Whether or Not Bacteriophages are a Viable Alternative to Antibiotics

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Whether or Not Bacteriophages are a Viable Alternative to Antibiotics

Antibiotics are drugs or medicines used to treat bacterial infections. There are two main mechanisms that antibiotics employ to treat a bacterial infection. They can kill the bacteria or prevent it from reproducing, labeled bactericidal and bacteriostatic, respectively.

Antibiotic resistance is becoming an ever-growing issue all around the globe. The rate of bacterial evolution far exceeds our current rate of development of antibacterial agents. If bacteria become completely resistant to our antibiotics then we will have to survive like we did in the past – where any infection could kill. What is being done to prevent this? New antibiotics are being researched and developed, and this is getting the attention of investors and large pharmaceutical companies. Unfortunately, there’s not been a new class of antibiotics discovered since the 1980s. Scientists are working on developing new organic compounds – even nanotechnology (tiny machines that will fight bacteria one by one inside your body).

Europe has banned giving antibiotics to farm animals to boost their growth, however this still happens in some places e.g. China, which is why some super-resistant bugs have surfaced there.

Chinas overuse of antibiotics is severe and is one of the reasons why China has the worlds most rapid growth rate of resistance (22% average growth in a study spanning 1994 to 2000). In China, antibiotics are regarded as a cure-all medicine, a panacea, and is overprescribed. Viral infections such as the common cold are not affected by antibiotics however an estimated 75% of patients with seasonal influenza are prescribed antibiotics, and the rate of antibiotics prescription to inpatients is 80%. This is one of the main reasons for high antibiotic resistance in China. Pathogens such as MRSA superbug are able to thrive as they adapt to Chinas antibiotic heavy environment.

There are many factors behind Chinas overuse of antibiotics. Firstly, the perception of antibiotics as a cure-all drug causes many Chinese patients to demand them even when they are not necessary. Additionally, they may request the newest antibiotics, perceiving them to be more effective. This causes problems because misusing antibiotics is what leads to the development of antibiotic resistance, which claims an estimated 33,000 lives a year within the EEA. Financial incentives also play a significant role in antibiotic overprescriptions. In many hospitals, doctors’ incomes are closely linked to their prescription of specific drugs, and bonuses from hospitals and kickbacks from companies augment their incomes.

An audit study suggested that antibiotics abuse in China is not driven by patients actively demanding antibiotics, but is largely a supply-side phenomenon. Tackling the problem of antibiotic-resistant bacteria has already cost us billions of pounds. Progressively fixing one of many causes of antibiotic resistance growth will help to reduce the amount of effort and time required to overcome this issue. In China, the problem of antibiotic overuse is not just a technical problem but also a social problem, which will require re-educating the public and the doctors on antimicrobial usage. According to Dr. Chen Zhu, Minister of Health, P.R China, The ultimate solution to this problem is to undertake health reform which is to improve the compensation mechanism for public hospitals, to increase the income of doctors, to gradually eliminate the practice of hospitals subsidizing their medical services with drug sales and to promote the basic drug system. Once public health reforms have been consolidated in China, the rigamarole of minimizing antibiotic resistance will have been greatly reduced and hopefully, we will begin to see a reversal in the increasing number of antibiotic-resistance bacterial infections in the future.

Methicillin (aka meticillin) is an antibiotic that is used to treat bacterial infections caused by organisms of the genus Staphylococcus. It was developed in 1959 as a type of antibiotic called a penicillinase-resistant penicillin, which means it was modified to make it resistant to penicillinase (a bacterial enzyme that can inactivate the antimicrobial effect of the drug). Methicillin-resistant strains of bacteria were initially detected in Europe, as early as the 1960s, which eventually rendered the drug useless for clinical purposes. Some naturally-resistant strains were detected in some countries even before the use of methicillin. It is likely that these original strains initially spread through natural populations of S.aureus via horizontal transfer and recombination, which is where DNA from one organism is transferred to another organism that is not its offspring. It is thought that these original strains went on to develop into unique and diverse strains within hospitals, as a result of selection by exposure to antibiotics and by cross-infection. This problem still persists almost 60 years later; a strain known as Methicillin-resistant S.aureus (MRSA) is pandemic, causing infection in tens of thousands of hospital patients and healthy individuals worldwide each year. The article published by Ayliffe in 1997 reported that all MRSA strains were currently susceptible to vancomycin or teicoplanin, however the first reports of VRSA (vancomycin-resistant S.aureus) were reported in the US in 2002. Vancomycin was originally planned to be a last resort drug for complicated infections caused by Staph bacteria. In the span of 16 years, one of our most potent treatments was rendered useless by some strains of the bacteria.

A bacteriophage is a virus which infects and replicates within bacteria and archaea. They are the most abundant organism within the biosphere with an estimated viral population of greater than 1031 or approximately 10 million per cubic centimeter of any environmental niche where bacteria or archaea reside. Bacteriophages were discovered by Frederick Twort in 1915 and independently in 1917 by Felix DHerelle. DHerelle observed them and realized that phages had the potential to kill bacteria that cause disease in humans, as well as in plants and animals and advocated for the use of phages as therapeutic agents pre-antibiotic era (before the discovery of penicillin). In 1933, he co-founded an institute for phage research in the Soviet Republic of Georgia. In the West, scientific efforts turned to the miraculous discovery of penicillin and research on phage therapy was abandoned. However, with the recent development of antibiotic resistance, phage therapy is regaining a lot more attention. Several reports have indicated the effectiveness of bacteriophages against pathogenic bacteria that causes infections in humans or animals via phage therapy.

In addition to bacteriophages, phage lytic proteins also provide successful elimination of pathogenic bacteria. The two main classes of phage lytic proteins are VALs and VAPGHs. These virion-associated lysins (VAL) are produced toward the end of the lytic cycle. Endolysins are highly specialised enzymes produced by the phage to digest the bacterial cell wall and are responsible for the progeny phage release. They have high specificity, dont harm the natural flora and have a low chance of bacterial resistance, making them ideal for fighting against antibiotic-resistant bacteria. (Fischetti, 2010) On the other hand, Virion-associated peptidoglycan hydrolases (VAPGH) act in the first step of the phage lytic cycle. They locally degrade the peptidoglycan of the bacterial cell wall during infection. Unlike, lysins, VAPGHs create a small hole through which the phage tail can eject its genetic material (the start of the phage lytic cycle). Paul et al. identified a phages gene that encoded a muralytic enzyme, which was lethal to S.aureus (the aforementioned bacteria). They experimented with the gene until they produced a protein that retained the antistaphylococcal activity. Then, they combined their new gene with a staphylococcal cell wall-binding protein to produce chimeric protein P128. (Paul et al., 2011) P128 showed potent antistaphylococcal activity on clinical isolates of S.aureus including MRSA and against the genus Staphylococcus in general. It was even effective against MRSA in a rat nasal colonization model. Not only was this a success, it also demonstrates how VAPGHs and VALs could be developed for other pathogenic bacteria. A later study into P128 found that it was bactericidal against every S.aureus strain tested, including many clinically relevant S.aureus strains. Perhaps, most interesting of all was that the P128 protein was able to kill S.aureus, which was recovered from healthy people, under conditions representing physiological conditions. These results are promising for the future prospects of bacteriophages and their clinical applications.

Parfitt highlights the importance of distinguishing between lytic and lysogenic bacteriophages. When lysogenic phages insert their genetic material into the bacteria, their genes are integrated into the bacterias genome. When the bacteria divides, the phages genes are also replicated, however this presents problems as they could cause horizontal spread of antibiotic resistance genes among related bacteria. These lysogenic phages are unlikely to get approval due to their evident disadvantages. Nonetheless this should not detract from the positive effects of lytic phages, which can not spread this antibiotic resistance.

Compared to antibiotics, the price of getting treatment appears to be a significant barrier to inclusive access to phage therapy. At the Phage Therapy Centre, the estimated cost of out-patient care is USD $3000-$5000, which can vary depending on the complexity of the condition. (Phagetherapycenter.com, 2018) Despite its expensive costs, this has improved a lot in just over 12 years, as a course of treatment used to cost between USD $8000 and $20,000 and even these exorbitant prices might outdo conventional antibiotics in the case of multidrug-resistant bacteria eg MRSA. According to an article published by Health Leaders, the average treatment costs for drug-resistant staph infections were about USD $38,500 and more than USD $40,700 for MSSA-associated (methicillin susceptible S.aureus) pneumonias. These estimates may not be accurate as an article in the Clinical Infectious Diseases journal estimates the average costs to be roughly USD $34,526 for MSSA-related hospitalization costs and USD $34175 for MRSA-related hospitalization costs. Furthermore, patients with MRSA-related infections had a higher mortality rate than patients with MSSA-related infections. This may imply that the actual cost of treatment may be higher for these patients and reinforces the idea that multi-drug resistant bacteria are a major problem in current medicine.

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