Comparing proximate outcomes during different categories of phage therapy progress. In passive treatment, only cell killing must occur as a proximate outcome, though cell lysis as well as in situ amplification of phage numbers may occur as well. By definition, though, they do not have to happen for passive treatment to successfully clear a bacterial infection (hence use of dashed, grayed arrows towards the bottom of this column). Phage active penetration into bacterial biofilms appears to be dependent on some form of phage enzymatic activity other than those required to physiologically or genetically kill bacteria. Here this is indicated as bactericidal infection occurring in combination with bacterial lysis, with the latter contributing to further phage penetration into biofilms and/or improved phage-infection physiology. Such phage activity potentially may also improve antibiotic [223] or disinfectant [224] penetration into biofilms or at least their effectiveness against biofilms. Phage in situ amplification, though potentially helpful towards further phage penetration, nonetheless in this case is not necessarily absolutely required (dashed, gray arrow). Payne and Jansen [52] describe an intermediate state between active and passive treatment that they term “mixed passive/active” (here, for clarity, “passive-active”). This treatment approach involves a combination of dosing with large numbers of phages and subsequent phage population growth. It is the opinion of this author that this latter approach, possibly in combination with multiple dosing, likely either should or does represent a default approach to effecting phage therapy treatments. This represents supplying relatively large phage numbers to bacterial infections—in single or multiple doses—though nonetheless supplying phage numbers that are less than completely overwhelming (i.e., less than completely inundative) with the assumption that phage in situ population growth will enhance those numbers local to either planktonic bacteria or instead bacterial biofilms or microcolonies. See Abedon [225, 226] for consideration of the latter. The reduced but not eliminated requirement for lysis and amplification in the case of “passive-active” is indicated using solid but gray arrows rather than dashed gray arrows. Lastly, active treatment by definition is dependent on both lysis and in situ phage amplification (black, solid arrows).
