Bacteriophage pharmacodynamics studied in an in vitro pharmacokinetic model of infection

Bacteriophage therapy offers an alternative way to counter the menace of increasing antimicrobial resistance. Despite its use in clinical practice for many decades the basic tools to study the translational pharmacodynamics of phages are not available and it is recognized that lack of understanding of phage pharmacokinetics/pharmacodynamics (PK/PD) is a severe limitation in individual patient use and clinical trial design.

Traditional in vitro PK/PD evaluation tools were used to assess the antibacterial effect of single exposures of a bacteriophage cocktail against four strains of Escherichia coli with potentially different patterns of response to phage. Initially, time-kill curves (TKCs) were performed over 48 h and subsequently a dilutional in vitro model (IVM) was used to assess the antibacterial effects over 72 h.

In TKCs, the four E. coli strains showed different patterns of kill and regrowth when exposed to phage, with two strains showing a sustained drop in bacterial viable count and two showing initial kill and regrowth. Using the IVM similar bacterial PD patterns were observed, and phage titre increased inversely and consistently with E. coli kill.

An in vitro dilutional model can be used to study the antibacterial effect of a phage cocktail on E. coli showing strain-to-strain variation in bacterial killing and bacteriophage titre. Such models can be used to provide more nuanced information on phage PK/PD and translationally useful information for dosing in humans.