Is there a future for phage therapy?

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With fears of a post-antibiotic era, as old and new antibiotics alike are failing rapidly to resistant bacteria, a more dynamic solution is needed. A solution that can keep up with bacterial resistance mutation for mutation with its own tenacity for ‘life.' This solution may well have been found with bacteriophage therapy. After preliminary studies gave false hopes and false negatives the majority of the scientific world turned away as it embraced antibiotics. Institutes in Georgia and Poland carried on with research in humans, but questions are still asked of the efficacy of phage therapy as many of the studies failed to include a placebo. Now with the publicaion of a new study showing the ability of phage to rescue moribund mice infected with VRE (clinically very important resistant bacteria.) Outlined below is a history, advantages and stumbling blocks of phage therapy a brief synopsis of some of the studies conducted and asks is there a future for phage therapy and is the perception of phage therapy justified?IntroductionA brief historyBacteriophages were probably first observed by Ernest Hankin, in 186, suggesting that an unidentified substance (small enough to pass through fine porcelain filters,) in the waters of the Ganges and Jumna rivers in India. This substance had a marked anti-bacterial activity, and was probably responsible for limiting epidemics of cholera. (1) Further similar observations were made the following 0 years by scientists across the world, although none of these investigators explored their observations. Then in 115 Frederick Twort published his observations of the phage phenomena in the Lancet and advanced a hypothesis that, amongst other possibilities, a virus may have been behind this effect. However, Twort never advanced his studies in this area, due to various reasons including financial difficulties.

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Two years later, Felix D'Herelle studying at the Institut Pasteur in Paris officially discovered bacteriophages. He observed small clear areas on agar plates he had first innoculated with Shigella strains and then treated with bacterium-free faecal samples from patients infected with Shigella. D'Herelle had no doubt to what caused the phenomena, he was adamant that it was a virus capable of parasitizing bacteria. It was D'Herelle that formed the name ‘bacteriophage' from the words "bacteria" and "phagein" (eat or devour in Greek,) and implied that the phages ate or consumed the bacteria. D'Herelle in 11 first used phages to treat dysentery; the day prior to administration to the patient he, along with other hospital staff, ingested the phage preparation to test its safety. Upon administration to the patient (a 1 year old boy,) of a single dose, the symptoms decreased in severity after 1hrs and the boy was returned to full health after days. The efficacy of this preparation seemed to be confirmed shortly afterwards, when additional patients having bacterial dysentery after a single dose of treatment had started to recover within 4 hours. D'Herelle continued his treatments and obtained promising results (1). So promising were these results that in the 10s other researchers began using phages as well as commercial laboratories began to sell phage preparations. It was at this point that the scientific community began to lose faith in bacteriophage therapy, as the natural limitations of phage therapy produced false-negative results in badly conceived and executed experiments. One trial involved pouring undisclosed amounts of phage into a public well in India and assessing the numbers of cholera cases subjectively. Following the replacement of hygienic measures as well as vaccination in some areas of cholera by indiscriminate phage treatment the results were disastrous. Along with the widespread success of Tetracycline the World Health Organisation reached the conclusion that investigations into phage therapy should not continue (). The public also lost faith as the commercial preparations boasted of efficacy against diseases as widespread from viral infections (e.g., Herpes, small pox, measles,) through to auto-immune diseases (cancers, leukaemias, nervous lesions,) to diseases that are multi-factorial (eczema.) These commercial preparations were also shown to contain almost zero viable phage when tested.The scientific style of D'Herelle also played a major part in the dismissal of phage therapy. When placed in contrast to other scientists of the period, whilst Pasteur conceived definitive repeatable experiments and used a persuasive style in argument and dialogue, D'Herelle failed repeatedly to conduct definitive experiments and was argumentative and antagonistic in dialogue and argument. D'Herelle refused many opportunities to integrate his theories with the discoveries of Nobel laureates Metchnikoff and Ehrlich (showing the make up of the innate host defences against infection,) D'Herelle instead insisted that phages were the only method of defence against infection. T. Van Helvoort (1) reviewed the style in which D'Herelle conducted his experiments and showed the constant lack of double-blind experimentation. In clinical settings D'Herelle systematically failed to include any form of placebo group. However in a clinical environment it is understandable, with ethical considerations, why a placebo group is not used, (even though antibiotic experimentation was conducted in a double blind manner,) but even when D'Herelle utilised phage therapy in treating an epidemic of diarrhoea in chickens he still neglected to include a placebo group, even when ethical considerations were not an issue.In addition to the damage D'Herelle did to his own credibility and phage therapy's credibility with his own adamance, D'Herelle's theories were attacked by Nobel laureate Jules Bordet (from which Bordetella Pertussis was named.) Bordet had not only an intense disliking for D'Herelle's science, but for the man himself and used his own influence to discredit D'Herelle. An ardent communist D'Herelle retreated from the criticism of the western scientific community and during the 10s and early 0s working with eminent Georgian bacteriologist Giorgi Eliava and other Georgian colleagues founded the Eliava Institute of Bacteriophage, Microbiology and Virology (EIBMV,) in Tbilisi. However, D'Herelle's plans to move to Tbilisi were cut short when in 17 Eliava was arrested by Stalin's NKVD, pronounced an enemy of the people and executed. D'Herelle moved back to Paris frustrated and disillusioned, and during the occupation he was incarcerated for not providing his skills with phage therapy to the German army. During imprisonment D'Herelle's health rapidly deteriorated and he only lived a few months after being liberated. During that time he was invited to an international symposium to try and bridge the gulf between him and the scientific community. However he had been isolated for too many years from modern developments and died in 14 adamant with the belief that bacteriophages were the body's only means of defence against infection.With the advent of antibiotics, using experiments that were far more thorough and credible, phage investigation disappeared almost completely from use in western medicine (the exceptions I will describe later.) Phages did however continue to be used in Eastern Europe through much of the former communist block, the use of which I will describe later.The perception of Bacteriophage therapyThe idea of using bacteriophage is deceptively simple Using viruses that are parasites to the bacteria to help kill and control bacterial infections. Being specific to prokaryotes, the viruses could then only kill the bacteria it is specific for, and leave human eukaryotic cells unharmed. However even though the scientific community admitted that the early phage experiments were badly conducted, a consensus was reached that phage therapy had no place in the antibiotic era. "What was the purpose?" it was argued, as antibiotics had quickly become akin to ‘wonder drugs'. Phages were just too unknown and unstudied to be of any use, the limitations exaggerated by the badly conducted experiments.JustificationsAs we venture into the 1st Century it is now apparent that our ‘wonder drugs' are quickly failing over used and unable to keep up with the continuing mutations of bacteria, mutations that granted resistance. It was postulated that new generations and new classes of antibiotics would be continually researched and used so that we would be able to keep pace with resistance, meeting bacteria's tenacity for life with our own ingenuity. No doubt should be cast that new classes of antibiotics will be found and that they will be very useful, but the pace of development and screening means that we are now too slow and antibiotics that we currently have will become obsolete. Another problem is that now bacteria, generally, are a lot better equipped to deal with antibiotics, even new ones, than they previously were. The incorporation of efflux pumps and protective enzymes can only further hinder any new antibiotics. The post-antibiotic era has been forecast and as more and more antibiotic resistant bacteria are found in hospitals around the world, a new approach is needed.AdvantagesParadoxically one of the biggest disadvantages of administering bacteriophage therapy may be its biggest advantage over the use of antibiotics as well as a long term viable therapeutic agent; its specificity. One of the mistakes early researches made was to neglect the specificity of the phages used, because phages typically have a very narrow host range, (sometimes only one variant of a species.) However in therapeutic use, if a panel of phages were used specific to a wide variety of variants or a phage was used specific to a wide variety of variants, then only those variants would be lysed. No other species would be effected, limiting the spread of resistance. I.e. an E.coli. phage could not adhere or provoke any response to Entrococcus faecium. Another advantage is that phage therapy minimises any response from gut flora, a major side effect from oral antibiotic therapy. Antibiotics are fixed immutable chemicals, which cannot adapt to simple bacterial mutations and so become obsolete very quickly (a mutation that confers resistance to a given antibiotic is predicted to occur every 106 divisions.) Even worse this mutation can then be passed to other species of bacteria via plasmids. For instance even though a particular bacterial strain may never have encountered a given antibiotic, if it receives resistance genes from other species that are exposed to a given antibiotic and is subjected to environment where all of its ‘competition' (i.e. other strains) are destroyed by the antibiotic, it will flourish and spread. However phages are ‘living' organisms in as much as that they have an innate drive for survival. Phages too, can undergo mutations, which can allow them to overcome bacterial mutations. In other words whilst antibiotics quickly fall behind in the ‘arms' race, because they cannot change; phages can keep up with the bacteria, mutation for mutation mutant phage tail fibres allow binding to mutant bacterial receptors and mutated phage DNA can escape bacterial mutant endonucleases. Problems also arise in antibiotic therapy because the antibiotic is metabolically destroyed as it works; therefore repeated doses are required. This gives rise to bacteria that are exposed to sub-lethal doses of antibiotic usually at the initiation of therapy, between doses (just before the next dose,) and commonly at the tail end of the course of therapy when the patient neglects to take the full course (usually the antibiotics have helped reduce the number of bacteria to asymptomatic level, but not entirely remove the infection.) A single phage is capable of exponential growth within the target bacterium, rapidly multiplying to produce anything from 00 to several thousand daughter phages depending on the phage and environment around the bacterium. These lyse the bacteria and these go on to infect other bacteria. If as is usual about 00 daughter phages are produced at the end of the 1st generation, then if all daughter phage go on to infect 1 bacterium each, there will be 40,000 phages at the end of the nd generation. And incredibly 8 million phage at the end of the rd cycle (). It is now quite clear to see why in many cases a single dose of phage is capable of quickly destroying an infection. In solely Lytic phages (the need for which I will outline below,) 1 phage is needed for the destruction of 1 bacterium, so there is no such thing as a sub-lethal dose in phage therapy.Another area of possible advantage is the nature of cost. With Vancomycin being weight for weight more expensive than gold and phage therapy being widely utilised in the institutes of Georgia and Poland, areas not noted for their prosperity, it may be a cheaper option than first thought.Problems and solutionsThe possibilities this therapy grants looks promising, but many of the problems that plagued the first investigators and are to blame for the perceptions of the scientific community are still problems with experiments todayThe use of phage strains whose host range was too narrow, meant many investigators were led to false negative results after they used ‘off the shelf' phage preparations. However investigators who screened and matched phages to bacteria in tests analogous to culture and sensitivity tests had true-positive results. Another possible route is to culture (maybe through genetic manipulation,) phages that are lytic to a given range of bacteria. In cases where the patient is in urgent need of treatment, a panel of phages can be administered offering blanket lytic activity for the most probable infectious bacteria.The phage preparations used were often crude bacterial debris; filter sterilised, still containing large loads of endo- and exo-toxins. These were administered orally, intravenously, intramuscularly, intraparenterally and intrathecally. Not surprisingly with the patients often in a weakened state, the ‘therapy' often caused more harm than doing nothing. Modern techniques such as Caesium chloride density centrifugation, banding and other modern techniques allow the removal of toxins from the lysate. Also in well conducted modern experiments a control group of uninfected animals are administered with the phage preparation to ensure its lack of toxicity.Conversely instead of filter sterilisation a lot of the phage preparations were sterilised by heating as well as addition of mercurials and oxidisation agents. These methods are now known to inactivate the phages by disruption of the coat proteins. What compounded these mistakes was the lack of sensitivity testing after inactivation; the investigators expected full phage activity even after these disruptive methods. One of the major problems that still exists in phage therapy is the action of the immune system and the Reticulo Endothelial System (R.E.S.) to the phages (recognised as foreign proteins.) The action of the R.E.S. was first documented by Merril et al. in 17 where they injected high concentrations of lambda phage into non-immune germ free mice. The phages were found to be rapidly cleared by the spleen, liver and other filtering organs of the R.E.S., this was not however due to Gunther Stent's hypothesis that phages were inactivated by antibodies (the main reason cited as to why bacteriophage therapy would fail in humans.) The phages found in the spleen were still perfectly viable as therapeutic agents for more than 4hrs after filtration, but were trapped so unable to reach the point of infection. To combat the R.E.S. activity Merril et al. developed the serial passage method (4) to select a long-circulating phage from wild-type (stock) phages. This involved the administration of various strains of phage to E.Coli infected mice (one of the strains of E.Coli. being a mutator strain, so increasing the probability that the phages would mutate as well and these mutations would give increased evasion from the R.E.S.). Then 7hrs after administration blood samples were taken and the phages in the blood sample were grown on plates of susceptible E.Coli and then reinjected. This cycle of injection, isolation and regrowth in bacteria was repeated nine more times. Then the number of phages left in the blood after a period of 18hrs was measured for both the long-circulating isolates and the original wild-type isolates. The results were that there was at least a 1,000-fold higher number of phage in the long-circulating isolate as opposed to the wild-type. The efficacy of the phages was then tested the mice that received only E.Coli were moribund within 4 hours and died within 48hrs. The mice that received either the types of phage were unaffected. The mice that received both E.Coli. and then 0 minutes later the wild-type phage became very ill exhibiting the symptoms of severe illness (lethargy, ruffled fur, hunchback posture, and partially closed eyes with exudate around the eyes,) but made a full recovery within 100 hours. The mice that received E.Coli and then 0 minutes later the long-circulating phage only showed minor signs of illness (mild lethargy and ruffled fur,) before full recovery within 100 hours. Also in the study it was shown that the long-circulating phages performed better at rescuing mice that were moribund than standard wild-type phages. Further to this the group discovered after genetic sequencing, the long-circulating phages had a single point mutation, A - G had occurred in the phage gene encoding the major head protein E. This had the effect of substituting a basic amino acid (lysine,) for an acidic one (glutamic acid,) causing a double charge shift readily seen on -D electrophoresis. Computer modelling predicted that the mutation occurred in the loop of the E protein that sticks out into space and interacts with the external environment, and conceivably this mutation would change the interaction between the phage and the receptors of the microcirculation in the spleen (). As advances are made in the human genome and genetic manipulation of phages; it may be possible in future to expand upon the work of selecting long-circulating traits in phages and engineer other long-circulating properties into phages. Another problem in early phage experiments was the failure to distinguish between lytic and lysogenic phages. Lysogenic phages do not always lyse the host bacterium, but integrate portions of their genome into the bacterial genome as ‘prophages.' Whilst this led to problems in experimentation as it did not provide rapid lysis and exponential growth and therefore decreased efficacy. Lysogenic properties could also prove a major problem in widespread therapy the prophage's genome could be combined with the bacterial genome in such a way as to produce resistance in that bacteria to certain phages and as a part of the bacterial genome it could be passed to other bacteria. A possible scenario could be that the viral genome was combined and gave rise to an entirely novel bacterium that had never been seen before. These are dangers that can arise if lysogenic phages were used on wide scale. To ensure against this, lytic bacteria should be screened for and selected for with any lysogenic traits thoroughly selected against during propagation. As well as problems encountered in the past there are problems still to be dealt withAccording to studies by S.Slopek et al. (187) neutralising antibodies appear within a few weeks of first administration of phages to animals and humans. Given the time lag antibodies would not seem likely to interfere with acute treatment lasting a week or so, but in chronic treatment and/or recurrent infections the neutralising antibodies might prevent some proportion of administered phage being able to adhere to the bacterial target. In treating chronic/recurrent infections it may be possible to administer a higher dose of phage, to compensate for those that are rendered non-viable by interaction with neutralising antibodies. This also poses risks, because the possibility of the toxicity of antibody-phage complexes has not yet been investigated (5).Opsonins may restore vulnerability of even long-circulating phages to the R.E.S. and also prior exposure to the phage will likely accelerate a dangerous immune reaction.These are all valid concerns, but only through extensive testing will definitive solutions be found. Preclinical studies in animalsThe extensive testing done by H.Williams Smith and M. B. Huggins during the 180s has proved invaluable in furthering the case that well conducted thorough testing proves that phage therapy works. Their proving of phage therapy's superiority in treatment of Experimental Escherichia coli Infections in mice over antibiotics was a major step forward in 18 (8). This was almost a template of how to conduct an experiment of this nature they screened and tested the efficacies of different strains of phage (had they isolated from sewage,) in vitro. They then used the potent strains to test the efficacy of the phage against E.Coli. Also important, they included a control group, given no phage.The results were that at x 107 phages injected intramuscularly no mice died and even as low as x 104 phages injected intramuscularly or even x 10 phages injected intravenously produced full recovery and zero fatalities. All mice died if denied treatment by phage. Perhaps more telling was the study of phages against antibioticsTreatment No. of doses % diedExtract of E. Coli culture only 1 +Phage 1 6+Streptomycin 1 6+Streptomycin 8 10+Tetracycline 1 76+Tetracycline 8 4+Ampicillin 1 100+Ampicillin 8 86+Chloramphenicol 1 100+Chloramphenicol 8 6+Trimethoprim and sulphafurazole 1 +Trimethoprim and sulphafurazole 8 86As can be seen in the findings one dose of phage was marginally more effective to 8 doses of Streptomycin and greatly superior to 8 doses of tetracycline, ampicillin, chloramphenicol or Trimethoprim plus sulphafurazole. "The marked superiority of phage (R) over one dose of streptomycin emphasised its self-perpetuating nature in the presence of susceptible bacteria, a most desirable characteristic for any antibacterial agent. Their work on Calves, Piglets and Lambs (6) may also prove extremely useful in the development in the use of bacteriophage therapy in agriculture to replace the overuse of prophylactic antibiotics which is a major source of resistance especially for enterococcal infections that are exposed via the food chain. From the outset they saw positive results proving that phages given prophylactically protected calves, piglets and lambs (complex mammals,) from otherwise lethal doses of E.coli in the environment. Even when exposed to faeces containing lethal dose calves did not fall ill due to prophylactic spraying of phage in the living space. In their conclusions they make several observations That strains of E.Coli that were resistant to phages used or developed resistance through the experiment, showed marked decrease in virulence and pathological potential whist antibiotic resistant bacteria showed no change in virulence or pathological potential. If this is common for all bacteria has yet to be shown. Also of interest is the report that Calves infected with E.Coli and were subsequently rescued with phage were not infectious to other calves. Even if uninfected calves were exposed to the faeces (which contained a lethal dose of E.Coli) of infected animals treated with phage, they themselves did not contract any E.Coli. Not only that but the phage in uninfected calves (treated with phage prophylactically,) survived longer than E.Coli. in infected faeces. The authors also suggested that the more a suitable phage is used in an infected community the better the control of the clinical disease in that community. It is not difficult to extrapolate this suggestion to a hospital setting where there is a large pool of infectious disease brought in from quite different communities, the proximity of immuno-compromised individuals and the widespread use of antibiotics. In a later paper Williams Smith, Huggins and K. Shaw tested what kind of factors affected the viability of phages in possible environments (7). Their experiments show it was quite possible for antibodies, generated from previous exposure to the phage, to interfere with the functioning of the phage, but this was overcome by administering higher doses of phage or antigenically different phage (possible avenue of genetic manipulation,). Orally taken phage preparations were destroyed at physiological pH of the stomach (pH .0,) but phages were readily absorbed into the blood if taken orally with CaCO or similar alkali agent or with food. They also undertook investigations into the damage disinfectants did to phage preparations if phage solutions were to be used in the general environment formaldehyde and sodium hypochlorite destroying phages at low concentrations, and (with mild variations between phages,) phenol and chloroxylenol having little effect on phages even at high concentrations. This is quite clearly of use if phage preparations were to sprayed or used in general cleaning as a disinfectant in a hospital environment. Of more use was the investigation of the effect of temperature on phages. The results varied marginally between phages, but the vast majority of phages were most virulent at 7oC. The phages' virulence declined sharply below 0-4oC and most importantly at pyrexic temperatures phages also showed marked decrease in virulence above 40oC. This is of vital importance in use of infections that cause pyrxia, but the authors expressed hope in the form that not all phages showed this effect and some were most virulent at 40-4oC. They also went on to demonstrate that slight variations in the strains of phages conferred large differences in the optimum temperature of virulence. This is obviously an area of further study.One of the latest animal experiments provides even more support for using phage therapy in treatment of clinically important resistant bacteria. A report by B. Biswas, S. Adhya et al. published in January 00 () demonstrated the usefulness of phage therapy in treating Vancomycin-Resistant Enterococcus faecium (VRE). In the introduction the authors described briefly why VRE was important to work with and described the limitations encountered in treating VRE with new classes of antibiotic It appears that quinupristin-dalfopristin has only limited use against VRE in that it is bacteriostatic and bacteria have already been isolated resistant to analogues of its components and so a ‘reservoir' exists already for resistance for this particular antibiotic. Linezolid (the first member of a new class of antibiotics- the oxzazolodinones,) is also bacteriostatic and resistance occurred rapidly to its first use in clinical trials. The group found that mice injected with the maximum dose ( x 10 pfu,) of the phage 45 minutes after challenge by a lethal dose of VRE showed only slight lethargy for the first 4 hours. Those mice not in receipt of any phage died within 48 hours. At 0hrs following administration of phage the mean bacterial titre of the phage treated animals was 00-fold lower than mice given a placebo (008l of PBS.) "This reduction in bacterial titres reflected the lower morbidity and mortality observed in the treated group." In another experiment it was shown that a single injection of phage could rescue 100% of the mice from an otherwise lethal dose of VRE even when treatment was delayed to 5 hours after inoculation with VRE. If the treatment was delayed 18 hours (at which point the mice were observed to be severely ill severe lethargy, ruffled fur, hunched posture and exudate accumulation around partially closed eyes,) then 60% survived and were completely recovered within 6 hours. If treatment was delayed for 4 hours (where all mice observed were moribund,) phage therapy rescued 40% of these and they regained full health in 10 hours. Whilst a 40% survival rate may not seem high, it is 40% more than no treatment or administration of vancomycin. The group also began to answer some of the critics of bacteriophage therapy who had dismissed the phenomena to a non-specific immune response stimulated by the viruses. The group of mice injected with heat inactivated phage had exactly the same response as the group injected with placebo (PBS.) The immunological response was also tested; 5 monthly injections of the phage were administered. Whilst both levels of IgG and IgM were increased massively after months no anaphylactic reactions, changes in core temperature or other adverse events were recorded. Human trialsThe most detailed polish papers on phage therapy in humans were written by Slopek et al. at the L.Hirszfeld Institute of Immunology and Experimental Therapy. These papers were summarised in the final paper in the series published (10). 1 out of 18 cases of suppurative bacterial infection had a good therapeutic result. And of those 18, 0% cases were antibiotic resistant (however no records of the antibiotics used are given.) The observations described however are subjective16% showed complete recovery71% complete healing of lesions and liquidation of suppurative process5% had marked improvement of local state with partial haling of lesions and negative result of bacterial culture. 6% had ‘transient' improvement and was difficult to describe. The investigators noticed that those above 60 years old, % that didn't respond well to treatment, as opposed to only 5% of patients below 1 years old and 1% of patients between 0-5. There was no significant difference between female of male patients and the efficacy of the phage. The methods of administration were oral and local application. The investigators did not inject i.v. because they wanted to minimise the shock to the patient from possible anaphylaxis. When applying orally the phages were administered times a day, in a 10ml ampoule; 0 minutes before a meal and after neutralisation of gastric juice (gelatum and baking soda or a glass of Vichy water given.)When locally applied on wounds, moist applications were recommended times every 4-hour period. During the course of the treatment a constant check was kept on the bacterial type causing the infection so the phage applied could be changed if necessary. (One method of keeping checks on resistance.) Phages were also used prophylactically for 14 days if negative bacterial culture found. The majority of successful treatment took place when the phages were administered orally and locally. This may have been due to double the amount of phage in these patients or simply due to the combined therapy; more investigation will be needed in this field. cases out of 18 suffered ‘side effects' displayed intolerance at oral administration and 1 had allergic symptoms at local application. No further information is given about these very important cases.General observations included that close observation for the first 8 days is advised because during days -5 of phage therapy; hepatalgia occurred lasting several hours (due to mass liberation of endotoxins from lysis of bacteria.) In some cases of sepsis increase of temperature noted on days 7-8 lasting 4 hours.The major criticism of the work in Poland is the lack of placebo group (due to the financial constraints,) which unfortunately renders this work as promising but somewhat anecdotal evidence in favour of phage therapy.One of the most extensive trials carried out on phage therapy use in humans was conducted in Tbilisi during 16 and 164. (1) (the original being in Georgian, I'm relying on the interpretation of Sulakvelidze at al.) A total of 0,76 children (6 months old 7 years old,) diagnosed with bacterial dysentery took part in the study. 17,044 children were given Shigella phages orally (once a week,) and 1,75 children were not given phage. During the 10 day study period, it was noted from clinical diagnoses that the incidence of dysentery was .8 fold higher in the placebo group than the phage group and from culture confirmed cases the incidence of dysentery was .6 fold higher in the placebo group than the phage treated group. There was also a . fold reduction in the incidence of diarrheal diseases of unknown origin among children treated with phage as opposed to the placebo group. This may have been due to misdiagnoses of some dysentery cases or maybe due to the phage being active against more than one type of gastrointestinal pathogens.Other clinical studies carried out in Tbilisi seem to follow the scientific rigour of its founder with numerous promising studies of phage therapy in action but a constant lack of placebo controls. This may yet again be not only due to financial constraints but also ethical considerations when using phage on a day to day basis as the Institute at Tbilisi. It seems that the institute in Georgia, maybe in part to the lack of international recognition, has now devoted itself to furthering its own studies, instead of trying to convince the western scientific community that phage therapy actually works For the scientists working at Tbilisi they know it works. It seems also that language still remains a formidable barrier for the passage of knowledge into main stream science with most of the papers on human trials being published in Russian, Georgian and Polish, they remain almost ignored by the scientific community. Conclusions For the western scientific community it seems that more evidence is required of its efficacy in animals before trials move in to the human stage and despite the work done on phage therapy, questions still remain unanswered. The effect of chronic treatment of phages in humans still remains unknown in fact serious study of the mechanisms of attachment to bacteria, the interactions between phages and the RES still are required. The method and localisation of passage of phages from the gut lumen into the blood stream is still unknown. Minimal work has been done of the life span of not only the phages in the body but also the antibodies raised up against them. What if phages are administered to hypersensitive people or pregnant women? Would the phages cross to the placenta? Would these pose a risk to the foetus or the mother? Would phage be found in colostrum? At what concentration could phage be toxic to the patient? (So far it appears that phages are entirely non-toxic but up to what point?)So despite these unknowns and the legacy left by D'Herelle and other bacteriophage investigators whos misadventures almost resigned phage therapy to an interesting anecdote in medical history; what is the future of bacteriophage therapy?The future looks very promising; with unmatched superior efficacy over antibiotics proven conclusively in animals, its non-toxicity shown in animals and the potential of rescuing moribund conditions. As advancements are made in genetics and sequencing of bacteriophages and their hosts continues, our knowledge of the mechanisms of their action will also increase. The work done in mice with VRE is an excellent example of how useful phage therapy could be. Although treatable with other antibiotics VRE remains potentially very dangerous because of the possibility of transferral of vancomycin resistance genes to Multiple Resistant Staphylococcus Aureus (MRSA.) If ever a virulent form of MRSA emerged with complete Vancomycin resistance (so far only intermediate resistant forms have been discovered,) that would leave medicine with no antibiotic to treat infections a true ‘superbug.' Phage therapy could not only treat this bacteria if it ever arose, but would also prevent the generation of such a bacteria if used in combination therapy with antibiotics. Phage investigators are not seeking to replace antibiotic therapy with phage, but to find methods of complimenting the two. Administering both phage and antibiotic would severely limit the generation of completely resistant bacteria. Since the mechanisms of action of each agent are almost entirely removed from each other for instance if a bacteria had resistance to one of the agents used, that mechanism of resistance would grant the bacteria no protection from the other agent and vice versa. In the introduction I outlined a brief list of the advantages of bacteriophage therapy over antibiotics, this list is not intended to prove the superiority of phage over antibiotics, it is merely to try and show that phage therapy could be a vital addition to overcome problems in existing therapy. I also gave a brief account of the general public and scientific perception of phage therapy and unfortunately a lot of the criticism levelled at phage therapy in D'Herelle's era remain to this day lack of placebo controlled trials. This however doesn't mean that this attitude towards phage therapy has to continue indefinitely and with the production of more conclusive, well conducted studies, the criticism against phage therapy should give way to increased enthusiasm for this potentially world changing ‘historical anecdote.' (1) Sulakvelidze A, Zemphira A, et al. 001. Minireview of Bacteriophage Therapy. Antimicrobial Agents and Chemotherapy, 45.. 64-65() Barrow P.A., Soothill J.S. 17. Bacteriophage therapy and prophylaxis rediscovery and renewed assessment of potential. Trends in Microbiology, 5.7. 68-71() Carlton R.M. 1. Phage therapy Past History and Future Prospects. Archivum Immunologiae et Therapiae Experimentalis, 47, 67-74(4) Merril et al. 16. Long Circulating bacteriophage as antibacterial agents. Proc. Natl. Acad. Sci. USA, , 188-1(5) Lederberg J. 16. Smaller fleas… ad infinitum Therapeutic bacteriophage redux. Proc. Natl. Acad. Sci. USA. , 167-168(6) Williams Smith H., Huggins M. B., 18. Effectiveness of Phages in Treating Experimental Escherichia coli Diarrhoea in Calves, Piglets and Lambs. Journal of General Microbiology, 1, 65-675(7) Williams Smith H., Huggins M. B., Shaw K. M., 187. Factors Influencing the Survival and Multiplication of Bacteriophages in Calves and in Their Environment, 1, 117-115(8) Williams Smith H., Huggins M. B., 18. Successful Treatment of Experimental Escherichia coli Infections in Mice Using Phage its General Superiority over Antibiotics() Biswas B., Adhya S., et al. 00. Bacteriophage Therapy Rescues Mice Bacteremic from a Clinical Isolate of Vancomycin-Resistant Enterococcus faecium.(10) Slopek et al. 18 Results of bacteriophage treatment of suppurative bacterial infections. Archivum Immungiae et Therapaiae Experimentalis, 1, 67

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