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The growing potential for Phage therapy
The misuse of antibiotics has accelerated the development of antibiotic resistance in bacteria to a point where clinicians are finding it hard to treat bacterial infections with the drugs available to them. Phage therapy; the process of using bacteriophages to prevent and treat bacterial infections offers us a potential solution to this growing problem. This POSTnote discusses the current application and growing future potential of phage therapy. It also focuses on the scientific background and method behind phage therapy as well as the policy implications in modern medicine.
– Phage therapy was successfully used before the invention of antibiotics.
– Increased antibiotic resistance amongst bacteria has led to a renewed interest in the applications of phage therapy today.
– Scientific developments in understanding phages have led to critical improvements in phage therapy.
– Researchers from across the world have begun to focus on better understanding phage therapy to treat antibiotic resitant bacterial infections.
Fig 1. Diagram Illustrating the structure of a bacteriophage. This is an illustration taken from (GrahamColm,2008).
What are Bacteriophages ?
Bacteriophages are viruses that infect bacteria and then replicate within them; a bacteriophage’s structure is made up of proteins that encapsulate an RNA or DNA genome (see Fig.1). Bacteriophages are lethal to bacteria due to their replication process which can be either a lytic or lysogenic cycle (Box 1). The lytic cycle begins with the attachment of the bacteriophage to a specific receptor on the surface of the host bacterial cell; once attached the bacteriophage injects its genetic material into the bacterial cell. This means the viral genetic material can use the bacterial metabolic machinery for its own processes; the viral genome encodes for proteins that are necessary for its own replication as well as lytic enzymes that help hydrolyse the bacterial cell wall from within. The replication process results in hundreds of virions (complete virus particles) being produced inside the cell; leading to a high internal osmotic pressure. The build-up of this high internal osmotic pressure along with the lytic proteins is what results in the lysis of the bacterial cell (Clokie et al,2011). Cell lysis results in the death of the bacterial cell and the release of the bacteriophages progeny into the surrounding environment.
Box 1 – Lysogenic Phages
The basis of the lysogenic cycle is characterised by the integration of the viral genetic material into the bacterial hosts genome. Lysogenic Bacteriophages do not result in immediate lysis of the host cell; this means they are not used therapeutically. This is because the bacteria can acquire new DNA via the virus which might lead to expression of increased antibiotic resistance or pathogenicity by the bacteria. Our focus throughout this POSTnote will be on the growing potential for use of ‘lytic phages’
The basis of Phage therapy
The independent co-discovery of bacteriophages by Fredrick Twort (in 1915) and Felix d’Hérelle (in 1917) led to the understanding that there were viruses capable of parasitizing bacteria (Chanishvili,2012). The aim of phage therapy is to kill the bacterial cells causing the infection using these bacteriophages.
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The bacteriophages required are generally found in water samples taken from sources which are likely to be filled with bacteria, sewage outlets for example. The samples are centrifuged to remove particulates and then applied to agar plates cultured with the bacteria causing the infection, if the bacteria die, bacteriophages are present, and the mixture goes on to be centrifuged again with a collection of phages residing at the top. (Twest and Kropinski,2009). The phages are collected and amplified further upon cultures of the pathogenic bacteria causing infection, once amplified the phages are filtered and collected as a solution (see Fig.2). This solution can be then applied to infections orally, topically or even vaporised and inhaled to target the bacterial infection. (Bodier-Montagutelli et al,2016)
The Rise and Fall of Phage therapy
The British Empire sanctioned the use of phage therapy to treat cholera in Punjab, India during a 1931 epidemic; the trial resulted in a 90% reduction of mortality within the group who received phage therapy compared to the group who relied on traditional medicine (Lin, Koskella and Lin,2017). The use of Phage therapy was commercialised after a fair amount of success in field trials, commercial labs were opened in Brazil, the USA and British India and they began to ship their phage preparations across the globe. (Lin, Koskella and Lin,2017). This commercial era of phage therapy did not last long due to a multitude of reasons.
Fig 2. An Image of a singular dosage ampule of Eliava pyophage. A phage preparation which targets bacterial cells that lead to pus causing infections. This image and its description are taken from (Kutter et al,2010)
Storage was a particularly an issue as the commercial phage preparations were sold with so much preservative that the phage itself was inactivated, this led to many clinicians complaining that Phage therapy was ineffective (Summers,2012). There was also the fact that phages have very specific targeting mechanisms, most phages are able to bind exclusively to one receptor and many are only able to infect one strain of a bacterium. The intense variation that presented itself in bacteria required an equivalent phage library with just as much phage variation to combat these bacterial strains, such a library was simply not feasible to produce and maintain in the 1940s (Nilsson,2014).
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Clinicians who had patients with bacterial infections often turned to the newly invented antibiotics for treatment. Antibiotics offered everything that phage therapy couldn’t, they were easy to store and transport, most came in tablet form and thus were easy to administer to patients, and possibly the most important reason; antibiotics were extremely effective in treating a broad spectrum of infections without having to undergo specific development (Summers,2012).
Current uses and Development
The need for Phage therapy today
Box 2 – Antibiotic Resistance
Antibiotic Resistance is a trait that can develop in bacteria due to random mutations or simply occur as a natural resistance. Antibiotics accelerate the evolutionary process in bacteria by only killing non-resistant bacteria, thus allowing the once rare ‘resistant’ bacteria to flourish. Inter-Bacterial transfer of resistance genes from the survivors can also occur giving rise to even more antibiotic resistant bacteria. Some bacteria can develop resistance to multiple antibiotics and become, multi-drug resistant. The increased occurrence of multi-drug resistant bacteria is due to the overuse of antibiotics and improper prescription methods which leads to ineffective and partial treatment that leaves the multidrug resistant bacteria with less competition.
The current rise of antibiotic resistance within pathogenic bacteria (Box 2) has proved particularly challenging for clinicians who are finding it harder and harder to treat an increasing amount of bacterial infections with no other medical alternative than the ineffective antibiotics available to them. Methicillin-Resistant Staphylococcus Aureus (MRSA) infections have been an issue in the NHS for over 20 years (Fig.3) and the World Health Organisation estimates that “50,000 lives are lost each year to antibiotic-resistant infections across Europe and USA” (WHO.int,2018). Phage therapy offers us a potential solution as an effective alternative to antibiotics due to its ability to target multi-rug resistant bacterial infections.
Fig 3. A Graph illustrating the recurring MRSA problem faced by the NHS. This graph and its data are taken from (Office for National Statistics,2018).
Benefits of Phage therapy and Modern Improvements
At first the ability of antibiotics to target a vast range of targets was seen only as a positive but what we have come to understand is that the blanket approach in treating bacterial infections can result in the lysis of commensal microbiota (naturally occurring microorganisms at the site of infection). (Jernberg et al,2010). The specificity that phage therapy brings might be a welcome change as it would only target the pathogens with no collateral damage to the patient.
Phage therapy has also been regarded as generally safer than antibiotics in terms of side effects, due to the naturally occurring nature of bacteriophages humans have already been exposed to them since birth and thus side effects have not been reported in any clinical trials till date. (Vandenheuvel, Lavigne and Brüssow,2015). Phages have very high affinities to their bacterial hosts, this means that if applied successfully the bacteriophages will be able to easily target the infection, thus making phage therapy a very effective treatment. (Vandenheuvel, Lavigne and Brüssow,2015).Previous attempts to commercialise phage therapy in the 20th century faced a lot backlash from clinicians. This was largely due to the lack of stability of the solutions, key developments in improving stability of aqueous phage solutions such as stability enhancers as well as developments in refrigerated transport since then have helped improve long term stability to a certain regard. (Vandenheuvel, Lavigne and Brüssow,2015)
Narrow host range remains a problem but modern improvements in microbiology and virology can reduce the severity of this problem when adapting phage solutions for clinical use. Modern screening methods allow for quick identification of bacteria, this means there’s less guesswork involved when it comes to picking what phage preparation to use. The formation of globally connected phage libraries is also a technology available to us, this allows us to create the most appropriate and effective ‘phage cocktails’ by comparing data on a global scale to get the most effective treatment for patients. (Adhya, Merril and Biswas,2014).
So, in theory phage therapy provides a specific , safe, relative stable and effective treatment for bacterial infections; but how do we know it could possibly work in practice?
Phage therapy in Practice today
Phage therapy continued as a key treatment for bacterial infections across the Soviet Bloc through the Cold War. The Eliava Institute in Tbilisi, Georgia has been a leading research centre in Phage therapy through its 95-year history. It has played a vital role in developing phage-based treatments against tuberculosis, salmonellosis, dysentery and even anthrax. (Eliava-Institute,2018). Today the Eliava institute is host to the worlds ‘most extensive bacterial strain and bacteriophage collection in the world’. The Institute also plays a very important role in the development of phage cocktails that are used by Georgian clinicians to treat bacterial infections.(Eliava-Institute,2018). The global rise in antibiotic-resistant bacterial infections has also led to the opening of commercial clinics that offer phage therapy to an international clientele.
The Phage Therapy Centre is one such clinic which has developed advanced methods of delivering phage-based therapeutics to patients suffering from antibiotic-resistant bacterial infections. The treatments can range from $3000 to $20,000 in cost and utilises contemporary technologies such as ‘artificial polymer skins’ that are implanted with phages, these phages go onto target the bacterial cells causing infection when placed over a wound (Parfitt,2005).
The case of Tom Patterson has been a leading example of implemented Phage therapy outside Georgia, Poland or Russia. After being diagnosed with an antibiotic-resistant Acinetobacter baumannii infection that had developed resistance to the last resort antibiotics the only hope Tom had of survival was the implementation of phage therapy. After managing to collect three different appropriate phage samples, a solution was created and purified by a research team at San Diego State University. The Food and Drug Administration of The USA granted an emergency approval and the solution was applied via both catheters and Intra Venous drip. After 3 days of Phage therapy Tom managed to get out of the coma he was in and began a long road to his eventual recovery. (STAT,2018)
Phage therapy was the only thing that could eventually stop the infection that would have otherwise killed Tom. Since then the very first Phage therapy Centre has been opened at the University of California, San Diego. (STAT,2018) It has the responsibility of co-ordinating the search for appropriate phages as well as running controlled clinical trials before any commercial approval can be given by the FDA. The foundation of such an institution along with the acceptance of a national Phage Directory signifies a very large shift in the attitude towards phage therapy in the West.
The Future of Phage therapy and its modern constraints
There is still a long way to go before phage therapy can be accepted globally. The costs associated with patient trials has greatly hindered the ability of the process to be pursued for commercial application in many countries. There is also the fact that the water-based suspensions most often used in Phage therapy still present a problem when it comes to long term storage, (Vandenheuvel, Lavigne and Brüssow,2015) this means that phage solutions cannot be stockpiled as easily as antibiotics in preparation for a pandemic. Although traditional phage therapy might be facing some critical issues in its process of global commercialisation there has been other very exciting advancements regarding phages.
The ability to isolate the lytic enzymes produced by bacteriophages has been regarded as a key breakthrough in the use of phage-oriented pharmaceuticals. This is because it gives us the potential to incorporate these enzymes into more traditional drug delivery methods that don’t have the setbacks a phage-based delivery method might. (Lin, Koskella and Lin,2017). The gene alteration technology CRISPR has also opened up new avenues for phage therapy. The ability to produce ‘bioengineered phages’ is now a possibility, which means that there are opportunities to produce phages that will be able to infect selected targets, thus potentially removing the need for hosting a phage library. The future holds a lot of exciting new possibilities and signifies an ever-growing potential for phage therapy.
The regulation of phage therapy falls under the European Parliament’s regulatory Directive 2001/83/ EC. (Pelfrene et al,2016) This outlines that there must be further authorization on any biological therapeutics before commercial patient treatment can begin. As the United Kingdom heads into a future that may be independent of the EU, we need to focus on making our own informed legislation regarding phage therapy.
A fairly recent review sanctioned by the UK government and carried out by Jim O’Neil at the University of Liverpool regarded phage therapy as a ‘potential alternative’ to antibiotics when it came to the treatment of antibiotic resistant bacterial infections. (University of Liverpool,2018). Increased research into the potential of phage therapy is a great step in combating antibiotic-resistant bacterial infections but steps have to be taken to prevent antibiotic-resistant bacterial infections and their spread right now. The NHS has taken steps to reduce antibiotic usage in attempts to combat the rise of multi-drug resistant bacterial infections. A £150 million initiative to combat antibiotic over usage launched in 2016 was the largest healthcare service scheme of its time to address the problem of growing antibiotic over usage. (NHS England,2016)
The NHS initiative only acts as a short-term solution to the very long-term problem of antibiotic-resistant bacterial infections. Phage therapy does offer us a sustainable solution; but until there is a regulatory institution and suitable support infrastructure in place to support and maintain a vast phage library, we can’t consider phage therapy as a viable alternative to antibiotics.
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