PHAGE THERAPY
The Use of Bacteriophages Against Infections
by Amiran Meipariani, PhD, Academician
Felix d'Herelle the discoverer of bacteriophages, was of the opinion that all bacteriophages belong to the same biological origin, but this was disproved in later research.
It was discovered that there are different groups of special bacterial viruses, which are widely spread throughout nature. The bacteriophages coexist in the same environments as where microbes are reproducing. The bacteriophages can be found everywhere in human and animal intestines, in running water, in the soil and in the cell of microbes.
The research of the bacteriophage phenomena has exceptional importance in the history of microbiology. The simplicity of their cultivation, short generations, exact accountability, helped to clarify not only the structure of viruses, but also the relationship between bacteria and viral particles.
Using an electron microscope in the process of research definitely enriched our knowledge about the nature of bacteriophages. It was discovered that the majority of bacteriophages have the shape of spermatozoids. It has a head, which contains nucleic acid and a tail. Some phages have a very short tails or no tail at all.
According to their different structures, the bacteriophages belong to different morphological groups. Bacteriophages and viruses contain nucleic acid and protein. The majority of phages contain deoxyribonucleic acids, but some contain ribonucleic acid. The bacteriophages are more resistant to physical and chemical factors than human viruses. Phages are inactivated at high temperatures (60 to 70 degrees Celsius), but are resistant to low temperatures for long periods of time. Bacteriophages are also very sensitive to acids.
There is an interdependency between bacteriophage and microbe cells. Their interaction usually ends with the destruction of the microbial cell. For example, if we have an infection called absorption, the bacteriophage is not reproducing within the cells and the microbe cells are kept alive. In some cases, when the microbe cell in infected by the bacteriophage, lysogenic conditions are produced, as the bacteriophage's genome integrates itself with the microbe's genome. The microbial cells will lyse and die.
The relationship between the bacteriophage cells and the microbe cells has four stages of development:
Adsorbability: There are the receptors on the wall of the bacterial cell, which attract certain bacteriophages. It is possible to adhere hundreds of bacteriophages on the wall of one bacterium, although one bacteriophage is enough for destruction of the microbe.
The adsorbed bacteriophage transfers its own nucleic acid into the microbial cell. The mechanism of this transfer can happen in different ways, but it is not yet fully understood.
Then biosynthesis of bacteriophage starts, nucleic acid is transferred into the microbe and bacteriophage proteins are being produced inside the microbe. The proteins will late! be used to assemble new bacteriophage.
This is a process of morphogenesis of bacteriophage, filling of the bacteriophage with nucleic acid and complete its development.
The bacteriophage is separating from the microbial cell. This is the process of destruction of the microbe and the release of new bacteriophages. The bacteriophage is self-reproducing only in a suitable microbe cell and reproduces individual bacteriophages such as: dysentery bacteriophages, which cause destruction of dysentery microbes, and staphylococcus and streptococcus bacteriophages, which are destroying the staphylococcus and streptococcus.
It has been almost 60 years since bacteriophage were discovered and used as a therapy agent in medical practice. Since the discovery of the phage and up to present, research of phage as a therapeutic agent has been a difficult and controversial process. Some scientists were in doubt of the bacteriophage and its use in medical practice. Dr. d'Herelle and his scientists proved that their doubts had no foundation.
When we are talking about the use of bacteriophages, we have to remember those who believed in phage-therapy. Their names are: Eliava, Mikaladze, Tsulukidze, Antadze, Kvitaishvili, Maslokovets, Kazarnovskaia, Krestovnikova, I Makashvili, Viskovski, Fisher, Pokrovskaia, Karpov, and Timakov. Their scientific researches saved hundreds of lives. The process of phage-therapy can be divided into several periods.
Part of the scientific community believed that the discovery of bacteriophage would help doctors to treat infectious diseases successfully. At that time, the bacteriophage-therapy was a powerful agent against dysentery, typhoid, sepsis and cholera. During the 1920's, there were enough materials about the spread of phages in the environment and its biological nature. The bacteriophages were discovered to fight against all infectious diseases. The development of sulfonamides and antibiotics significantly reduced the interest towards phage- therapy. Theoretical research of nature and reproduction of bacteriophage took a very important place in biological science during 1945-1955.
The bacteriophage became a unique model in research for molecular biology. Research of bacteriophages helped to clarify the exact role of deoxyribonucleic acid in heredity and also other important questions in molecular biology. For example, the blue print of DNA-RNA-protein, discovery of informational RNA (ribonucleic acid), research of genetic coding, etc. The research in theoretical biology diminished the role of bacteriophages in treatments against infectious diseases. The importance of theoretical research of bacteriophages put the practical use into second place. At the same time, successful use of antibiotics completely isolated bacteriophage-therapy. Later it was discovered that antibiotics had some disadvantages, like high mutation rates of microbes toward resistance to the antibiotics. The irrational use of antibiotics created different kinds of allergies, lack of intestinal bacteria (especially among children), etc.
Pathology of intestinal infections is 30% and up, among all the infections in the human population. By statistical information of the International Health Organization, almost 500 million people have intestinal infection annually. According to this information, the preventive medicine in very important in therapy of intestinal infections. The scientific development of bacteriophage is closely connected with its practical use.
F. d'Herelle successful experiment motivated the scientists to consider the phage-therapy a very important agent as a treatment of dysentery. There were enough materials to consider the bacteriophage the right preventative agent to treat intestinal infection, dysentery and typhoid sepsis.
Analyzing all those materials about phages against dysentery and typhoid sepsis, there were some mistakes about dosage of medication, time of use, and the most important part -- the quality of medication, and specification of phage. The bacteriophage against dysentery can be used in two ways: first – the bacteriophage as a curative agent and second the bacteriophage as a preventative agent.
The specific treatment of dysentery by the bacteriophage depends not only on its ability to destroy the microbes, but also when and how many times it is used. The bacteriophage must be specific, polyvalent with a wide spectrum of activity. It is very important to give this medication to the patient in the beginning stage of intestinal infection, before any serious pathological changes take place.
The research has proved, that when bacteriophage is used in the first stage of infections (during the first 5-6 days) 64% of the patients after 24 hours of administering the drug showed a clear clinical improvement; and after 48 hours, a complete cure. Not only clinical recovery shows the value of bacteriophage therapy, but also bacteriological sanitation.
The treatment of chronic dysentery with phage was not perfect. The doctors tried to create better and more effective drugs. One of the drugs developed was well-adapted bacteriophage with wide spectrum. It was administered in the complex therapy of dysentery.
In many cases, the results were more effective than treatments with antibiotics and sulfonamides. During the chronic form of dysentery, microbes from patients were treated with specially adapted bacteriophages. Children with chronic dysentery were given bacteriophage 2-3 times a day (5-15 milliliters) during 3 days. The period of recovery decreased from 1 year to 3-6 months. The treatment with other drugs takes at least 9 months to show similar results.
The clinical experience shows that desirable therapeutic results can also be reached using bacteriophage in large quantities. In case of late treatment, it is recommended to increase the dosage and quantity of drugs. The research by the noted Georgian scientist, Professor Kvitaishvili, shows that bacteriophage treatment can be more effective than antibiotics and sulfonamides in case of dysentery. The right calculations of time and specific qualities have to be taken into consideration. There is no doubt that bacteriophage is one of the strongest biological agents and rational use can advance the fight against dysentery.
Today, antibiotics are used to treat tuberculosis, cholera, typhoid, sepsis, etc. In spite of all successful use of antibiotics, lately it has been discovered that some microbes are resistant to them. It can be hereditary or caused by mutation. In 1940, Abraham and Chase found penicillinase as a neutralizer of antibiotic - penicillin. Years of research showed that the percentage of microbe resistance to antibiotics grows not only in dysentery microbes but in other microbes as well.
The Japanese scientist --Watanabe, performed some very interesting research regarding antibiotic resistance of microbes. He was mentioning that antibiotic treatment in medical practice gave a big hope to doctors, that all the infectious diseases would be cured, but it did not happen. The cause was the resistance of microbes to the antibiotic and sulfondmides. This phenomenon is called "Infectious Resistance." The mechanism of the resistance is based on genetic analysis and proved to be hereditary.
"Infectious Resistance" is quite dangerous, because it might involve all kinds of microbes and create complex difficulties, especially in treatments of intestinal infection. Irrational use of antibiotics caused lots of unwanted results, such as lack of bacteria, when micro-flora of the intestines is destroyed, allergy syndrome, etc. That is why it is very interesting to quote Watanabe, "If we will not stop irrational use of antibiotics and other synthetic drugs, we will end up back in the time when medicine had not yet discovered antibiotics."
The last 10 years of research confirmed once more that use of antibiotics especially against dysentery, created resistant forms of microbes in the human body and environment. With growth of resistance other biological changes occurring in microbes such as: fermenting activities, antigen, virulent, reaction toward physical and chemical factors. The study of these changes of microbes from the use of antibiotics has not only theoretical, but also practical importance which is connected to treatments with antibiotics and antibacterial drugs, such as bacteriophage. The research shows that antibiotics do not inactivate the bacteriophage.
Based on these factors, combined treatment using bacteriophages and antibiotics was initiated. Once again, the research proved effective use of bacteriophage, for acute and chronic dysentery. The combined therapy proved to be effective, when the patient first is given bacteriophage, then antibiotic. The result of therapy is much better when started in the beginning stage of infection.
It has to be noted that bacteriophages are safe and do not have side effects.
For acute forms of dysentery, among children, specific bacteriophage of dysentery was used. The patients were given the drug every day during 7 days. After therapy, the result was positive. There was 78% of clinical and bacterial recovery, which means it was not necessary to give patients the antibiotics. For intestinal infection, caused by pathogenic microbes, they used combined therapy, after antibiotics they used bacteriophages against Proteus and intestinal bacillus. After therapy 67.7% of patients were recovered and 29.7% of patents improved, 2.5% had no result.
The results of dysentery treatment proved effectiveness of preventative use of the drug. The length of circulation period of bacteriophage was established along with its effect on the micro-flora of intestine, the time of receiving the drug, intervals and its dosage.
The research proved the effectiveness of bacteriophage. The children up to 3
years old were given 3 milligrams of drugs; the adults took 5 milligrams of
drug 3 times a day with 7 -day intervals. Increased dosage up to 15 milligrams
of drugs and shorter intervals (from
Use of bacteriophage as a preventative agent against the dysentery was proven, when people who were in contact with sick patients had been given bacteriophage. As a result, most of them were not infected by dysentery. The majority of scientists are saying that the bacteriophage is most effective as a curative and preventative agent against dysentery. It is safe and without side effects.
The combined drug use against the intestinal infections among children contained bacteriophages to fight dysentery, intestinal bacillus and Proteus microbes. The drug was given to children during an epidemic season. As a result of phagetherapy, the level of intestinal infections decreased 9 times, with 5 day intervals, because increased concentration of phages in the intestines created the right conditions to resist the microbes (which cause disease).
Antidysentery bacteriophage was used not only as a curative and preventative agent, but also as an agent of gave good results in the second stage of treatment. Bacillus was a positive second stage of therapy. Each stage of therapy meant use of the drug once for 4 days.
The department of children's intensive care in Leningrad Medical Institute proved, that during pneumonia, contaminated wounds, burns, sepsis, the main cause of infection is pseudomonas (an acute pusforming microbe). For this preventative therapy, they used bacteriophage, created in the Tbilisi Institute of Vaccine. During 5 days, children were given 10-30 milligrams of drug daily.
After therapy, tile bacterial research proved that 83.6% of cases reproduction of the microbes stopped without any side effects.
The effectiveness of bacteriophage increased when the phage-cultures came from an infected human body. Finding the therapeutic effect of specific phage was possible with bacterial analysis - with controlled temperature, index of peripheral blood, and wound condition. After therapy, 66.6% of the result was good and effective. The result was better when the phage was used directly in the wound area.
The effect was less favorable, when phage was used in deeper wounds. The time factor is very important. Early therapy gives better results. Today, phage-therapy of typhoid sepsis belongs to the past. Antibiotic therapy completely replaced phage-therapy of typhoid sepsis, but phage-therapy, as a preventative agent is still very important.
We use phage-therapy against typhoid sepsis with the same success, as when we used it against dysentery infection. We had good clinical result using the bacteriophage during the explosion of typhoid sepsis. After therapy, the level of infection decreases, and later disappears. After recovery from typhoid sepsis, some patients are still carrying the bacteria, which creates potential spreading of the microbe.
The fight against "germcarriers," and their sanitation demands systematic observation and research. After scientific experiments on animals, researchers concluded that bacteriophage for fighting typhoid sepsis is acting not only as an agent to lyse microbes, but also as an immunogene drug. Using Salmonella. typhimurium bacteriophage in massive quantities during anti-epidemic period as a prevention reduced the number of cases, during the period of one month. Compared to the previous year, the number of illnesses decreased six times.
The percentage of sanitation in controlled areas was 4.4 and 9% in treated group. The same positive result was given, when bacteriophage was used against typhoid sepsis explosion. The results were interesting, when bacteriophage was inserted to the animal by internal application. It was discovered that you could find the phage in the blood after 2-9 days, in mesenteric gland and spleen after 2-10 days, in the lever after 3-8 days, in the fecal content 4-10 days.
The process of cleansing the body from typhoid sepsis microbe takes 1-9 days. At the .same time, phagocytic process becomes very active. It has practical importance to know how long bacteriophage stays in the human body, when periodically taken. By experiment it was proved, that during a 3-hour period, bacteriophage completely spread throughout the body. Later findings have sporadic nature and it slowly disappear. Increased intake of dosage (10-15 milligrams) stabilizes the time of spreading and cleansing period.
The bacteriophage stays longer in the reticuloendothelial system, especially in the spleen and in the large intestine. In the blood system, phage can be found in 30 minutes after intake. Intensive reproduction of bacteriophages from children's intestines starts in the first 3 days. The increased dosage and interval between intakes of the drug makes circulation and reproducing period much longer. The scientists think that higher concentration of phage in the human body increases effectiveness of the drug.
For the purpose of sanitation of chronic bacterial-carriers during the typhoid sepsis infection, increased use of dosage is proven to be effective. In infectious pathology, diarrhea and colitis are common among children. For treatment of those diseases, polyvalent bacteriophages are used with success. French scientist, F. d'Herelle, used the polyvalent intestine phage as a curative agent first.
The components of polyvalent intestine phages are: dysentery, typhoid sepsis, paratyphoid, salmonella, proteusis is staphylococcus, streptococcus, enterococcus, pseudomonas and intestinal bacillus, fighting bacteriophages.
Nowadays, the components of intestine phage depend on what kinds of micro- flora are circulating in a certain geographical zone. The activity of independent components in combined drugs is stable -their action is the same, as each of them in separate use.
The advantage of intestine phage, in comparison with other drugs in therapy of acute intestine diseases, lies in its polyvalent nature. It is effective to use this drug from the first days, before the beginning of investigation. Multiple content of phages gives us the chance to use this drug in the very first day of the treatment before any bacteriological research begins.
The majority of scientists, who used polyvalent intestine phages for treatments, concluded that bacteriophage and its biological qualities which are based on direct interaction with microbes, has to belong to the kind of drugs, that are effectively fighting intestinal infections. Use of intestine phage as preventative treatment gives us much better results than any other drug. This effect is based on its specific safety of its intake.
The research by Logoladze of intestine phage is quite interesting. According to this experiment, 452 children were treated by intestine phage, 110 with antibiotics and 29 with complex intestine phagetherapy. The recovery of its intake period among the children with intestine phage therapy was 9 days, with antibiotic therapy 29 days and with complex 15 days.
The length or recovery of its intake period in the group that used only intestine phage lasted for 9 days; recovery from antibiotic treatment for 29 days, and combined for 15 days. It has to be noted that use of intestine phage shows its effectiveness on the very next day. The recovery of the majority of children under phage therapy was starting at 4th, 5th, 6th day. Recovery period under antibiotic and combined treatment is much longer - starts at the third day and continues during 15 to 29 days.
There was interesting research done by scientists from Saratov Medical Institute's Children's Department of infectious Diseases (Stoliarova, German, Trifonov, and Milnikova). They used phagetherapy against dysentery caused by salmonella and proteusis.
The patents were treated with phages during 7-10 days. Also they were given symptomatic treatment. Some children took only antibiotics. This therapy lasted 17 days: 42.2% of the patients had unstable bowel movement, 26.7% of the same bowel movement symptom, 30.9% with secondary producer of cause.
The scientists decided to use extra therapy with polyvalent salmonella bacteriophage. After tile therapy, 66.2% of patients recovered completely, and 16.9 with better resistant conditions. The period of time spent in the clinic lasted 25.6 days. For ones that had not used phagetherapy, treatment stretched to30.5 days. 53.3% of patients recovered, 33.2% were in better condition, and 13.3% without any results. The patients were staying in the clinic 34.7 days. Scientists (Tsereteli, Kiknadze and others) studied the polyvalent -salmonellosis bacteriophage at the Tbilisi Institute of Vaccine.
Results of the 10 years of research proved that use of bacteriophages against intestinal infections has strong scientific background. It is very effective, safe and has no side effects. Use of bacteriophages for supuratavie inflammation, surgical, urological, gynecological and infectious allergies has to be noted. The reason for successful used of the bacteriophage in above-mentioned diseases, based on the existence of bacteriophages that are produced to fight against it, purulent infections and the possibility of a relationship between phage and its cause.
According to statistics of Saratov's Scientific Research Center, Staphylococcus and Streptococcus bacteriophages (made at the Tbilisi Institute of Vaccine) were used for infectious-allergic rinosinusopathy, infectious-allergic bronchial asthma, during neurodermatosis, caused by hyodermatosis. Among the 118 patients subjected to staphylococcus phage-therapy, 90.3% of the patients had positive results, streptococcus phage-therapy success rate was 94.1 %, combined phage- therapy of both gave 99% effectiveness.
Infections caused by diverse (phyogenic) microbes have mix infection character. In this condition, treatment is very difficult. There are very few active antibiotics with wide spectrum, and the quantities of resistant microbes are steadily increasing. Because of these conditions, demand to create new forms and possibilities occurred. Phyobacterophages are characterized to have positive results in cases of mixed infections, in short periods of time, an infected wound is healing faster and the patients' condition improves. Among newborn babies infected with pink eye, when etiologic factor is multifaceted and treatment with antibiotics is limited, staphylococcus and phyobacteriophages are used. A drug for treatment of infected eyes was given in quantities of two drops, 4-6 times a day. Results were positive in all cases. Purulence had disappeared on the second day. The complete sanitation and clinical effect were reached on the 3- 7th day without side effects.
During the process of phagetherapy and chronic phagetherapy, knowing the cause is important, along with etiological factors, which had gone through big changes since the 1940s. Different kinds of dysentery and other infections made it difficult to produce suitable bacteriophages, but research to increase the effectiveness of phage drugs, had positive results anyway. Nowadays, the medical institutions have produced effective and safe drugs with a wide spectrum.
In 1979, French scientist P. Nicole mentions in the bulletin of
Liquidation of the process of infection, among children during epidemic of gram- negative microbes. The chronic infection of urethra.
The phagetherapy phage are not just a "primitive" drug, but a strong, effective agent:
Two groups of microbes: Salmonella and other bacteria, such as Klobsiella, Serratia, Proteus and Providencia, which spread epidemic and post-surgical non- epidemic infections, besides staphylococcus and acute purulent bacillus. Widespread different kinds of bacteria, which are resistant to all known antibiotics.
The different kind of bacteria, which are resistant against all known antibiotics. osteomylitis
The phages are curative agents for abscesses, boils, Septicemia and Pyelonephritis infection of the urethra, where gram-positive and gram-negative microbes cause diseases, afterburn purulent inflammation process, and skin infection. It has to be noted:
Post-surgical infections which cannot be controlled with antibiotic therapy --there are also staphylococcus, enterococcus, green purulent bacillus; Serratia, Klebsiella, Providencia, etc.
Epidermal infections among newborn babies --pathogenic intestinal bacillus, especially Enteritis and Salmonella. typhimurium,
The persistent urethra infection cause of Providencia, Serratia and Proteus microbes.
According to these infections, the medical institutions producing phages decided: to produce combined phages, with wide-spectrum of effectiveness, the Tbilisi Institute of Vaccine is the pioneer of producing phyo- and intestine phages –the best agents against purulent microbes and intestinal infections. Both drugs were tested in clinics successfully. The phyobacteriophage produced in the Tbilisi Institute of Vaccine was used as a therapy agent in Moscow Children's Medical Clinic for newborn babies with severe enterecolitis diseases. When it comes to heavy forms of the illness, combined bacteriophagetherapy is recommended. Within the middle ear, chronic purulent which was caused by staphylococcus and green purulent microbes, phagetherapy showed that the length of antibiotic therapy was 2.5 times longer than phagetherapy process.
The antibiotic therapy needs 8-10 doses, and phage therapy needs 2-4 doses (in the ear during 2-10 days they used 1-2 times antibiotics and bacteriophage eardrops.) It is known that all inflammation processes among newborn babies are followed by lack of intestinal bacteria, which is caused by Staphylococcus and fermentation qualities, changed by intestinal bacillus, Proteus and fungus.
The antibiotic therapy in many cases destroys the biosystem, which increases complications. The treatment of enterocolitis, caused by pathogenic microbes and method of decontamination (selective influence of antibiotics on microbes) antibiotics and other chemical therapy has some negative effects, which destroys intestinal normal micro-flora.
In this case, as a clinical and bacteriological point of view, the polyvalent phage effects on conditional-pathogenic microbes without changing normal flora. The patients were given bacteriophage with Bifidobacteria and other patients were given antibiotics. The bacteriological researches confirmed that after 7-10 days of antibiotictherapy, the intestinal pathogenic flora was decreasing, without bifidobacteria flora, establishing dyspeptic syndrome on the background of lack of intestinal bacteria of II-III degree.
The phage therapy effect on conditional-pathogenic flora and on the increasing quantity of bifidoflora. The clinical recovery increase of patients weight were confirming and specification of phage. It is necessary to establish dosage of phages and of intake. It has to be established that the place of injection of drugs and to-select the quantity of patients according to bacterial researches. It is necessary to produce preventative-therapeutic bacteriophages, against conditional-pathogenic microbes like: Klebsiella, providencia, etc.
Air spray bacteriophages should be developed for local application. Half intetic phage drugs Should be as effective as an injection in the bone. The bacteriophage can be used not only like preventative therapy agent, but also diagnostic agent of infectious diseases, as identification and differentiation of cause. Today it is known the positive effect of bacteriophage against epidemics. Besides typhoid sepsis phages, there are Salmonella. paratyphi, Staphylococci. E. coli, Salmonella. typhimurium, Shigella. dysenteriae, Brucella and other phages.
The growth of titer of phage is a well-known method. It is necessary, represented by Timacov and Coldfavre.
The blueprint of the phage becomes more sophisticated and easy to get. The collection of typical phages is in reach with new specific phages like, cultivated enlarged and complete original phage blueprint toward Salmonella. typhimurium, pathogenic intestinal bacillus and salmonella paratyphoid microbes. It is a very interesting factor to use the phage to find out the level of pollution in the environment. Specific phage is produced to help to find out the source of infections and ways of spreading it.
It is known that a contact of patients with infected things and medical personnel cause the spread of infections. Also we have to know the mechanism of microbe pollution through air. According hou3e-contact infection phagetherapy the scientists received very impressive results -after phagetherapy, the level of dysentery decreased 3-6 times, hospital salmonella infections 3-14 times and in some cases it disappeared completely. After scientific experiments, it was found that phages not only are adsorbing on the microbe surface, but also self- reproducing in the environment.
In Kemerov's maternity house in
The newborn babies' purulent infections were 2.3 times less in the experimental department than in the observation department. The coefficient of effectiveness was from 2-6. The maximum level of diseases in the physiological department was obvious after 2-3 weeks of delivery. 2-3 weeks after delivery, during the illnesses in the experimental group level of birth increased but in this group illness is 2.5 limes lower in every thousand child. It reaches from 4.3 to 6.0.
After phagetherapy decreased, the frequency of purulent infections increased by 2-3 times. In the department with phagetherapy, the acute intestinal infections decreased 2.4 times. The main sources of intestinal infections are Klebsiella, Citerobacter and unknown microorganisms. The intestinal infections among the newborn babies start within 1 week of birth, in 6.1 % of the patients. The infections are decreasing after 2-3 weeks, by half in the observational group.
The case is the opposite in the experimental group:
There is no incident of infection within 1 week of birth, which has certain epidemiological meaning. The level of the intestinal infections increases after 3- 4 weeks. To use phyophage in the environment decreases the purulent-sepsis infections 2-3 times and intestinal infections --2.4 times.
The bacteriophage can be used to study the mechanism of the purulent-sepsis epidemiological process. The patient, instruments and personnel are the sources of infections. As a rule, infecting by purulent infection happens in the procedural department. The Soviet scientists spent lots of time and energy to study theoretical and practical sides of bacteriophage. The Tbilisi Scientific Institute of Vaccine is one of the well-known and important centers producing bacteriophages.
Today there is ongoing research on development of bacteriophage and its use in medical practice for discovering new phages. The 60 years of experience of phagetherapy gives us the right not to agree with the American scientist, Stent's idea that the last paragraph in the history of phages is closed and there is not need to go back.
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