Phage Therapy: The Answer to Multidrug Resistant Bacteria?

illustration by Nick Rogers

Illustration by Nick Rogers

One of the major issues facing modern medicine is the rising prevalence of multidrug resistant bacteria. Most of the current strategies for dealing with this problem are preventative: minimizing the number of people infected, stopping the spread of the resistant pathogens, tracking them when they do crop up, and using antibiotics more responsibly [1]. For those who do have the misfortune of contracting a resistant illness, treatment relies on identifying the microorganism responsible and selecting antibiotics to which it is still vulnerable. As resistance continues to increase in severity among disease-causing bacteria, it seems that the only hope for treatment lies in finding new antibiotics. This strategy has worked — so far.

A classic example is MRSA (methicillin-resistant Staphylococcus aureus), a resistant strain of a relatively common bacterium responsible for many hospital-acquired infections. When it first began to spread, a wide variety of frontline drugs were found to be ineffective in treating it; luckily, an older antibiotic, vancomycin, was successful. MRSA eventually began to develop resistance to vancomycin as well, but by then researchers had had enough time to develop new drugs, such as linezolid and quinupristin/dalfopristin [2].

However, new strains of multidrug resistant bacteria are beginning to emerge, and antibiotic development is no longer progressing at the rate it was when MRSA emerged [2]. From 2008 to 2012, only 2 new drugs were approved by the FDA; a startling drop from the 16 approvals in the period from 1983 to 1987. There are three main reasons for the stagnation of antibiotic development. First, the most easily identified agents have already been identified, meaning that each successive generation of drugs developed requires more in depth research, funding, and time. Second, pharmaceutical companies find that short-course antibiotics have poor returns relative to drugs for chronic conditions. Lastly, FDA regulations have become increasingly impractical and confusing [9]. In light of the potential failure of antibiotics in treating multidrug resistant diseases, an older alternative is coming to light: phage therapy.

Bacteriophages, often just called phages, are a class of viruses that exclusively infect bacteria. They spread by injecting their genetic material into a bacterium and hijacking the host’s own cellular machinery to multiply rapidly; this continues until the cell bursts, killing the host and releasing the next generation of phages to infect more bacteria. Phages were first discovered about a century ago in Europe, when their disease-fighting properties were noted [3]. It was soon discovered that people with certain diseases could be deliberately exposed to phage “infections” to cure their illness. This was the start of phage therapy.

Research into phage therapy quickly grew in Eastern Europe. However, a combination of factors led to it never becoming prevalent outside this region. In the initial years, inconsistent results made many scientists wary to pursue a still poorly understood mechanism of disease treatment [3]. Nearly simultaneously, the miraculous development of antibiotics exploded and drew much more attention than phage therapy ever did. Following this, the outbreak of World War II broke lines of communication in both directions: the Western world turned to antibiotics, while many Soviet states used phage therapy instead. To this day, phage therapy remains important in Russia, Georgia, and Poland [4].

As the Western world is coming to realize, phage therapy has several advantages over antibiotics. Antibiotics are static chemicals, whereas the microorganisms they target are living creatures capable of mutation; this is the principal mechanism of resistance. On the other hand, phages are capable of evolving in tandem with their intended targets, so resistance via mutation would be less of a concern [5]. Even if a strain of bacteria does manage to become immune to the phages intended to attack it, another can always be selected — there are an estimated 1031 phages on the planet [3], all potentially capable of treating a disease. (For comparison, there are “only” 1024 stars in the observable universe! [6])

Another important point to note is the recent trend in biomedical sciences that shows that our bodies harbor a great number of beneficial bacteria, known as our microbiome or microbiota. Perhaps the most important subset is our gut microbiota. These bacteria supply essential nutrients, break down indigestible substances, support and strengthen our immune system, and help prevent infection from harmful bacteria [7]. Modern antibiotics tend to be broad-spectrum, harming not just the illness-causing bacteria but also the beneficial bacteria native to our bodies. When these bacteria experience die-offs, they leave us vulnerable to colonization by disease-causing bacteria [8]. By contrast, phages target one species of bacteria at a time [4].

It seems as though phages might be another miracle solution, akin to the discovery of antibiotics — but there are some obstacles slowing or preventing the development of phage therapy. As mentioned previously, phages are capable of evolving; while this usually allows them to keep up with resistance mutations in their bacterial hosts, it is theoretically possible that they could acquire mutations that are harmful to humans [5]. Additionally, in a process known as lateral gene transfer, phages may acquire genes from other phages or even from bacteria. Phage-phage gene swapping could create novel substances that trigger immune reactions, while phage-bacteria gene swapping could allow the phage to gain genes responsible for virulence.

For these reasons, the FDA has strict guidelines for conducting trials to determine the viability of phage therapy; regulations are a major hurdle to bypass. One rule is that each individual phage or mixture of phages must go through its own clinical trial. However, since many human infections harbor multiple bacterial species, and phage therapy often includes multiple strains of phage per each individual target species, treatment is usually a custom-made blend of hundreds of phages for each patient [5]. It would obviously be impossible to test all possible combinations of phages, making this regulation a huge stumbling block. Another issue is the age of phage therapy. As it is nearly a century old, it is unlikely that a pharmaceutical company would be able to patent any phage treatment, leaving them with no guarantee that they could recoup costs, let alone make a profit [4].

As drug resistance in pathogenic bacteria continues its upward trend, our healthcare system will be forced to confront the rising threat. Our decision to delve more deeply into the possibilities presented by phage therapy, or to forge onwards in our attempts to discover and develop new antibiotics, will certainly have a large impact on the field of medicine into the foreseeable future.

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'Phage Therapy: The Answer to Multidrug Resistant Bacteria?' have 3 comments

  1. March 31, 2016 @ 4:49 PM Ed Hatch

    Great article! Any chance the references for the endnotes could be added?


    • March 31, 2016 @ 4:54 PM Frontiers Magazine

      They should be in the hyperlinks! (Hard to see due to the blue background, we’ll fix this soon)


  2. March 31, 2016 @ 6:00 PM Ed Hatch

    My bad, the hyperlinks are there, just hard to see. Thanks.


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