1) Bacteriophages (more commonly called phages) belong to different families of viruses, widely represented in all environments of nature, soil, water, air and are capable of lysing bacteria. It is known that man is in continuous contact with phages, as these are ubiquitously present in water (about 104-108 / ml), in the soil (109/g), and in the human organism (they have been isolated from saliva and feces).

2) With respect to their natural targets, phages show an extremely narrow host spectrum, linked to the recognition of specific bacterial receptor molecules to which they bind uniquely through viral structures with an attachment function (plate and fibers).

3) Phage activity is very specific. In fact, they only attack their natural host without having any influence on the rest of the microscopic flora. This is a fundamental aspect of phages, especially in relation to their potential therapeutic use in humans, since they are able to attack exclusively bacterial cells, not having the ability to enter and reproduce in any eukaryotic cell (including human ones), for which they are therefore totally harmless.

4) The ability of phages to have a specific target, to destroy a specific bacterium, and to replicate exponentially within the bacterium it infects identifies the potential role in the treatment of bacterial infections.

5) Phages have additional advantages over antibiotics:

a) they are ecologically safe (for plants, animals and humans)

b) they are easy to prepare in pharmaceutical preparations

c) easy to apply

d) they have no significant side effects even if prepared in multicomponents (cocktails)

6) The growing incidence of antibiotic resistant pathogens is leading scientists to rediscover the possibility of developing phage therapy as a reliable therapeutic alternative.

7) The therapeutic use of phages has a long history, dating back to the first isolation in 1917 in Paris, by Felix D'Herelle, who prepared a solution for the treatment of dysentery.

8) This branch of microbiology had a notable development until the 1930s, when the discovery of penicillin led to the abandonment of these lines of research.
Especially for the wide spectrum and the speed of use
of antibiotic therapy, against the highly selective action of phages.

9) A second reason for abandoning phage therapy was the difficulty, present at that time, of characterizing the etiological agent of a specific infectious pathology and the absence of established protocols to accurately identify in vitro the susceptibility of the bacterium to phage.

THE DEVELOPMENT OF PHAGUS IN THE FORMER SOVIET UNION

1) Lower production costs and development of therapeutic protocols. Less pressure from the multinationals of the
drug.

2) Phages remained in the Pharmacopoeia of the USSR even in the 60s and 70s, when the world saw the peak of efficacy and distribution of antibiotics.

3) They were used in particular for the treatment of dysentery, purulent infections, such as infections of burns, wounds and organ inflammation.

METHOD OF PREPARATION AND APPLICATION OF PHAGES

Phage preparations can be crafted in two main ways:
a) Cocktail of phages directed against some species of pathogens which are generally the cause of certain infections
b) Personalized therapies In this case, the development of the therapy requires:

1) Absolute need to know and characterize the pathogen that causes the infection we want to treat.

2) Before treatment, the pathogen must be tested in vitro against the available phage library in order to select the most effective phage for therapeutic application.

3) At the present time, the success of the therapeutic use of phages depends on the diagnostic laboratory and the availability of a library of well-characterized phages.

4) Phage selection in the preparation of therapeutic cocktails is the key factor in preventing the selection of phage resistant bacteria.

5) The phages used must have a sure lytic activity on the target bacterium, and a possible transfer of virulent genes through lysogenicity or transduction must be excluded. In the best-case scenario, the DNA of the phage chosen for therapeutic purposes should be sequenced to ensure that it does not include genes for toxins, islets of pathogenicity, or genes that can integrate into the bacterial DNA genome.

6) Prepare a preparation that remains stable from the moment of its production to use in the field.

7) Knowledge of phage biology is essential to avoid bacterial resistance to phages. Although the event is rarer than the onset of resis

THE ROLE OF THE ELIAVA INSTITUTE OF TBILISI GEORGIA

1) The Eliava Institute, founded in the 1920s, produces phages for the treatment and prophylaxis of intestinal and purulent infections. It is the Institute with the greatest clinical experience in the world in this field.

2) The preparations produced are readily available and can be administered in different ways: oral (solutions or tablets), local (swabs, creams), endorectal, aerosol, intrapleural, aerosol, intravenous.

3) There is a substantial literature produced by the institute on the subject carried out in collaboration with some institutes in Switzerland, Belgium, United Kingdom. In Italy there is no experience in this regard.

POSSIBLE DEVELOPMENTS AND STRATEGIC IMPORTANCE OF RESEARCH ON PHAGES

Based on the existing results and the emergency related to antibiotic resistance, phage therapy is therefore currently of great interest, especially for treating infections that do not respond to conventional antibiotic-based therapy.

Consequently, in recent years there has been a marked increase in the number of publications and international conferences on the subject (Bacteriophages, London 2016; Phage therapy-TID-Paris 2016), in which the need for clinical studies has been repeatedly stressed. controlled and randomized, which can provide adequate clinical data for a scientifically rigorous evaluation of the efficacy of phage therapy.

In a document published in 2015 (EMA / 389257/2015, http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/07/WC500189409.pdf) the EMA (European Medicine Agency) emphasizes the potential importance of phage therapy in the light of the growing diffusion of antimicrobial resistance, while complaining about the scarcity of randomized and controlled clinical trials that allow to evaluate its efficacy and safety.

The Eliava Institute is historically the most important phage research center, collaborates with numerous international centers (in USA, Canada, UK, Germany, Ireland, Denmark, Belgium, Switzerland, France), has a library of phages already selected and tested against the major strains of human antibiotic-resistant pathogens, and has a long and proven experience in the use of phage therapy.

THE PROBLEM OF EXPERIMENTATION

Given that phage therapy could play a key role in fighting multi-resistant bacterial infections and in decreasing the costs of infection control and therapy in the coming years, many European researchers and governments have understood the strategic role of research in this sector, but the introduction of therapy in Italy and in the European Union encounters major obstacles from a regulatory point of view.

First of all, phages, being products present in nature and not of synthesis, cannot be protected by intellectual property, that is by patents. This makes them less attractive to the pharmaceutical industry. The other aspect that makes management by pharmaceutical companies complex is the need for considerable know-how for the personalization of therapies and for the preparation of phage cocktails.

Phage preparations, having therapeutic activity, cannot fall into the category of food supplements (as happens for probiotics for example) but rather biological drugs, and like these, they would need to follow the experimental and clinical process before their authorization. as therapeutic agents. This applies to direct administration to humans and animals. As agents to be used in the environment, the regulations are obviously less stringent and some phage-based preparations are already authorized by the EFSA (European Food Safety Authority) for the prevention of some foodborne infections.

AIMS AND BACTERIOPHAGES

On the basis of a scientific collaboration agreement with the EPTC (Eliava Phage Therapy Center), AIMS is responsible for promoting the use of bacteriophages on patients suffering from infectious diseases who do not respond to antibiotic treatments and for which reasonable alternatives are not available. therapeutic. In the absence of approval by the European regulatory agencies of the drug, the therapy can be administered to patients who need it, based on the criteria defined in the Declaration of Helsinki. In fact, despite the absence of a defined regulatory framework, many European countries, in particular Belgium, France, Germany, have started some clinical experiences within hospitals.

The doctors of AIMS evaluate, together with their colleagues at the EPTC, the candidates' applicability for therapy with bacteriophages on the basis of clinical and microbiological findings. They coordinate the treatment with the doctors treating the patients, to whom they do not replace but integrate themselves so that patients can continue their conventional treatments (in particular antibiotic therapy), with which bacteriophages do not interfere, but rather, in many cases, determine an increased susceptibility of the infection to drug treatment. They follow the patients in their therapeutic path making sure that they follow the current guidelines in the treatment of their specific pathology.