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.

Keywords: bacteriophage; immune response; phage circulation; phage clearance; phage penetration; phage therapy; pharmacokinetics.

Figure 1

Factors affecting phage gut transit and phage penetration in animals and humans. Summary of systematic analysis; red—highly significant influence of a factor, yellow—significant influence of a factor, ānd gray—insignificant (Tables S1 and S2) [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Factors affecting phage gut transit in animals and humans analyzed by categories, results of systematic analysis presented in forest plots. Vertical lines represent average effect within a category, horizontal bars represent confidence interval 95%; red (normal line)—highly significant influence of a factor, yellow (dashed line)—significant influence of a factor, gray (dotted line)— insignificant, U—unspecified, and ß—regression coefficient. Number of relevant reports available for analysis is given in parentheses. (Tables S1 and S2) [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Factors affecting phage penetration in animals and humans analyzed by categories, results of systematic analysis presented in forest plots. Vertical lines represent average effect within a category, horizontal bars represent confidence interval 95%; red (normal line)—highly significant influence of a factor, yellow (dashed line) –significant influence of a factor, gray (dotted line)—insignificant, U—unspecified, and ß—regression coefficient. Number of relevant reports available for analysis is given in parentheses (Tables S1 and S2) [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Selected factors specific for phage penetration after oral administration, results of systematic analysis presented in forest plots. Vertical lines represent average effect within a category, horizontal bars represent confidence interval 95%. No statistical significance was observed (gray, dotted line). U—unspecified and ß—regression coefficient. Number of relevant reports available for analysis is given in parentheses (Table S2)

Figure 5

Correlation between phage dose in oral administration and the efficiency of phage passage to blood. ‐0, phage was not detected in any individual, 1, phage detected in not more than 50% of individuals, 2, phage detected in more than 50% but less than 100% of individuals, 3 to 100% of individuals were positive for a phage (calculated from all 43′oral‘ experiments presented in Table S2) [Color figure can be viewed at wileyonlinelibrary.com]

Figure 6

Routes of bacteriophage access to the body A, phage circulation in tissues B, and phage clearance in animals and humans C [Color figure can be viewed at wileyonlinelibrary.com]