per ml for the multiple phage-host combinations tested (16) and has been said to have broad implications for the propagation of phages in natural environments and in terms of their use as antimicrobial therapies (7,8). The mechanism of this delay in phage replication has not been widely investigated or discussed.One explanation for the apparent threshold density would be a requirement on the part of the phage for the host cell to be in a particular metabolic state and that this state is only reached when the cell density is 10 4 CFU/ml or more. Small molecules called autoinducers or quorum factors are known to be secreted into the environment by bacteria and, by their accumulation as the number of cells increases, to allow the bacteria to monitor their local population density (3). These soluble signaling molecules alter the expression of dozens of genes and thereby regulate the metabolic state when the sensing bacteria are expo...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Overcoming the Phage Replication Threshold: a Mathematical Model with Implications for Phage Therapy

Kasman

Westwater

et al. 2002

J Virol

192

161

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“…Both of these counterintuitive, yet clinically important issues, only make sense when viewed as density-dependent phenomena constrained by critical time points. Even if variation amongst individual patients cannot be resolved at a clinical level, a quantitative understanding of phage}bacteria kinetics is still of signi"cant bene"t (Payne & Jansen, 2000), for it informs us which aspects of phage biology might best be engineered so as to enhance the prospects of phage therapy.…”

Section: Discussionmentioning

confidence: 99%

Understanding Bacteriophage Therapy as a Density-dependent Kinetic Process

Payne

Jansen

2001

Journal of Theoretical Biology

214

229

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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 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).…”

Section: Phage Biocontrol In Food Materialsmentioning

confidence: 99%