Phage application in medicine

Phages are useful where bacteria are unwanted. This rather egocentric point of view does not acknowledge the underestimated role and vast biodiversity of phages in nature but, for applicative use of phages it briefly reflects what makes them so attractive. Already in 1917 when Felix d’Hérelle discovered phages independently from Frederick Twort (1915) their potential application for medical therapy was imaginable and was soon dominating early scientific approaches using phages; however, without being able to visualize the phages (a phage is only visible in an electron microscope). It was the lytic effect “making bacterial cultures glassy and sick” as it had been discovered by Twort that made phages attractive. As phages specifically attack bacteria only while leaving all other organisms or cells intact and because phages are targeting a limited number of strains within a bacterial species, they are a logic, biological, natural, antibacterial agent with a high specificity of action. Phages and their host bacteria must fit, otherwise, the bacteria are left unaffected. What does it mean that they must fit? It is the bacterial cell surface receptor that is recognized by a phage, but this alone does not mean a phage will be a successful lytic agent, there are many complex steps within the bacterial cell that must work properly in order to generate a new phage generation and even the release of the phage progeny is an enzyme-driven controlled process.

  Lytic phages for therapy purposes must either be isolated from natural habitats (often sewage water) by “screening” them against the respective bacterial strain (option 1) or, there might be a collection with holdings of many characterized phages per bacterial species where phages are kept in non-purified laboratory quality (option 2) or, there might be a collection of a number of characterized phages per bacterial species already highly purified as pharmaceutical preparations that might be directly used in hospitals (option 3) to target the unwanted bacteria. It would be most desirable to establish option 3 in order to react fast in individual patient cases and to have some hospital facilities functioning as centers for phage therapy. However, option 1 is not realistic, too much time is needed from ad hoc phage isolation until having a purified phage preparation available. The DSMZ is globally one of few supply culture collections expanding its collection of characterized phages against clinically most relevant bacteria that are mentioned on the WHO priority list so that under option 2, a growing diverse phage collection might feed into option 3. Option 3 is highly relevant for future but currently not yet reality and only in the medium run.

There are principally two avenues of clinical phage application: either, a fixed phage cocktail licensed as a product is used or, an individualized phage mixture is prepared from single purified phage preparations in a hospital pharmacy for a patient. Fixed cocktails are in the centre of interest in case of systematic clinical trials (Randomized Controlled Trial, RCT). An example is the consortional German project Phage4Cure, publicly funded by the Federal Ministry of Education and Research (BMBF). The other strategy is called the magistral pathway and requires a phagogram prior to phage use to identify the most suitable phages in order to combine a tailor-made specific cocktail. The project PhagoFlow represents the magistral pathway and is the first German consortional project, publicly funded by the Federal Joint Committee (G-BA). The magistral pathway works the better the more different phages are available ready-to-use which means highly purified for application in patients and it is reasonable to prioritize pathogens according to the WHO list of the most worrying bacteria.    

All expertise and knowledge of phage biology and the many decades of successful phage therapy allow the statement that phages do not cause unwanted side effects. Well-selected phages typically lyse target bacteria quickly and completely if pronounced bacterial phage insusceptibility development does not occur.. Principally, the availability of potential therapy phages against a bacterial strain will never be limited as novel phages can be found again. Therefore, a potential development of bacterial multiresistance against phages is irrelevant compared to antibiotic multiresistance (AMR). Furthermore, it is irrelevant for phage application whether or not the bacterium is (multi-)resistant to antibiotics.It should be stated also that there are difficult-to-treat infections not caused by AMR bacteria and where phage therapy would be highly desirable for other reasons. It is also confirmed by experts that phages are able to penetrate biofilms more effectively than antibiotics which has several reasons that cannot be discussed here.

Physicians applying phage therapy have profound expertise in phage biology and cooperate with phage biologists who have characterized the phages properly before application. As mentioned above, only appropriately purified phage preparations can be used that fulfil the requirements by the respective national licensing authorities. Different methods are used by physicians to apply phages at the localization of the bacterial infection. There are no fixed therapy schemes or general recommendations yet, all individual phage therapy approaches require joint consulting and involving ethics committees. However, this of course cannot be subject of this website and does not fall into DSMZ expertise.

It should be pointed out that phage therapy has many preconditions that cannot be discussed here. Basically, it is highly relevant to have large phage collections, sometimes called “phage libraries” to select most suitable phages for research & development projects to investigate the potential of phages for different applications, their safety and efficacy. In vitro and preclinical research must be done to evaluate the suitability of single phage entities or phage cocktails that have been combined for certain therapy projects or clinical trials. Phage purification according to the national regulations is a must so that side effects of phage applications are minimized or excluded. Finally, phages are unusual therapeutics, their anisometric structure and size is much different compared to any other drugs, their effect self-regulating. An adapted regulative framework in Europe is discussed.