Running head: PHAGE THERAPY

Phage Therapy: Its the End of the World as we know it

Amber Jones Radcliffe
Western Washington University

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Phage Therapy: Its the End of the World as we know it
Intro

Several years ago now, my two young children of 6 and 8 contracted a virulent form of E.
coli O157: H7 and threw our entire family into a tailspin that left an indelible imprint on my life.
Ill never forget talking to the Nephrologist about the prognosis and treatment of the condition
causing my sons kidneys and other organs to shut down, while my sons small little body was
being pumped full of an unbelievable cocktail of drugs to treat his myriad of symptoms.
Because this bacterial infection is a gram negative strain, we cannot use antibiotics to try to
fight it. Gram negative bacteria when destroyed, release their toxins, causing a second wave of
illness that can actually be more harmful than the pathogen, itself. Our only hope at this point is
to make him as comfortable as possible and hope his body can fight it off on its own. I had just
taken a microbiology course only a few months before, so I asked the Doctor if phage therapy
would help.
How do you know about phage therapy?? the Doctor inquired incredulously. He knew
about it, even though it was still just an experimental approach that the US was reconsidering as
a means to fight the growing threat of intractable multi-drug resistant bacterial infections that
were becoming a worldwide epidemic. Unfortunately, phage therapy would have the same effect
as antibiotics in this case; it would lyse the bacterial cells and start a cascade effect that could be
deadly. I understood this at the time, but I was grasping at straws and would have gone to
Timbuktu for the remedy, if it would help. Luckily, after a month in the hospital with kidney
failure, dialysis, and pancreatitis, both of my children managed to fight it off and I was left with
an insatiable desire to find a better way to fight untreatable bacterial infections, other than time
and prayers.

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Bacteriophages, otherwise known as phages, are naturally occurring viruses that only
seek out and destroy one particular type of bacteria. Phage therapy has been around for
approximately 90 years, originally found in 1917. By the 1930s, US scientists were using
phages to treat a variety of bacterial infections. Not only did they effectively fight infections,
they did not harm host cells, or alter a persons beneficial bacteria (Potera, 2013). Lytic
bacteriophages are extremely specific obligatory intracellular parasitic viruses that inject their
own genetic material into a bacterial cell, high-jacking the bacterias own organelles to mass
produce an explosion of clone viruses, destroying the bacterial cell. Not only are phages finicky,
they can be selective even for a specific subspecies within a species (Wittebole, De Roock, Opal,
2014). That translates to effective infection fighting, but only if the right phage is chosen for the
right pathogen. Therefore mixtures are often employed to improve the likelihood of finding an
appropriate match. Furthermore, because phages self-propagate, only a very small dose is
required to be effective, making phage therapy potentially inexpensive to produce. (Abhilash, 1)
The exquisite specificity of phage therapy is both its strength and its weakness. Critics
point out that a drawback of phage therapy is the time that must be taken to appropriately
identify the pathogen in order to select the appropriate phages. Though I would argue that
identification is a necessary step regardless of treatment, new ways are being developed to speed
up this process. One such solution is the KeyPath MRSA/MSSA blood culture test. It determines
the strain of S. aureus in five hours, requires no specialized equipment to use, and is already
approved by the Food and Drug Administration (FDA) for use. (FDA, 2016)
While I acknowledge that antibiotics have served us well since the discovery of penicillin
and have saved countless lives throughout the years, bacteria are adept at developing resistance
at alarming rates. In fact, multi-drug resistant pathogens are now considered one of the great

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health care crises of modern day medicine and we are running out of new antibiotics. I believe
that the answer for this growing problem is phage therapy because it is effective, affordable and
is a springboard for innovation.
Process
This topic has been researched and studied so extensively, that thousands of clinical
studies have been conducted on the topic. Therefore this topic was best researched through more
comprehensive literature reviews and meta-analysis. I pulled from a variety of articles that
detailed the history and progression of bacteriophage therapy from past to present, but that also
discussed the criticisms and solutions posed by current research. I also included key direct
studies that cited pivotal information to some of my arguments. These included human and
animal studies, meta analysis, cohort studies and the like. I used CINHAL and Medline search
engines with the key word searches of bacteriophage, phage, multi-drug infection, sepsis, and
other MESH terms.
Efficacy
We have all heard that there is a growing problem in medicine. People are developing
new, resistant strains of infection and pharmaceutical companies are losing the battle, with a
variety of increasingly ineffective antibiotics available to fight the newest super infections. Why?
If drug companies make money from new drugs, it seems that this would be a golden
opportunity, ripe for the picking. One of the problems facing drug companies today is that new
antibiotics are increasingly difficult to find, develop and test. Pharmaceutical companies are on
the hook for millions of dollars to develop, research, test and trial new antibiotics, which requires
a large investment of time (De Vos, Rose, Jennes, Pirnay, 2012). Because bacteria divide rapidly
in optimal conditions, they also mutate rapidly, which can therefore develop resistance to

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antibiotics in as little as days. (Pray, para 1) Therefore, a pharmaceutical company can

theoretically begin the process of developing a new antibiotic that is already obsolete before it is
ready to market. In a free market system, the problems are just too costly to justify investment
for drug companies.
Antibiotics have also been grossly misused over the years. In addition to human misuse,
agriculture is a major source of over-application for boosting production and therefore produces
widespread resistance, accelerating the problem (Potera, 2013). Meanwhile, people are dying at
alarming rates, requiring new and improved ways to combat the problem (Wittebole et al., 2014)
When a patient is treated with antibiotics, their entire microbial ecosystem is destroyed.
The bacterial imbalance caused by treatment with antibiotics can lead to serious secondary
infections, often extending hospitalization time, expense and mortality. This doesnt occur with
phage therapy (Abhilash, Vidya, Jagadevi, 2008). Studies show that phage therapy doesnt just
have little impact on the microbiota, but careful surveys of the microbiome of healthy adult
volunteers confirmed the preservation of their pre-existing gut flora after phage therapy. In
addition, after treatment with a 9-phage cocktail, there was no secondary overgrowth infection to
contend with (Wittebole et al., 2014).
Allergies are another common problem with antibiotics, which is not only inconvenient,
but can be life threatening and reduce the variety of treatment options for infection. This is not a
problem with phage therapy; no one has been found to have allergies to phages (Abhilash et al.,
2008). An allergy to phages would be like having an allergy to water; not only are they prevalent
in the body, but there is no way to avoid them. In fact, phages are more abundant than bacteria,
literally ubiquitous to our everyday natural environment (Svoboda, 2009). To put the sheer

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magnitude of phages into perspective, we are literally composed of more phages than anything
else, living or otherwise. Not only are phages everywhere and reside in the trillions in everyone,
but scientists are beginning to understand the necessity of the microbes to our immunity and are
increasingly viewed as a type of non-host immune system (Barr, Rita, Mike, Whiteson, Erb,
Pogliano, Stotland, et al., 2013).
Another way that phages particularly outperform antibiotics, is their remarkable ability to
penetrate biofilms, a polysaccharide matrix that encapsulate and protect gram negative bacteria.
Most antibiotics are ineffective against biofilms, but if they are uniquely capable of penetrating
the biofilm barrier, they are ineffective against the intracellular environment. (De Vos et al.,
2012) In addition, biofilms can protect bacteria from industrial cleansers such as bleach,
allowing for subsequent infestation (Potera, 2013). This is not an issue for phages, which are
equipped with targeted enzymes that treat biofilms like an appetizer for the main course.
Consequently, phages have unlimited access inside the bacterial cell, which scientists are already
exploiting by combining phages with antibiotics, to maximize effectiveness and, hopefully
minimize antibiotic resistance (Wright, para 3). Another novel use of phage therapy is through
its remarkable specificity: they can be used to diagnose infection. After all, they will only attack
and lyse one variety of bacteria, which can be tracked (Potera, 2013).
Within the US, foodborne illness is a widespread problem that causes 9.4 million cases of
food poisoning annually, hospitalizes approximately 56,000 and results in over 1,350 deaths,
according to the Centers for Disease Control and Prevention. Listeria monocytogenes is one such
food borne microbe that is extremely problematic for the food industry and causes listeriosis,
which has a fatility rate of approximately 20%.

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ListShield by Intralytix is the first phage product approved as a food additive by the
FDA and specifically targets L. monocytogenes in prepared deli meats and poultry. L.
monocytogenes is a microbe that contaminates both dairy products and raw produce. It grows
even when refrigerated and causes serious problems for the food industry because it is so
difficult to eliminate. According to the manufacturer, their product eliminates 95% of all L.
monocytogene microbes (Potera, 2013).
Another product called EcoShield, is used as a spray on red meat before it is ground
into hamburger in order to kill Escherichia coli O157:H7, which causes 62,000 foodborne
illnesses in the US every year. Because E coli O157:H7 is so potent, only a very small amount
can infect a very large batch of hamburger. Thanks to biofilms, E coli O157:H7 can live on raw
produce, and hard surfaces even with the use of industrial cleansers. The manufacturer of
EcoShield claims an efficacy of 95% in only 5 minutes and the USDAs tests found that the
product removed 100 percent of E coli within a day. Both commercial products are, odorless,
tasteless, invisible, and noncorrosive. Now, there are more products being developed for
agriculture, veterinary medicine, wound healing and oral care (Potera, 2013).
Affordability
The affordability of phage therapy is an inherent strength of this antimicrobial. They can
be found anywhere bacteria are found, because they are attracted to their prey. Because bacteria
are nimble and can adapt quickly to external attacks through adapted resistance, phage are
equally as agile and evolve right alongside bacteria. Therefore, in order to find a phage for a new
pathogenic form of bacteria, a person has to look no further than the sample taken, where the
complimentary phages are attracted like bees to honey. Propagating phages takes around two
weeks from start to finish, unlike the process to develop a drug which takes years. Due to the

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relative economy of phages, they would be an excellent solution for developing nations
(Abhilash et al., 2008).
In addition to the culture and propagation process, the majoriy of the true cost of
introducing phage therapy to the US is the FDA approval process. The FDA must regulate phage
therapy if it is to be used on humans for medical use. Though the FDA has approved products for
agriculture and food production, it is considered an organic food additive and is not being used as
a drug (Casto, Hurwitz, Kou, Mansour, Mayzel, Policke, & Woolf, 2016). In fact, as long as a
product is used directly to treat human disease, the FDA requires that each individual phage be
approved separately. In addition to trialing each unique phage for approval, if any of the phages
mutate during testing, regardless of harm, the trial would be thrown out. The very characteristic
that makes phages so effectivethat expert ability to shape-shiftmakes it difficult for them to
pass muster with the U.S. regulatory authorities (Svoboda, 2009).
Phage Therapy must be vetted for medical use, the same way any new drug would. In
order to be approved, an Investigational New Drug application must be completed for each type
of phage. For traditional drugs, the FDA wants each component of a drug combination to be
proven safe and effective both individually and in combination. For phage cocktails, that means
the activity, potency, and stability of each phage must be demonstrated, said a spokesperson
from the FDA, Rita Chappelle. Considering that there are potentially hundreds, if not thousands
of each bacteriophage that may be used for treatment, the logistics and costs become staggering
(Potera, 2013).
Another way that phage therapy is cost effective, is as a potential source of revenue for
the pharmaceutical industry. Because lysogenic phages transfer their own DNA into a cell, there
are all kinds of potential for introducing susceptibility back into bacteria. Phages can have

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modified DNA incorporated into their genome, which is transferred directly to their target
bacteria. For example, in the case of MRSA which is methicillin resistant, phage can be used to
transfer sensitivity back into staphylococcus. Researchers have already demonstrated that this
can be done. Additionally, phage can be used to carry an antibiotic on its surface, which brings
the drug precisely where its needed (Viertel, Mareike, Ritter, Hans-Peter, 2014). This would be a
tremendous advantage for pharmaceutical companies, making existing antibiotics effective once
more and reducing external pressure to develop new antibiotics (Wittebole et al., 2014)
Innovations
Phages offer a tremendous wealth of options for bioengineers, who are finding novel
ways to modify phages for our benefit. In addition to the modified phages described previously,
bioengineers have also created non-lytic bacteriophages for gram negative infections (Viertel et
al., 2014 ). As described by the doctor in the introduction, gram negative bacteria such as E. coli
release endotoxins when lysed. However, this problem can be overcome with the engineering of
non-lytic phages, that destroy bacteria without releasing endotoxins. Preliminary studies for nonlytic phages are promising; resulting in decreased inflammatory reactions compared to
antibiotics (Viertel et al., 2014). M13R is an example of an engineered non-lytic phage,
developed by a group of bioengineers, with a system of programmed death controlled by two
modules: a stable toxin and an unstable antidote that neutralised the toxin effect (Hagens, Blsi,
2003). In addition to drastically reduced endotoxin release upon cell death, they have the added
benefit of not propagating within the cell, eliminating any concern of widespread release of
genetically modified viruses (Viertel et al., 2014).
Phages are being used for a variety of applications. They are being produced as biocides
for surfaces that are difficult to sanitize, such as soft surfaces like curtains, uniforms or chairs.

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Such a product could also be used to prevent infection on medical devices, catheters and even
sutures. The University of Pittsburgh has been developing a phage nasal spray that has the
potential to prevent TB transmission (Potera, 2013). Even cancer treatment is being pursued,
with promising results, after inadvertently discovering antitumor activity following phage
inoculation. A preliminary study showed that tumor-specific phages caused neutrophils to
phagocitize a tumor without any other external interventions (Eriksson, Tsagozis, Lundberg,
Parsa, Mangsbo, Persson, Harris, Pisa, 2009).
Dendritic cells, which are a component of the innate immune defense against invaders
and tumors, are synergistically enhanced by phages. Clinical studies demonstrate that the
presence of phages not only prevent further tumor growth, but facilitate enhanced dendritic
tumor destruction. Phages also increase the anti-tumor activity of leukocytes, which are the
mainstay of immunity, and are being studied with further clinical research (Elzbieta, Rossowska,
Weber-Dabrowska, Zabocka, Grski, 2008). Other innovations for cancer treatment include bioengineered phages, that display and present anticancer peptides that find, detect, and facilitate
cellular uptake of targeted drugs to fight the tumors, and not the surrounding tissues (Jin, Jin,
Hong, 2014). Cancer is one of the biggest health problems of modern day, so its heartening to
think that phages might be part of the solution.
Another way that phages are being developed, is by isolating lysins and holins, which are
the active agents that phages employ to destroy bacterial cells. In contrast to bacteriophages that
target a specific bacterial cell, lysins and holins are non-discriminate annihilators of a variety of
bacteria, allowing for general application (Potera, 2013). Lysins may also be a useful backdoor
method for FDA approval. Its simpler to have one or two isolated enzymes approved, which

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would get the foot in the door for approval, generating more acceptance overall for phages
(Casto et al., 2016).
Lysins are only effective against gram positive bacterial infections such as staph,
(because the enzyme cant get through the gram negative cell membrane) but they have the
unique advantage that bacteria cannot become resistant to them (Viertel et al., 2014). Scientists
are developing powerful, engineered lysins that are projected to be effective against MRSA and
Streptococcus pneumonia which has implications for treatment in areas where these infections
are rampant such as hospitals, daycare centers, long term care facilities and also military
barracks.
Synthesis
Not only are bacteriophages an omnipresent, natural presence in our bodies, they keep
our flora in check. As scientists learn more about the natural microbiota of the body and its
critically essential role to the immune system, bacteriophages become even more significant,
because they sit at the top of the microbial food chain, managing every aspect of our bodys
flora.
Therefore, its strange to consider that one of the criticisms of phage therapy is their
effect on the immune system, specifically on antibodies or changes in leukocyte levels. Phages
do affect the immune system, activating the immune system to produce antibodies against them,
which limits the total number of phages that can circulate. However, the flip side of that coin, is
that phages also enhance the activities of the immune system. Based on the evidence, its clear
that phages are an important factor in controlling and destroying tumors, by influencing the
activities of the innate immune system. In addition, many of the best minds in scientific research

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are finding that the microbiota, which solidly includes phages, is not just beneficial to the
immune system, but is a central component of the immune system, itself. This radical new way
of seeing the microbial community in our bodies, may take time to gain traction in the medical
community, but clinical studies are bearing it out. Phages are not just omnipresent, but have coevolved to optimize their hosts immunity, which in turn ensures their own survival. They are a
symbiotic bridge between bacteria and the immune system that modify, suppress and activate in
a continuous dance that is simultaneously self-serving and advantageous to us.
Where does all of this fit into modern medicine? Currently, medical facilities are engaged
in an all out war against infection, employing every tool at their disposal to prevent and fight
infection. Hospitals are fighting infection on two fronts; both community-acquired infection and
also Hospital Acquired Infection, otherwise known as HAIs. HAIs require improved infection
control with every interaction between medical professionals and the patient to not only prevent
cross-contamination, but also prevent unnecessary antibiotic resistant super-infections. One of
the ways hospitals employ to combat the problem are antimicrobial cleansers and soaps, which
are used for hand washing, hard surface cleansing and equipment decontamination. At first
glance, such products may appear to be in conflict with phage therapy, but as the growing
mountain of evidence illustrates; such cleansers may be complimented by the addition of phages,
which could be chosen to fight specific bacterial strains that are resistant, enhancing efficacy.
In contrast to combining antibiotics with phages, there are plenty of circumstances where
they should be used alone. Examples include people with antibiotic allergies, those with
secondary super-infections, such as C. difficile, and multi-drug resistant organisms that require a
specific, brand new variety of phage for the job. Each example is a perfect illustration that
antibiotics are not just failing to work, but are also causing harm. Not so with phages, which

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have almost no downsides, except their inability to be tied down. In short, the very attributes that
make phages so inexpensive, nimble and versatile, are the very same characteristics that make
them hard to embrace by the only entity that stands between phage therapy and the US
pharmaceutical market: the FDA. Its precisely because the FDA cannot categorize, patent and
control bacteriophages, that keep them from the American public.
Though it appears to be an insurmountable problem to approve phages with our current
system, given time, the FDA will have to be re-tooled to accept this dramatically different form
of treatment. Perhaps the only way to do this is to wait until the public is desperate for an
alternative. Public outcry and irrefutable evidence that phage therapy not only works, but is not a
threat to safety will be the impetus required for such a large reformation. The scientific
community will play a key role in persuading the powers that be, but the FDA is just a
government entity and cannot stand in the way of medical breakthroughs that may be the only
thing that can protect people.
The inherent unpredictability of viruses cannot be the sticking point preventing forward
momentum with a therapy that can be such a benefit to society. Because phages can mutate and
swap genetic DNA sequences with bacteria, critics are understandably suspicious of anything so
capricious. In particular, it is concerning to authors such as Wittebole et al. that phages could
theoretically transfer pathogenicity to bacteria, increasing virulence. While I can understand the
insecurity that unknown variables present, I remain skeptical that a virus would create problems
like that for itself. By focusing on the uncertain nature of phages, detractors are overlooking
lifes most fundamental imperative: preservation of self. After all, the virus is the predator and
must parasitize their complementary bacteria or die. It would not only be counterproductive for
the virus to ensure its own demise, but counter-evolutionary.

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Conclusion
Worst case scenarios aside, phage therapy and all of its potential for novel applications
continues to be studied and tested, proving more effective and affordable than previously
expected. Not only does phage therapy have exciting benefits in the fight against life threatening
infection, but the potential for innovation is undeniable and must be pursued. I believe phage
therapy will overcome the uncertainty and concerns common with anything new. In particular,
FDA approval is a formidable obstacle, but I believe that like the phage, our first priority is the
preservation of the human race. Therefore, Im confident that the growing threat, combined with
the substantial evidence in favor of phages, will bring about the necessary changes needed to the
government, in order to accept this prospective treatment. Given more time, phage therapy will
ironically be the old solution needed for the new future of infection control. And not a moment
too soon when lives are at stake.

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References
Abhilash, M., Vidya, A., Jagadevi, T. Bacteriophage therapy: A war against antibiotic resistant
bacteria. The Internet Journal of Alternative Medicine. 2008 Volume 7 Number 1.
Barr, J.J., Rita, A., Mike, F., Whiteson, K.L., Erb, M.L., Pogliano, J., Stotland, A., et al.
Bacteriophage Adhering to Mucus Provide a Nonhost-Derived Immunity. Proceedings of the
National Academy of Sciences 110, no. 26 (June 25, 2013): 1077176.
doi:10.1073/pnas.1305923110.
Casto, A., Hurwitz, A., Kou, K., Mansour, G., Mayzel, A., Policke, R., . . . & Woolf, A. (2016).
Bacteriophages: The answer to antibiotic resistance? James Madison Undergraduate Research
Journal, 3 (1), 36-41. Retrieved from http://commons.lib.jmu.edu/jmurj/vol3/iss1/4/
De Vos, D., Rose, T., Jennes, S., Pirnay, J. Bacteriophages for the treatment of severe infections: A
new option for the future? EWMA Journal 12, no. 2 (May 2012): 2328 6p.
Elzbieta, P., Rossowska, J., Weber-Dabrowska, D.D., Zabocka, A., and Grski, A. Bacteriophages
support anti-tumor response initiated by DC-based vaccine against murine transplantable colon
carcinoma. Immunology Letters 116, no. 1 (February 15, 2008): 2432.
doi:10.1016/j.imlet.2007.11.004.
Eriksson, F., Tsagozis, P., Lundberg, K., Parsa, R., Mangsbo, S.M., Persson, M.A.A., Harris, R.A.,
and Pisa, P. Tumor-specific bacteriophages induce tumor destruction through activation of
tumor-associated macrophages. The Journal of Immunology 182, no. 5 (March 1, 2009): 3105
11. doi:10.4049/jimmunol.0800224.
Hagens, S. and Blsi, U. (2003), Genetically modified filamentous phage as bactericidal agents: a
pilot study. Letters in Applied Microbiology, 37: 318323. doi:10.1046/j.1472765X.2003.01400.x
Jin, S.E., Jin, H.E., Hong, S.S. Targeted delivery system of nanobiomaterials in anticancer therapy:
From cells to clinics. BioMed Research International, 2014,(February 19, 2014): e814208.
doi:10.1155/2014/814208, 10.1155/2014/814208.
Potera, Carol. Phage renaissance: New hope against antibiotic resistance. Environmental Health
Perspectives 121, no. 2 (February 2013): A4853 1p. doi:10.1289/ehp.121-a48.
Pray, Leslie. Mutation rates and antibiotic resistance | Learn Science at Scitable. Accessed May 7,
2016. http://www.nature.com/scitable/topicpage/Antibiotic-Resistance-Mutation_Rates-and%20MRSA-28360.
Svoboda, Elizabeth. The next phage | Popular Science. Popular Science, March 31, 2009.
http://www.popsci.com/scitech/article/2009-03/next-phage.
U.S. Food and Drug Administration. June 2, 2016. 510(k) Premarket Notification. Retrieved from
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K102342.

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Viertel, T., Mareike, K., Ritter, Hans-Peter H., Viruses versus bacterianovel approaches to phage
therapy as a tool against multidrug-resistant pathogens. Journal of Antimicrobial Chemotherapy
69, no. 9 (September 1, 2014): 232636. doi:10.1093/jac/dku173.
Wittebole, X., De Roock, S., & Opal, S. M. (2014). A historical overview of bacteriophage therapy as
an alternative to antibiotics for the treatment of bacterial pathogens. Virulence, 5(1), 226235.
Wright, A., Hawkins, C., nggrd, E., and Harper, D. A controlled clinical trial of a therapeutic
bacteriophage preparation in chronic otitis due to antibiotic-resistant pseudomonas aeruginosa; a
preliminary report of efficacy. Clinical Otolaryngology 34, no. 4 (August 1, 2009): 34957.
doi:10.1111/j.1749-4486.2009.01973.x.