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An Alternative for Antibiotics: Phage Therapy (PT) Yellowduck1 The discovery of penicillin in the late 1930’s brought along new advances in medicine and extensive use of antibiotics. Within a few years bacteria became resistant to antibiotics, and thus became ineffectiveBack in the 1930’s? A few years after the discovery? Say what? (Kunin, 1993). In a monthly scientific journalyou don’t say this! Where is the transtion? Something like: This is evident if one looks at…, Antimicrobial Agents and Chemotherapy (AAC), the number of papers concerning antimicrobial resistance increased from 11% in 1972 to 34% in 1997 (Swartz, 2000).-So we are not talking about the 1930’s? We are talking about now? Even novel antibiotics like what? Be specific. Where is the evidence. Do not make claims without evidence. cannot keep pace with the ever-growing numbers of resistant bacteria. This poses a great challenge to the medical community, and a pressing need exists to find suitable alternatives. You need to improve this account of antibiotics. Phage therapy (PT) potentially offers such a substitute. Phages, or bacteriophages, are viruses that infect bacterial cells and kill them, including those that are resistant to antibiotics (Gorski, 2009; Hanlon, 2007).-This last sentence, should it be here? It hangs in the middle of nowhere. This should be in your next paragraph. Improve the antibiotic intro/history. Phages are found in aquatic environments and have evolved with bacteria. There are lysogenic and lytic phages.-I just read this to my grandma over the phone and all I heard was silence… They are dependent on bacteria to replicate, and invade their host to assemble new phages with the bacteria’s machinery. I am stopping here. This is not understandable to the general reader. You need to think about the reader. Lytic? Lysogenic? I don’t think so. In PT lytic phages are used. The life cycle of these phages begins with its attachment to their host. These viruses are very specific, and each will only attach to one type of bacteria. The bacteriophage then inserts its DNA into the host, which carries instructions to make new phage particles. Using the tools of the bacteria and the instructions from the phage, viral components are made inside the bacteria. In the final step, the bacterial cell lyses, or explodes, releasing all the phages and killing the host. Over 100 phages are released each time a cell lyses, each with the ability to begin the cycle again and invade and kill more bacteria (Hanlon, 2009). PT is actually not a new finding but it is going through a revival of interest. In fact, they were used decades before antibiotics to treat bacterial infections. D’Herelle, a scientist from Paris in 1910 co-discovered bacteriophages and promoted PT. He coined the name “bacteriophage,” meaning that the phages “eat” bacteria (Sulakvelidze, 2001). D’ Herelle and other scientists made a number of successful PT studies. The first time D’Herelle used bacteriophages therapeutically was in 1919. He treated a 12-year-old boy with dysentery and saw recovery within 24 hours. However, a number of negative results were acquired and led to a decline of PT. The wrong phages were selected to use against their specific host. Sometimes lysogenic phages were used instead of lytic ones, and often they were also not properly prepared to use for treatment. The lack of understanding for phages at that time resulted in poorly done experiments with controversial conclusions. At the same time antibiotics were discovered which seemed simpler and more effective. These combined effects caused the west to close its door on clinical use and research on PT. However, research continued in the former Soviet Union and Eastern Europe as antibiotics became popular in the West (Hanlon, 2007). The research that sustained in Europe were not all highly controlled, and do not reach the modernday standards of investigation but results are still valuable. Numerous publications for the use of PT in humans are available. A notable extensive study in the Soviet Union tested for the effectiveness of Shigella phages against bacterial dysentery. A total of 31,000 children in the streets less than seven years old were used in this study. On one side of the street 17,000 children were given Shigella phages and 13,000 children on the other side of the street did not receive any. It was observed that the infections were reduced by 2.6 fold in the treated children. Many more clinical studies were conducted, demonstrating the effectiveness of phages. To name a few, they were used to treat surgical wound, urinary tract, eye, and staphylococcal lung infections (Sulakvelidze, 2001). In 1952, the Hirszfeld Institute was established in Poland. There, bacteriophages were produced and studied and a large number of publications come from this institute. Since then, they have also taken steps to bring PT to patients who have had failed antibiotic treatment (Sulakvelidze, 2001; Gorski, 2007). The relatively recent comeback of PT came about in the west when resistant antibiotic pathogens became an increasing challenge. The clinical studies in Europe helped bring along this revival. In contrast to research in the past these studies are controlled and meet current standards of investigation (Gorski, 2009). A study done by Capparelli, et al. (2007) observed the use of PT in mice to kill staphylococcal bacteria that were resistant to antibiotics. This pathogen causes many dangerous and life threatening symptoms including inflammation, abscesses (swelling/sores), and pneumonia. The authors concluded from this study that the phage was able to rescue 97% of the mice, and eliminate the bacteria. Even when the phage was given 10 days after the mice were infected, the phage was successful in killing the bacteria. Additionally, the study found that there were no side effects from treatment, and the mice were all healthy when the trials ended. Many more similar studies confirm the effectiveness of this therapy. There is concern whether PT may find the same future as antibiotics; wouldn’t bacteria develop resistance to bacteriophages just like they did with antibiotics? Many papers have addressed and given different solutions to this issue. In comparison to antibiotics, in a shorter period of time bacteria can resist greater amounts of antibiotics than they can resist phages (Hanlon, 2007). Harcombe and Bull (2005) also tested whether using several types of phages at once can reduce the chances of resistance. They concluded that when phages are used against two species of bacteria, the competition between the bacterium reduces the bacteria’s ability to develop resistance to their specific phage. Moreover, if resistance does develop it should be possible to isolate a new strain of phage quickly because of their abundance on this planet (Sulakvelidze, 2001).There are 1032 bacteriophages on earth, which is ten times more than bacteria (Hanlon, 2007). Another setback to using PT is the reticuloendothelial system (RES) in bacteria. The RES removes viruses from the organism to a number insufficient to kill the host. In 1996 Merril et al., proposed a way to select phages that are capable of avoiding removal by the RES. This method which they called the “serial passage” works similarly to natural selection. Compared to the original, the processed phages were more successful in treating the infected mice (Merril, et al., 1996). PT is currently is being considered for regular clinical treatment. There have been steps taken to evaluate their effect on humans. In 2005 the first safety test in recent English literature for oral phages was conducted. The scientists concluded from the data that phages can be safely administered with no severe side effects (Bruttin, et al, 2005). To have a chance of success with PT there are a number of steps to be taken. More undisputable evidence is needed from basic research and clinical trials. Furthermore, centers specialized in PT could be established similar to the one in Poland (Gorski, 2009). With the knowledge accumulated in Europe and the advances made there can be more success in putting PT to use this second time (Hanlon, 2007). Word count including citations: 1182 References Alisky, J., Iczkowski, K., Rapoport, A., Troitsky, N., (1998). Bacteriophages show promise as antimicrobial agents. Journal of Infection. 36, 5-15. Bruttin, A., & Brussow, H., (2004). Human Volunteers Receiving Escherichia coli Phage T4 Orally: a Safety Test of Phage Therapy. Antimicrobial Agents And Chemotherapy, 49, 2874-2878. Capparelli, R., Parlato, M., Borriello, G., Salvatore, P., Iannelli, D., (2007). Experimental Phage Therapy against Staphylococcus aureus in Mice. Antimicrobial agents and chemotherapy. 51, 2765-2773. Gorski, A., Miedzybrodzki, R., Borysowskj, J., Weber-Dabrowska, B., Lobocka, M., Fortuna, W., Filby, G. (2009). Bacteriophage therapy for the treatment of infections. Current Opinion in Investigational Drugs. 10, 766774. Harcombe, W.R., & Bull, J.J. (2005). Impact of Phages on Two-Species Bacterial Communities. Applied and Environmental Microbiology, 71, 5254-5259. Kucharewicz-Krukowska, A., and Slopek, S. (1987). Immunogenic effect of bacteriophage in patients subjected to phage therapy. Arch. Immunol. Ther. Exp,5, 553-561. Knunin, C, M., (1993). Resistance to antimicrobial drugs—a worldwide calamity. Annals of internal medicine, 118, 557-561. Merril, C.R., Biswas, B., Carlton, R., Jensen, N.C., Creed, G.J., Zullo, S., … S. Adhya. (1996). Long-circulating bacteriophage as antibacterial agents. Proc. Natl. Acad. Sci. 93,3188-3192. Sulakvelidze, A., Alavidze, Z., Morris, J., (2001). Bacteriophage Therapy. Antimicrobial agents and Chemotherapy.45, 649-659. Swartz, M. N., (2000). Impact of Antimicrobial Agents and Chemotherapy from 1972 to 1998. Antimicrobial Agents and Chemotherapy, 44, 2009-2016. Hanlon, G.W., (2007). Bacteriophages: an appraisal of their role in the treatment of bacterial infections. International Journal of Antimicrobial Agents.118-128