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

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          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.

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          Most cited references173

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          Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals.

          In addition to metabolic differences, the anatomical, physiological, and biochemical differences in the gastrointestinal (G.I.) tract of the human and common laboratory animals can cause significant variation in drug absorption from the oral route. Among the physiological factors, pH, bile, pancreatic juice, and mucus and fluid volume and content can modify dissolution rates, solubility, transit times, and membrane transport of drug molecules. The microbial content of the G.I. tract can significantly affect the reductive metabolism and enterohepatic circulation of drugs and colonic delivery of formulations. The transit time of dosage forms can be significantly different between species due to different dimensions and propulsive activities of the G.I. tract. The lipid/protein composition of the enterocyte membrane along the G.I. tract can alter binding and passive, active, and carrier-mediated transport of drugs. The location and number of Peyer's patches can also be important in the absorption of large molecules and particulate matter. While small animals, rats, mice, guinea pigs, and rabbits, are most suitable for determining the mechanism of drug absorption and bioavailability values from powder or solution formulations, larger animals, dogs, pigs, and monkeys, are used to assess absorption from formulations. The understanding of physiological, anatomical, and biochemical differences between the G.I. tracts of different animal species can lead to the selection of the correct animal model to mimic the bioavailability of compounds in the human. This article reviews the anatomical, physiological, and biochemical differences between the G.I. tracts of humans and commonly used laboratory animals.
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            Phage therapy in clinical practice: treatment of human infections.

            Phage therapy is the application of bacteria-specific viruses with the goal of reducing or eliminating pathogenic or nuisance bacteria. While phage therapy has become a broadly relevant technology, including veterinary, agricultural, and food microbiology applications, it is for the treatment or prevention of human infections that phage therapy first caught the world's imagination--see, especially, Arrowsmith by Sinclair Lewis (1925)--and which today is the primary motivator of the field. Nonetheless, though the first human phage therapy took place in the 1920s, by the 1940s the field, was in steep decline despite early promise. The causes were at least three-fold: insufficient understanding among researchers of basic phage biology; over exuberance, which led, along with ignorance, to carelessness; and the advent of antibiotics, an easier to handle as well as highly powerful category of antibacterials. The decline in phage therapy was neither uniform nor complete, especially in the former Soviet Republic of Georgia, where phage therapy traditions and practice continue to this day. In this review we strive toward three goals: 1. To provide an overview of the potential of phage therapy as a means of treating or preventing human diseases; 2. To explore the phage therapy state of the art as currently practiced by physicians in various pockets of phage therapy activity around the world, including in terms of potential commercialization; and 3. To avert a recapitulation of phage therapy's early decline by outlining good practices in phage therapy practice, experimentation, and, ultimately, commercialization.
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              Population and evolutionary dynamics of phage therapy.

              Following a sixty-year hiatus in western medicine, bacteriophages (phages) are again being advocated for treating and preventing bacterial infections. Are attempts to use phages for clinical and environmental applications more likely to succeed now than in the past? Will phage therapy and prophylaxis suffer the same fates as antibiotics--treatment failure due to acquired resistance and ever-increasing frequencies of resistant pathogens? Here, the population and evolutionary dynamics of bacterial-phage interactions that are relevant to phage therapy and prophylaxis are reviewed and illustrated with computer simulations.
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                Author and article information

                Contributors
                dabrok@iitd.pan.wroc.pl
                Journal
                Med Res Rev
                Med Res Rev
                10.1002/(ISSN)1098-1128
                MED
                Medicinal Research Reviews
                John Wiley and Sons Inc. (Hoboken )
                0198-6325
                1098-1128
                19 March 2019
                September 2019
                : 39
                : 5 ( doiID: 10.1002/med.2019.39.issue-5 )
                : 2000-2025
                Affiliations
                [ 1 ] Bacteriophage Laboratory Institute of Immunology and Experimental Therapy, Polish Academy of Sciences Wrocław Poland
                [ 2 ] Research and Development Center Regional Specialized Hospital Wrocław Poland
                Author notes
                [*] [* ] Correspondence Krystyna Dąbrowska, Bacteriophage Laboratory, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland. Email: dabrok@ 123456iitd.pan.wroc.pl

                Author information
                http://orcid.org/0000-0002-1518-3183
                Article
                MED21572
                10.1002/med.21572
                6767042
                30887551
                d381f76e-7843-4b59-a898-91268dacc68c
                © 2019 The Authors. Medicinal Research Reviews Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 08 December 2018
                : 23 January 2019
                : 26 February 2019
                Page count
                Figures: 6, Tables: 0, Pages: 26, Words: 14799
                Funding
                Funded by: National Science Centre
                Award ID: UMO‐2012/05/E/NZ6/03314
                Award ID: UMO‐2015/18/M/NZ6/00412
                Award ID: UMO‐2018/29/B/NZ6/01659
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                med21572
                September 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:30.09.2019

                bacteriophage,immune response,phage circulation,phage clearance,phage penetration,phage therapy,pharmacokinetics

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