Phage therapy: What factors shape phage pharmacokinetics and bioavailability? Systematic and critical review

Abstract

Bacteriophages are not forgotten viruses anymore: scientists and practitioners seek to understand phage pharmacokinetics in animals and humans, investigating bacteriophages as therapeutics, nanocarriers or microbiome components. This review provides a comprehensive overview of factors that determine phage circulation, penetration, and clearance, and that in consequence determine phage applicability for medicine. It makes use of experimental data collected by the phage community so far (PubMed 1924‐2016, including non‐English reports), combining elements of critical and systematic review. This study covers phage ability to enter a system by various routes of administration, how (and if) the phage may access various tissues and organs, and finally what mechanisms determine the courses of phage clearance. The systematic review method was applied to analyze (i) phage survival in the gut (gut transit) and (ii) phage ability to enter the mammalian system by many administration routes. Aspects that have not yet been covered by a sufficient number of reports for mathematical analysis, as well as mechanisms underlying trends, are discussed in the form of a critical review. In spite of the extraordinary diversity of bacteriophages and possible phage applications, the analysis revealed that phage morphology, phage specificity, phage dose, presence of sensitive bacteria or the characteristics of treated individuals (age, taxonomy) may affect phage bioavailability in animals and humans. However, once phages successfully enter the body, they reach most organs, including the central nervous system. Bacteriophages are cleared mainly by the immune system: innate immunity removes phages even when no specific response to bacteriophages has yet developed.

Pseudomonas aeruginosa PA5oct Jumbo Phage Impacts Planktonic and Biofilm Population and Reduces Its Host Virulence

“…The obstacle presented by generalised transduction cannot eliminate jumbo phages from the discussion about phage therapy. It is worth remembering that even in the worst scenario, where the bacteriophage capsid is packed with bacterial genes, most often the possibility of transmission is low due to the very rapid clearance of phages by mononuclear phagocytic system [64].…”

The global preclinical antibacterial pipeline

“…Although phages have been used historically in topical formulations (mostly skin) 43 , phage preparations are being developed for intravenous, aerosol or diverse locally applied formulations 44 . The immense size of phages compared with small-molecule antibiotics poses pharmacokinetic challenges, and important scientific questions remain regarding availability at the site of infection and determining the best dosing regimen 45 . In general, natural and engineered phage cocktails dominate our sample.…”

Phage therapy for severe bacterial infections: a narrative review

“…When administering phages orally, concern has been raised regarding recombination between modular phage genomes in the gut, although there has been little evidence from trials to date to resolve this one way or the other . Phages generally have poor oral bioavailability, but intravenous delivery is efficient to virtually all organs and tissues and first‐dose kinetics can be modelled to some extent by standard techniques, especially after initial parenteral dosing. Original observations, recently repeated overseas and in Australian studies of severe sepsis, show that intravenous phage is cleared typically in the first 60 minutes.…”