Despite the temptation to use bacteriophages in all situations where bacterial pathogens are involved, a thorough and comprehensive analysis of the project is required before developing any phage product, including technical feasibility, cost, competitive environment, etc. Marketing strategy is also an important factor: some phage-containing drugs are better positioned as medicines, but others can be used as biologically active additives-probiotics that are sold without a prescription. The fact is that the ability of lytic bacteriophages to destroy certain pathogenic bacteria without affecting the normal bacterial flora allows them to be used not only for treatment, but also for the prevention of many bacterial diseases. For example, phage preparations targeting pathogens that cause diarrhea may well become a dietary supplement for the prevention of acute intestinal infections such as shigellosis. By the way, about the successful use of phages against Shigella spp. In humans, a number of publications in the scientific literature of the former USSR attest (Goodridge, 2013). Such probiotics will be indispensable for people who travel a lot to countries where the incidence of bacterial diarrhea is high. A more complex scenario involves the use of lytic phages to treat, for example, bacterial complications of wounds involving several types of pathogens at once. Effective treatment in this case requires complex phage preparations, such as Georgian Pyobacteriophage and the Russian Piobacteriophage Complex (manufactured by NPO Microgen). In the USA, a multivalent drug containing eight lytic phages has been successfully tested against three types of pathogenic bacteria characteristic of infected wounds (E. coli, Staphylococcus aureus and Pseudomonas aeruginosa (Rhoads et al., 2009). The production and quality control of such drugs requires much more effort, therefore it is preferable to develop and sell them as a traditional medicine. And, of course, the cost of development, regulatory strategies, and time frames for commercialization of different products will also vary significantly.

Phage-containing drugs can quickly and adequately respond to the emergence of new highly effective pathogenic clones and phage-resistant mutants in bacterial populations. Since phages have evolved together with bacteria for more than 3 billion years (Lenski, 1984), if necessary, phages with the ability to kill any bacterial “target” can be relatively easily isolated from the environment. From a practical point of view, this requires monitoring the sensitivity of the pathogen and updating phage-containing preparations as necessary. As for the first condition, testing bacteria for antibiotic sensitivity is standard practice in all major hospitals. These procedures can be easily adapted to bacteriophages by increasing the throughput of equipment and implementing phage-specific protocols. However, there may be difficulties from a regulatory point of view. The renewal of phage preparations by replacing old strains with new, more effective ones was successfully carried out in the former USSR and Eastern European countries. But this practice is new to Western regulatory authorities, for whom every change in a drug is the subject of a new regulatory application. Such requirements will hinder the development of new effective agents based on bacterial viruses targeting one or more pathogens (Sulakvelidze, 2012). A positive aspect can be considered the flexibility of the FDA (American Food and Drug Administration) regarding the use of phages to ensure food safety. The FDA has allowed several such drugs to be updated in the future in response to the appearance of new phage-resistant strains of bacterial pathogens in food (Woolston & Sulakvelidze, 2015). Whether such an approach can be implemented for human treatment remains to be seen. However, it is necessary to do this, otherwise we will not be able to optimally use all the strengths of phage therapy in healthcare. The next problem arises in connection with the situation when phages are selected individually for each patient. Since lytic phages are highly specific, commercial phage preparations may not be effective enough against specific strains that predominate in a particular hospital or isolated from a particular patient, as was repeatedly shown by Soviet researchers (Zhukov-Verezhnikov et al., 1978). One approach to solving this problem is to test all isolated bacterial strains for phage sensitivity in search of the most therapeutically active viruses. This type of “personalized medicine” is becoming increasingly popular in the world, including in terms of choosing the most effective antibiotic. Thus, in order for phage therapy to reach its full potential, phages must be “custom-made.” From a technical point of view, this is quite feasible: for example, it is possible to collect large libraries of characterized lytic phages and develop a technology for rapid screening of their activity against isolated bacterial pathogens. But it will require some creative thinking from regulators. Finally, it is necessary to think through the logistics so that this approach is also commercially viable. At first, it may be advisable to create a small number of support clinics or centers with well-trained staff, where appropriate technologies will be implemented. The number (size) of these centers may subsequently increase as a personalized approach to treatment gains more and more supporters among medical professionals.

One of the most intriguing potential applications of bacteriophages is their use as probiotics for fine–tuning the microflora of the gastrointestinal tract and/or other organs such as the skin, mouth, and vagina. Most of the bacteria are found in the gastrointestinal tract, which is colonized by abundant and diverse microflora, which plays an important role not only in the formation of feces, but also in the protection of mucous membranes, regulation of immunological tolerance and synthesis of vitamin K. Numerous factors (antibiotic treatment, malnutrition, psychological and physical stress, etc.) can cause changes in the composition intestinal microflora, which contributes to the development of various chronic and degenerative diseases, including rheumatoid arthritis. One of the approaches to the treatment of these disorders is the use of drugs with beneficial, “probiotic” microorganisms, which, when ingested in sufficient quantities, prevent the spread of potentially pathogenic strains and restore the normal microbial balance of the gastrointestinal tract, improving overall health. Traditionally, such “cocktails” contain various bacteria (most often lacto- and bifido-) and are sold as food additives, as well as in the form of beverages, infant formulas, etc. (Schrezenmeir & de Vrese, 2001). Nowadays, bacterial probiotics are gaining popularity all over the world. However, lytic bacteriophages that attack “problematic” bacteria can also be used as probiotic food additives. The main difference between bacterial and phage probiotics lies only in the nature of their effect on pathogens: “probiotic” bacteria do not allow or prevent dangerous “interventionists” from colonizing the organ, while phages simply kill them. At the same time, phagobiotics will have to act very gently on the microflora as a whole due to their high activity only against specific bacterial species. In addition, such drugs should be compatible (in fact, synergistic) with bacterial probiotics. This approach can serve as a platform for the development of a new class of “super probiotics.” And it’s not even about the name: it’s important that phagobiotics can solve many potential health problems, since they can be used as new means of preventing such significant infectious diseases of bacterial etiology as, for example, shigellosis, caries caused by Streptococcus mutans, skin and eye diseases (acne, chronic blepharitis and endophthalmitis caused by Propionibacterium acnes), “women’s diseases” (bacterial vaginosis caused by Fusobacterium nucleatum). The production base of the American biotech company Intralytix, Inc. (Baltimore, USA) The phagobiotic approach also opens up possibilities for the prevention of non-communicable diseases such as obesity and certain cancers, the development of which, as modern research shows, can be provoked by certain bacteria of the gastrointestinal tract. Such bacteria include, for example, E. coli type B2, Bacteroides fragilis and Salmonella Typhi, which are sometimes called “oncobacteria”. Indeed, a close association has been established between hepatobiliary cancer (liver and biliary tract cancers) and chronic gallbladder infection caused by this salmonella (Dutta et al., 2000). Phages that will target such bacteria can, in principle, reduce the incidence of certain types of malignant tumors. Finally, bacteriophages can also be used as a unique tool for studying the functional organization of mammalian microbiomes. For example, they can be used to destroy or significantly reduce the number of specific bacterial species in the gastrointestinal tract of laboratory animals, which will be a “probiotic version” of the so-called genetic knockout. By examining the local and systemic physiological changes that followed this intervention, it is possible to assess the role of these bacteria in the microbiome and their importance for maintaining health. No other currently available antibacterial agents provide such an opportunity to “target” a specific subgroup of bacteria.

The concept of using bacteriophages to ensure food safety is slowly but steadily gaining acceptance in the United States. More and more food manufacturers are recognizing the advantage of using bacterial viruses; consumers themselves are learning more about bacteriophages and their widespread distribution in the environment. Phages can be used in a really safe and environmentally friendly way to reduce the number of pathogenic bacteria (listeria, pathogenic strains of E. coli, Salmonella, etc.) in food products without losing their nutritional value and while maintaining normal, often beneficial microflora. To do this, the appropriate lytic bacteriophages are added to the products (for example, sprayed on the surface) in the required concentration. If there are no target bacteria in the products, then over time the phages will simply disappear. In recent years, the FDA has already approved several such drugs to ensure food safety (Sulakvelidze, 2012; Woolston & Sulakvelidze, 2015). The first officially recognized phage-containing preparation for food products (including ready-to-use products) was ListShield from Intralytix, Inc. By the way, it is currently the only phage-based drug approved by the FDA as a dietary supplement. The drug is active against the bacterium Listeria monocytogenes, which causes a serious disease that can lead to serious complications and even death in people with weak immune systems. Several more phage–containing preparations for food products have been assigned GRAS status (Generally Recognized As Safe). It is likely that most, if not all, phage-containing drugs for food safety (and possibly for “probiotic” applications) will be sold in the United States in this status. Most phage preparations for food processing (including ListShield) do not contain preservatives and do not change the composition, taste, aroma and color of products. Some of them are kosher and halal and are included in the list of “organic materials” by an international non-profit organization. The National Review Institute, which defines the conditions necessary for high-quality production and processing of organic products. In fact, these phage preparations have been recognized as suitable for use in the production of organic food products (Woolston & Sulakvelidze, 2015). In order for phage therapy to become widely available worldwide, it is certainly necessary to solve a number of technical and other problems (Sulakvelidze & Kutter, 2005; Sulakvelidze, 2011). However, given the existing potential of bacteriophages for the safe and effective treatment of diseases caused by multidrug-resistant bacteria, it is long overdue to make every effort to introduce this natural antibacterial approach into modern medicine. As for the probiotic use of phages, several such drugs will obviously be developed in the coming years, and it is possible to start with phagobiotics for the prevention and treatment of diarrhea of a well-established bacterial etiology (for example, the same shigellosis). Ultimately, the phagobiotic approach can be used to maintain the normal bacterial flora as a whole, which will serve as the prevention of many diseases, including those of a non-infectious nature. In this sense, phages can play an important role in our lives, representing a unique tool for studying, fine-tuning and strengthening the most important “microbial organ” of our body. Literature Alisky, J., K. Iczkowski, A. Rapoport and N. Troitsky. Bacteriophages show promise as antimicrobial agents // J. Infect. 1998. V. 36(1). P. 5—15. Bergh, O., K. Y. Borsheim, G. Bratbak and M. Heldal. High abundance of viruses found in aquatic environments // Nature. 1989. V. 340(6233). P. 467—468. Breitbart, M., I. Hewson, B. Felts, et al. Metagenomic analyses of an uncultured viral community from human feces // J. Bacteriol. 2003. V. 185(20). P. 6220—6223. Lenski, R. E. Coevolution of bacteria and phage: are there endless cycles of bacterial defenses and phage counterdefenses? J. Theor. Biol. 1984. V. 108(3). P. 319—325. Maciorowski, K. G., S. D. Pillai and S. C. Ricke. Presence of bacteriophages in animal feed as indicators of fecal contamination // J. Environ Sci. Health. 2001. V. 36(5). P. 699—708. Rhoads, D. D., R. D. Wolcott, M. A. Kuskowski, et al. Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial // J. Wound Care. 2009. V. 18(6). P. 237—238, 240—233. Sulakvelidze, A. Challenges of bacteriophage therapy. Industrial Pharmaceutical Microbiology // N. Hodges and G. Hanlon. Passfield, England, Euromed Communications, Ltd. 2012. S13.11—S13.20. Sulakvelidze, A., E. Kutter. Bacteriophage therapy in humans. Bacteriophages // Biology and Application. E. Kutter, A. Sulakvelidze. Boca Raton, FL, CRC Press. 2005. P. 381—436. Woolston, J., A. Sulakvelidze. Bacteriophages and food safety eLS. Chichester, John Wiley & Sons, Ltd. 2015. Zhukov-Verezhnikov, N. N., L. D. Peremitina, E. A. Berillo et al. (1978). Therapeutic effect of bacteriophage preparations in the complex treatment of suppurative surgical diseases // Sov. Med. 1978. V. 12. P. 64—66. Source: First-hand science