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| Deepwide Reports > Articles |
Phages - General InformationCopy of my letter sent to the editor of the Eastern Daily Press, 11th Oct. 2007.General Information about Bacteriophages What are phages and how do they "work"? Bacteriophages (phages) are viruses that infect bacteria. Typical phages have hollow heads (where the phage DNA or RNA is stored) and tunnel tails, the tips of which have the ability to bind to specific molecules on the surface of their target bacteria. The viral DNA is then injected through the tail into the host cell, where it directs the production of progeny phages often over a hundred in half an hour. These "young" phages burst from the host cell (killing it) and infect more bacteria. Can therapeutic phages be developed against any infection? Therapeutic phages can potentially be developed against any bacterial infection. Obviously, because of their "mode of action", phages can not be used to treat viral infections (e.g., influenza or herpes). Can any phage be used for developing therapeutic phage preparation? No. In general, there are two major types of phages, lytic and lysogenic.Only the lytic phages (also known as virulent phages) are a good choice for developing therapeutic phage preparations.Lytic phages multiply inside the cell, and release a burst of phages through the membrane, thus lysing the cell. Lysogenic phages, on the other hand, integrate their DNA into the host DNA creating a prophage. Prophage can escape from the original host (by cutting not only its DNA back, but possibly some genes of the host bacterium as well) and can integrate into a different one (the process is called transduction). Such phages are inappropriate candidates for phage therapy because of their "mode of action," and because they can lead to transfer of virulence genes and those mediating resistance to antibiotics. How safe are the therapeutic phages? Phages are considered to be very safe for therapeutic use. So far only a very few side-effects have been reported in the patients undergoing phage therapy; those that were seen seemed directly associated with the therapeutic process. For example, pain in the liver area (lasting several hours) was reported in one study conducted in Poland. The authors suggested that this might be related to extensive liberation of endotoxins as the phage were destroying the bacteria most effectively. It should be mentioned that this also happens when antibiotics are used. Are there any reports on phage-based clinical trials? Yes. The first reported application of phages for treating infectious diseases of bacterial origin came from Bruynoghe and Maisin in France in 1921. The international literature contains several hundred reports on phage therapy, with the majority of the publications coming from researchers in the former Soviet Union and Eastern European countries. Many of those studies were of poor scientific quality, as they did not include follow ups and appropriate controls. In some cases, successful treatment with phages was reported for diseases of viral and/or allergenic origin which does not make much scientific sense. In the English language, the most detailed descriptions have come from the Institute of Immunology and Experimental Medicine of the Polish Academy of Sciences [Slopek S., et al., 1983, Slopek S., et al., 1987]. Briefly, phage therapy was used on 550 patients, at 10 clinical and hospital departments, in three different cities. Major infecting agents included Staphylococci, Pseudomonas, Escherichia, Klebsiella, and Salmonella. Rates of success ranged from 75 to 100% (92% overall). The overall success rate was even higher (94%) for the 518 cases were antibiotic therapy was shown to be ineffective. Medline citations (published during 1966-1996) on the therapeutic use of phages in humans were recently reviewed in the Journal of Infection [Alisky J., et al]; the overall reported success rate for phage therapy was found to be in the range of 80-95%. Why is there so much controversy about the efficacy of phages? Phages were previously never given a fair and scientifically well-thought-through evaluation; quite often, the conclusions made about the phage therapy or even the nature of phages were unbelievably naïve as assessed from what we know about phages today. Among specific reasons contributing to the early problems of phage therapy, as well as the questions on their efficacy, were: * Failure to select specific phages against the target bacteria in vitro, before using them in in-vivo models and/or in patients; * Lack of availability and/or reliability of bacterial laboratories for carefully identifying the pathogens involved, therefore making selection of specific phage impossible; * Use of single phages in infections which involved mixtures of different bacteria; * Failure to neutralize gastric acidity prior to oral phage administration; * Lack of knowledge that when treating bloodstream infections, endotoxins can be released as a result of lysis of bacteria which could lead to a further deterioration of the patient's condition (which is a potential problem with antibiotics as well); * Lack of understanding of the heterogeneity and "mode of action" of phage (e.g., differences between lytic and lysogenic phages in respect to their ability to act as therapeutic agents); How do phages compare to antibiotics? General comparisons between phages and antibiotics are described below: Advantages: Bacteriophages. Very specific*, affects the targeted bacterium only; therefore, "dysbiosis" (and chances of developing secondary infections) is avoided. No side effects have been described so far - Is able to self-reproduce as long as corresponding host-bacteria are present in the environment. Therefore the need to repeatedly administer the phage is greatly reduced. Since phage is targeted to receptors on bacterial membrane or capsule, which are important virulence determinants, development of phage-resistance usually means changes in those structures and may, therefore, lead to attenuation of the strains in virulence. Selecting a new phage (e.g., against phage-resistant bacteria) is a rapid process and frequently can be accomplished in days. Production is simple and relatively inexpensive . Antibiotics. Can be used without knowing exact characteristics of the disease-causing bacteria. Disadvantages Bacteriophages. Because of the high specificity of phages, the disease-causing bacterium has to be identified before the phage therapy can be started. Antibiotics. Non-specific action that targets not only the pathogenic microorganisms but also a normal microflora. This can affect the microbial balance in the gut, which, in turn, often leads to serious secondary infections. Multiple side effects, including yeast infections, intestinal disorders, and allergies. - Repeated administrations are often needed Antibiotic resistant bacterial strain remains pathogenic. Developing a new antibiotic (e.g., against drug-resistant bacteria) is a time consuming process and may take several years. Production is expensive. * Some researchers consider the high specificity of phages to be their disadvantage against antibiotics, as explained in "disadvantages" section. However, there is an extensive experience in developing "cocktails" of phages, which include active phages against selected pathogens. Have phages ever been licensed for human use? Yes. Phage therapy products were licensed for sale in the United States in 1930s. The Ministry of Health of the former Soviet Union routinely licensed active phage preparations for the use in humans. ; It is likely that therapeutic phages used (and sold) in Eastern Europe were also licensed by appropriate public health authority (e.g., ministry of health). Have phages ever been produced for commercial use? Yes. In the 1930s, a large US pharmaceutical company listed phages among its biological therapies and offered them for sale. Phages were used at the Institute Pasteur in Paris, France, and were sold in Eastern Europe, and all over the territory of the former Soviet Union. Can the bacteria develop resistance against phages? Bacteria can develop resistance against both antibiotics and phages. However, there are some very important differences to favor phages in this context: Development of a new antibiotic is a very expensive and time consuming process; it can take over 10 years and several million dollars to develop, and to bring to the market, a new antibiotic. Developing of a new phage, on the other hand, can potentially be accomplished in days, at a much lower expense. Science may approach a point when no effective antibiotics can be chemically developed (at least for a while) to treat certain multi-drug resistant micro-organisms. Since selection of active phages is a natural process, evolutionary arguments support the idea that active phage can be selected against every resistant bacterium, by an ever ongoing process of natural selection. Thomas Hausler's excellent book on the history of phage therapy; from the early days under Stalin's rule to modern times. The answer to MRSA Deepwide Site Map Thomas Hausler's excellent book 'Viruses-v-Superbugs'
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