Phage therapy

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Phage therapy, viral phage therapy, or phagotherapy is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections.^[1][2][3] This therapeutic approach emerged at the beginning of the 20th century but was progressively replaced by the use of antibiotics in most parts of the world after the Second World War. Bacteriophages, known as phages, are a form of virus^[4] that attach to bacterial cells and inject their genome into the cell.^[5] The bacteria's production of the viral genome interferes with its ability to function, halting the bacterial infection.^[5] The bacterial cell causing the infection is unable to reproduce and instead produces additional phages.^[4] Phages are very selective in the strains of bacteria they are effective against.^[5]

Advantages include reduced side effects and reduced risk of the bacterium developing resistance, since^[5] bacteriophages are much more specific than antibiotics. They are typically harmless not only to the host organism but also to other beneficial bacteria, such as the gut microbiota, reducing the chances of opportunistic infections.^[6] They have a high therapeutic index; that is, phage therapy would be expected to give rise to few side effects, even at higher-than-therapeutic levels.^[7] Because phages replicate in vivo (in cells of living organism), a smaller effective dose can be used.^[8]

Disadvantages include the difficulty of finding an effective phage for a particular infection; a phage will kill a bacterium only if it matches the specific strain.^[5] However, virulent phages can be isolated much more easily than other compounds and natural products.^[8] Consequently, phage mixtures ("cocktails") are sometimes used to improve the chances of success.^[9] Alternatively, samples taken from recovering patients sometimes contain appropriate phages that can be grown to cure other patients infected with the same strain.^[10] Ongoing challenges include the need to increase phage collections from reference phage banks, the development of efficient phage screening methods for the fast identification of the therapeutic phage(s), the establishment of efficient phage therapy strategies to tackle infectious biofilms, the validation of feasible phage production protocols that assure quality and safety of phage preparations, and the guarantee of stability of phage preparations during manufacturing, storage, and transport.

Phages tend to be more successful than antibiotics where there is a biofilm covered by a polysaccharide layer, which antibiotics typically cannot penetrate.^[11] Phage therapy can disperse the biofilm generated by antibiotic-resistant bacteria.^[12] However, the interactions between phages and biofilms can be complex, with phages developing symbiotic as well as predatory relationships with biofilms.^[9]

Phages are currently being used therapeutically to treat bacterial infections that do not respond to conventional antibiotics,^[2][1][13] particularly in Russia^[14] and Georgia.^[15][16][17] There is also a phage therapy unit in Wrocław, Poland, established in 2005, which continues several-decades-long research by the Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences, the only such centre in a European Union country.^[18] Phages are the subject of renewed clinical attention in Western countries, such as the United States. In 2019, the United States Food and Drug Administration approved the first US clinical trial for intravenous phage therapy.^[19]

Phage therapy has many potential applications in human medicine as well as dentistry, veterinary science, and agriculture.^[20] If the target host of a phage therapy treatment is not an animal, the term "biocontrol" (as in phage-mediated biocontrol of bacteria) is usually employed, rather than "phage therapy".^[9]