History of Phage therapy against Superbugs

Phage Therapy is the therapeutic use of lytic bacteriophages (virus that cause bacterial cell lysis) to treat pathogenic bacterial infections.Initially described almost a century ago by William Twort, and independently discovered shortly thereafter by Félix d'Herelle (considered by many as the founder of bacteriophages and its therapeutic implication: the phage therapy).D'Hérelle said that the phages always appeared in the stools of Shigella dysentery patients shortly before they began to recover.He "quickly learned that bacteriophages are found wherever bacteria thrive: in sewers, in rivers that catch waste runoff from pipes, and in the stools of convalescent patients".

Why scientist loose interest in first place on phages as antibacterial agent?

While knowledge was being accumulated regarding the biology of phages and how to use phage cocktails correctly, early uses of phage therapy were often unreliable.Since the early 20th century, research into the development of viable therapeutic antibiotics had also been underway, and by 1942 the antibiotic penicillin G had been successfully purified and saw use during the Second World War. The drug proved to be extraordinarily effective in the treatment of injured Allied soldiers whose wounds had become infected. By 1944, large-scale production of Penicillin had been made possible, and in 1945 it became publicly available in pharmacies. Due to the drug's success, it was marketed widely in the U.S. and Europe, leading Western scientists to mostly lose interest in further use and study of phage therapy for some time.

Read about: Bacteriphages used to treat cholera

Why there is renewed interest worldwide in the ability of phage therapy?

As a result of the development of antibiotic resistance since the 1950s and an advancement of scientific knowledge, there has been renewed interest worldwide in the ability of phage therapy to eradicate bacterial infections and chronic polymicrobial biofilm (including in industrial situations)

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Advantage of using phages as antibacterial agent

Bacteriophage treatment offers a possible alternative to conventional antibiotic treatments for bacterial infection.

• It is conceivable that, although bacteria can develop resistance to phage, the resistance might be easier to overcome than resistance to antibiotics
• Bacteriophages are very specific, targeting only one or a few strains of bacteria. Traditional antibiotics have more wide-ranging effect, killing both harmful bacteria and useful bacteria such as those facilitating food digestion. The species and strain specificity of bacteriophages makes it unlikely that harmless or useful bacteria will be killed when fighting an infection.
•  Enzybiotics are a new development at Rockefeller University that create enzymes from phage. Purified recombinant phage enzymes can be used as separate antibacterial agents in their own right
• Phage Therapy also has the potential of preventing or treating infectious diseases of corals. This could assist with decline of coral around the world
• A few research groups in the West are engineering a broader spectrum phage, and also a variety of forms of MRSA treatments, including impregnated wound dressings, preventative treatment for burn victims, phage-impregnated sutures

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Obstacles and disadvantages of using phages

• The high bacterial strain specificity of phage therapy may make it necessary for clinics to make different cocktails for treatment of the same infection or disease because the bacterial components of such diseases may differ from region to region or even person to person. In addition, this means that 'banks' containing many different phages must be kept and regularly updated with new phages
• Further, bacteria can evolve different receptors either before or during treatment. This can prevent phages from completely eradicating bacteria.
• The need for banks of phages makes regulatory testing for safety harder and more expensive under current rules in most countries. Such a process would make difficult the large-scale use of phage therapy.
•  patent issues (specifically on living organisms) may complicate distribution for pharmaceutical companies wishing to have exclusive rights over their "invention", which would discourage a commercial corporation from investing capital in this
• No lytic phage has yet been discovered for Clostridium difficile, which is responsible for many nosocomial diseases, but some temperate phages (integrated in the genome, also called lysogenic) are known for this species; this opens encouraging avenues but with additional risks as discussed below. 
• Funding for phage therapy research and clinical trials is generally insufficient and difficult to obtain, since it is a lengthy and complex process to patent bacteriophage products. Scientists comment that 'the biggest hurdle is regulatory', whereas an official view is that individual phages would need proof individually because it would be too complicated to do as a combination, with many variables. Due to the specificity of phages, phage therapy would be most effective with a cocktail injection, which is generally rejected by the U.S. Food and Drug Administration (FDA). Researchers and observers predict that for phage therapy to be successful the FDA must change its regulatory stance on combination drug cocktails
• Public awareness and education about phage therapy are generally limited to scientific or independent research rather than mainstream media.The negative public perception of viruses may also play a role in the reluctance to embrace phage therapy

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Comparison of the Prophylactic and/or
Therapeutic Use of Phages and Antibiotics

Bacteriophages	Antibiotics	Comments
Very specific (i.e., usually affect only the targeted bacterial species); therefore, dysbiosis and chances of developing secondary infections are avoided .	Antibiotics target both pathogenic microorganisms and normal microflora. This affects the microbial balance in the patient, which may lead to serious secondary infections.	High specificity may be considered to be a disadvantage of phages because the disease-causing bacterium must be identified before phage therapy can be successfully initiated. Antibiotics have a higher probability of being effective than phages when the identity of the etiologic agent has not been determined.
Replicate at the site of infection and are thus available where they are most needed .	They are metabolized and eliminated from the body and do not necessarily concentrate at the site of infection.	The "exponential growth" of phages at the site of infection may require less frequent phage administration in order to achieve the optimal therapeutic effect.
No serious side effects have been described.	Multiple side effects, including intestinal disorders, allergies, and secondary infections (e.g., yeast infections) have been reported .	A few minor side effects reported  for therapeutic phages may have been due to the liberation of endotoxins from bacteria lysed in vivo by the phages. Such effects also may be observed when antibiotics are used .
Phage-resistant bacteria remain susceptible to other phages having a similar target range.	Resistance to antibiotics is not limited to targeted bacteria.	Because of their more broad-spectrum activity, antibiotics select for many resistant bacterial species, not just for resistant mutants of the targeted bacteria .
Selecting new phages (e.g., against phage-resistant bacteria) is a relatively rapid process that can frequently be accomplished in days or weeks.	Developing a new antibiotic (e.g., against antibiotic-resistant bacteria) is a time-consuming process and may take several years .	Evolutionary arguments support the idea that active phages can be selected against every antibiotic-resistant or phage-resistant bacterium by the ever-ongoing process of natural selection.

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