Are bacteriophages an effective way of treating antibiotic resistant infections

Are bacteriophages an effective way of treating antibiotic resistant infections?
Introduction
Antibiotic resistance occurs when a microorganism is able to withstand the effects of antibiotic drugs. It has been described as one of the biggest threats to global health, with it being estimated that it would account for 50 million deaths per annum costing £66 trillion worldwide by 2050. There have been concerns about antibiotic resistance since the beginning of their widespread use. Alexander Flemming in his 1945 Nobel Prize speech stated that, “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with penicillin-resistant organisms”. Yet despite these warnings, antibiotics have been constantly overused and misused. Examples of this include the use of antibiotics for growth promotion in animals and prescriptions being given by health professionals outside current guidelines. This has led to the rise of ‘superbugs’ that are resistant to all antibiotic therapy. In our globally connected world, such superbugs have the potential to create a pandemic on a scale never seen before. While there are some new antibiotics in development, these are not expected to be effective against most superbugs. There is another possible solution, though – bacteriophages.
40201851397000Bacteriophages (or phages for short) are viruses that kill bacteria. They consist of either DNA or RNA enclosed by a capsid (the protein coat of a virus). Phages are ruthless killers of bacteria. They bind to receptors on the bacteria cell membrane, allowing the phage to puncture through the membrane and inject its DNA into the host cell. This supresses the transcription of the bacteria cell’s DNA and phage specific proteins are produced instead. New phages are then assembled inside the host cell. This disrupts the bacteria cell membrane, resulting in the bacteria effectively vomiting out large numbers of phage into the surrounding environment .

Phages have been used to treat bacterial infections since the 1900’s however their success rate at treating these infections was previously inconsistent. This led to them being replaced by antibiotics with their more reliable outcomes. Recent research has, however, proved that phages can be a safe and effective way of treating drug resistant bacterial infections.
The research
Phages can claim to be the deadliest beings on the planet, killing half the world’s bacteria every 48 hours. This makes them an incredibly useful tool in the fight against superbugs, however it does raise issues around safety. These were addressed in a recent study undertaken by the European Union. Researchers wanted to test the safety of two bacteriophage drugs that could be used to treat E. coli and P. aeruginosa – both of which are multi-drug resistant – in burn wound infections. This is especially important as infections from E. coli and P. aeruginosa can lead to sepsis, which causes 50% of deaths among burn victims. Clearly, the development of a safe bacteriophage drug would be a key development in such conditions.
According to the report, there was “no serious adverse event” during the 13-month trial. This led the researchers to conclude that, in certain circumstances, bacteriophage drugs are safe to use . Clinical trials focusing on the safety of bacteriophage drugs were also conducted in the US, UK and Belgium. These too demonstrated that bacteriophage drugs had no significant side effects and therefore were safe to use . These trials provide the evidence base needed to show that bacteriophage drugs have no short-term side effect and are therefore safe to use for certain periods of time.
The conclusions about safety can be explained by phages being highly specific to each bacterium. When phages lock onto a bacteria cell membrane, they form a phage-host system . Phages can only attach to a specific receptor in the bacteria cell membrane, so they can only attack certain bacteria that have a receptor that they can bind to. This makes it impossible for them to infect eukaryotic cells as there is simply no receptor in the cell membrane for the phage to bind to. This is why phages do not cause illness in humans .
Another notable study looking at using phages to treat antibiotic- resistant infection was carried out by the University of Liverpool in 2018. This focused on the effectiveness of phage treatment and looked at how phage therapy could be used to treat infections cause by Pseudomonas aeruginosa, a multi-resistant bacteria that can cause life-threatening lung infections, especially in patients with cystic fibrosis. The researchers used a murine model (carrying out the experiment on rats) but ensured the study closely resembled a human infection by infecting rats through their respiratory system. The results are shown on the graph below:
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CFU (colony forming unit) is way of estimating the number of bacteria cells in sample. In this case CFU shows the number of P.Aeruginosa bacteria per millilitre. The study looked at two strains of P. Aeruginosa: LESB65 AND NP22_2. In the initial experiment, phages were administered 72 hours after the rats were infected and the CFU was recoded 24 hours after the initial phage treatment. The graph shows a clear reduction in the CFU per ml in both strains, although there is a more significant difference in the LESB65 strain. The results are statistically significant because the error bars do not overlap. This supports the hypothesis that phage therapy can be successfully used to treat lung infections caused by p. aeruginosa.
The next stage in this research was to examine whether the effectiveness of the bacteriophage drugs was influenced by the time of administration following infection
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Treatment 1 was given 48 hours after injection with CFU counted 48 hours after treatment., Treatment 2 was given 60 hours after infection and CFU counted at 72 hours. Treatment was administered 144 hours and 156 hours post infection with CFU being counted at 168 hours. Both Treatment 1 and Treatment 2 resulted in the complete clearance of P. aeruginosa from the lungs. Although treatment 3 did not complete clear the infection, it still significantly reduced the CFU of P. aeruginosa in the lungs. This adds to the evidence supporting the use of phages in treating antibiotic-resistant infections
Evaluation
Research into phages indicates that they have a role in the control of antibiotic-resistant superbugs. It can be argued that phages are a superior treatment to antibiotics even when the antibiotic resistance is not considered. Their advantage is that they have a high specificity to their bacteria. This means that they won’t kill ‘good’ bacteria, which in turn reduces the likelihood of secondary infection . Phages also co-evolve with bacteria meaning that the risk of drug resistance is eliminated .
There are, however, a number of limitations to their use in treating antibiotic-resistant infections need to be overcome. While there is a wide and increasing body of evidence about their use, most of this has been pre-clinical (such as the University of Liverpool study) and there is still uncertainty as to whether their use would lead to similar outcomes in humans. There has also been a focus on safety rather than effectiveness, as demonstrated in the ‘phagoburn’ study. More Phase 3 clinical trials are needed before conclusions can be made about the effectiveness of phage therapy in humans. The lack of clinical trials has, in turn, made drug companies unwilling to invest in the research needed to create successful bacteriophage drugs .

There are also some disadvantages to the high specificity of phages. This that they cannot be ‘broad spectrum’ with the bacterial infection needing to be identified prior to administration of any therapy. This explains why phage therapy was ineffective when first used in the 1900s – doctors simply did not know which phage treated which infections. A recent breakthrough in genome sequencing could eliminate this problem It is now possible to sequence the genome of a bacteria in just a few days, therefore the strain of bacteria causing the infection can be quickly identified and the appropriate phage treatment administered. Previously, it would considerably longer to identify the strain as a bacteria sample had to be grown in the lab.
The high specify of phages also creates another problem which still needs to be solved. As they are so specialised, phages are unable to access human cell and therefore cannot treat infections where the bacteria entered human cells. Some researchers have proposed that genetic engineering could be used to overcome this problem, but this is highly speculative as we don’t yet have the technology to place phage into human cells (see footnote 15).
There is a role for bacteriophages in the treatment of antibiotic resistance, yet we are still some distance from phages being a reliable solution to this growing problem. There is a clear argument for research and investment in phage treatment. This is essential to make treatments using phage a success.
References
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DSMZ, year published unknown, What are bacteriophages (phages) and how do they work?
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(accessed 13/06/2018)
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http://thorax.bmj.com/content/72/7/666 (accessed 14/06/2018)

Phage Therapy centre, Year published unknown, What is phage therapy?
http://www.phagetherapycenter.com/pii/PatientServlet?command=static_phagetherapy(accessed 14/06/2018)
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An information video on bacteriophage
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The advantages and disadvantages of phage therapy


(accessed 14/06/2018)
The Royal Society, date published unknown, Resistance is futile
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