Is A Virus The Answer To Antibiotic Resistant Superbugs?

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The Bacteriophage: A Friendly Virus

Bacteriophages, viruses which attack and destroy bacteria that are 40 times their own size, were first discovered by British bacteriologist Frederick Twort, in 1915. For Twort, who worked at a time when microscopes would not allow him to actually see his discovery, these little bacteria hunters were just something he observed, but two years later in 1917, a French-Canadian scientist working at the Pasteur Institute in Paris developed a fascination with them which would last a lifetime. He coined the name bacteriophage. 1 Penicillin wasn't discovered until 1928.

The word phage is a combining form that means "one who eats" or simply "eater of things." We see it also in words like phagocyte, which are cells in the body which attack and absorb, or 'eat', harmful bacteria, dead cells, or foreign particles. When the word phage is used alone, however, it is almost always short for bacteriophage.

By the early 1930's, it was known, although still considered experimental, that bacteriophages could attack and destroy bacteria in the human body without harming the human host. At that time, it was phages, not antibiotics, which were being used to treat bacterial infections. Companies like Eli Lilly and E.R. Squibb even marketed their own phage preparations.

Phage therapy was used in the United States and in Asia to treat many different types of infections. The results were inconsistent, but it is not clear whether this was due to faulty preparations, which may have rendered the virus inert, or a failure to match the phage to the infection, or limited research 1

Bacteriophages Versus Antibiotics

The advantage of antibiotics is that one antibiotic is effective against a wide range of bacteria. Bacteriophages, however, are specific in the particular bacteria they attack. A phage or a group of phages must be matched to the invading pathogen. The wide range of antibiotics caused them to easily preempt bacteriophage therapy in the West. However, in the Soviet Union, where it was difficult to get antibiotics, phage therapy continued to be used, and since the fall of communism, phages have continued to be developed and refined.

However, it is a myth that antibiotic resistance is a newly discovered problem. It is also a myth that penicillin, once introduced, immediately stopped any and all interest in bacteriophage therapy. Scientists began realizing that bacteria could quickly adapt and develop resistant strains to penicillin and sulfa-based drugs almost as soon as they began being used. There was even early work on using both antibiotics and phage therapy together. These early studies were not really followed up in the west but combination treatments are still used in Russia, Georgia, and Poland. 1

Where Is Phage Therapy Used?

Bacteriophage therapy is an officially registered medicine in several East European countries such as Georgia, Armenia, Ukraine, and Russia, where it is considered quite standard by both doctors and patients. 2 In the United States, as well as in the EU, no whole phage or phage-derived therapy is currently approved for medical use 3, except in Belgium, which is developing a phage therapy framework. 4

Antibiotic Resistance

Now, due to the widespread, and sometimes irresponsible, use of antibiotics, bacteria are evolving resistance to the drugs. Some infections are now resistant to even the most powerful antibiotics. Staphylococcus aureus, the cause of commons 'staph infections' are notorious in their ability to develop resistance to antibiotics. These bacteria were, in the past, naturally susceptible to almost every type of antibiotic ever developed, something that is not necessarily a good thing. Now, waves of MRSA infections, or Methicillin-resistant S. aureus, are becoming common and rising to epidemic levels. 6 Vancomycin-resistant enterococci and a variety of gram-negative organisms, such as Klebsiella and Pseudomonas species are also resistant to multiple
different antibiotics.

Transmission electron micrograph of multiple bacteriophages attached to a bacterial cell wall, magnification approximately 200,000.

Image by Dr Graham Beards via wikimediaImage Credit

Transmission electron micrograph of multiple bacteriophages attached to a bacterial cell wall, magnification approximately 200,000.

Image by Dr Graham Beards via wikimediaImage Credit

The Eliava Institute in Georgia

The video here concerns the Eliava Institute in Georgia, the world leader in phage production, which has been treating patients with phage therapy since 1923. Patients from all over the world, who find their illness resistant to antibiotics, travel there to be treated.

Eliava Institute carries six standard phages. When a patient comes in, the bacteria responsible for their infection is identified and then a determination is made as to whether one of the six standard preparations will work against the pathogen. If it is found that the bacteria respond to one of these phages, then the patient can simply pick up the required phage at the pharmacy.

If a match is not found, then the bacterial sample is taken to the laboratory to be checked against the institute's collection of laboratory phages. The bacteria is spread onto a petri dish and then a spot of various phages are placed on the dish. The dish is incubated overnight, and any clear spots indicate the areas where phages successfully attacked the bacteria. The more clear the spots, the more effective the phage. From there, the phage selected is developed into a drug preparation to be administered under the supervision of the doctor. The drug might be drunk, or applied to the skin, inhaled, or injected, depending on the site of the infection.

How Bacteriophages Attack Bacteria

Bacteriophages are actually used as part of a cocktail of different phages because of the specificity of different phages. However, once a bacteriophage encounters the right pathogenic bacteria, they attach themselves to the cell wall of the organism and inject their DNA directly into the cell. Then, like other viruses, they hijack the machinery of the cell to replicate themselves, multiplying and making many copies inside the host organism. Then they release a lysin which breaks open the cell wall, releasing the virus copies to invade other bacteria. 2 Meanwhile, the bacterial cell itself basically explodes like a balloon. The bacterium is destroyed. This method of virus propagation is called the lytic cycle. An example is the T4 bacteriophage which infects Escherichia coli found in the human intestinal tract.

This is not the only life cycles bacteriophages can have. Some, called temperate bacteriophages, can also display a lysogenic cycle, where the viral genome is incorporated into the genome of the host cell, which is then passed on to subsequent bacterial progeny. An example of a prophage is the λ (lambda) virus, which also infects the E. coli bacterium. 5 This cycle allows the virus to pass on its genetic identity without lysing the host organism, but such a virus can become lytic when environmental circumstances trigger this cycle. Some phages, through mutation, have lost their ability to display a lysogenic cycle and are obligatory lytic phages.

Phage Derived Drugs

Bacteriophage lysins themselves are being developed as a drug against infectious bacteria. Although bacteria may eventually become resistant to endolysin-based drugs, this may take many decades to occur, even as much as a century.

However, lysin therapies, no matter how effective, are like conventional therapies in that they are static. Once used, the only way to increase their number in the body is to re-administer. Bacteriophages are unique in that they multiply their numbers, by the millions, in response to the presence of specific bacteria. And unlike bacteriophage-derived drugs, which would entail the granting of patents and injections of millions of dollars, resulting in expensive drugs, bacteriophages are relatively cheap and can more often be used locally rather than systemically, while still maintaining effectiveness. It is, however, this lack of commercial interest which may be hampering the development of these techniques.

Can Bacteriophage Therapy Be Approved in the U.S.?

Another problem hampering the approval of bacteriophage therapies in the United States is that the current drug approval process is based on chemical-based drugs. We simply do not have a mechanism in place for approving therapies based on living organisms. And the use of a virus in the human body, although they do not directly infect the tissues of human beings, introduces complex pharmacodynamic and pharmacokinetic properties which will be difficult to understand. We have learned much about the phages possess different biological, physical, and pharmacological properties of antibiotics, but we still no little in regards to bacteriophages. Phage-derived drugs, such as the above-mentioned endolysins, are already suitable for the current drug-approval process.

It is possible for phage therapy to be approved in the United States but there are many roadblocks. Not the least of these is a lack of economic viability. Future use may rest on alternative approval pathways including adaptive licensing or new legislation involving the individual's "right to try." 3

If phage-based products are used to treat infections, resistance will one day, again, become a problem, requiring a desperate search for new therapies. It is, of course, possible for bacteria to evolve resistance to bacteriophages as well. However, one distinct advantage is that the bacteriophages can evolve right along with the bacteria. There are still many questions as to how effective they really are, and whether bacterial resistance, which can begin happening immediately, is an insurmountable problem. It is not clear that bacteriophages can completely eliminate all the infectious bacteria in a human's body. They may, however, reduce the bacterial load to such a degree that the body can now handle the infection, or they may help weaken the bacteria, making them more susceptible to antibiotics. You will notice, if you watch the video on this page, as well as other such videos, that patients report positive result, but there is little talk of a miracle recovery.

Phages Are Already Inside You

Before you think, it can't possibly be safe to put a load of virus inside the body, know that you already have bacteriophages inside you. They are, in fact, the most numerous members of your gut microbiome where the help regulate the bacterial population in the gut. They can even transmigrate through the intestinal mucosa and move into the lymph system and into internal organs. There is conflicting evidence as to their protective role and their potential harm but evidence is mounting that they play a protective role against gut pathogens.

Posted on 09 Apr 2018 18:48

Sources
1. Kuchment, Anna. The Forgotten Cure: the Past and Future of Phage Therapies. Springer, 2012.
2. Igrejas, Gilberto, et al., editors. “Surveying Antimicrobial Resistance: Approaches, Issues, and Challenges to Overcome.” Frontiers Research Topics, 2017, doi:10.3389/978-2-88945-141-8.
3. Cooper, Callum J., et al. “Adapting Drug Approval Pathways for Bacteriophage-Based Therapeutics.” Frontiers in Microbiology, vol. 7, 2016, doi:10.3389/fmicb.2016.01209.
4. Pirnay, Jean-Paul, et al. “The Magistral Phage.” Viruses, vol. 10, no. 2, 2018, p. 64., doi:10.3390/v10020064.
5. “Virus Infections and Hosts.” OpenStax CNX, Rice University, cnx.org/contents/fL0VrVv_@3/Virus-Infections-and-Hosts.
6. Chambers, Henry F., and Frank R. Deleo. “Waves of Resistance: Staphylococcus Aureus in the Antibiotic Era.” Nature Reviews Microbiology, vol. 7, no. 9, 2009, pp. 629–641., doi:10.1038/nrmicro2200.
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