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BACTERIOPHAGES: a New Old Biomedical Technology

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BACTERIOPHAGES: a New Old Biomedical Technology POLICY BRIEF 10 August 2010 BACTERIOPHAGES: A New Old Biomedical Technology Antibiotic resistance is a challenge that calls for good Limited 2009). Bacterial counts and symptoms were science as well as ingenuity. Although we will always reduced. Encouraged, the company is moving on to a need new antibiotics, there are alternative therapeutic larger trial. In the United States, Intralytix successfully approaches worth considering. One example is concluded a preliminary safety trial of bacteriophage bacteriophage therapy. Bacteriophages—or ―phages‖— therapy of venous leg ulcers (Wolcott et al. 2009). Other exist in abundance in nature, including in and on the clinical trials (P. aeruginosa and S. aureus in burns and human body. Phages are viruses that infect bacteria genetically engineered bacteriophages) are under way and use the bacterial cell’s genetic apparatus to in the United Kingdom. produce more phages. In the process, they kill their host. By harnessing phages’ natural ability to destroy Bacteriophages have shown promise as tools for bacteria, infections can be cleared. infection control as well. Scientists from the University of Strathclyde have chemically bonded phages to nylon After Felix d’Herelle’s discovery and isolation of the first products such as strips, sutures and implantable beads bacteriophage in 1917, the long-sought cure for (The Medical News 2005), which they use during bacterial infections seemed to be at hand. But with the surgery. This preparation is effective against most dawn of the antibiotic era in 1941, when penicillin was major epidemic methicillin-resistant Staphylococcus discovered, the western medical establishment lost aureus (MRSA) strains. Bacteriophages on sutures can interest in phages. Meanwhile, phage therapy was alive prevent wounds from becoming infected (The Medical and well in the Soviet Union, isolated from the West by News 2005). When tagged with ―luciferase cassettes,‖ the Cold War. Widespread claims of success in curing phages light up once they successfully infect bacteria. disease—accurate or not—lacked the support of This makes them useful not only for diagnosing controlled experiments and were largely ignored by the bacterial infections but for quickly determining antibiotic rest of the world. susceptibility (Kropinski 2006). Still experimental today, we should not be surprised if one day these Modern Phage Successes applications are routine. Recent studies have been conducted under rigorous Phages in Food Safety scientific control. Phage therapy has cured or controlled Pseudomonas aeruginosa infections in mice; Work on therapeutic phages will undoubtedly continue, Escherichia coli diarrhea in calves, piglets, and lambs; but phages and their proteins may also find a place in E. coli septicemia and meningitis in chickens and diagnostics, infection control, veterinary treatments, and calves; multidrug resistant Klebsiella pneumoniae in agriculture. In the United States, phages are already in mice; methicillin-resistant Staphylococcus aureus in use in food safety. One approved product, Intralytix’s mice; and vancomycin-resistant enterococci LMP-102, targets Listeria monocytogenes with a six- bacteraemia in mice. phage cocktail that is sprayed on meat, seafood, and poultry products before packaging. Intralytix, and other A few trials in humans have been reported recently. companies, are developing similar treatments for Biocontrol, in the United Kingdom, completed a small, Salmonella and a particularly virulent type of E. coli. double-blind placebo-controlled clinical trial of chronic ear infections caused by P. aeruginosa (Biocontrol treatment with the same phages may not work a second Potential Advantages and Disadvantages of Phage time. It may be that phages can be genetically modified Therapy to evade the immune system but this is still unknown (Donlan 2009). Cost and Sustainability Phages are inexpensive and quick to produce (Inal 2003). New phages can sometimes be selected in days Other Applications or weeks. In contrast, the process of discovering and testing a new antibiotic can take decades. Like with Besides direct treatment of infected patients, creative antibiotics, bacteria can also develop resistance to scientists may find a host of uses for phages, including phages. But unlike antibiotics, phages are dynamic and reducing bacterial levels in places such as hospitals can evolve alongside bacteria in a mutually escalating and food processing plants. The U.S. Environmental arms race (Donlan 2009). Because of concerns about Protection Agency recently registered Intralytix’s LMP- resistance, phages are usually used in tandem, with 102 phage preparation for various environmental multiple phages directed against a specific pathogen. applications targeted at eradicating or reducing Even if the bacteria being targeted have evolved contamination with L. monocytogenes (as in food resistance to one phage, there remains a high likelihood processing plants) (Intralytix, 2009). that they will be killed by the other phage, minimizing both the risk of treatment failure and the possibility that Regulatory Obstacles resistance will be passed on to new generations of Although phage therapy seems to be a viable bacteria. As antibiotic resistance mechanisms do not alternative or complement to antibiotic therapy, the affect phages, phage therapy provides an ideal way to market for phages is not yet completely defined. The treat highly antibiotic resistant microorganisms, such as U.S. Food and Drug Administration (FDA) has not yet the Acinetobacter species found to infect soldiers issued guidelines for regulating phages for human returning from Iraq. therapeutic use, in part because the laws and regulations governing approval of medical therapies is Few Side Effects based on our understanding of conventional drugs (or One particular advantage of phage therapy is the vaccines, for preventive interventions). Phages are apparent lack of serious side effects (Sulakvelidze and unlike drugs in some important ways, and so they Kutter 2005). So far, phages have been well tolerated, challenge the FDA’s methods. It would be impractical to while antibiotics have a range of side effects. There are test every phage in large-scale randomized trials— concerns about possibly harmful molecules released potentially thousands of phages may be used. That’s when bacterial cells burst because of phage activity— not to say that the method of selecting and preparing specifically, endotoxins released from the cell walls of the phages could not be tested. It would, however, be a bacteria killed by phages into a patient’s bloodstream. deviation from current practice. The same side effects may occur after antibiotic therapy, and various approaches (corticosteroid Phage cocktails could be deployed against bacteria therapy, for example) used to reduce the problem while the disease-causing bacteria are still being fully during antibiotic therapy may also be used during identified, but that creates another stumbling block for phage therapy (Donlan 2009; Sulakvelidze and Kutter the FDA. Current rules require that every component of 2005). These issues remained unresolved, however, a combination treatment be first tested individually. because there has been little experience with them. Incentives Immune Responses Companies may be discouraged from entering the Sustaining the presence of phages in the human body market because of uncertainty over intellectual property long enough to treat infection is a one of the main rights. Phages are, after all, naturally occurring living challenges of phage therapy. A patient’s immune organisms. While individual phages seem to be system will inactivate phages in the body with regular patentable, there are plenty of other phages in the use; they can be quickly excreted and the immune environment that may be isolated and used to formulate system develops antibodies against the phage. So, a competing phage preparation. In addition, public acceptance of phage therapy is not References yet fully tested, and regulatory strategies and obstacles are still not fully defined for various applications. Still, 1. Jensen M.A., Farque S.M., Mwkalanos J.J. and Levin with the ever-increasing problem of drug resistance, B.R. 2006. Modeling the role of bacteriophage in the and the current positive momentum toward control of cholera outbreaks. Proceedings of the National Academy of Sciences 103(12): 4652 4657 development of new, natural (―green‖), and safe – 2. Biocontrol Limited. 2009. The Biological Answer to alternatives to antibiotics and chemical disinfectants, Antibiotic Resistance. http://www.biocontrol- phage-based products seem poised for increased ltd.com/LinkClick.aspx?fileticket=gaEgQS548fs%3D&ta recognition and growth in the years ahead. bid=70&mid=444&forcedownload=true (accessed 01/07/10). 3. Bruttin, A. and H. Brussow. 2005. Human volunteers The Road Ahead for Phage Therapy receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrobial Agents and Some companies have invested in early stage clinical Chemotherapy 49(7): 2874–2878. trials, but following up with subsequent trials is very 4. Donlan, R.M. 2009. Preventing biofilms of clinically costly—too costly for start-up companies, particularly relevant organisms using bacteriophage. Trends in when even successes may not be rewarded because of Microbiology 17(2): 66–72. regulatory hurdles. A small investment by the National 5. Inal, J.M. 2003. Phage therapy: a reappraisal of Institutes of Health in clinical
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