Phage Therapy: A safe solution for life-threatening infections
Abstract
Antibiotic resistance is a growing global threat in need of a viable solution, especially in cases of life-threatening infection. Phage therapy has gained momentum in Western medicine for its ability to target resistant infections, but remains an experimental treatment. This paper analyzes concerns regarding the safety of phages, especially as it relates to potential negative immune reactions of patients. A review of the literature found no phage related adverse events have been reported throughout several small and large scale studies, composed of both healthy and immunocompromised individuals. Along with these studies, widespread use of phage therapy in Eastern Europe, approval of phage products for food applications, and known risks of antibiotics provide support for medical approval of phage therapy.
Introduction
According to the World Health Organization, antibiotic resistant infections are one of the most pressing global threats of our time (2018). As researchers work to find new antibiotics to fight these infections, the bacteria being targeted are finding new ways to evade them in a biological arms race. Penicillin, the first antibiotic, was used to treat humans starting in 1942. Resistance to it was found in Staphylococcus aureus starting in 1947, less than five full years since its first use. Since then, S. aureus has become a “superbug” that plagues hospitals, resistant to multiple antibiotics currently available (McKinstry & Edgar, 2005, p. 430). S. aureus is not the only bacteria that has developed resistance. In 2017,the World Health Organization (WHO) released a list of 12 that were in urgent need of new treatments (WHO, 2017). These bacteria can cause a range of potentially life-threatening diseases, especially in some of the immunocompromised patients they target.
In a dire case, Tom Patterson, of San Diego, was clinging to life in the intensive care unit (ICU) after exhausting antibiotic options to treat his infection of Acinetobacter baumannii. His wife, Steffani Strathdee, an infectious disease epidemiologist, was determined to find a solution when the doctors treating him were at a loss. Her research led to phage therapy, which ultimately saved Tom’s life. Strathdee, working in conjunction with the head of infectious disease at the hospital, set out to locate a strain of bacteriophages that Tom’s infection was susceptible to and gain approval from the Food and Drug Administration (FDA) to use them. Her connections to researchers throughout the country helped to facilitate the difficult process of finding a match. The FDA approved the phage strains for compassionate use and, hours from death, the phages were administered intravenously. Five days later he came out of the coma, after fighting the infection for nearly four months (Pawlowski, 2019).
Tom’s case illustrates both the urgency of the problem antibiotic resistant bacteria impose and a viable solution to it. Abandoned in Western medicine after the commercial success of antibiotics, phage therapy is being reevaluated at an increasing scale. Sustained use in Eastern Europe has sparked interest in phages from Western countries grappling with the growing threat of resistance. Bacteriophages are unique in their ability to treat infections: highly specific, ubiquitous and efficient. They can greatly reduce or even clear colonies of target bacteria in hours. With advances in technology since the original discovery, scientists have a greater understanding of how to effectively utilize phages to treat infections (Lin, Koskella, & Lin, 2017, pp. 165). Based on all available evidence, phage therapy has been proven safe for administration in critical cases without the need for a compassionate use waiver from the Food and Drug Administration.
Background
Bacteriophages are a natural “predator” of bacteria and have become a logical solution to the growing problem of resistance. Phage therapy utilizes strains of bacteriophages that target clinically relevant bacteria by isolating and culturing them in a laboratory, then administering them to resistant infections topically, orally or intravenously. Phages have a high degree of specificity, which requires the analysis for bacterial susceptibility to known phage strains. After identification and administration, phages infect the intended bacteria and replicate before destroying the bacterial cell as part of their natural life cycle. This means the therapy is both self-amplifying, an attribute not seen in antibiotic therapy, and self-limiting since they can only reproduce in the targeted cells (Lin, Koskella, & Lin, 2017, pp. 162-164).
Discovered in 1915, the use of bacteriophages to treat bacterial infection was plagued by issues with purity and effectiveness (Lin, Koskella, & Lin, 2017, p. 164). Over the last century, there have been large advancements in technology that have helped to make phage therapy more feasible and reliable. Researchers are now able to identify the presence of phages more easily and sequence their genome to analyze their suitability in treatment. After isolation, technology enables phage strains to be purified and cultured for medical or commercial use, and ensures that active phages are being supplied. This progress has allowed scientists to overcome a major impediment from the past (Comeau et al, 2008, 307).
Phages exist throughout the world, in any environment where bacteria exist. There are an estimated 1031 phages globally, with the densest populations occurring in seawater. This ubiquity means that humans are regularly in contact with bacteriophages from their own microbiome and their environment. Only an exceedingly small fraction of phages have been identified and sequenced, but scientist are diligently working to increase this (Comeau et al, 2008, 307). In time, researchers could potentially identify at least one strain of phages to combat every clinically relevant antibiotic resistant bacteria.
Phage Safety
The most pressing consideration for making phage therapy available in Western countries is concerns about safety. Many people find the idea of using viruses to treat bacterial infections counterintuitive. Viruses are something that people generally try to avoid coming into contact with (Pawlowski, 2019). However, humans are constantly exposed to bacteriophages due to their ubiquity. Many of the bacteria that constitute our normal microbiota, and cause opportunistic infections, have been found to have prophages. Prophages are the genetic code of a bacteriophage that has been incorporated into the bacterial genome (J. Doss, personal communication, November 15, 2019). Dr. Ratzlaff, professor of Immunology at Old Dominion University noted that phage ubiquity means it is possible a patient will have already been exposed to the same phage strain being used to treat their infection (personal communication, November 14, 2019).
While phages cannot cause infection in humans, it is possible there could be immunological interactions that pose a safety risk. Ratzlaff noted that there would be two major considerations when addressing the possible immune responses to phage therapy: antibodies and method of application. If a patient has had contact with the strain of phages being used for treatment of an infection, then they could have antibodies that would react to subsequent exposure. At this time, there are no documented adverse immune-related events from phage exposure or therapy. It is possible that large doses could stimulate an undesirable immune response, and should be considered prior to phage application (personal communication, November 14, 2019).
The severity of that response would likely be correlated to the method of phage administration. According to Ratzlaff, topical delivery of phages would pose the least risk due to the natural barrier of dermal tissues. Oral treatment would pose a slightly higher risk when considering the possibility of diffusion into tissues outside of the gastrointestinal tract. Likewise, local application of phages, through injection to site of infection, would have a similar risk of diffusion to oral treatment. Ratzlaff indicated the highest concern for adverse immune reactions would be with intravenous administration, as a result of more widespread exposure within the body (personal communication, November 14, 2019).
The potential for adverse reactions has been comprehensively reviewed through several studies which found no evidence of human toxicity. One study found that 23% of patients and 11% of healthy individuals had antibodies to a phage for Staphylococcus before it was administered therapeutically. Despite that, no adverse reactions have been reported as a result of phage therapy (Housby and Mann, 2009, 537). Bruttin and Brüssow were among the first to test the potential for toxicity from oral phage therapy. They subjected fifteen healthy adults to low and high dosages of phages through drinking water, with no adverse events that could be linked to phage application (2005, pp. 2874-2875).
Additionally, the safety of intravenous administration of phages has been thoroughly studied. The most comprehensive data comes from the work of Ochs and collaborators. Based in Seattle, they have spent over forty years studying the effects of large dose intravenous injection of phages to a varied population that included autoimmune deficient children, adults and healthy volunteers. While their study was focused on immunopathology, no adverse effects have been reported that are attributable to the phages. This backs up previous smaller studies of IV phage administration throughout the world and indicates negative immune reactions are exceedingly unlikely (Speck and Smithyman, 2016, pg. 2).
The FDA points to a lack of clinical safety trials in its hesitancy to approve phage therapy for more widespread use. According to Janis Doss, a graduate researcher in bacteriophages at Old Dominion University, one reason for this is the scientific cultural differences between two regions. She indicated the Eliava Institute of Bacteriophages, Microbiology and Virology in Tbilisi, Georgia, highlights individual cases as proof of safety and efficacy (personal communication, November 15, 2009). Within the Soviet Union, scientific advancements were often less regulated than is commonly required throughout Western societies. There was little need for clinical data to support the treatments provided, so researchers focused on advancement of the science without interest in publication of their findings. It’s possible the concentration of their efforts toward solutions is part of what has enabled them to be so successful in the development of phage therapy. The Eliava Institute is working to further develop their phage products (Eliava Phage Therapy, N.D.), and reportedly understands the need for comprehensive clinical trial data to secure approval of their products by regulating agencies in the West (J. Doss, personal communication, November 15, 2009).
The FDA is not entirely opposed to the use of phages in human applications. Along with the United States Department of Agriculture, they have approved a phage product for use in food preparations. LISTEX, created by EBI Food Safety in The Netherlands, has been given the status of Generally Recognized As Safe for all food products. Viewed by many as an endorsement of phage safety by these regulatory agencies, the decision was based on existing literature detailing animal and human studies (Housby & Mann, 2009, p. 537). This approval serves to underscore the evidence in favor of phage safety is sufficient for human administration.
In addition to all of the evidence provided above, one important feature of phage safety is its specificity. While many see this as a challenge in widespread use of phages, their highly specific nature is, in fact, an attribute when it comes to safety. Since phages will only infect, and subsequently kill, specific strains of bacteria, there will be less impact to a patient’s normal microbiota. This is a treatment so narrowly focused that phages effective against one species of bacteria may not work on the same species of bacteria halfway across the world (Lin, Koskella, & Lin, 2017, pp. 167-168).
In contrast, antibiotics have widely known side effects and complications, that include allergic reactions (Lin, Koskella, & Lin, 2017, pp. 167-168) and secondary infections. These secondary infections are the result of the broad nature of antibiotic activity, which decimates the patient’s normal flora and allows opportunistic bacteria to grow. One of these is Clostridium difficile, which can cause fever, diarrhea, stomach pain and nausea. In severe cases, patients with C. difficile infection can suffer complications that include bloody stool, rapid heart rate, dehydration, weight loss and kidney failure (Mayo Clinic, N.D.). These serious complications are not found with phage therapy, due to its specificity, and provide context for the risks deemed acceptable by the FDA in approved medical treatments.
Conclusion
The problem of antibiotic resistance urgently needs a solution. Steps have been taken by the medical community to limit the spread of resistance and resistant infections. However, the success in containing or reducing infection rates of some resistant strains is overshadowed by the rise of newly resistant strains. The Centers for Disease Control recently released a report indicating infection rates are double that of previous estimates, causing over 35,000 deaths each year in the United States alone. Adding in deaths from secondary infection of C. difficile, that number increases to over 48,000 people (Centers for Disease Control, 2019).
As a sophomore in college, Megan Hinz learned firsthand how serious these infections and their treatments can be. Fighting for her life in the ICU, doctors struggled to find an antibiotic to successfully treat her toxic shock syndrome from infection caused by methicillin-resistant S. aureus (MRSA). Treatment was complicated by side effects and allergic reactions from the powerful intravenous antibiotics being administered. Once the MRSA infection was clearing, she faced a new battle: a secondary infection from Clostridium difficile in her intestinal tract due to destruction of her normal gut flora by the antibiotics treating the initial infection. This required additional antibiotics for treatment, with more side effects and addiotnal time in the hospital. By the time she was released, two weeks after she was first admitted, her body was weak and took months to fully recover (M. Hinz, personal communication, November 20, 2019).
Approval of medical phage treatments in Western medicine is imminent. The history of success in Eastern European countries serves as a long-term proof of concept for phage therapy and should be recognized as a large-scale safety study. Additional safety concerns are understandable for any new medical treatment, but without merit in the case of phages. Further delaying safety approvals puts the most vulnerable people’s lives at risk. There is an abundance of evidence indicating the safety of phages to treat life-threatening infections and it is our duty, as scientists and humans, to make it available to those in peril.
References
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