Bacteriophage Ecology Group
Phage Therapy References
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© Phage et al. last updated on Tuesday, December 07, 2004
  1. Phage Therapy. Merril,C.R., Scholl,D., Adhya,S. (2005). In Calendar,R. (ed.), The Bacteriophages. Oxford University Press, Oxford. [TOP OF PAGE]

  2. "My enemy's enemy is my friend." Using phages to fight bacteria. Bradbury,J. (2004). Lancet 363:624-625. [first paragraph] Bacteriophages, viruses that prey upon bacteria, typically attack only a single bacterial strain. This specificity, together with the killing capacity of "phages", says phage researcher Martin Loessner, makes them the "natural enemies" of bacteria. "We are now endeavouring to make this enemy our friend", says Loessner, a professor of food microbiology at the Swiss Federal Institute of Technology in Zurich, turning phages into potentially important allies in our battle against bacteria. [TOP OF PAGE]

  3. Recent pre-harvest supplementation strategies to reduce carriage and shedding of zoonotic enteric bacterial pathogens in food animals. Callaway,T.R., Anderson,R.C., Edrington,T.S., Genovese,K.J., Harvey,R.B., Poole,T.L., Nisbet,D.J. (2004). Animal health research reviews / Conference of Research Workers in Animal Diseases 5:35-47. Food-borne bacterial illnesses strike more than 76 million North Americans each year. Many of these illnesses are caused by animal-derived foodstuffs. Slaughter and processing plants do an outstanding job in reducing bacterial contamination after slaughter and during further processing, yet food-borne illnesses still occur at an unacceptable frequency. Thus, it is imperative to widen the window of action against pathogenic bacteria. Attacking pathogens on the farm or in the feedlot will improve food safety all the way to the consumer's fork. Because of the potential improvement in overall food safety that pre-harvest intervention strategies can provide, a broad range of preslaughter intervention strategies are currently under investigation. Potential interventions include direct anti-pathogen strategies, competitive enhancement strategies and animal management strategies. Included in these strategies are competitive exclusion, probiotics, prebiotics, antibiotics, antibacterial proteins, vaccination, bacteriophage, diet, and water trough interventions. The parallel and simultaneous application of one or more preslaughter strategies has the potential to synergistically reduce the incidence of human food-borne illnesses by erecting multiple hurdles, thus preventing entry of pathogens into the food chain. This review emphasizes work with Escherichia coli O157:H7 to illustrate the various strategies. [TOP OF PAGE]

  4. In vitro and in vivo bacteriolytic activities of Escherichia coli phages: implications for phage therapy. Chibani-Chennoufi,S., Sidoti,J., Bruttin,A., Kutter,E., Sarker,S., Brüssow,H. (2004). Antimicrob. Agents Chemother. 48:2558-2569. Four T4-like coliphages with broad host ranges for diarrhea-associated Escherichia coli serotypes were isolated from stool specimens from pediatric diarrhea patients and from environmental water samples. All four phages showed a highly efficient gastrointestinal passage in adult mice when added to drinking water. Viable phages were recovered from the feces in a dose-dependent way. The minimal oral dose for consistent fecal recovery was as low as 10(3) PFU of phage per ml of drinking water. In conventional mice, the orally applied phage remained restricted to the gut lumen, and as expected for a noninvasive phage, no histopathological changes of the gut mucosa were detected in the phage-exposed animals. E. coli strains recently introduced into the intestines of conventional mice and traced as ampicillin-resistant colonies were efficiently lysed in vivo by phage added to the drinking water. Likewise, an in vitro phage-susceptible E. coli strain freshly inoculated into axenic mice was lysed in vivo by an orally applied phage, while an in vitro-resistant E. coli strain was not lysed. In contrast, the normal E. coli gut flora of conventional mice was only minimally affected by oral phage application despite the fact that in vitro the majority of the murine intestinal E. coli colonies were susceptible to the given phage cocktail. Apparently, the resident E. coli gut flora is physically or physiologically protected against phage infection. [TOP OF PAGE]

  5. New dawn for phage therapy. Dixon,B. (2004). The Lancet infectious diseases 4:186 [first two paragraphs] Perhaps Antony Twort was 10 years too early in publishing his father Frederick's biography. A marvellous portrait of the eccentric co-discoverer of the bacteriophage, whose work helped to usher in the era of molecular biology, the book appeared only after numerous rejections from publishers (Lancet Infect Dis 2003; 3: 58). It also received little review attention, because literary editors are largely unaware of the role of science and scientists in shaping the modern world. ¶ However, the decade since publication of In Focus, Out of Step (Stroud, UK: Alan Sutton) has seen increasing interest in phages, especially in administering them therapeutically. Most recently there have been promising advances towards real applications. Now, thanks to work in Vienna, Austria, the major obstacle to phage therapy seems well on the way to being removed. At a time when antibiotic resistance is provoking real concern even in the most sober quarters, this is excellent news. [TOP OF PAGE]

  6. Optimizing concentration and timing of a phage spray application to reduce Listeria monocytogenes on honeydew melon tissue. Leverentz,B., Conway,W.S., Janisiewicz,W., Camp,M.J. (2004). J. Food Prot. 67:1682-1686. A phage cocktail was applied to honeydew melon pieces 1, 0.5, and 0 h before contamination with Listeria monocytogenes strain LCDC 81-861 and 0.5, 1, 2, and 4 h after contamination. The phage application was most effective when applied 1, 0.5, or 0 h before contamination with L. monocytogenes, reducing pathogen populations by up to 6.8 log units after 7 days of storage. This indicates that under commercial conditions, if contamination occurs at the time of cutting, phage would have to be applied as soon as possible after cutting the produce. However, all phage applications from 1 h before to 4 h after contamination and all phage concentrations ranging from 10(4) to 10(8) PFU/ml reduced bacterial populations on honeydew melon pieces. Higher phage concentrations were more effective in reducing pathogen populations. A phage concentration of approximately 10(8) PFU/ml was necessary to reduce the pathogen populations to nondetectable levels immediately after treatment, and pathogen growth was suppressed by phage concentrations of 10(6) through 10(8) throughout the storage period of 7 days at 10ºC. In an attempt to enhance the effectiveness of the phage cocktail on low pH fruit, such as apples, the phage was applied in combination with MnCl(2). This combination, however, did not enhance the effectiveness of the phage on apple tissue. The results from this study indicate that the effectiveness of the phage application on honeydew melon pieces can be optimized by using a phage concentration of at least 10(8) PFU/ml applied up to 1 h after processing of the honeydew melons. [TOP OF PAGE]

  7. Population and evolutionary dynamics of phage therapy. Levin,B.R., Bull,J.J. (2004). Nat. Rev. Microbiol. 2:166-173. Following a sixty-year hiatus in western medicine, bacteriophages (phages) are again being advocated for treating and preventing bacterial infections. Are attempts to use phages for clinical and environmental applications more likely to succeed now than in the past? Will phage therapy and prophylaxis suffer the same fates as antibiotics--treatment failure due to acquired resistance and ever-increasing frequencies of resistant pathogens? Here, the population and evolutionary dynamics of bacterial-phage interactions that are relevant to phage therapy and prophylaxis are reviewed and illustrated with computer simulations. [TOP OF PAGE]

  8. Evaluation of a cocktail of three bacteriophages for biocontrol of Escherichia coli O157:H7. O'Flynn,G., Ross,R.P., Fitzgerald,G.F., Coffey,A. (2004). Appl. Environ. Microbiol. 70:3417-3424. Escherichia coli O157:H7 is an endemic pathogen causing a variety of human diseases including mild diarrhea, hemorrhagic colitis, hemolytic-uremic syndrome, and thrombotic thrombocytopenic purpura. This study concerns the exploitation of bacteriophages as biocontrol agents to eliminate the pathogen E. coli O157:H7. Two distinct lytic phages (e11/2 and e4/1c) isolated against a human strain of E. coli O157:H7, a previously isolated lytic phage (pp01), and a cocktail of all three phages were evaluated for their ability to lyse the bacterium in vivo and in vitro. Phage e11/2, pp01, and the cocktail of all three virulent phages resulted in a 5-log-unit reduction of pathogen numbers in 1 h at 37°C. However, bacteriophage-insensitive mutants (BIMs) emerged following the challenge. All tested BIMs had a growth rate which approximated that of the parental O157 strain, although many of these BIMs had a smaller, more coccoid cellular morphology. The frequency of BIM formation (10(-6) CFU) was similar for e11/2, pp01, and the phage cocktail, while BIMs insensitive to e4/1c occurred at the higher frequency (10(-4) CFU). In addition, BIMs commonly reverted to phage sensitivity within 50 generations. In an initial meat trial experiment, the phage cocktail completely eliminated E. coli O157:H7 from the beef meat surface in seven of nine cases. Given that the frequency of BIM formation is low (10(-6) CFU) for two of the phages, allied to the propensity of these mutants to revert to phage sensitivity, we expect that BIM formation should not hinder the use of these phages as biocontrol agents, particularly since low levels of the pathogen are typically encountered in the environment. [TOP OF PAGE]

  9. Phage offer a real alternative. Schoolnik,G.K., Summers,W.C., Watson,J.D. (2004). Nature biotechnology 22:505-506. A News and Views piece by Steven Projan in your February issue offers a gratuitous, pessimistic assessment for the prospects of phage therapy per se (Nat. Biotechnol. 22, 167-168, 2004). We believe Projan's criticisms are overly broad and fail to consider the published literature and the impact that contemporary phage biology is having on the development of phage therapeutics. We would not have been moved to respond to his comments were it not for our view that the pharmaceutical industry's capacity to develop truly novel chemical antibiotics or antibacterials is being outstripped through the evolution of antimicrobial resistance by a broad array of infectious agents. Thus, in the spirit of a constructive dialogue, we—participants at a Cold Spring Harbor Banbury Conference—offer the following rejoinder. [TOP OF PAGE]

  10. [Bacteriophages as antibacterial agents]. Shasha,S.M., Sharon,N., Inbar,M. (2004). Harefuah 143:121-5, 166. Bacteriophages are viruses that only infect bacteria. They have played an important role in the development of molecular biology and have been used as anti-bacterial agents. Since their independent discovery by Twort and d'Herelle, they have been extensively used to prevent and treat bacterial infections, mainly in Eastern Europe and the former Soviet Union. In western countries this method has been sporadically employed on humans and domesticated animals. However, the discovery and widespread use of antibiotics, coupled with doubts about the efficacy of phage therapy, led to an eclipse in the use of phage in medicine. The emergence of antibiotic resistant bacteria, especially strains that are multiply resistant, has resulted in a renewed interest in alternatives to conventional drugs. One of the possible replacements for antibiotics is the use of bacteriophages as antimicrobial agents. This brief review aims to describe the history of bacteriophage and early clinical studies on their use in bacterial disease prophylaxis and therapy, and discuss the advantages and disadvantages of bacteriophage in this regard. [TOP OF PAGE]

  11. Therapeutic use of bacteriophages. Soothill,J., Hawkins,C., Anggard,E., Harper,D. (2004). The Lancet infectious diseases 4:544-545. [first two paragraphs] We respond to two articles, published in The Lancet and The Lancet Infectious Diseases on the use of bacteriophages as therapeutic agents. Jane Bradbury gave much attention to uncontrolled work from eastern Europe, but did not include the extensive, carefully controlled, and positive work of Smith and colleagues. The findings of our recent research challenge Bernard Dixon's discussion of the effects of bacteriophage-induced lysis and the usefulness of inhibiting bacteriophage replication. ¶ We have done the first regulatory approved clinical study of the efficacy of bacteriophage therapy, addressing chronic, antibiotic resistant Pseudomonas aeruginosa ear infections in pet dogs that have not responded to conventional therapy. Dixon proposed that endotoxins released as a result of bacterial lysis lead to side effects, particularly circulatory shock, and that this is a problem with bacteriophage medicine for human beings. We do not know of any published evidence that bacteriophage multiplication or lysis of bacteria resulting from the use of bacteriophages has been associated with circulatory shock in patients. In carefully conducted animal experiments, including those of Smith and colleagues such effects have not been noted. In our research we minimised any such theoretical issue by focusing on local rather than systemic infections. [TOP OF PAGE]

  12. Toward rational control of Escherichia coli O157:H7 by a phage cocktail. Tanji,Y., Shimada,T., Yoichi,M., Miyanaga,K., Hori,K., Unno,H. (2004). Applied Microbiology and Biotechnology 64:270-274. Twenty six phages infected with Escherichia coli O157:H7 were screened from various sources. Among them, nine caused visible lysis of E. coli O157:H7 cells in LB liquid medium. However, prolonged incubation of E. coli cells and phage allowed the emergence of phage-resistant cells. The susceptibility of the phage-resistant cells to the nine phages was diverse. A rational procedure for selecting an effective cocktail of phage for controlling bacteria was investigated based on the mechanism of phage-resistant cell conversion. Deletion of OmpC from the E. coli cells facilitated the emergence of cells resistant to SP21 phage. After 8 h of incubation, SP21-resistant cells appeared. By contrast, alteration of the lipopolysaccharide (LPS) profile facilitated cell resistance to SP22 phage, which was observed following a 6-h incubation. When a cocktail of phages SP21 and SP22 was used to infect E. coli O157:H7 cells, 30 h was required for the emergence of cells (R-C) resistant to both phages. The R-C cells carried almost the same outer membrane and LPS components as the wild-type cells. However, the reduced binding ability of both phages to R-C cells suggested disturbance of phage adsorption to the R-C surface. Even though R-C cells resistant to both phages appeared, this work shows that rational selection of phages has the potential to at least delay the emergence of phage resistance. [TOP OF PAGE]

  13. Old dogma, new tricks--21st Century phage therapy. Thiel,K. (2004). Nature biotechnology 22:31-36. As antibiotic resistant bacteria threaten a public health crisis, biotechnology is turning to bacteriophages, nature's tiniest viruses. But can phage therapy overcome its historical baggage? [TOP OF PAGE]

  14. Models of phage growth and their applicability to phage therapy. Weld,R.J., Butts,C., Heinemann,J.A. (2004). J. Theor. Biol. 227:1-11. Phage therapy is complicated by the self-replicating nature of phage. It is difficult to extrapolate from in vitro phage growth data to in vivo expectations, difficult to interpret in vivo data and difficult to generalize from one in vivo situation to another. Various generic models of phage growth have been used as the theoretical basis for understanding the kinetics of phage therapy. Here, we have experimentally tested the efficacy of such simple models to predict, qualitatively and quantitatively, the growth of phage and the phage proliferation threshold in vitro. Naturally occurring, antibiotic-resistant bacteria were used to measure the growth of phage in vivo. In homogenous, in vitro environments, the models were predictive of T4 phage growth on Escherichia coli RR1. However, the models were not able to predict growth of T4 phage or K1-5 phage in the more complex environment of the rat's digestive tract. To explore fully the kinetics of phage therapy, more complex models need to be devised. We suggest that it may be necessary to consider and model the interactions between phage growth parameters and bacterial growth parameters. [TOP OF PAGE]

  15. Genetically engineered phage delivers antimicrobial agents to bacteria. Anonymous (2003). Vaccine Weekly May 28, 5. A genetically engineered phage to deliver antimicrobial agents to bacteria provides an alternative therapy for treatment of bacterial infections. ¶ According to recent research from the United States, "The emergence and increasing prevalence of multidrug-resistant bacterial pathogens emphasizes the need for new and innovative antimicrobial strategies. Lytic phages, which kill their host following amplification and release of progeny phage into the environment, may offer an alternative strategy for combating bacterial infections. In this study, however, we describe the use of a nonlytic phage to specifically target and deliver DNA encoding bactericidal proteins to bacteria." ¶ "To test the concept of using phage as a lethal-agent delivery vehicle, we used the M13 phagemid system and the addiction toxins Gef and ChpBK," said Caroline Westwater and colleagues at the Medical University of South Carolina. "Phage delivery of lethal-agent phagemids reduced target bacterial numbers by several orders of magnitude in vitro and in a bacteremic mouse model of infection." ¶ The researchers concluded, "Given the powerful genetic engineering tools available and the present knowledge in phage biology, this technology may have potential use in antimicrobial therapies and DNA vaccine development." ¶ Westwater and her coauthors published their study in Antimicrobial Agents and Chemotherapy (Use of genetically engineered phage to deliver antimicrobial agents to bacteria: an alternative therapy for treatment of bacterial infections. [TOP OF PAGE]

  16. Phage-enabled amperometric assay valuable for pathogen analysis. Anonymous (2003). TB & Outbreaks Week April 6, 55. A phage-enabled amperometric assay could be valuable for pathogen analysis. ¶ In a recent study from Israel, researchers described "a novel electrochemical method for the rapid identification and quantification of pathogenic and polluting bacteria." ¶ "The design incorporates a bacteriophage, a virus that recognizes, infects, and lyses only one bacterial species among mixed populations, thereby releasing intracellular enzymes that can be monitored by the amperometic measurement of enzymatic activity," explained T. Neufeld and colleagues at Tel Aviv University. ¶ "As a model system, we used virulent phage typing and cell-marker enzyme activity (beta-D-galactosidase), a combination that is specific for the bacterial strain Escherichia coli (K-12, MG1655)," Neufeld and coworkers wrote. They found that "filtration and preincubation before infecting the bacteria with the phage enabled amperometric detection at a wide range of concentrations, reaching as low as 1 colony-forming unit/100 mL within 6-8 hours." ¶ "In principle, this electrochemical method can be applied to any type of bacterium-phage combination by measuring the enzymatic marker released by the lytic cycle of a specific phage," the researchers concluded. ¶ Neufeld and coauthors published their study in Analytical Chemistry (Combined phage typing and amperometric detection of released enzymatic activity for the specific identification and quantification of bacteria. Anal Chem, 2003;75(3):580-585). [TOP OF PAGE]

  17. Phage therapy could remove E. coli O157:H7 from livestock. Anonymous (2003). TB & Outbreaks Week June 10, 15. A bacteria-killing virus found in the feces of some sheep could help remove the dangerous food-borne bacteria Escherichia coli O157:H7 from livestock. ¶ Researchers from Evergreen State College in Olympia, Washington, discussed their findings at the 103rd General Meeting of the American Society for Microbiology on May 19, 2003. ¶ "Here we report a promising new natural way of reducing pathogen concentrations in livestock. This takes advantage of bacteriophages - bacteria-killing viruses, harmless to humans and other animals, which have been used extensively as antibiotics in Eastern Europe and the former Soviet Union for over 50 years," says Michael Dyen, one of the study researchers. ¶ Dyen and his colleagues reported on a new bacteriophage (CEV1) that they isolated from the feces of sheep naturally resistant to gut colonization by E. coli O157:H7. Preliminary trials of CEV1 in the lab have shown that it can be produced easily and can efficiently infect and kill the bacteria under proper conditions. In model systems reflecting the cow/sheep gut, CEV1 completely eliminated the bacteria in 11 days. ¶ "CEV1 and other carefully-selected phages against E. coli O157:H7 could be used to develop an effective management strategy to eradicate this pathogen from livestock," says Dyen. ¶ Outbreaks of E. coli O157:H7 have been linked to the consumption of hamburger meat, alfalfa sprouts, unpasteurized fruit juice, and even drinking water; more than 75% of the cases can be directly traced to contamination from carrier ruminants. The most recent data suggest that about 28% of the cattle presented for slaughter in the U.S. harbor O157:H7, and similar numbers have been reported in Canada and Europe. Infected livestock show no signs of illness and the levels are generally low, making contaminated animals hard to identify. Current prevention methodologies have centered on reducing meat contamination in the slaughterhouse and testing all products for human consumption as they leave. ¶ "At present, there are few therapeutic treatments for victims of this potentially deadly infectious agent except supportive therapy to manage the complications of cellular damage," says Dyen. "Our work focuses on removing O157:H7 from the food chain.". [TOP OF PAGE]

  18. Therapy uses viruses as natural antibiotics. Anonymous (2003). The Seattle Times January 21(January 21). FORT WAYNE, Ind. - Stepping barefoot on a nail in April changed the path of Fred Bledsoe's life. ¶ The puncture wound seemed innocuous, but because he's diabetic and wounds are hard to heal, Bledsoe cleaned it carefully. ¶ The Fort Wayne man never imagined that the antibiotic-resistant bacteria that infected his foot would land him in a local hospital for 10 weeks of unsuccessful treatment, then send him halfway around the world in search of a cure. ¶ The treatment that worked, called bacteriophage, is available only in Russia and parts of Eastern Europe and the former Soviet Union. Tbilisi, Georgia, is the world's center for development and use of these naturally occurring viruses that destroy specific bacteria. ¶ It is where Bledsoe, 46, found his miracle cure. ¶ He and his family are spearheading efforts to raise awareness in the United States about phage treatment and help with research to get Food and Drug Administration approval for its use here. ¶ In September, after 2 1/2 months of intravenous antibiotics in a U.S. hospital, doctors told Bledsoe only amputation would stop the spread of staphylococcus. The bacteria was creating oozing wounds on his toes, foot and leg. Dead tissue slowly crept upward. ¶ "They actually had the amputation scheduled," he said. Then he called his sister, Saharra Bledsoe, who was out of town. ¶ "I told him, 'Don't do anything until I get home.' I heard my mother's voice say, 'You didn't come this far to fail.' I knew God had another plan," Saharra Bledsoe said. ¶ Washington connection ¶ When she returned, she happened to see a CBS "48 Hours" show called "Silent Killers." Canadian musician Alfred Gertler told of his yearlong battle with an antibiotic-resistant foot infection that was cleared using phage treatment given in Tbilisi. ¶ From the show, Saharra Bledsoe learned of Betty Kutter, a professor at The Evergreen State College in Olympia, who has done extensive phage research. The professor had connections to Eliava Institute in Georgia, a world-renowned center for developing and manufacturing therapeutic phages. ¶ Saharra Bledsoe contacted Kutter and began making arrangements to take her brother to Tbilisi. ¶ But Fred Bledsoe was skeptical when he heard where he was going and the method of treatment. His brother, Dr. Larry Bledsoe, a Fort Wayne internal medicine specialist, was doubtful, too. ¶ "On the other hand, it was intriguing, the idea of viruses fighting bacteria. So, I went and researched it and found it had been used in the past in this country. There were very few side effects. I felt it was safe," said Larry Bledsoe. ¶ The Bledsoe family chipped in and Fred Bledsoe and his sister were able to buy the $1,200-a-piece round-trip tickets to Tbilisi. ¶ "We were treated like celebrities," Saharra Bledsoe said. They were the first blacks ever to be treated at the Republic of Georgia Regional Hospital, which works closely with the Eliava Institute. ¶ And, "as far as I know, they are the first Americans to be treated there," Kutter said. ¶ Cultures of the bacteria in Fred Bledsoe's foot were taken. A phage solution, containing viruses that work against the three bacteria found in his foot, was injected into the infected areas twice a day for two weeks. Then a phage powder was used for several days. In less than three weeks, tests showed the bacteria were gone. The wounds healed. ¶ Not a new treatment ¶ Scientists have known of the existence of bacteriophages since the early 1900s. ¶ The viruses have the ability to attach to the surface of a specific bacterial cell. After a specific kind of phage finds its bacterial cell "match," the viral DNA is injected into the host cell. In minutes, the virus multiplies until it takes over and kills the cell. ¶ Phage therapy can be used to kill specific pathogens without disturbing beneficial bacteria. They pose no risk to anything other than their specific bacterial host, said Zemphira Alavidze, a phage researcher at the Eliava Institute. ¶ Phages were used in the 1930s in the United States, before penicillin was discovered. ¶ In fact, the American Medical Association did a review of bacteriophage therapy but dismissed its effectiveness at that time because, without the technological ability to see viruses, there was no proof they were living organisms. Besides, pharmaceutical companies were finding more effective antibiotics. ¶ "In Georgia, phages are the meat and potatoes of treatment," said Kutter, who has a Ph.D. in biophysics from the University of Rochester, N.Y. Kutter first traveled to Tbilisi in 1990 to examine bacteriophages of a specific E. coli bacterium. It was then that she learned bacteriophages were widely used there as antibiotics. ¶ "I'm a serious, hard-core scientist. I was very skeptical. It took a while of seeing things happen, talking to people, before I started taking it seriously," she said. ¶ A rush to bring phage to U.S. ¶ Drug-resistant bacteria, such as methicillin-resistant staph aureus (MRSA) has been a growing concern in medical circles in the United States. Staph is one of the three bacteria found in Fred Bledsoe's foot. ¶ There has been a gradual rise in MRSA since 1980, said Dr. William Jarvis of the Centers for Disease Control and Prevention in Atlanta. Some blame overuse or misuse of antibiotics. ¶ The "big gun" used against antibiotic-resistant bacteria has been vancomycin, but cases of vancomycin-resistant staph are cropping up too, according to the CDC. ¶ People should understand that phage treatment will not replace antibiotics, said Dr. Terry Brown, president of Intralytix, a Baltimore-based company researching agricultural and other uses for phage. The company is looking at how phages can keep meat-processing equipment and plants free of potentially deadly bacteria such as listeria. ¶ The company also holds the international license to make, market and distribute PhageBioDerm, a phage patch used to treat burns and other skin wounds. Although PhageBioDerm is used in Georgia, it is not yet available in the United States. ¶ Kutter said for U.S. citizens to access phage, "it will have to be manufactured here. It will not work to import it. (Georgian) standards would not meet FDA approval." ¶ According to the October 2002 issue of Science magazine, there are about two dozen companies worldwide in a frenzy to make phage treatment available in Western markets. ¶ Exponential Biotherapies Inc. of Port Washington, N.Y., has completed FDA State I, or safety, trials of a phage effective against a bacterial strain called vancomycin-resistant enterococci. ¶ The company hopes to launch clinical trials of the phage later this year. [TOP OF PAGE]

  19. Application of host-specific bacteriophages to the surface of chicken skin leads to a reduction in recovery of Campylobacter jejuni. Atterbury,R.J., Connerton,P.L., Dodd,C.E.R., Rees,C.E.D., Connerton,I.F. (2003). Appl. Environ. Microbiol. 69:6302-6306. Retail poultry products are widely purported as the major infection vehicle for human campylobacteriosis. Numerous intervention strategies have sought to reduce Campylobacter contamination on broiler carcasses in the abattoir. This study reports the efficacy of bacteriophage in reducing the number of recoverable Campylobacter jejuni cells on artificially contaminated chicken skin. [TOP OF PAGE]

  20. Isolation of naturally occurring bacteriophage from sheep that reduce populations of Escherichia coli O157:H7 In Vitro And In Vivo. Callaway,T., Edrington,T., Varey,P., Raya,R., Brabban,A., Kutter,E., Jung,Y., Genovese,K., Elder,R., Nisbet,D.J. (2003). 5th International Symposium on 'Shiga Toxin(Verocytotoxin) - Producing Escherichia coli Infections' , O-16. Bacteriophage that specifically target bacteria have been used to treat bacterial infections in humans as an alternative to antibiotics. Previous research has examined the use of bacteriophage to control food-borne pathogenic bacteria in food animals, however results have been inconclusive. Sheep (n=32) were transported from open range pasture to College Station, TX. Feces were collected and enriched for bacteriophage via standard procedures and 46% were positive for naturally-occurring bacteriophage. A phage (CEV-1) was isolated into pure culture via filtration prior to further characterization. Microscopic examination revealed that the phage had a characteristic T-even phage morphology. Molecular studies indicated that the genome was approximately 180 kb in size and that the capsid protein shared 94% homology with the gp23 capsid protein of T4 bacteriophage. CEV-1 bacteriophage killed strains (n=18) of E. coli O157:H7 as well as K-12, O43:H7, O126:H7, O158:H7 and Omulti:H7 in in vitro activity assays; however other bacterial species (e.g. Salmonella, Streptococcus) were not affected by this phage. Treatment of pure cultures of E. coli O157:H7 with CEV-1 in a 10:1 PFU/CFU ratio resulted in a rapid (6 h) significant (P < 0.05) decrease in concentrations of viable cells (10**8 to 10**4 CFU/ml). Addition of CEV-1 to in vitro ruminal and fecal fermentations containing E. coli O157:H7 resulted in a reduction of approximately 2 log10 CFU/ml E. coli O157:H7. Sheep not naturally shedding bacteriophage (n=8) were experimentally challenged with E. coli O157:H7 and then inoculated with bacteriophage CEV-1. Concentrations of E. coli O157:H7 were numerically but not significantly (P>0.05) reduced (approximately 2 log10 CFU/g digesta) in the rumen, cecum and colon. Although it appears that bacteriophage treatment could be used to reduce E. coli O157:H7 in food animals, further research is crucial prior to implementation. [TOP OF PAGE]

  21. Reduction of experimental Salmonella and Campylobacter contamination of chicken skin by application of lytic bacteriophages. Goode,D., Allen,V.M., Barrow,P.A. (2003). Appl. Environ. Microbiol. 69:5032-5036. Lytic bacteriophages, applied to chicken skin that had been experimentally contaminated with Salmonella enterica serovar Enteritidis or Campylobacter jejuni at a multiplicity of infection (MOI) of 1, increased in titer and reduced the pathogen numbers by less than 1 log10 unit. Phages applied at a MOI of 100 to 1,000 rapidly reduced the recoverable bacterial numbers by up to 2 log10 units over 48 h. When the level of Salmonella contamination was low (< log10 2 per unit area of skin) and the MOI was 10^5, no organisms were recovered. By increasing the number of phage particles applied (i.e., MOI of 10^7), it was also possible to eliminate other Salmonella strains that showed high levels of resistance because of restriction but to which the phages were able to attach. [TOP OF PAGE]

  22. Bacteriophage biocontrol and bioprocessing: application of phage therapy to industry. Goodridge,L., Abedon,S.T. (2003). SIM News 53:254-262. Here we take a slightly different tack from the mostly clinical considerations of phage therapy, emphasizing instead the role of phages as a means of selectively reducing bacterial loads in nonclinical settings. Since the phrase phage therapy carries a connotation of medical doctors administering phages as living drugs to suffering patients, we instead employ the alliterations bacteriophage biocontrol and bacteriophage bioprocessing to describe, as we review here, the more generalized application of phages as everything from biocontrol agents on the farm to the bioprocessing of certain foods. We also provide a primer on phage-based methods of bacterial diagnosis. [TOP OF PAGE]

  23. New insights into the possible role of bacteriophages in transplantation. Gorski,A., Nowaczyk,M., Weber-Dabrowska,B., Kniotek,M., Boratynski,J., Ahmed,A., Dabrowska,K., Wierzbicki,P., Switala-Jelen,K., Opolski,A. (2003). Transplant. Proc. 35:2372-2373. Due to the increasing prevalence of drug-resistant bacterial infections in the "post-antibiotic era," bacteriophages (bacterial viruses, BP) may be useful to administer to transplant recipients without exposing them to an increased risk of rejection, which occurs consequent to some viral infections. Herein we present evidence that at least some coliphages (T4) do not pose such risk. Interestingly, they may produce immunosuppressive effects extending transplant survival. Our data suggest that BP may be used in clinical transplantation to treat drug-resistant bacterial infections and perhaps as an adjunct to immunosuppressive therapy. [TOP OF PAGE]

  24. New insights into the possible role of bacteriophages in host defense and disease. Gorski,A., Dabrowska,K., Switala-Jele,K., Nowaczyk,M., Weber-Dabrowska,B., Boratynski,J., Wietrzyk,J., Opolski,A. (2003). Medical Immunology 2:2 Background: While the ability of bacteriophages to kill bacteria is well known and has been used in some centers to combat antibiotics - resistant infections, our knowledge about phage interactions with mammalian cells is very limited and phages have been believed to have no intrinsic tropism for those cells. ¶ Presentation of the hypothesis: At least some phages (e.g., T4 coliphage) express Lys-Arg-Gly (KGD) sequence which binds b3 integrins (primarily aIIbb3). Therefore, phages could bind b3+ cells (platelets, monocytes, some lymphocytes and some neoplastic cells) and downregulate activities of those cells by inhibiting integrin functions. ¶ Testing the hypothesis: Binding of KGD+ phages to b3 integrin+ cells may be detected using standard techniques involving phage - mediated bacterial lysis and plaque formation. Furthermore, the binding may be visualized by electron microscopy and fluorescence using labelled phages. Binding specificity can be confirmed with the aid of specific blocking peptides and monoclonal antibodies. In vivo effects of phage - cell interactions may be assessed by examining the possible biological effects of b3 blockade (e.g., anti-metastatic activity). ¶ Implication of the hypothesis: If, indeed, phages can modify functions of b3+ cells (platelets, monocytes, lymphocytes, cancer cells) they could be important biological response modifiers regulating migration and activities of those cells. Such novel understanding of their role could open novel perspectives in their potential use in treatment of cardiovascular and autoimmune disease, graft rejection and cancer. [TOP OF PAGE]

  25. Genetically modified filamentous phage as bactericidal agents: a pilot study. Hagens,S., Bläsi,U. (2003). Lett. Appl. Microbiol. 37:318-323. AIMS: To evaluate the ability of a filamentous phage encoding lethal proteins to kill bacteria without host-cell lysis. METHODS AND RESULTS: Bacterial survival was determined after infection of a growing Escherichia coli culture with phage M13 encoding either the restriction endonuclease BglII gene or modified phage lambda S holin genes. The genetically engineered phage exerted a high killing efficiency while leaving the cells structurally intact. When compared with a lytic phage, the release of endotoxin was minimized after infection with the genetically modified phages. CONCLUSIONS: Genetically engineered phage can be used for efficient killing, concomitantly minimizing endotoxin release. SIGNIFICANCE AND IMPACT OF THE STUDY: This feasibility study provides a possible strategy for the use of genetically engineered phage as bactericidal agents by optimizing the advantages and minimizing potential risks such as release of pyrogenic cell wall components. [TOP OF PAGE]

  26. Evaluation of aerosol spray and intramuscular injection of bacteriophage to treat an Escherichia coli respiratory infection. Huff,W.E., Huff,G.R., Rath,N.C., Balog,J.M., Donoghue,A.M. (2003). Poult Sci 82:1108-1112. Two studies were conducted to determine the efficacy of either aerosol or i.m. injection of bacteriophage to treat an Escherichia coli respiratory infection in broiler chickens. An additional two studies were conducted to enumerate the bacteriophage in the blood of birds at 1, 2, 3, 4, 5, 6, 24, and 48 h after being sprayed or injected i.m. with bacteriophage. Five birds were bled at each period. In study 1, there were 10 treatments with three replicate pens of 10 birds. The treatments consisted of an untreated control, heat-killed bacteriophage spray, active bacteriophage spray, E. coli challenge at 7 d of age, and E. coli challenge followed by spraying the birds with heat-killed bacteriophage or active bacteriophage at 2, 24, or 48 h after challenge. In study 2 there were 11 treatments with three replicate pens of 10 birds per pen. The treatments were untreated controls, birds injected i.m. in the thigh with heat-killed or active bacteriophage, E. coli challenge at 7 d of age, PBS challenge, E. coli challenge followed by injection of heat-killed or active bacteriophage immediately after challenge or at 24 or 48 h after challenge. In both studies the E. coli challenge consisted of injecting 10(4) cfu into the thoracic air sac. Treatment of this severe E. coli infection with the bacteriophage aerosol spray significantly reduced mortality from 50 to 20% when given immediately after the challenge but had little treatment efficacy when administered 24 or 48 h after challenge. The i.m. injection of bacteriophage significantly reduced mortality from 53 to 17%, 46 to 10%, and 44 to 20% when given immediately, 24, or 48 h after challenge, respectively. Only a few birds sprayed with bacteriophage had detectable bacteriophage in their blood with an average of 96 pfu/mL 1 h after bacteriophage administration, and no bacteriophage was detected 24 and 48 h after bacteriophage administration. All birds injected i.m. with bacteriophage had detectable levels of bacteriophage in their blood at levels of 10(4) pfu/mL of blood up to 6 h after bacteriophage administration, and four of the five birds had detectable bacteriophage in their blood at an average level of 70 pfu/mL of blood 24 h after bacteriophage administration. The relative inefficiency of the spray treatment to the i.m. injection treatment may be due to the inability to get bacteriophage into the blood at high concentrations when the birds are sprayed versus the consistent high titers achieved with the i.m. injection of bacteriophage. These data provide support to the concept that bacteriophage may be an effective alternative to antibiotics in animal production when they are administered in a way that delivers high titers of the bacteriophage to the critical site of the bacterial infection. [TOP OF PAGE]

  27. Bacteriophage treatment of a severe Escherichia coli respiratory infection in broiler chickens. Huff,W.E., Huff,G.R., Rath,N.C., Balog,J.M., Donoghue,A.M. (2003). Avian Diseases 47:1399-1405. A bacteriophage to a serotype 02, nonmotile Escherichia coli was isolated from municipal waste treatment facilities and poultry processing plants. A study was conducted to determine the efficacy of multiple vs. single intramuscular (i.m.) injections of bacteriophage to treat a severe E. coli respiratory infection. The birds were challenged at 7 days of age by injection of 6 x 10(4) colony-forming units (cfu) of E. coli into the thoracic air sac followed by an i.m. injection into the thigh with either heat-killed or active bacteriophage. There were 16 treatments with three replicate pens of 10 birds. There were four control treatments, which included untreated birds, birds injected with either heat-killed or active bacteriophage, and birds challenged only with E. coli. In the remaining treatments, birds were injected with heat-killed or active bacteriophage either once immediately after E. coli challenge or immediately after challenge and at 8 and 9 days of age, once at 8 days of age or at 8, 9, and 10 days of age, and once at 9 days of age or at 9, 10, and 11 days of age. Mortality was significantly decreased from 57% to 13% in the birds given a single i.m. injection of bacteriophage immediately after E. coli challenge, and there was complete recovery in birds treated immediately after challenge and at 8 and 9 days of age, which was a significant improvement from the single injection treatment. There was a significant reduction in mortality from 57% to 10% in the birds treated with bacteriophage once at 8 days of age and those birds treated at 8, 9, and 10 days of age, with no difference between single or multiple treatments. The mortality in the single or multiple phage treated birds that started at 9 days of age was reduced from 57% to 28% and 27%, respectively, but was not statistically different from the control. These data suggest that bacteriophage can be an effective treatment when administered early in this experimental E. coli respiratory disease and that early multiple treatments are better than a single treatment. The efficacy of bacteriophage treatment diminishes as it is delayed, with no difference between single or multiple treatments. Bacteriophage may provide an effective alternative to antibiotics, but like antibiotic therapy, the effectiveness of phage to rescue animals decreases the longer treatment is delayed in the disease process. [TOP OF PAGE]

  28. [Bacteriophage therapy]. Huovinen,P. (2003). Duodecim; laaketieteellinen aikakauskirja 119:581-583. [TOP OF PAGE]

  29. Phage therapy: a reappraisal of bacteriophages as antibiotics. Inal,J.M. (2003). Archivum Immunologiae et Therapiae Experimentalis 51:237-244. The concept of phage therapy to treat bacterial infections was born with the discovery of the bacteriophage almost a century ago. After a chequered history, its current renaissance is fueled by the dangerous appearance of antibiotic-resistant bacteria on a global scale. As a mark of this renewed interest, the unanswered problems of phage therapy are now being addressed, especially for human use. Phage therapy in the agricultural, food-processing and fishery industries is already being successfully applied, and this review, whilst being aware of the potential drawbacks, emphasizes the need for further carefully controlled empirical data on its efficacy and safety in treating human and animal disease, especially in view of its numerous advantages over antibiotics. Finally the potential of phage therapy against bioterrorism and the emergence of second generation phage antibacterials based on phage-derived single-protein lysis systems are addressed. [TOP OF PAGE]

  30. Alternatives to antibiotics: bacteriocins, antimicrobial peptides and bacteriophages. Joerger,R.D. (2003). Poult Sci 82:647640 Bacteriocins, antimicrobial peptides, and bacteriophage have attracted attention as potential substitutes for, or as additions to, currently used antimicrobial compounds. This publication will review research on the potential application of these alternative antimicrobial agents to poultry production and processing. Bacteriocins are proteinaceous compounds of bacterial origin that are lethal to bacteria other than the producing strain. It is assumed that some of the bacteria in the intestinal tract produce bacteriocins as a means to achieve a competitive advantage, and bacteriocin-producing bacteria might be a desirable part of competitive exclusion preparations. Purified or partially purified bacteriocins could be used as preservatives or for the reduction or elimination of certain pathogens. Currently only nisin, produced by certain strains of Lactococcus lactis subsp. lactis, has regulatory approval for use in certain foods, and its use for poultry products has been studied extensively. Exploration of the application of antimicrobial peptides from sources other than bacteria to poultry has not yet commenced to a significant extent. Evidence for the ability of chickens to produce such antimicrobial peptides has been provided, and it is likely that these peptides play an important role in the defense against various pathogens. Bacteriophages have received renewed attention as possible agents against infecting bacteria. Evidence from several trials indicates that phage therapy can be effective under certain circumstances. Numerous obstacles for the use of phage as antimicrobials for poultry or poultry products remain. Chiefly among them are the narrow host range of many phages, the issue of phage resistance, and the possibility of phage-mediated transfer of genetic material to bacterial hosts. Regulatory issues and the high cost of producing such alternative antimicrobial agents are also factors that might prevent application of these agents in the near future. [TOP OF PAGE]

  31. [Bacteriophage therapy: Stalin's forgotten medicine]. Kaulen,H. (2003). Dtsch Med Wochenschr 128:307 [TOP OF PAGE]

  32. [Bacteriophage therapy: Stalin's forgotten medicine]. Kaulen,H. (2003). Deutsche medizinische Wochenschrift 128:307 [TOP OF PAGE]

  33. [Bacteriophages for treatment and prophylaxis of infectious diseases]. Lazareva,E.B. (2003). Antibiot. Khimoter. 48:36-40. [TOP OF PAGE]

  34. Biocontrol of Listeria monocytogenes on fresh-cut produce by treatment with lytic bacteriophages and a bacteriocin. Leverentz,B., Conway,W.S., Camp,M.J., Janisiewicz,W.J., Abuladze,T., Yang,M., Saftner,R., Sulakvelidze,A. (2003). Appl. Environ. Microbiol. 69:4519-4526. The fresh-cut produce industry has been the fastest-growing portion of the food retail market during the past 10 years, providing consumers with convenient and nutritious food. However, fresh-cut fruits and vegetables raise food safety concerns, because exposed tissue may be colonized more easily by pathogenic bacteria than intact produce. This is due to the higher availability of nutrients on cut surfaces and the greater potential for contamination because of the increased amount of handling. We found that applied Listeria monocytogenes populations survived and increased only slightly on fresh-cut Red Delicious apples stored at 10°C but increased significantly on fresh-cut honeydew melons stored at 10°C over 7 days. In addition, we examined the effect of lytic, L. monocytogenes-specific phages via two phage application methods, spraying and pipetting, on L. monocytogenes populations in artificially contaminated fresh-cut melons and apples. The phage mixture reduced L. monocytogenes populations by 2.0 to 4.6 log units over the control on honeydew melons. On apples, the reduction was below 0.4 log units. In combination with nisin (a bacteriocin), the phage mixture reduced L. monocytogenes populations by up to 5.7 log units on honeydew melon slices and by up to 2.3 log units on apple slices compared to the control. Nisin alone reduced L. monocytogenes populations by up to 3.2 log units on honeydew melon slices and by up to 2.0 log units on apple slices compared to the control. The phage titer was stable on melon slices, but declined rapidly on apple slices. The spray application of the phage and phage plus nisin reduced the bacterial numbers at least as much as the pipette application. The effectiveness of the phage treatment also depended on the initial concentration of L. monocytogenes. [TOP OF PAGE]

  35. Diagnostic and therapeutic applications of lytic phages. Mandeville,R., Griffiths,M., Goodridge,L., McIntyre,L., Ilenchuk,T.T. (2003). Analytical Letters 36:3241-3259. The ability of lytic phages to rapidly kill and lyse infected bacteria, the specificity of phages for particular bacteria, and the ability of phages to increase in number during the infection process make phages excellent potential diagnostic and therapeutic agents for fighting bacterial disease. However, temperate phages are of little use in phage diagnostics and therapy. [TOP OF PAGE]

  36. Bacteriophage therapy: an alternative to conventional antibiotics. Mathur,M.D., Vidhani,S., Mehndiratta,P.L. (2003). The Journal of the Association of Physicians of India 51:593-596. Bacteriophage therapy is an important alternative to antibiotics in the current era of multidrug resistant pathogens. We reviewed the studies that dealt with the therapeutic use of phages from 1966-1996 and few latest ongoing phage therapy projects via internet. Phages were used topically, orally or systemically in Polish and Soviet studies. The success rate found in these studies was 80-95% with few gastrointeslinal or allergic side effects. British studies also demonstrated significant efficacy of phages against Escherichia coli, Acinetobacter spp., Pseudomonas spp and Staphylococcus aureus. US studies dealt with improving the bioavailability of phage. Problems faced in these studies have also been discussed. In conclusion, phage therapy may prove as an important alternative to antibiotics for treating multidrug resistant pathogens. [TOP OF PAGE]

  37. Experimental protection of mice against lethal Staphylococcus aureus infection by novel bacteriophage fMR11. Matsuzaki,S., Yasuda,M., Nishikawa,H., Kuroda,M., Ujihara,T., Shuin,T., Shen,Y., Jin,Z., Fujimoto,S., Nasimuzzaman,M.D., Wakiguchi,H., Sugihara,S., Sugiura,T., Koda,S., Muraoka,A., Imai,S. (2003). J. Infect. Dis. 187:613-624. The protective effects of bacteriophages were assessed against experimental Staphylococcus aureus infection in mice. Of the S. aureus phages isolated in the study, phi MR11 was representatively used for all testing, because its host range was the most broad and it carries no genes for known toxins or antibiotic resistance. Intraperitoneal injections (8 x 108 cells) of S. aureus, including methicillin-resistant bacteria, caused bacteremia and eventual death in mice. In contrast, subsequent intraperitoneal administration of purified phi MR11 (MOI > or = 0.1) suppressed S. aureus-induced lethality. This lifesaving effect coincided with the rapid appearance of phi MR11 in the circulation, which remained at substantial levels until the bacteria were eradicated. Inoculation with high-dose phi MR11 alone produced no adverse effects attributable to the phage. These results uphold the efficacy of phage therapy against pernicious S. aureus infections in humans and suggest that phi MR11 may be a potential prototype for gene-modified, advanced therapeutic S. aureus phages. [TOP OF PAGE]

  38. Antibacterial therapy with bacteriophage genotypically modified to delay inactivation by the host defense system. Merril,C.R., Carlton,R.M., Adhya,S.L. (2003). Exponential Biotherapies, Inc. and The United States of America as represented by the Department of Health. 464412(5,660,812). New York, NY; Washington, DC. The present invention is directed to bacteriophage therapy, using methods that enable the bacteriophage to delay inactivation by any and all parts of the host defense system (HDS) against foreign objects that would tend to reduce the numbers of bacteriophage and/or the efficiency of those phage at killing the host bacteria in an infection. Disclosed is a method of producing bacteriophage modified for anti-HDS purposes, one method being selection by serial passaging, and the other method being genetic engineering of a bacteriophage, so that the modified bacteriophage will remain active in the body for longer periods of time than the wild-type phage. [TOP OF PAGE]

  39. The prospect for bacteriophage therapy in Western Medicine. Merril,C.R., Scholl,D., Adhya,S.L. (2003). Nat. Rev. 2:489-497. Bacteriophage (phage) have been used for clinical applications since their initial discovery at the beginning of the twentieth century. However, they have never been subjted to the scrutiny -- in terms of the determination of efficacy and pharmaco-kinites of therapeutic agents -- that is required in countries that enforce certification of marketed pharmaceuticals. There are a number of historical reasons for this deficiency, including the overshadowing discovery of antibiotics. Neverhteless, present efforts to develop phage into reliable antibacterial agents have been substantially enhanced by knowledge gained concerning the genetics and physiology of phage in molecular detail during the past 50 years. Such efforts will be of importance given the emergence of antibiotic-resistant bacteria. [TOP OF PAGE]

  40. Role for bacteriophages? Viruses that fight bacteria. Miller,F. (2003). WATT Poultry USA April(April), 8. Faced with the potential loss of traditional antibiotics, scientists at the University of Arkansas Division of Agriculture and the USDA Agriculture Research Service are updating century-old technology to fight illness-causing bacteria in poultry by infecting them with viruses known as bacteriophages. [TOP OF PAGE]

  41. [Bacteriophage therapy and colleague Martin Arrowsmith]. Nevasaari,K. (2003). Duodecim; laaketieteellinen aikakauskirja 119:1367 [TOP OF PAGE]

  42. Bacteriophage control of Pseudomonas plecoglossicida infection in ayu Plecoglossus altivelis. Park,S.C., Nakai,T. (2003). Dis. Aquat. Org. 53:33-39. Two previously isolated phages were used to examine the therapeutic effects against Pseudomonas plecoglossicida infection in ayu Plecoglossus altivelis. Phage PPp-W4 (Podoviridae) inhibited the in vitro growth of P. plecoglossicida more effectively than Phage PPpW-3 (Myoviridae), and a mixture (PPpW-3/W-4) of the 2 phages exhibited the highest inhibitory activity. In phage therapy experiments, ayu were fed P. plecoglossicida-impregnated feed (10(7) CFU fish(-1)) and then fed phage-impregnated feed (10(7) PFU fish(-1)). Mortalities of fish receiving PPpW-3, PPpW-4, PPpW-3/W-4, and a control fish receiving no phages were 53.3, 40.0, 20.0 and 93.3%, respectively. Phage (PPpW-3/W-4)-receiving fish also showed high protection against water-borne infection with P. plecoglossicida. In a field trial, when phage (PPpW-3/W-4)-impregnated feed was administered to ayu in a pond where the disease occurred naturally, daily mortality of fish decreased at a constant level (5% d(-1)) to one-third after a 2 wk period. The causal relationship of phages in this phenomenon was verified by the long-lasting appearance of administered phages in the kidneys of the fish, and a disappearance of P. plecoglossicida from apparently healthy fish. Neither phage-resistant organisms nor phage-neutralizing antibodies were detected in diseased fish or apparently healthy fish, respectively. These results indicate the potential for phage control of the disease. [TOP OF PAGE]

  43. Pharmacokinetic principles of bacteriophage therapy. Payne,R.J.H., Jansen,V.A.A. (2003). Clinical Pharmacokinetics 42:315-325. Use of bacteriophage to control bacterial infections, including antibiotic-resistant infections, shows increasing therapeutic promise. Effective bacteriophage therapy requires awareness of various novel kinetic phenomena not known in conventional drug treatments. Kinetic theory predicts that timing of treatment could be critical, with the strange possibility that inoculations given too early could be less effective or fail completely. Another paradoxical result is that adjuvant use of an antibiotic can sometimes diminish the efficacy of phage therapy. For a simple kinetic model, mathematical formulae predict the values of critical density thresholds and critical time points, given as functions of independently measurable biological parameters. Understanding such formulae is important for interpreting data and guiding experimental design. Tailoring pharmacokinetic models for specific systems needs to become standard practice in future studies. [TOP OF PAGE]

  44. Development of a novel method of lytic phage delivery by use of a bacteriophage P22 site-specific recombination system. Platt,R., Reynolds,D.L., Phillips,G.J. (2003). FEMS Microbiol. Lett. 223:259-265. Bacteriophage therapy represents a potential alternative to the use of antibiotics to control proliferation of pathogenic bacteria. As an alternative to the strategy where a limited number of doses of large numbers of lytic bacteriophages are administered, a novel method delivery system was developed so that phages are continually released into the culture. Specifically, a non-pathogenic Escherichia coli strain was constructed that was lysogenic for a lytic mutant of bacteriophage lambda. This lysogen was shown to be effective at decreasing the number of lambda-sensitive E. coli in vitro. Construction of this E. coli strain was accomplished by development of a plasmid-based system utilizing the site-specific recombination machinery of bacteriophage P22 to integrate DNA constructs into the host chromosome. This recombination system is useful for strain construction and other genetic manipulations in both E. coli and Salmonella enterica serovars. [TOP OF PAGE]

  45. Virus cleans up food poisoning bug. Randerson,J. (2003). NewScientist. com April 23:A virus that kills the food-poisoning bacterium E. coli O157:H7 has been discovered in sheep. The virus could help eliminate the bacterium in farm animals, greatly reducing the chance of human infections. ¶ O157:H7, a toxic strain of the normally harmless gut bug E. coli, is a major cause of food poisoning. Three-quarters of cases can be traced directly to livestock, which harbour the bug without becoming ill. Meat can be contaminated when the animals are slaughtered, and manure can also be a source of infections. ¶ So Andrew Brabban at Evergreen State College in Washington state and his team wanted to test different antibiotics to find those which would eliminate the bugs from farm animals. First, they had to infect sheep with E. coli. But they hit an unexpected problem: the bacteria just kept disappearing from the animals. The team re-infected the sheep three times, and every time the bacteria mysteriously vanished. ¶ It turned out that the sheep harbour a bacteria-killing virus, or bacteriophage, that infects certain E. coli strains. When the team tested the phage against the food-poisoning bug in the lab, they found it kills 16 out of 18 toxic strains. "That includes all the big ones you've ever heard about," says Brabban, such as the strain responsible for an outbreak at Jack in the Box fast-food outlets in the US in 1993, which left four people dead. But the phage, christened CEV1, only kills eight out of 73 harmless E. coli strains. ¶ Exponential infection ¶ Brabban now hopes to use the phage to wipe out O157:H7 in herds and flocks. In a small trial in sheep, the phage reduced numbers of the toxic bacterium by 99 per cent in just two days, he told a meeting of the Society for General Microbiology in Edinburgh earlier in April. ¶ And using bacteriophages has all sorts of advantages. Phages are far more discriminating than antibiotics, so the natural microbial flora of animals' guts should not be affected. Also, while antibiotics are expensive and must be given to every animal, infecting just one animal with the CEV1 phage is likely to be enough to pass the phage to a whole herd or flock - and the numbers of the phage will rise exponentially as long as there are host bacteria left to infect. ¶ What is more, the phage seems to persist in animals, suggesting it continues to replicate in a harmless E. coli strain after all the O157:H7 bacteria have been destroyed. Finally, while bacteria can develop resistance as they do to antibiotics, the phage can out-evolve them. ¶ Brabban thinks that giving the phage to animals is more practical than using it to treat people. For instance, killing E. coli 0157:H7 releases large quantities of its toxin, which can make a patient's condition worse. And animal treatment would not have to meet the strict safety standards for human therapies, one reason why phage still are not used in the West. However, the team will need to show that the phage will not have an adverse effect on human gut flora if they are passed to people via food. [TOP OF PAGE]

  46. Los bacteriófagos como herramienta para combatir infecciones en acuicultura [abstract is in English, manuscript is in Spanish]. Ronda,C., Vázquez,M., López,R. (2003). Revista AquaTIC 18:3-10. Bacteriophages (phages), the most abundant entities in nature, have been proposed as therapeutic agents since they were isolated in the early years of the last century. The current antibiotic resistance of most pathogenic microorganisms together with the technical achievements in the study of phages has led to reconsider the work carried out for scientists of the former Soviet Union and to propose the use of bacterial viruses as a real therapeutical alternative. In this minireview we analyze the most relevant contribution on phage therapy in Aquaculture as well as the new possibility that offer the use of phage and phage products, like the lytic enzymes, named enzybiotics, as an alternative tool in therapy. [TOP OF PAGE]

  47. Set a microbe to kill a microbe: drug resistance renews interest in phage therapy. Thacker,P.D. (2003). J. Am. Med. Assoc. 290:3183-3185. Phage therapy predated antibiotics by decades, but was largely supplanted when these drugs became available. Now, however, the emerging threat posed by antibiotic-resistant pathogens is spurring a sesurgence of interest in phage, as a potential therapy to cure or prevent infetions and as a tool to kill food-borne pathogens. [TOP OF PAGE]

  48. Efficacy and durability of Bacillus anthracis bacteriophages used against spores. Walter,M.H. (2003). J Environ Health 66:9-15, 24. Antibiotics and vaccines help fight anthrax disease, but there are no anthrax spore control methods suitable for use in environments where humans are present. The work reported in this article indicates that bacteriophages may help reduce risk from anthrax spores. Dose-response studies demonstrated that higher concentrations of mixed Bacillus anthracis bacteriophages (3.5 x 10(8) plaque-forming units per milliliter) inhibited subsequent growth of bacteria when sprayed on B. anthracis spores. Phages also were tested for durability under conditions designed to simulate environments possibly encountered during mass phage production, storage, and use against anthrax spores. They remained infectious at temperatures from -20ºC to 37ºC, under filtration, aerosolization, and treatments with perspiration and blood. Phages were sensitive to temperatures over 55ºC and to desiccation. Ultraviolet light reduced spore viability more than phage infectivity under similar conditions. The potential for personal or environmental decontamination of anthrax spores with phages is discussed. [TOP OF PAGE]

  49. Bacteriophages as an efficient therapy for antibiotic-resistant septicemia in man. Weber-Dabrowska,B., Mulczyk,M., Gorski,A. (2003). Transplant. Proc. 35:1385-1386. [first paragraph] Acute bacterial infection-induced sepsis, with shock, metabolic acidosis, oliguria, or hypoxemia, remains a major medical challenge, especially at a time when experts believe that we may be returning to the pre-antibiotic era, arising from increasing antibiotic resistance In the USA alone there are at least 500,000 cases of sepsis annually, with mortality rates ranging from 30% to 50% (ie, 150,000 to 250,000 deaths). Assuming a U.S. population of approximately 270 million and a total world population of >6 billion, this would mean at least 11 million cases of sepsis worldwide with at least 3 to 5 million deaths annually (or probably more, as American health-care standards are generally much higher than in many other countries). Several treatments designed to reduce sepsis-associated mortality have been unsuccessful; therefore, finding an effective new therapy for sepsis is urgently needed. [TOP OF PAGE]

  50. Use of genetically engineered phage to deliver antimicrobial agents to bacteria: an alternative therapy for treatment of bacterial infections. Westwater,C., Kasman,L.M., Schofield,D.A., Werner,P.A., Dolan,J.W., Schmidt,M.G., Norris,J.S. (2003). Antimicrob. Agents Chemother. 47:1301-1307. The emergence and increasing prevalence of multidrug-resistant bacterial pathogens emphasizes the need for new and innovative antimicrobial strategies. Lytic phages, which kill their host following amplification and release of progeny phage into the environment, may offer an alternative strategy for combating bacterial infections. In this study, however, we describe the use of a nonlytic phage to specifically target and deliver DNA encoding bactericidal proteins to bacteria. To test the concept of using phage as a lethal-agent delivery vehicle, we used the M13 phagemid system and the addiction toxins Gef and ChpBK. Phage delivery of lethal-agent phagemids reduced target bacterial numbers by several orders of magnitude in vitro and in a bacteremic mouse model of infection. Given the powerful genetic engineering tools available and the present knowledge in phage biology, this technology may have potential use in antimicrobial therapies and DNA vaccine development. [TOP OF PAGE]

  51. Suppression of Salmonella growth by wild-type and large-plaque variants of bacteriophage Felix O1 in liquid culture and on chicken frankfurters. Whichard,J.M., Sriranganathan,N., Pierson,F.W. (2003). J. Food Prot. 66:220-225. The bacteriophage Felix O1, a member of Myoviridae, is specific for, and possesses a broad host range within, the genus Salmonella. This work explores a Felix O1 phage-based intervention for Salmonella enterica serotype Typhimurium DT104 that is potentially applicable at several stages of animal production and processing. A variant of Felix O1 was obtained that produces a larger, clearer plaque phenotype (LP) on Salmonella Typhi than wild-type Felix O1 (WT) does, not unlike r mutants of phage T4. LP exhibited slightly more extensive overall suppression of Salmonella Typhi in brain heart infusion (BHI) broth, as ascertained on the basis of culture turbidity (optical density at 600 nm). Both phage variants suppressed log phase BHI broth cultures containing 8.2 x 10(6) CFU of Salmonella Typhimurium DT104 per ml. A PFU/CFU ratio of 1.0 was effective for WT and LP, whereas increasing the PFU/CFU ratio to 5.0 did not increase suppression. Untreated Salmonella-contaminated frankfurters were compared with treated samples (PFU/CFU ratio, 1.9 x 10(4)) to test WT and LP for their ability to suppress Salmonella growth on chicken frankfurters contaminated with 300 CFU of Salmonella Typhimurium DT104. Suppression levels of 1.8 and 2.1 log units were achieved with WT and LP, respectively (P = 0.0001), but no difference was found between the performances of the two variants (P = 0.5088). [TOP OF PAGE]

  52. Treatment of post-burns bacterial infections by bacteriophages, specifically ubiquitous Pseudomonas spp. notoriously resistant to antibiotics. Ahmad,S.I. (2002). Med Hypotheses 58:327-331. Post-burn microbial infections are a major problem in recovering from the trauma of third-degree burns, and the survival of patients can depend upon the severity of the burn and the infections encountered. Within 24 hours, patients can start suffering from opportunistic bacterial attacks, which can vary from simple infection, such as those easily treatable by antibiotics, to more complicated types, which may have natural or acquired resistance to drugs. Infection by multiple drug-resistant bacteria can create additional complexity to the problem. As an alternative to treating bacterial infections by antibiotics, bacteriophages have been in use in certain parts of the world, such as at Tbilisi in Georgia and in Poland, and this approach has now been more widely recognized. Results have shown that phage therapy has an 80% success rate against Enterococcus infections and up to 90% against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Here it is proposed that bacteriophages can effectively be used for the treatment of post-burn infections, particularly the ubiquitous opportunistic pathogens, Pseudomonas spp., known to be notoriously resistant to a variety of antibiotics. This kind of treatment may be of particular importance in Third World countries where the incidence of burns and infections, due to lack of stringent safety regulations and proper hygiene respectively, may be more common and where cocktails of antibiotics may be less affordable. Phages that can possibly be employed in the treatment and their advantages compared to the use of antibiotics are also highlighted. [TOP OF PAGE]

  53. Bacteriophage composition useful in treating food products to prevent bacterial contamination. Averback,P., Gemmell,J. (2002). Nymox Pharmaceutical Corporation. 718093(6,461,608). St. Laurent, CA. The present invention is directed to novel bacteriophage compositions useful in treating food products to prevent bacterial contamination. [TOP OF PAGE]

  54. Strategies for improving the efficacy of bacteriophages for controlling bacterial spot of tomato. Balogh,B. (2002). University of Florida. Bacterial spot, caused by the bacterium pv. vesicatoria, is one of the major tomato diseases in Florida. The disease is routinely controlled by the application of copper-mancozeb, a mixture of chemical pesticides; however, there is no adequate control measure when the environmental conditions are conducive for disease development. A novel method for controlling this disease is the application of a mixture of bacteriophages, viruses that infect bacteria. However, these control agents are rapidly degraded by harmful environmental factors such as sunlight or desiccation, which delimits the efficacy of phage treatment. It has been hypothesized that the efficacy of phage treatment could be enhanced if the longevity of the viruses was increased. ¶ Three formulations were developed that enhanced the longevity of bacteriophages on plant foliage. These formulations were (i) PCF (0.5% pregelatinized corn flour (PCPF 400, Lauhoff Grain Co., Danville, IL ) + 0.5% sucrose), (ii) Casecrete (0.5% Casecrete NH-400, a water-soluble casein protein polymer (American Casein Company, Burlington, NJ)+ 0.5% sucrose + 0.25% PCPF 400)), and (iii) skim milk (0.75% powdered skim milk + 0.5% sucrose). The use of these formulations resulted in a 4,700, 38,500 and 100,000-fold increase in phage populations two days after application compared to the non-formulated phage populations. ¶ The PCF, Casecrete and skim milk formulations and the non-formulated phages all significantly reduced disease severity in field trials on tomato compared to the standard copper-mancozeb treatment by 22, 33, 27 and 19%, respectively. The PCF and the Casecrete formulations reduced the disease severity compared to the non-formulated phage by 11 and 21% in average in three field experiments, respectively. The skim milk formulation reduced the disease severity by 10% compared to the non-formulated phage application in one field experiment. ¶ The co-application of skim milk-formulated phages and copper-mancozeb treatment resulted in a superior disease control efficacy, which was significantly better than the control achieved by any of the treatments. The integration of phage application with Actigard treatment resulted in a significant increase in efficacy only with the PCF formulation but not with Casecrete formulation. The lowest phage titer that significantly reduced disease development in greenhouse experiment was 106 PFU/ml. [TOP OF PAGE]

  55. Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium. Biswas,B., Adhya,S., Washart,P., Paul,B., Trostel,A.N., Powell,B., Carlton,R., Merril,C.R. (2002). Infect. Immun. 70:204-210. Colonization of the gastrointestinal tract with vancomycin-resistant Enterococcus faecium (VRE) has become endemic in many hospitals and nursing homes in the United States. Such colonization predisposes the individual to VRE bacteremia and/or endocarditis, and immunocompromised patients are at particular risk for these conditions. The emergence of antibiotic-resistant bacterial strains requires the exploration of alternative antibacterial therapies, which led our group to study the ability of bacterial viruses (bacteriophages, or phages) to rescue mice with VRE bacteremia. The phage strain used in this study has lytic activity against a wide range of clinical isolates of VRE. One of these VRE strains was used to induce bacteremia in mice by intraperitoneal (i.p.) injection of 109 CFU. The resulting bacteremia was fatal within 48 h. A single i.p. injection of 3 x 108 PFU of the phage strain, administered 45 min after the bacterial challenge, was sufficient to rescue 100% of the animals. Even when treatment was delayed to the point where all animals were moribund, approximately 50% of them were rescued by a single injection of this phage preparation. The ability of this phage to rescue bacteremic mice was demonstrated to be due to the functional capabilities of the phage and not to a nonspecific immune effect. The rescue of bacteremic mice could be effected only by phage strains able to grow in vitro on the bacterial host used to infect the animals, and when such strains are heat inactivated they lose their ability to rescue the infected mice. [TOP OF PAGE]

  56. Killing of Mycobacterium avium and Mycobacterium tuberculosis by a mycobacteriophage delivered by a nonvirulent mycobacterium: A model for phage therapy of intracellular bacterial pathogens. Broxmeyer,L., Sosnowskai,D., Miltner,E., Chacón,O., Wagner,D., McGarvey,J., Barletta,R.G., Bermudez,L.E. (2002). J. Infect. Dis. 186:1155-1160. Mycobacterium avium causes disseminated infection in patients with acquired immune deficieny syndrome. Mycobacterium tuberculosis is a pathogen associated with the deaths of millions of people worldwide annually. Effective therapeutic regimens exist that are limited by the emergence of drug resistance and the inability of antibiotics to kill dormant organisms. The present study describes a system using Mycobacterium smegmatis, an avirulent mycobacterium, to deliver the lytic phage TM4 where both M. avium and M. tuberculosis reside within macrophages. These results showed that treatment of M. aviuminfected, as well as M. tuberculosis infected, RAW 264.7 macrophages, with M. smegmatis transiently infected with TM4, resulted in a significant time- and titer-dependent reduction in the number of viable intracellular bacilli. In addition, the M. smegmatis vacuole harboring TM4 fuses with the M. avium vacuole in macrophages. These results suggest a potentially novel concept to kill intracellular pathogenic bacteria and warrant future development. [TOP OF PAGE]

  57. Dynamics of success and failure in phage and antibiotic therapy in experimental infections. Bull,J.J., Levin,B.R., DeRouin,T., Walker,N., Bloch,C.A. (2002). BMC Microbiol 2:35 BACKGROUND: In 1982 Smith and Huggins showed that bacteriophages could be at least as effective as antibiotics in preventing mortality from experimental infections with a capsulated E. coli (K1) in mice. Phages that required the K1 capsule for infection were more effective than phages that did not require this capsule, but the efficacies of phages and antibiotics in preventing mortality both declined with time between infection and treatment, becoming virtually ineffective within 16 hours. RESULTS: We develop quantitative microbiological procedures that (1) explore the in vivo processes responsible for the efficacy of phage and antibiotic treatment protocols in experimental infections (the Resistance Competition Assay, or RCA), and (2) survey the therapeutic potential of phages in vitro (the Phage Replication Assay or PRA). We illustrate the application and utility of these methods in a repetition of Smith and Huggins' experiments, using the E. coli K1 mouse thigh infection model, and applying treatments of phages or streptomycin. CONCLUSIONS: 1) The Smith and Huggins phage and antibiotic therapy results are quantitatively and qualitatively robust. (2) Our RCA values reflect the microbiological efficacies of the different phages and of streptomycin in preventing mortality, and reflect the decline in their efficacy with a delay in treatment. These results show specifically that bacteria become refractory to treatment over the term of infection. (3) The K1-specific and non-specific phages had similar replication rates on bacteria grown in broth (based on the PRA), but the K1-specific phage had markedly greater replication rates in mouse serum. [TOP OF PAGE]

  58. Phage therapy of local and systemic disease caused by Vibrio vulnificus in iron-dextran-treated mice. Cerveny,K.E., Depaola,A., Duckworth,D.H., Gulig,P.A. (2002). Infect. Immun. 70:6251-6262. Vibrio vulnificus is a gram-negative bacterium that contaminates filter-feeding shellfish such as oysters. After ingestion of contaminated oysters, predisposed people may experience highly lethal septicemia. Contamination of wounds with the bacteria can result in devastating necrotizing fasciitis, which can progress to septicemia. The extremely rapid progression of these diseases can render antibiotic treatment ineffective, and death is a frequent outcome. In this study, we examined the potential use of bacteriophages as therapeutic agents against V. vulnificus in an iron-dextran-treated mouse model of V. vulnificus infection. Mice were injected subcutaneously with 10 times the lethal dose of V. vulnificus and injected intravenously, either simultaneously or at various times after infection, with phages. Treatment of mice with phages could prevent death; systemic disease, as measured by CFU per gram of liver and body temperature; and local disease, as measured by CFU per gram of lesion material and histopathologic analysis. Two different phages were effective against three different V. vulnificus strains with various degrees of virulence, while a third phage that required the presence of seawater to lyse bacteria in vitro was ineffective at treating mice. Optimum protection required that the phages be administered within 3 h of bacterial inoculation at doses as high as 108 PFU. One of the protective phages had a half-life in blood of over 2 h. These results demonstrate that bacteriophages have therapeutic potential for both localized and systemic infections caused by V. vulnificus in animals. This model should be useful in answering basic questions regarding phage therapy. [TOP OF PAGE]

  59. Est-ce que les bactériophages pourraient être une thérapie antimicrobienne efficace pour résoudre le problème de la résistance bactérienne aux antibiotiques ? Colbert,M., Guilmette,M. (2002). [TOP OF PAGE]

  60. Bacteriophages: potential treatment for bacterial infections. Duckworth,D.H., Gulig,P.A. (2002). BioDrugs 16:57-62. Bacteriophages (phages) are viruses of bacteria that can kill and lyse the bacteria they infect. After their discovery early in the 20th century, phages were widely used to treat various bacterial diseases in people and animals. After this enthusiastic beginning to phage therapy, problems with inappropriate use and uncontrolled studies and ultimately the development of antibacterials caused a cessation of phage therapy research in the West. However, a few institutions in Eastern Europe continued to study and use phages as therapeutic agents for human infections. The alarming rise in antibacterial resistance among bacteria has led to a review of the Eastern European studies and to the initiation of controlled experiments in animal models. These recent studies have confirmed that phages can be highly effective in treating many different types of bacterial infections. The lethality and specificity of phages for particular bacteria, the ability of phages to replicate within infected animal hosts, and the safety of phages make them efficacious antibacterial agents. Although there are still several hurdles to be overcome, it appears likely that phage therapy will regain a role in both medical and veterinary treatment of infectious diseases, especially in the scenario of emerging antibacterial resistance. [TOP OF PAGE]

  61. Combined antimicrobial effect of nisin and a listeriophage against Listeria monocytogenes in broth but not in buffer or on raw beef. Dykes,G.A., Moorhead,S.M. (2002). Int. J. Food Microbiol. 73:71-81. The effect of nisin and listeriophage LH7, alone and in combination, on the growth and survival of two strains of Listeria monocytogenes in broth and two model food systems, with appropriate controls, was determined. Growth curves for both bacterial strains in tryptic soy broth incubated at 7 or 30 degrees C, and with the addition of nisin and/or listeriophage at lag, mid-exponential or early stationary phase, were obtained by measuring absorbance at 550 nm. Numbers of mixed populations of both L. monocytogenes strains in phosphate buffered saline (pH 5.5) and on vacuum-packaged fresh beef, both stored for 4 weeks at 4 degrees C, and with the addition of nisin and/or listeriophage, were determined. This was achieved by plating appropriately diluted samples on both Tryptic Soy Agar and Modified Oxford Agar to determine both L. monocytogenes numbers and the presence of sub-lethal injury. In broth nisin alone, reduced levels or prevented growth of the two strains under the conditions studied, but regrowth to levels equivalent to those of untreated cells, occurred. Listeriophage LH7 alone, on the other hand, had no effect in broth under the conditions studied. Notably, however, a mixture of nisin and listeriophage displayed a combined effect in broth and reduced levels of cells substantially without regrowth under the conditions studied. In both model food systems only nisin appeared to be active, in a manner consistent with existing literature, and no combined action was apparent. The use of nisin and listeriophage has potential to control L. monocytogenes in foods but a further understanding of the interactions in this complex system needs to be achieved before it could be applied practically. [TOP OF PAGE]

  62. [The bacteriophages and their gene products as antimicrobial agents]. Garcia,E., Lopez,R. (2002). Rev. Espan. Quimioter. 15:306-312. The viruses that infect bacteria (bacteriophages or phages) were first isolated about 90 years ago. Phages have been fundamental tools in the development of molecular biology. Phages were early hypothesized as therapeutic agents for combatting pathogenic bacteria. However, the discovery and successful use of antibiotics to treat infectious diseases hindered this aim. the development of bacterial resistance to most available drugs has recently led researchers to test the possibilities of using phages as therapeutic agents. We review here recent achievements in this field, taking into consideration former bias in handling phages as well as previous achievements carried out in Eastern Europe where bacteriophages have been employed for decades as an alternative to antibiotics. [TOP OF PAGE]

  63. Control of Brochothrix thermosphacta spoilage of pork adipose tissue using bacteriophages. Greer,G.G., Dilts,B.D. (2002). J. Food Prot. 65:861-863. Adipose tissue discs were coinoculated with Brochothrix thermosphacta and homologous bacteriophages (phages) to determine the effects these had on phage multiplication, bacterial growth, and off-odor development during storage at 2 degrees C or under simulated retail display at 6 degrees C. In the presence of about 10(5) bacteria/cm2 and an equivalent number of phages, there was a 3-log increase in phage numbers and a 2-log decrease in bacterial numbers, and objectionable off-odors were suppressed during refrigerated storage. Up to 68% of the surviving bacterial population were resistant to phages. The storage life of adipose tissue could be increased from 4 days in controls to 8 days in phage-treated samples by preventing the development of off-odors associated with the growth of B. thermosphacta. Phages may provide a novel approach to extending the storage quality of chilled meats. [TOP OF PAGE]

  64. Novel phage-based treatment effective against mycobacterial infections. Greer,M. (2002). TB & Outbreaks Week October 22, 8. Researchers in the United States have developed a novel technique for fighting tuberculosis and other mycobacterial infections. ¶ While effective treatment options are already available for afflicted patients, standard antimicrobial agents are "limited by the emergence of drug resistance and the inability of antibiotics to kill dormant organisms," according to Lawrence Broxmeyer and colleagues at Med-America Research in Whitestone, New York and other institutions in California, Nebraska, and Texas. ¶ To overcome these problems, nonpathogenic mycobacteria could be used to deliver bacteriophage viruses to attack infected cells, Broxmeyer and coauthors argued. ¶ The researchers assessed the antimicrobial efficacy of Mycobacterium smegmatis organisms carrying the lytic TM4 phage virus, introducing these virus-laden microbes into tuberculosis-infected macrophage cultures. The amount of viable intracellular pathogens dropped significantly after phage treatment, according to the report. ¶ Similar results were seen in cultures of cells infected with M. avium, study data showed. This organism is responsible for life-threatening opportunistic infections in HIV/AIDS patients although it is generally harmless in people with normal immune function. ¶ TM4-induced reductions in bacilli levels were both time- and dose-dependent (Killing of Mycobacterium avium and Mycobacterium tuberculosis by a mycobacteriophage delivered by a nonvirulent mycobacterium: a model for phage therapy of intracellular bacterial pathogens. Journal of Infectious Diseases, October 15, 2002;186(8):1155-1160). [TOP OF PAGE]

  65. Prevention of Escherichia coli infection in broiler chickens with a bacteriophage aerosol spray. Huff,W.E., Huff,G.R., Rath,N.C., Balog,J.M., Donoghue,A.M. (2002). Poult Sci 81:1486-1491. Bacteriophage to an Escherichia coli isolate that is pathogenic in poultry were isolated from municipal sewer treatment facilities or poultry processing plants. Three studies were conducted to determine the efficacy of aerosol administration of bacteriophage to prevent an E. coli respiratory infection in broiler chickens. In all three studies the experimental design consisted of nine treatments with three replicate pens of 10 birds. Three treatments were not challenged with E. coli and consisted of unsprayed birds, birds sprayed with a diluent control, and birds sprayed with a combination of two bacteriophages. Six treatments were challenged with E. coli by injecting 104 cfu into the thoracic air sac when birds were 7, 8, or 10 d of age after being sprayed at 7 d of age with either a diluent control or a combination of two bacteriophages. In Studies 1 and 2, BW at 2 wk of age of all the birds challenged with E. coli, regardless of spray treatment, were decreased significantly from the unchallenged controls, except in Study 2 for the birds sprayed with bacteriophage and challenged at 10 d of age. There was a significant decrease in mortality in Studies 1 and 2 when the birds were challenged with E. coli immediately after bacteriophage administration and in Study 2 in birds challenged at 10 d of age. In Study 3 a suspected pre-existing E. coli infection resulted in mortality in the unchallenged, unsprayed controls, and in the diluent sprayed controls of 20 and 27%, respectively. The mortality in the unchallenged bacteriophage sprayed birds was 3%, representing a significant decrease. Mortality in Study 3 was significantly decreased in the bacteriophage-sprayed birds challenged with E. coli immediately or 1 d later but not 3 d after bacteriophage administration. The decrease in BW at 2 wk of age in challenged birds indicates that bacteriophage treatment did not provide complete protection; however, in all three studies mortality was significantly decreased, indicating that aerosol spray of bacteriophage may be practical for administration of bacteriophage and may provide an alternative to the use of antibiotics in poultry production. [TOP OF PAGE]

  66. Prevention of Escherichia coli respiratory infection in broiler chickens with bacteriophage (SPR02). Huff,W.E., Huff,G.R., Rath,N.C., Balog,J.M., Xie,H., Moore,P.A.J., Donoghue,A.M. (2002). Poult Sci 81:437-441. Bacteriophages are viruses that can infect and kill bacteria. Three studies were conducted to determine the efficacy of bacteriophage to prevent an Escherichia coli respiratory infection in broiler chickens. In the first study 3-d-old-birds were challenged with an air sac inoculation of 103 cfu of E. coli per mL mixed with either 103 or 106 pfu of bacteriophage, or 104 cfu E. coli mixed with 104 or 108 pfu of bacteriophage. In the second study, drinking water of birds to 1 wk of age was treated with 103 or 104 pfu of bacteriophage per mL and birds were air sac challenged with 103 cfu of E. coli, or water was treated with 104 or 106 pfu of bacteriophage per milliliter and birds were challenged with 104 cfu of E. coli. In the third study, birds were air sac challenged at 1 wk of age with 104 cfu of E. coli and given 105 or 106 pfu of bacteriophage per mL of water from 1 d of age to 2 wk of age. In Studies 1 and 2, there were two replicate pens per treatment with 10 birds per pen, and in Study 3, there were four replicate pens per treatment with 10 birds per pen. The studies were all concluded when the birds were 3 wk of age. In Study 1, BW was decreased at 1 and 2 wk of age in the birds that were challenged with 103 or 104 cfu of E. coli and was decreased at 2 wk of age in the birds challenged with 104 cfu of E. coli mixed with 104 pfu of the bacteriophage. Mortality was decreased from 80% in the birds challenged with 103 cfu of E. coli to 25 and 5% when mixed with 103 or 106 pfu of the bacteriophage, respectively. Mortality was decreased from 85% in birds challenged with 104 cfu of E. coli to 35% when mixed with 104 pfu of the bacteriophage, and no mortality occurred when mixed with 106 pfu of bacteriophage. There was essentially no protection observed in Studies 2 and 3 when the birds were challenged with 103 or 104 cfu of E. coli with bacteriophage present in their drinking water at any level. These data suggest that bacteriophage can protect birds from a respiratory challenge with E. coli, but that adding the bacteriophage to the drinking water offered no protection to the birds. The complete protection of the birds observed in Study 1 suggests that bacteriophage may possibly be developed as an alternative to antibiotic use in poultry. [TOP OF PAGE]

  67. Viral Trojan horse for combating tuberculosis. Johnston,N. (2002). Drug Discov Today 7:333-335. The emergence of pathogenic bacteria resistant to one or more antibiotics has outpaced the development of new drugs. Using bacteriophage, Raul Barletta (Dept of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, NE, USA) and colleagues at the California Pacific Medical Center (San Francisco, CA, USA) have devised a promising new approach to killing the intracellular pathogens Mycobacterium avium, which commonly afflicts AIDS patients, and Mycobacterium tuberculosis, the causative agent of tuberculosis. Their findings were presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy hosted by the American Society for Microbiology in Chicago, IL, USA [1]. [TOP OF PAGE]

  68. [Effect of bacteriophage on the lipid peroxidation process and antioxidant protective enzymes in experimental uveitis]. Karimova,M.K., Bakhritdinova,F.A. (2002). Vestnik oftalmologii 118:38-40. Experimental uveitis features distinct hyperlipoperoxidation in damaged eye tissues, blood serum and the liver. The activity of antioxidant defense (AOD) enzymes decreases in tissues and blood of experimental animals whereas catalase compensatorily activates in hepatic tissue. Experimental therapy of uveitis with gentamycin and bacteriophage results in reducing hyperlipoperoxidation, increased activity of AOD enzymes but no complete normalization is observed. This manifested in preservation of inflammations to a certain degree. [TOP OF PAGE]

  69. Overcoming the phage replication threshold: a mathematical model with implications for phage therapy. Kasman,L.M., Kasman,A., Westwater,C., Dolan,J., Schmidt,M.G., Norris,J.S. (2002). J. Virol. 76:5557-5564. Prior observations of phage-host systems in vitro have led to the conclusion that susceptible host cell populations must reach a critical density before phage replication can occur. Such a replication threshold density would have broad implications for the therapeutic use of phage. In this report, we demonstrate experimentally that no such replication threshold exists and explain the previous data used to support the existence of the threshold in terms of a classical model of the kinetics of colloidal particle interactions in solution. This result leads us to conclude that the frequently used measure of multiplicity of infection (MOI), computed as the ratio of the number of phage to the number of cells, is generally inappropriate for situations in which cell concentrations are less than 10(7)/ml. In its place, we propose an alternative measure, MOI(actual), that takes into account the cell concentration and adsorption time. Properties of this function are elucidated that explain the demonstrated usefulness of MOI at high cell densities, as well as some unexpected consequences at low concentrations. In addition, the concept of MOI(actual) allows us to write simple formulas for computing practical quantities, such as the number of phage sufficient to infect 99.99% of host cells at arbitrary concentrations. [TOP OF PAGE]

  70. Deleterious impact of a virulent bacteriophage on survival and biocontrol activity of Pseudomonas fluorescens strain CHAO in natural soil. Keel,C., Ucurum,Z., Michaux,P., Adrian,M., Haas,D. (2002). Mol. Plant-Microbe Interact. 15:567-576. Many biotic and abiotic factors affect the persistence and activity of beneficial pseudomonads introduced into soil to suppress plant diseases. One such factor may be the presence of virulent bacteriophages that decimate the population of the introduced bacteria, thereby reducing their beneficial effect. We have isolated a lytic bacteriophage (phi)GP100) that specifically infects the biocontrol bacterium Pseudomonas fluorescens CHA0 and some closely related Pseudomonas strains. phiGP100 was found to be a double-stranded-DNA phage with an icosahedral head, a stubby tail, and a genome size of approximately 50 kb. Replication of phiGP100 was negatively affected at temperatures higher than 25 degrees C. phiGP100 had a negative impact on the population size and the biocontrol activity of P. fluorescens strain CHA0-Rif (a rifampicin-resistant variant of CHA0) in natural soil microcosms. In the presence of phiGP100, the population size of strain CHA0-Rif in soil and on cucumber roots was reduced more than 100-fold. As a consequence, the bacterium's capacity to protect cucumber against a root disease caused by the pathogenic oomycete Pythium ultimum was entirely abolished. In contrast, the phage affected neither root colonization and nor the disease suppressive effect of a phiDGP100-resistant variant of strain CHA0-Rif. To our knowledge, this study is the first to illustrate the potential of phages to impair biocontrol performance of beneficial bacteria released into the natural soil environment. [TOP OF PAGE]

  71. Phagotherapy: myths and realities. Krylov,V. (2002). Rus. Acad. Sci. Pres. 4:40-46. The current situation of uncontrolled uses of medicinal preparations, pollution of nature with toxic wastes and other adverse phenomena of this kind have produced what experts call another spiral in the eovlution of bacteria—the development of their multiple-resistant strains. As often as not, many expensive antibiotics of the last generation (vancomycin, imipenem, etc.) turn out to be powerless. And the way medical experts see it—the way out of this situation—consists in pioneering some alternative therapies. The most promising of these is believed to be phagotherapy—the use of specific bacterial viruses (bacteriophages or phages). [TOP OF PAGE]

  72. Recombinant phages. Mardh,S. (2002). 603153(6,497,874). The present invention relates to bacteriophages for use in the treatment or prophylaxis of bacterial infections, especially mucosal bacterial infections such as Heliobacter pylori infections, in particular, it relates to modified filamentous bacteriophages, e.g. M13 phages, for such use, which bacteriophages present at the surface a recombinant protein comprising (i) a first component derived from a bacteriophage surface protein; and (ii) a second component comprising variable region sequences of an antibody to provide a bacterial antigen binding site, said second component rendering said bacteriophage capable of binding to and thereby inhibiting growth of bacterial cells involved in the etiology of said infection. [TOP OF PAGE]

  73. A novel sustained-release matrix based on biodegradable poly(ester amide)s and impregnated with bacteriophages and an antibiotic shows promise in management of infected venous stasis ulcers and other poorly healing wounds. Markoishvili,K., Tsitlanadze,G., Katsarava,R., Morris,J.G., Jr., Sulakvelidze,A. (2002). Int. J. Dermatol. 41:453-458. Healing of poorly vascularized and venous stasis ulcers is often refractory to therapy, particularly when they are infected. Systemic antibiotic therapy may be of little benefit in this setting because of poor penetration of the antibiotic into the wound and the frequent associated emergence of bacterial strains resistant to common antimicrobial agents. Given the clinical significance of these problems, there is a need to explore alternative management approaches for these difficult-to-treat wounds. PhagoBioDerm is a novel wound-healing preparation consisting of a biodegradable polymer impregnated with an antibiotic and lytic bacteriophages, which was recently licensed for sale in the Republic of Georgia (one of the former Soviet Union republics). In 1999-2000, in Tbilisi, Georgia, 107 patients who had ulcers that had failed to respond to conventional therapy were treated with PhagoBioDerm alone or in combination with other interventions. The wounds/ulcers healed completely in 67 (70%) of 96 patients for whom follow-up data were available. In 22 cases in which microbiologic data were available, healing was associated with the concomitant elimination of, or a reduction in, specific pathogenic bacteria in the ulcers. Our findings suggest that this slow-release biopolymer is safe and of possible benefit in the management of refractory wounds, and they support the apparent utility of bacteriophages in this setting. Further studies, including carefully designed clinical trials, will be required to rigorously evaluate the efficacy of this novel wound dressing preparation. [TOP OF PAGE]

  74. Application of actinomycetes to soil to ameliorate water repellency. McKenna,F., El Tarabily,K.A., Petrie,S., Chen,C., Dell,B. (2002). Lett. Appl. Microbiol. 35:107-112. AIMS: The aim of this study was to develop a novel isolation technique using a mixture of Bacillus and Streptomyces phages to selectively isolate wax-utilizing non-streptomycete actinomycetes effective in ameliorating water repellency in a problem soil. METHODS AND RESULTS: Phages added to a soil suspension reduced the dominance of Bacillus and Streptomyces isolates and significantly increased the number of non-streptomycete actinomycetes on isolation plates. Promising isolates, grown on a medium containing beeswax as sole carbon source, were selected for application to water repellent soil. Their addition significantly reduced water repellency. CONCLUSIONS: Phage application significantly increased the isolation of non-streptomycete actinomycetes. Wax-utilizing isolates were found to significantly reduce water repellency in a problem soil. SIGNIFICANCE AND IMPACT OF THE STUDY: The phage technique can be used for the routine isolation of non-streptomycete actinomycetes. Beeswax medium can be used to selectively isolate wax-utilizing micro-organisms with the potential to ameliorate water repellency in soil. [TOP OF PAGE]

  75. The genome of bacteriophage phiKZ of Pseudomonas aeruginosa. Mesyanzhinov,V.V., Robben,J., Grymonprez,B., Kostyuchenko,V.A., Bourkaltseva,M.V., Sykilinda,N.N., Krylov,V.N., Volckaert,G. (2002). J. Mol. Biol. 317:1-19. Bacteriophage phiKZ is a giant virus that efficiently infects Pseudomonas aeruginosa strains pathogenic to human and, therefore, it is attractive for phage therapy. We present here the complete phiKZ genome sequence and a preliminary analysis of its genome structure. The 280,334 bp genome is a linear, circularly permutated and terminally redundant, A+T-rich double-stranded DNA molecule. The phiKZ DNA has no detectable sequence homology to other viruses and microorganisms, and it does not contain NotI, PstI, SacI, SmaI, XhoI, and XmaIII endonuclease restriction sites. The genome has 306 open reading frames (ORFs) varying in size from 50 to 2237 amino acid residues. According to the orientation of transcription, ORFs are apparently organized into clusters and most have a clockwise direction. The phiKZ genome also encodes six tRNAs specific for Met (AUG), Asn (AAC), Asp (GAC), Leu (TTA), Thr (ACA), and Pro (CCA). A putative promoter sequence containing a TATATTAC block was identified. Most potential stem-loop transcription terminators contain the tetranucleotide UUCG loops. Some genes may be assigned as phage-encoded RNA polymerase subunits. Only 59 phiKZ gene products exhibit similarity to proteins of known function from a diversity of organisms. Most of these conserved gene products, such as dihydrofolate reductase, ribonucleoside diphosphate reductase, thymidylate synthase, thymidylate kinase, and deoxycytidine triphosphate deaminase are involved in nucleotide metabolism. However, no virus-encoded DNA polymerase, DNA replication-associated proteins, or single-stranded DNA-binding protein were found based on amino acid homology, and they may therefore be strongly divergent from known homologous proteins. Fifteen phiKZ gene products show homology to proteins of pathogenic organisms, including Mycobacterium tuberculosis, Haemophilus influenzae, Listeria sp., Rickettsia prowazakeri, and Vibrio cholerae that must be considered before using this phage as a therapeutic agent. The phiKZ coat contains at least 40 polypeptides, and several proteins are cleaved during virus assembly in a way similar to phage T4. Eleven phiKZ-encoded polypeptides are related to proteins of other bacteriphages that infect a variety of hosts. Among these are four gene products that contain a putative intron-encoded endonuclease harboring the H-N-H motif common to many double-stranded DNA phages. These observations provide evidence that phages infecting diverse hosts have had access to a common genetic pool. However, limited homology on the DNA and protein levels indicates that bacteriophage phiKZ represents an evolutionary distinctive branch of the Myoviridae family. [TOP OF PAGE]

  76. Bacteriophage therapy of infectious disease in aquaculture. Nakai,T., Park,S.C. (2002). Res. Microbiol. 153:13-18. Bacteriophages may be candidates as therapeutic agents in bacterial infections. Here we describe the protective effects of phages against experimentally induced bacterial infections of cultured fish and discuss the potential for phage therapy in aquaculture. [TOP OF PAGE]

  77. From Russia with gloves Ex-Soviet Union viruses could fill antibiotic gap. Pearson,H. (2002). Nature . Russian remedies could take out hardy US bacteria. Long-abandoned by Western medicine, viruses that naturally kill microbes are being imported as a potential substitute for antibiotics. ¶ The emergence of multi-drug-resistant bacteria is intensifying the search for antibiotic replacements. Bemoaning the problem, clinician Glenn Morris of the University of Maryland in College Park got an idea from a colleague from the former Soviet republic of Georgia. Morris explains: "He said, 'why don't you use 'phage therapy?'; I said, 'what's 'phage therapy?'." ¶ 'Phages - more properly, bacteriophages - are viruses that are harmless to humans but kill bacteria. They were widely researched as a means to tackle disease until the 1940s. When potent antibiotics appeared on the scene, the West discarded them. ¶ Eastern Europe and the former Soviet Union pursued 'phage therapy, so 'phage creams, pills and plasters are commonly available there. Now Morris and his colleagues are carrying out basic tests to update the treatments for US product licenses. ¶ Worktops contaminated with the foodborne bacteria Listeria are clean within 24 hours of 'phage treatment, he told the Experimental Biology 2002 meeting in New Orleans on Sunday. Salmonella and Escherichia coli are similarly wiped out. 'Phages could be used in food production or packaging, Morris suggests. ¶ Unlike antibiotics, 'phages kill only a specific bacterial type, leaving other, beneficial bugs intact. For example, antibiotic resistant strains of the gut bacteria Enterococcus, which can cause dangerous infections after surgery or in chemotherapy patients, are also being tackled. ¶ We are naturally surrounded by 'phages. The type that Morris is using attack and multiply inside bacteria then split them apart to escape. The 'phages keep killing until their victims run out, and then quietly die. ¶ Cold science ¶ Part of the reason that the West dropped 'phages was that bacteria might evade them, says Richard Young, who studies pathogenic microbes at the Whitehead Institute in Cambridge, Massachusetts. A single change in the bacterial receptor to which they bind could render it resistant to the virus: "It was viewed as its Achilles heel," he says. ¶ A mixture of 30-40 different 'phages all aimed at the same bug should get around this problem. "A cocktail is important," agrees Heidi Kaplan, who studies antibiotic-resistant bacteria at the University of Texas Medical School in Houston. ¶ "US science tends to have a prejudice against Soviet science," adds Morris, who now collaborates with the Eliava Institute of Bacteriophage, Microbiology and Virology in Tbilisi, Georgia. But Morris is not alone in trying to bring down the scientific cold wall - two small biotech companies besides his are also on the case. [TOP OF PAGE]

  78. Les bactériophages, nouvelle perspective dans le traitement des maladies infectieuses? Resch,G., Meyer,J. (2002). Rev. Mens. Suisse Odontostomatol. 112:643-645. De nombreuses bactéries ont été identifiées, et cela depuis des décennies, comme étant des agents responsables de nombreuses maladies infectieuses de l'homme. Ainsi, il a été mis en évidence que certaines bactéries buccales jouent un rôle primordial dans l'étiologie de la carie et des pathologies du parodontium. Ces bactéries peuvent être, à leur tour, infectées par des virus appelés bactériophages. Ces bactériophages, qui sont des parasites obligatoires, sont capables d'altérer profondément les caractéristiques de leur hôte. Nous verrons, dans la suite, quelques aspects de la biologie de ces virus et de leur importance. [TOP OF PAGE]

  79. Bacteriophage therapy. Stalin's forgotten cure. Stone,R. (2002). Science 298:728-731. Bacteriophage therapy, pioneered in Stalin-era Russia, is attracting renewed attention in the West as a potential weapon against drug-resistant bugs and hard-to-treat infections. [first paragraph] TBILISI-Last December, three woodsmen in the mountains of Georgia stumbled upon a pair of canisters that were, oddly, hot to the touch. The men lugged the objects back to their campsite to warm themselves on a bitterly cold night. That turned out to be a terrible mistake: The canisters, Soviet relics once used to power remote generators, were intensely radioactive and burned two of the men severely. The victims were rushed to the capital, Tbilisi, where doctors plied them with antibiotics but failed to prevent staphylococcus bacteria from invading the deep wounds. Septic shock seemed just around the corner. Then a kinder legacy of the Soviet Union came to the rescue. [TOP OF PAGE]

  80. Bacteriophage therapy. Food and agriculture: testing grounds for phage therapy. Stone,R. (2002). Science 298:730 [first paragraph] Last month, the U.S. Food and Drug Administration tightened another screw in its effort to curb the spread of antibiotic resistance from the burgeoning use of agricultural drugs. The agency aired draft regulations requiring manufacturers to test potential livestock pharmaceuticals for their ability to help pathogens acquire resistance to human drugs. But farmers are concerned that they could be left with fewer weapons to combat Listeria and other foodborne pathogens that cause several hundred deaths each year in the United States alone."When farmers are told they can't use any antibiotics used in humans, they say, 'What do we use?'" says Toney Ilenchuk. His firm, Biophage Pharma in Montreal, Canada, believes it has part of the answer: bacteriophages against Salmonella and pathogenic strains of Escherichia coli. [TOP OF PAGE]

  81. New ways to treat bacterial infections. Taylor,P.W., Stapleton,P.D., Paul L.J. (2002). Drug Discov Today 7:1086-1091. There is an urgent need for fresh approaches to the treatment of bacterial infections because of the changing patterns of infectious disease and the emergence of bacterial strains resistant to current antibiotics. Modification of the cell phenotype to sensitize bacteria to components of the hosts' immune system or to previously ineffective antibiotics could prevent the emergence of the resistant genotype. In addition, the use of light-activated antibacterial agents and lytic bacteriophage specific for key pathogens should be considered as safe and inexpensive alternatives to conventional treatment regimens for certain non-systemic infections. [TOP OF PAGE]

  82. Viruses stop antibiotic-resistant bacteria. Travis,J. (2002). Science News 161(2), ??? Nearly a century ago, biologists discovered viruses that prey upon bacteria. When penicillin and other antibiotics emerged a few decades later, however, physicians largely abandoned their efforts to use these bacteriophages, or phages, to thwart infectious diseases. ¶ As more bacteria develop resistance to antibiotics, there's renewed interest in phages (SN: 6/3/00, p. 358). Scientists now report that these viruses can prevent mice from dying after being infected with an antibiotic-resistant bacterium. [TOP OF PAGE]

  83. Use of bacteriophages for control of Escherichia coli O157. Waddell,T.E., Mazzocco,A., Pacan,J., Ahmed,R., Johnson,R., Poppe,C., Khakhria,R. (2002). 873949(6,485,902). A method of reducing levels of E. coli O157 strains within the gastrointestinal tract of a ruminant animal using specific bacteriophage(s) is herein described. Also described is a pharmaceutical composition comprising at least one of said bacteriophages and a method for isolating or selecting bacteriophages useful in reducing E. coli O157 levels as described above. [TOP OF PAGE]

  84. Effect of phage therapy on the turnover and function of peripheral neutrophils. Weber-Dabrowska,B., Zimecki,M., Mulczyk,M., Gorski,A. (2002). FEMS Immunol. Med. Microbiol. 34:135-138. The aim of this investigation was to establish the impact of phage therapy on the turnover and function of circulating neutrophils in 37 patients with suppurative bacterial infections. We determined the levels of circulating neutrophils and their precursors before therapy, after 3 weeks of therapy, and at a distant time interval (3 months) following the beginning of therapy. In addition, we measured the ability of neutrophils to phagocytize Staphylococcus aureus in vitro. Eight healthy blood donors served as a control group. The results showed that, among the studied parameters, the significant changes involved neutrophil precursor count and the ability of neutrophils to phagocytize bacteria. The percentage of neutrophils in patients before therapy was lower than in healthy donors (mean 58.0, versus 61.4). This value dropped further in patients after 3 months of following the therapy (mean 55.6). The content of neutrophil precursors, on the other hand, was lower in healthy donors than in patients before therapy (mean 2.5, versus 3.8). After 3 weeks of the therapy and after 3 months, the levels of neutrophil precursors were significantly higher (mean 4.8 and 4.9, respectively) than in control donors. The phagocytic index was lower in patients before therapy than in control donors (mean 66.3, versus 70.1) and decreased further after 3 weeks of therapy (mean 59.0) and after 3 months (mean 59.6). The results of this investigation indicate that successful phage therapy accelerates the turnover of neutrophils, accompanied by a decrease in their ability to phagocytize bacteria. [TOP OF PAGE]

  85. The use of bacteriophages for treatment and prevention of bacterial disease in animals and animal models of human infection. Barrow,P.A. (2001). J. Chem. Technol. Biotechnol. 76:677-682. A brief history of the use of lytic bacteriophages in bacterial disease therapy is presented. After early disillusionment with the idea following poor experimental work, control of phages and field trials, studies were set up in the 1980's in the UK to study their use in farm animal infections. Work with E. coli septicaemia and diarrhoea has shown that phages can be highly effective prophylactically and therapeutically and more effective than antibiotics. There is considerable potential for their use in a limited number of infection types in both man and animals. [TOP OF PAGE]

  86. Phage treatment: can we utilise it for certain infective diseases in India? Bhatia,R.S. (2001). Journal of the Association of Physicians of India 49:590 [TOP OF PAGE]

  87. Phages and their application against drug-resistant bacteria. Chanishvili,N., Chanishvili,T., Tediashvili,M., Barrow,P.A. (2001). J. Chem. Technol. Biotechnol. 76:689-699. At the beginning of the 20th century the phenomenon of spontaneous bacterial lysis was discovered independently by Twort and d'Herelle. Despite the suggestion at that time by d'Herelle that these agents might be applied to the control of bacterial diseases in the west this idea was explored in a desultory fashion only and was eventually discarded largely due to the advent of extensive antibiotic usage. However, interest was maintained in countries of the former Soviet Union where bacteriophage therapy has been applied extensively since that time. Central to this work was the Eliava Institute of Bacteriophage, Microbiology and Virology in Tbilisi, Georgia, which was founded in 1923 through the joint efforts of d'Herelle and the Georgian George Eliava. Ironically, given his contributions to public health in the Soviet Union, Eliava was branded as an enemy of the people in 1937 and executed. d'Herelle never again returned to Georgia. In spite of these tragic events this institute remained the focus for phage therapy in the world and despite being continuously active in this field for 75 years, now struggles for its financial life. In the Eliava Institute, phages were sought for bacterial pathogens implicated in disease outbreaks in different parts of the Soviet Union and were dispatched for use in hospitals throughout the country. Although infections caused by a wide variety of bacterial pathogens have been treated, much of this has been published in Russian and is not readily available in the west. Work has also been carried out in Poland over many years and this has only recently been published in English. By contrast, interest in the west has been limited to a small number of enthusiasts and academics and until very recently little interest has been shown. The main reason that the medical and scientific communities are now beginning to take notice, is the continuing world-wide rise in the incidence of multiply-antibiotic-resistant bacterial pathogens and the absence of effective means for their control. Recent publicity over the work of the Eliava Institute has concentrated the minds of the western world on the potential for infectious disease control that bacteriophage offer, a procedure that is biologically more acceptable than antibiotic use and which has been in use for several decades already. [TOP OF PAGE]

  88. Use of bacteriophage for elimination of Vibrio vulnificus from oysters. Depaola,A., Gulig,P.A., Smith,J.G., et al. (2001). 570 [p67]. Orlando, FL, American Society for Microbology 101st General Meeting. 5-24-0001.[TOP OF PAGE]

  89. Progeny of the phage school. Dixon,B. (2001). ASM News 69:432-433. Frederick Twort, the eccentric polymath who discovered bacterial viruses, would have robustly welcomed the applications of bacteriophages now emergy, from therapeutics to environmental protection. [TOP OF PAGE]

  90. H-mutant bacteriophages as a potential biocontrol of bacterial blight of geranium. Flaherty,J.E., Harbaugh,B.K., Jones,J.B., Somodi,G.C., Jackson,L.E. (2001). Hortscience 36:98-100. Bacteriophages specific to Xanthomonas campestris pv. pelargonii (Xcp), the causal agent of bacterial blight of geranium, Pelargonium Xhortorum L.H. Bailey, were isolated from soil and sludge samples from Florida, California, Minnesota, and Utah. Sixteen phages were evaluated for their potential to lyse 21 Xcp strains collected from around the world. The Xcp strains varied in their susceptibility to the phage isolates with 4 to 14 phages producing a lytic or highly virulent reaction. A mixture of five h-mutants was developed from phages that exhibited