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 the broadest host-ranges and tested against the same Xcp strains. The h-mutant phage mixture lysed all 21 Xcp strains. Three experiments were designed to determine the efficacy of using a mixture of four h-mutant phages to control the spread of the bacterial blight pathogen on potted and seedling geraniums under greenhouse conditions. Plants surrounding diseased inoculated plants were treated with a phage mixture at 5 X 108 pfu/mL daily, biweekly, or triweekly, or treated with Phyton-27(R), at 2.0 mLcntdotL-1 every 10 or 14 days. In potted geraniums, daily foliar sprays of the phage mixture had reduced disease incidence and severity by 50% and 75%, respectively, relative to control plants after 6 weeks. In two plug experiments, the phage mixture applied daily also had reduced disease incidence and severity by 69% and 86%, and 85% and 92%, respectively, when compared with controls after 5 weeks. In all three experiments, disease incidence and severity were less for plants treated daily with phages than for those treated less frequently with phages or with Phyton-27(R). Chemical name used: copper sulfate pentahydrate (Phyton-27(R)). [TOP OF PAGE]

  91. Bacteriophage therapy for bacterial infections: Rekindling a memory from the pre-antibiotics era. Ho,K. (2001). Per. BiologyMed. 44:1-16. [LAST PARAGRAPH] Bacteriophage therapy for bacterial infections has thus evolved from a promising, yet flawed treatment in the pre-antibiotics era into a potentially powerful solution for a worldwide problem of bacteria with far more evasive abilities. Its colorful history is highlighted by a variety of contrasts: between unbridled enthusiasm and sobering realism; between artful application and rigorous experimental clarification; between an affinity for natural cure and for one decidedly more laboratory-derived. Although the future of bacteriophage therapy rests within speculative terrain, a revisitation of its roots-with close attention to the tensions and ambiguities-may offer those presently as enamored by its tantalizing allure as their counterparts 70 years ago instructive insights into recapturing and redefining its potential. [TOP OF PAGE]

  92. [Phagotherapy in terms of bacteriophage genetics: hopes, perspectives, safety, limitations]. Krylov,V.N. (2001). Genetika 37:869-887. The appearance and spreading of multidrug-resistant bacterial pathogens is a consequence of the large-scale use of antibiotics in medicine. In view of this, claims for the phage therapy were renewed: in recent studies, the natural phages and their products neutralizing various proteins, as well as the bacterial products often controlled by defective prophages (bacteriocins) were applied for treatment of bacterial infections. Constructs obtained by gene engineering are increasingly used to change some bacteriophage: properties to expand the spectrum of their lytic activity and to eliminate therapeutic drawbacks of some natural phages. In this review, the problem of phage therapy is discussed in general with respect to bacteriophage properties, their genetics, structure, evolution, taking into account long-term experience of the author in the field of bacteriophage genetics. Note that the general concept of phage therapy should be developed to ensure long-term, efficient and harmless phage therapy. [TOP OF PAGE]

  93. Phage therapy in terms of bacteriophage genetics: Hopes, prospects, safety, limitations. Krylov,V.N. (2001). Rus. J. Genet. 37:715-730. The appearance and spreading of multidrug-resistant bacterial pathogens is a consequence of the large-scale use of antibiotics in medicine. In view of this, claims for the phage therapy were renewed: in recent studies, the natural phages and their products neutralizing various proteins, as well as the bacterial products often controlled by defective prophages (bacteriocins) were applied for treatment of bacterial infections. Constructs obtained by gene engineering are increasingly used to change bacteriophage properties to expand the spectrum of their lytic activity and to eliminate therapeutic drawbacks of some natural phages. In this review, the problem of phage therapy is discussed in general with respect to bacteriophage properties, their genetics, structure, evolution, taking into account long-term experience of the author in the field of bacteriophage genetics. Note that the general concept of phage therapy should be developed to ensure long-term, efficient and harm-less phage therapy. [TOP OF PAGE]

  94. Use of bacteriophage therapy in surgical practice. Lakhno,V.M., Bordunovskii,V.N. (2001). Vestnik Khirurgii Imeni I. I. Grekova 160:122-125. [TOP OF PAGE]

  95. Efficacy of bacteriophage use in complex treatment of the patients with burn wounds. Lazareva,E.B., Smirnov,S.V., Khvatov,V.B., Spiridonova,T.G., Bitkova,E.E., Darbeeva,O.S., Mayskaya,L.M., Parphenyuk,R.L., Menshikov,D.D. (2001). Antibiot. Khimoter. 46:10-14. Results of clinical and laboratory evaluation of the treatment with pyobacteriophage in tablets of the patients with burn wounds are presented. It was shown that phagotherapy provided more rapid cure of pyoseptic complications, temperature normalization, wounds purification and lower lethality Bacteriological analysis of wound secretions revealed that after the treatment staphylococci and streptococci were cultured 2 times rarely, Proteus spp. Were isolated 1.5 times rarely, E. coli was not isolated. The amount of positive haemocultures also diminished. Investigation of immunologic status demonstrated statistically significant normalization of immunity on cell level. Phagocytosis level didn't change while in control group (without bacteriophage use) it became lower. Antibody level enhanced but less extensively than in control group. The results of trial demonstrates positive effect of phagotherapy use at the patients with burns. [TOP OF PAGE]

  96. The effect of bacteriophage treatment to reduce the rapid dissemination of Salmonella typhimurium in pigs. Lee,N., Harris,D.L. (2001). Proceedings of the American Association of Swine Veterinarians 32:555-557. Bacteriophage treatment significantly reduced the rapid dissemination of Salmonella typhimurium in tonsil and cecum, where the highest number of Salmonella was recovered in pigs experimentally infected with S. typhimurium. The rapid dissemination of Salmonella in market weight pigs prior to slaughter may pose a potential risk in contaminating pork products. Phage treatment should be considered as an intervention strategy to reduce the number of Salmonella in pigs. [TOP OF PAGE]

  97. Examination of bacteriophage as a biocontrol method for Salmonella on fresh-cut fruit: a model study. Leverentz,B., Conway,W.S., Alavidze,Z., Janisiewicz,W.J., Fuchs,Y., Camp,M.J., Chighladze,E., Sulakvelidze,A. (2001). J. Food Prot. 64:1116-1121. The preparation and distribution of fresh-cut produce is a rapidly developing industry that provides the consumer with convenient and nutritious food. However, fresh-cut fruits and vegetables may represent an increased food safety concern because of the absence or damage of peel and rind, which normally help reduce colonization of uncut produce with pathogenic bacteria. In this study, we found that Salmonella enteritidis populations can (i) survive on fresh-cut melons and apples stored at 5 degrees C, (ii) increase up to 2 log units on fresh-cut fruits stored at 10 degrees C, and (iii) increase up to 5 log units at 20 degrees C during a storage period of 168 h. In addition, we examined the effect of lytic, Salmonella-specific phages on reducing Salmonella numbers in experimentally contaminated fresh-cut melons and apples stored at various temperatures. We found that the phage mixture reduced Salmonella populations by approximately 3.5 logs on honeydew melon slices stored at 5 and 10 degrees C and by approximately 2.5 logs on slices stored at 20 degrees C, which is greater than the maximal amount achieved using chemical sanitizers. However, the phages did not significantly reduce Salmonella populations on the apple slices at any of the three temperatures. The titer of the phage preparation remained relatively stable on melon slices, whereas on apple slices the titer decreased to nondetectable levels in 48 h at all temperatures tested. Inactivation of phages, possibly by the acidic pH of apple slices (pH 4.2 versus pH 5.8 for melon slices), may have contributed to their inability to reduce Salmonella contamination in the apple slices. Higher phage concentrations and/or the use of low-pH-tolerant phage mutants may be required to increase the efficacy of the phage treatment in reducing Salmonella contamination of fresh-cut produce with a low pH. [TOP OF PAGE]

  98. Turning the phage on produce pathogens. McBride,J. (2001). Agricultural Research 2001(July), 12. Even bacteria have their nemesis. Tiny viruses, called phages, infect and kill bacteria naturally, including the foodborne pathogens that sometimes make humans so sick, they wish they were dead. ¶ So why not put these phages to work on fresh-cut fruit, thought ARS plant pathologists Britta Leverentz and William S. Conway at the Produce Quality and Safety Laboratory in Beltsville, Maryland. ¶ Since phages home in on a bacterium's surface proteins, they are very selective about their hosts. Phages specific for Salmonella, for instance, would leave beneficial bacteria free to multiply on fresh-cut produce and crowd out potential pathogens, Leverentz explains. ¶ What's more, these tiny viruses are natural, safe, and ubiquitous. A small dropperful of fresh water from a stream or lake, for example, contains an average 250 million phages. Before antibiotics, phages were used to treat human infections in the United States and are still used therapeutically in other parts of the world. ¶ Phages are already under study to control pathogens in poultry, meat, and eggs. Leverentz and Conway are the first to investigate their potential to reduce pathogens on fruits and vegetables— both whole and fresh-cut. They are working under a cooperative research and development agreement with Intralytix in Baltimore, Maryland, which is providing known phages for Salmonella Enteritidis. A patent application has been filed on the use of phages with produce. [TOP OF PAGE]

  99. Novel in vivo use of a polyvalent Streptomyces phage to disinfest Streptomyces scabies-infected seed potatoes. McKenna,F., El-Tarabily,K.A., Hardy,G.E.S.T., Dell,B. (2001). Plant Pathol. 50:666-675. A highly virulent and polyvalent Streptomyces phage was isolated from a potato field near Albany, Western Australia. The efficacy of the isolated phage to disinfest seed potato tubers artificially inoculated with a common scab-causing streptomycete was evaluated. The phage suspension was prepared in a mini-bioreactor. Diseased potatoes were bathed in a phage suspension (1X109 plaque-forming units per mL) for 24 h. The suspension was constantly circulated within a novel 25 L phage bath by means of an air-sparging pipe driven from an air compressor. Phage-treated scab-affected seed potatoes planted into free-draining polystyrene boxes containing steam-pasteurized field soil produced tuber progeny with significantly (P<0.05) reduced levels of surface lesions of scab (1.2%) compared with tubers harvested from nonphage-treated tubers (23%). The number of scab lesions was also significantly reduced (P<0.05) by phage treatment of mother tubers. No significant differences were recorded in weight, size or number of harvested tubers from phage-treated or nontreated mother tubers. This is the first in vivo study that has used Streptomyces phage to significantly disinfest seed potatoes of Streptomyces scabies and thereby reduce contamination of soil from seed-tuber-borne inoculum and reduce infection of daughter tubers. [TOP OF PAGE]

  100. Effect of phage on survival of Salmonella enteritidis during manufacture and storage of cheddar cheese made from raw and pasteurized milk. Modi,R., Hirvi,Y., Hill,A., Griffiths,M.W. (2001). J. Food Prot. 64:927-933. The ability of Salmonella enteritidis to survive in the presence of phage, SJ2, during manufacture, ripening, and storage of Cheddar cheese produced from raw and pasteurized milk was investigated. Raw milk and pasteurized milk were inoculated to contain 104 CFU/ml of a luminescent strain of Salmonella enteritidis (lux) and 108 PFU/ml SJ2 phage. The milks were processed into Cheddar cheese following standard procedures. Cheese samples were examined for Salmonella enteritidis (lux), lactic acid bacteria, molds and yeasts, coliforms, and total counts, while moisture, fat, salt, and pH values were also measured. Salmonella enteritidis (lux) was enumerated in duplicate samples by surface plating on MacConkey novobiocin agar. Bioluminescent colonies of Salmonella enteritidis were identified in the NightOwl molecular imager. Samples were taken over a period of 99 days. Counts of Salmonella enteritidis (lux) decreased by 1 to 2 log cycles in raw and pasteurized milk cheeses made from milk containing phage. In cheeses made from milks to which phage was not added, there was an increase in Salmonella counts of about 1 log cycle. Lower counts of Salmonella enteritidis (lux) were observed after 24 h in pasteurized milk cheese containing phage compared to Salmonella counts in raw milk cheese with phage. Salmonella enteritidis (lux) survived in raw milk and pasteurized milk cheese without phage, reaching a final concentration of 103 CFU/g after 99 days of storage at 8 degrees C. Salmonella did not survive in pasteurized milk cheese after 89 days in the presence of phage. However, Salmonella counts of approximately 50 CFU/g were observed in raw milk cheese containing phage even after 99 days of storage. In conclusion, this study demonstrates that the addition of phage may be a useful adjunct to reduce the ability of Salmonella to survive in Cheddar cheese made from both raw and pasteurized milk. [TOP OF PAGE]

  101. [Bacteria-killing viruses, Stalinists and "superbugs"]. Olsen,I., Handal,T., Lokken,P. (2001). Tidsskr Nor Laegeforen 121:3197-3200. In June 2000, the WHO warned that the level of resistance to drugs used to treat common infectious diseases is now reaching a crisis point. If world governments do not control infections better in order to slow down the development of drug resistance, entire populations could be wiped out by superbugs against which there is no efficient treatment. Development of resistance is due to both underuse and overuse of drugs, and strategies have been worked out, to slow down the development of resistance for instance by the Norwegian Ministry of Health and Social Affairs. The present article deals with an old principle, mainly developed behind the Iron Curtain, which is now attracting renewed attention in the west: the application of bacterial viruses (bacteriophages) in the fight against bacteria. According to clinical trials in Eastern Europe, mostly uncontrolled, phages have been used successfully in treatments against antibiotic-resistant bacteria, for instance in suppurative wound infections, gastroenteritis, sepsis, osteomyelitis and pneumonia. These encouraging data are supported by recent findings in well-controlled animal models demonstrating that phages can rescue animals from a variety of fatal infections. The present review discusses possible advantages and limitations of phage treatment in humans. [TOP OF PAGE]

  102. Biotech firm tries a novel tactic in fighting bacteria. Ozretich,J. (2001). Puget Sound Business Journal 21(51), 6. A small Bothell-based biotechnology company is working on the medical equivalent of fighting fire with fire. To combat infections caused by bacteria, it is using a class of viruses that infect the bacteria themselves. ¶ Phage Therapeutics Inc. hopes to use genetically engineered versions of these naturally occurring viruses, called bacteriophages, to treat diseases where antibiotic-resistant bacteria are becoming an increasing problem, such as staph infections and tuberculosis. [TOP OF PAGE]

  103. Understanding bacteriophage therapy as a density-dependent kinetic process. Payne,R.J.H., Jansen,V.A.A. (2001). J. Theor. Biol. 208:37-48. Studies of bacteriophage as therapeutic agents have had mixed and unpredictable outcomes. We argue that interpretation of these apparently paradoxical results requires appreciation of various density-dependent threshold effects. We use a mathematical model to delineate different categories of outcome, including therapy by simple inundation, by active biocontrol, and by delayed active biocontrol. Counter-intuitively, there are situations in which earlier inoculation can be less efficacious, and simultaneous inoculation with antibiotics can be detrimental. Predictions of therapeutic responses are made using formulae dependent on biologically meaningful parameters; experimental measurement of the parameters will be a prerequisite of application of the model to particular study systems. Such modelling can point to which aspects of phage biology might most fruitfully be engineered so as to enhance the viability of bacteriophage therapy. [TOP OF PAGE]

  104. Bacteriophages: biology and history. Sharp,R.J. (2001). J. Chem. Technol. Biotechnol. 76:667-672. Bacteriophages were initially considered to offer the key to the control of bacterial infections; early studies, however, proved largely unsuccessful. In the 1940s and 1950s, pioneering studies into the structure and physiology of host/phage interactions laid the basis for the development of molecular biology and a spectrum of new biotechnologically-based industries. Bacteriophages able to infect most procaryotic groups of organisms have been isolated, and are readily isolated from soil, water, and sewage and most environments colonised by bacteria. Ecologically, phages are as varied and as versatile as their hosts with some able to survive extremes of temperature (up to 95 °C) and extremes of pH as low as pH 1. [TOP OF PAGE]

  105. Designing better phages. Skiena,S.S. (2001). Bioinformatics 17 Suppl 1:S253-S261 We propose a method to engineer the genome of bacteriophages to increase their effectiveness as antibacterial agents. Specifically, we exploit the redundancy of the triplet code to design genomes that avoid restriction sites while producing the same proteins as wild-type phages. We give an efficient algorithm to minimize the number of restriction sites against sets of cutter sequences, and demonstrate that that phage genomes can be significantly protected against surprisingly large sets of enzymes with no loss of function. Finally, we develop a model to explain why evolution has failed to eliminate many possible restriction sites despite selective pressure, thus motivating the need for genome-level sequence engineering. [TOP OF PAGE]

  106. Attempts to utilize bacteriophage to combat Salmonella enterica serovar Enteritidis infection in chickens. Sklar,I.B., Joerger,R.D. (2001). Journal of Food Safety 21:15-29. Bacteriophage capable of lysing a nalidixic acid-resistant Salmonella enterica serovar Enteritidis strain (SeE Nalr ) were tested for the ability to reduce cecal Salmonella counts in young chickens infected with the bacterium. Qualitative analysis of cloacal swabs suggested that phage treatment can possibly reduce shedding of SeE Nalr, but average SeE Nalr counts of between 105 and 107 cfu of SeE Nalr per g of cecum were obtained even fiom phage-treated 14-day old birds and even when more than 107 plaque/onning units of phage were present per gram of cecal content. The average cecal SeE Nalr counts were generally between 0.3 and 1.3 orders of magnitude lower in phage-treated chickens than in untreated controls bird. The diference in counts was statistically not significant in three animal trials, but significant in two trials using feed particles as delivery vehicles for the phage. Although some of the SeE Nalr in the cecae of phage-treated chickens had developed resistance to some of the phage used, factors other than phage resistance must have contributed to the failure of the phage to substantially reduce SeE Nalr counts. [TOP OF PAGE]

  107. Bacteriophages as therapeutic agents. Sulakvelidze,A., Morris,J.G., Jr. (2001). Ann. Med. 33:507-509. The emergence of antibiotic resistance among pathogenic bacteria is one of the most critical problems of modern medicine, and novel, effective approaches for treating infections caused by multidrug-resistant bacteria are urgently required. In this context, one intriguing approach is to use bacteriophages (viruses that kill bacteria) to eliminate specific bacterial pathogens. Bacteriophage therapy was widely used around the world in the 1930s and 1940s, and it is still used in Eastern Europe and the former Soviet Union. However, phage therapy was all but abandoned in the West after antibiotics became widely available. Promising results from recent animal studies using phages to treat bacterial infections, together with the urgent need for novel and effective antimicrobials, should prompt additional rigorous studies to determine the value of this therapeutic approach. [TOP OF PAGE]

  108. Bacteriophage therapy. Sulakvelidze,A., Alavidze,Z., Morris,J.G., Jr. (2001). Antimicrob. Agents Chemother. 45:649-659. The emergence of pathogenic bacteria resistant to most, if not all, currently available antimicrobial agents has become a critical problem in modern medicine, particularly because of the concomitant increase in immunosuppressed patients. The concern that humankind is reentering the "preantibiotics" era has become very real, and the development of alternative antiinfection modalities has become one of the highest priorities of modern medicine and biotechnology. ¶ Prior to the discovery and widespread use of antibiotics, it was suggested that bacterial infections could be prevented and/or treated by the administration of bacteriophages. Although the early clinical studies with bacteriophages were not vigorously pursued in the United States and Western Europe, phages continued to be utilized in the former Soviet Union and Eastern Europe. The results of these studies were extensively published in non-English (primarily Russian, Georgian, and Polish) journals and, therefore, were not readily available to the western scientific community. In this minireview, we briefly describe the history of bacteriophage discovery and the early clinical studies with phages and we review the recent literature emphasizing research conducted in Poland and the former Soviet Union. We also discuss the reasons that the clinical use of bacteriophages failed to take root in the West, and we share our thoughts about future prospects for phage therapy research. [TOP OF PAGE]

  109. Bacteriophage therapy. Summers,W.C. (2001). Ann. Rev. Microbiol. 55:437-451. Bacteriophages were recognized as epizootic infections of bacteria in 1917 and were almost immediately deployed for antibacterial therapy and prophylaxis. The early trials of bacteriophage therapy for infectious diseases were confounded, however, because the biological nature of bacteriophage was poorly understood. The early literature reviewed here indicates that there are good reasons to believe that phage therapy can be effective in some circumstances. The advent of antibiotics together with the "Soviet taint" acquired by phage therapy in the post-war period resulted in the absence of rigorous evaluations of phage therapy until very recently. Recent laboratory and animal studies, exploiting current understanding of phage biology, suggest that phages may be useful as antibacterial agents in certain conditions. [TOP OF PAGE]

  110. Bacteriophages, method for screening same and bactericidal compositions using same, and detection kits using same. Takahashi,S. (2001). 242901(6,322,783). The bacteriophage has a high level of specificity to a certain specific pathogenic bacterium so that the bacteriophage can surely kill the pathogenic bacterium as a host through phogocytic [sic?] action. The bio-bactericidal material containing the bacteriophage can be applied to food such as fresh food, etc., and to places, etc. or to even persons for cooking food material such as restaurants, school kitchens, etc., or any other thing which requires disinfection from pathogenic bacteria, and it can kill pathogenic bacteria. The bio-bactericidal material containing a cocktail of two or more different kinds of the bacteriophages can kill corresponding kinds of pathogenic bacteria concurrently. Further, the phage can infect only the pathogenic bacterium as a host bacterium, and does not infect persons, making it very safe and useful. [TOP OF PAGE]

  111. Phage therapy of Campylobacter jejuni colonization in broilers. Wagenaar,J.A., Van Bergen,M.A.P., Mueller,M.A., Monie,K., Carlton,R.M. (2001). International Journal of Medical Microbiology 291(Supplement 31), 92-93. The effect of phage therapy in the control of Campylobacter jejuni colonized in broilers was tested. Phage treatment was studied as a preventive as well as a therapeutic measure. In the prevention group, broilers were colonized with C. jejuni during the course of a 10-day phage treatment that was initiated 3 days before the C. jejuni challenge. In the therapeutic group, broilers were phage treated for 6 days, starting 5 days after C. jejuni colonization of the broilers was initiated. Campylobacter counts (CFUs) and phage counts (PFUs) were performed on caecal contents of individual broilers, sacrificed on 3 consecutive days after phage treatment started, and twice a week thereafter for 4 weeks. The C. jejuni colonization was compared with controls, where were C. jejuni-colonized broilers that were not phage treated. All Campylobacter inoculations were performed by gavage at the age of 10 days. The phage preparation was administered by gavage, at the time points indicated. In the therapeutic group, a clear decline (3 logs) in C. jejuni counts was observed. In the prevention group, phage treatment delayed the onset of C. jejuni colonization, and kept the peak titers 2 logs lower, compared to controls. In both groups, the CFUs and PFUs rose and fell over time, and in opposite phase to each other. In both treatment groups, five days after the clear decline of CFUs due to phage treatment, there ensued a slight and gradual increase of the CFUs over time. The extent of recolonization was limited, never reaching the level of CFUs seen in the control group. The absence of clinical signs in the phage-only control group provides evidence that the treatment was harmless to broilers. Phage treatment is therefore very promising, and is the only non-antibiotic treatment known to us that consistently reduces C. jejuni colonization in broilers. [TOP OF PAGE]

  112. Bacteriophage therapy for infections in cancer patients. Weber-Dabrowska,B., Mulczyk,M., Górski,A. (2001). Clin. Appl. Immunol. Rev. 1:131-134. Cancer patients are known to be immunocompromised and susceptible to infections. We have used bacteriophages matched for specific bacterial isolates to treat antibiotic-resistant infections in those patients. Cure of infection was achived in all cases indicating very highefficacy of BP therapy. [TOP OF PAGE]

  113. Phage therapy: an alternative to antibiotics. Appeaning,M.A. (2000). Southern University. [TOP OF PAGE]

  114. Integrated management of bacterial leaf spot of mungbean with bacteriophages of Xav and chemicals. Borah,P.K., Jindal,J.K., Verma,J.P. (2000). J. Mycol. Plant Pathol. 30:19-21. The population of Xanthomonas axonopodis pv vignaeradiatae (Xav) was completely eliminated from mungbean seeds by lytic action of bacteriophage (XMP-1) and streptomycin when the seeds were treated with Xav, phages and streptomycin at a ratio/concentration of 1: 60 + 300 mug ml-1. These results confirmed the synergistic action between phage (XMP-1) and streptomycin, as their combination could eradicate Xav from mungbean seeds at a much lower concentration as compared to when used singly. Moreover, the seed treatment with phage lysate + streptomycin 300 mug ml-1 was also found most effective in checking seedling infection of mungbean by Xav. The seedling infection was 4 per cent as compared to 68 per cent in control. The percentage of seed germination was also increased to 86 per cent in comparison to 75 per cent in control. [TOP OF PAGE]

  115. Helicobacter pylori-antigen-binding fragments expressed on the filamentous M13 phage prevent bacterial growth. Cao,J., Sun,Y., Berglindh,T., Mellgard,B., Li,Z., Mardh,B., Mardh,S. (2000). Biochim. Biophys. Acta 1474:107-113. Colonization of the human stomach by Helicobacter pylori is associated with the development of gastritis, duodenal ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. H. pylori-antigen-binding single-chain variable fragments (ScFv) were derived from murine hybridomas producing monoclonal antibodies and expressed as a g3p-fusion protein on a filamentous M13 phage. The recombinant ScFv-phage reacted specifically with a 30-kDa monomeric protein of a H. pylori surface antigen preparation and by means of immunofluorescence microscopy the phage was shown to bind to both the spiral and coccoid forms of the bacterium. In vitro, the recombinant phage exhibited a bacteriocidal effect and inhibited specifically the growth of all the six strains of H. pylori tested. When H. pylori was pretreated with the phage 10 min before oral inoculation of mice, the colonization of the mouse stomachs by the bacterium was significantly reduced (P<0.01). The results suggest that genetic engineering may be used to generate therapy-effective phages. [TOP OF PAGE]

  116. Use of bacteriophage as therapy for disease caused by Vibrio vulnificus in iron dextran-treated mice. Cerveny,K.E., Doyle,T.J., Escudero,G.M., Duckworth,D.H., Gulig,P.A. (2000). Abstracts of the General Meeting of the American Society for Microbiology 100, 279. [TOP OF PAGE]

  117. Control of bacterial spot on tomato in the greenhouse and field with h-mutant bacteriophages. Flaherty,J.E., Jones,J.B., Harbaugh,B.K., Somodi,G.C., Jackson,L.E. (2000). Hortscience 35:882-884. A mixture of host-range mutant (h-mutant) bacteriophages specific for tomato race 1 (T1) and race 3 (T3) of the bacterial spot pathogen, Xanthomonas campestris pv. vesicatoria (Doidge) Dye was evaluated for biological control of bacterial spot on 'Sunbeam' tomato (Lycopersicon esculentum Mill.) transplants and field-grown plants for two seasons (Fall 1997 and Fall 1998). Foliar applications of bacteriophages were compared with similar applications of water (control) and of copper/mancozeb bactericides, the commonly used chemical control strategy for tomato seedling and field production. In 1997, the incidence of bacterial spot on greenhouse-grown seedlings was reduced from 40.5% (control) to 5.5% or 0.9% for bactericide- or bacteriophage-treated plants, respectively. In 1998, the incidence of bacterial spot was 17.4% on control plants vs. 5.5% and 2.7% for bactericide- and bacteriophage-treated plants, respectively, although these differences were not statistically significant at P ltoreq 0.05. Applications of bacteriophages to field-grown tomatoes decreased disease severity as measured by the area under the disease progress curve (AUDPC) by 17.5% (1997) and 16.8% (1998) compared with untreated control plants. Preharvest plant vigor ratings, taken twice during each field season, were higher in the bacteriophage-treated plants than in either bactericide-treated plants or nontreated controls except for the early vigor rating in 1998. Use of bacteriophages increased total weight of extra-large fruit 14.9% (1997) and 24.2% (1998) relative to that of nontreated control plants, and 37.8% (1997) and 23.9% (1998) relative to that of plants treated with the chemical bactericides. Chemical names used: manganese, zinc, carboxy-ethylene his dithiocarbamate (mancozeb). [TOP OF PAGE]

  118. Compositions containing bacteriophages and methods of using bacteriophages to treat infections. Ghanbari,H.A., Averback,P. (2000). 842653(6,121,036). Purified, host-specific, non-toxic, wide host range and virulent bacteriophage preparations that are effective in killing bacterial organisms in vivo are disclosed. Also disclosed are compositions containing these bacteriophages, methods of making the bacteriophage preparations and methods of treating bacterial infections using the compositions. Methods of treating bacterial infections using the compositions containing the bacteriophages in combination with conventional antibiotics also are disclosed. [TOP OF PAGE]

  119. Control of the eel (Anguilla japonica) pathogens, Aeromonas hydrophila and Edwardsiella tarda, by bacteriophages. Hsu,C.H., Lo,C.Y., Liu,J.K., Lin,C.S. (2000). J. Fisheries Soc. Taiwan 27:21-31. Aeromonas hydrophila and Edwardsiella tarda are the two major pathogens of the eel, Anguilla japonica. The prevalent method to control the diseases is antibiotics. Long term and large scale application of the drugs results in resistance which makes disease control difficult. In the nature, bacteriophages are an important factor in controling bacterial population. The purpose of this research is to study the capability of the phages to control the pathogens in pond water. Several bacteriophages of A. hydrophila and E. tarda were isolated from the water samples of southern Taiwan. In pure culture, the phages could reduce the host 3 orders of magnitude in 2 hr when the multiplicity of infection (moi) was above 11.5 at 25ºC. In the pond water with added A. hydrophila to 6 X 105 / ml, the number dropped 250 folds at phage moi of 0.23 in 8 hr with accompanying phage multiplication to the level of 106 PFU/ml in the water. Most (85%) of the surviving hosts were still vulnerable to the phage. The resistant strains (15%) appeared to be lysogens since the culture broth of the strains could form phage plaques on A. hydrophila. In the case of E. tarda, the bacteria subsided rapidly even in the absence of phage in 48 hr in the pond water. [TOP OF PAGE]

  120. Bacteriophages active against Helicobacter pylori in UK sewage: Natural born killers? Morton,D., Bardhan,K.D. (2000). Gastroenterology 118:AGA [TOP OF PAGE]

  121. Prokaryotic gene therapy to combat multidrug resistant bacterial infection [editorial]. Norris,J.S., Westwater,C., Schofield,D. (2000). Gene Therapy 7:723-725. [TOP OF PAGE]

  122. A Stalinist Antibiotic Alternative. Osborne,L. (2000). New York Times Magazine (Sunday, February 6), ??? A hoary Soviet method for fighting infections may prove invaluable in an age of antibiotic resistance. Maybe that's why pharmaceutical companies are flocking to a remote laboratory in Tbilisi. [TOP OF PAGE]

  123. Isolation of bacteriophages specific to a fish pathogen, Pseudomonas plecoglossicida, as a candidate for disease control. Park,S.C., Shimamura,I., Fukunaga,M., Mori,K.I., Nakai,T. (2000). Appl. Environ. Microbiol. 66:1416-1422. Two types of bacteriophage specific to Pseudomonas plecoglossicida, the causative agent of bacterial hemorrhagic ascites disease in cultured ayu fish (Plecoglossus altivelis), were isolated from diseased ayu and the rearing pond water. One type of phage, which formed small plaques, was tentatively classified as a member of the family Myoviridae, and the other type, which formed large plaques, was classified as a member of the family Podoviridae. All 27 strains of P. plecoglossicida examined, which were isolated from diseased ayu from geographically different areas in 1991 to 1999, exhibited quite similar sensitivities to either type of phage. One strain of P. plecoglossicida was highly virulent for ayu, and the 50% lethal dose (LD(50)) when intramuscular injection was used was 10(1.2) CFU fish(-1); in contrast, phage-resistant variants of this organism were less virulent (LD(50), >10(4) CFU fish(-1)). Oral administration of phage-impregnated feed to ayu resulted in protection against experimental infection with P. plecoglossicida. After oral administration of P. plecoglossicida cells of this bacterium were always detected in the kidneys of control fish that did not receive the phage treatment, while the cells quickly disappeared from the phage-treated fish. Bacterial growth in freshwater was lower in the presence of phage, and the number of phage PFU increased rapidly. These results suggest that it may be possible to use phage to control the disease caused by P. plecoglossicida. [TOP OF PAGE]

  124. Phage therapy: The peculiar kinetics of self-replicating pharmaceuticals. Payne,R.J.H., Phil,D., Jansen,V.A.A. (2000). Clinical Pharmacology and Therapeutics 68:225-230. The specter of antibiotic-resistant bacteria has provoked renewed interest in the possible use of bacteriophages to control bacterial infections. We argue that clinical application of phage therapy has been held back by a failure to appreciate the extent to which the pharmacokinetics of self-replicating agents differ from those of normal drugs. For self-replicating pharmaceutical agents, treatment outcome depends critically on various density-dependent thresholds, often with apparently paradoxical consequences. An ability to predict these thresholds and associated critical time points is a necessity if phage therapy is to become clinically practicable. [TOP OF PAGE]

  125. Phage therapy—advantages over antibiotics? Pirisi,A. (2000). Lancet 356:1418 As antibiotic-resistant bacteria continue to threaten standard therapies against bacterial infections, a new breed of antimicrobials may be on the horizon. Many researchers believe that bacteriophages—viruses that only infect bacteria—are a promising potential therapy for bacterial disease treatment. [TOP OF PAGE]

  126. Studies on phage control of pustule disease in abalone Haliotis discus hannai. Tai-wu,L., Xiang,J., Liu,R. (2000). J. Shelfish Res. 19:535 [TOP OF PAGE]

  127. Viruses that slay bacteria draw new interest. Travis,J. (2000). Science News 157(June 3), 358-??? For people with a damaged liver or too much iron in their blood, enjoying raw oysters from the Gulf of Mexico is a deadly gamble. Most of the oysters harbor Vibrio vulnificus, a bacterium responsible for almost all seafood-related deaths in the United States. Healthy people shrug off the microbe, but susceptible folks who get a full-blown infection have more than a 50 percent chance of dying. ¶ "You can be dead within 24 hours," says Paul A. Gulig of the University of Florida College of Medicine in Gainesville. Seeking a treatment that works faster than antibiotics do, he and his colleagues recently isolated a bacteria-killing virus, or bacteriophage, that targets V. vulnificus and can prevent the deaths of mice infected with it. ¶ Gulig's report was one of a handful on bacteriophage therapy presented last week at the American Society for Microbiology (ASM) meeting in Los Angeles. Other scientists described phages that attack bacteria that cause anthrax, wound and burn infections, and meat and poultry contamination…. [TOP OF PAGE]

  128. The return of the phage. Wakefield,J. (2000). Smithsonian 31(7), 43-??? As deadly bacteria increasingly resist antibiotics, researchers try to improve a World War I era weapon. [TOP OF PAGE]

  129. Effective phage therapy is associated with normalization of cytokine production by blood cell cultures. Weber-Dabrowska,B., Zimecki,M., Mulczyk,M. (2000). Archivum Immunologii et Therapiae Experimentalis 48:31-37. The aim of this study was to investigate the effect of phagotherapy on tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) serum levels and the ability of blood cells to produce these cytokines in culture. Fifty one patients with long-term, suppurative infections of various tissues and organs were enrolled. The ability of cells to secrete cytokines was tested using whole blood cell cultures, unstimulated or stimulated with lipopolysaccharide (LPS) from E. coli. In addition, cytokine serum levels were determined. Measurement of cytokine activity was performed using bioassays. We showed that TNF-alpha, but not IL-6 serum levels, were regulated upon division of patients into categories exhibiting initial: low, moderate and high cytokine levels. The low spontaneous production of IL-6 by blood cell cultures was elevated significantly on day 21 of phage therapy, whereas high release of this cytokine was inhibited. No such correlation was observed with LPS-induced IL-6 production in cell cultures when cells from low-, moderately- or highly-reactive patients were studied. Phage therapy modified TNF release according to the initial ability to produce that cytokine: it reduced TNF production in high responders and increased it in low responders. Patients infected only with Gram-positive bacteria demonstrated analogous changes in the spontaneous and LPS-induced TNF-alpha production as in the whole studied group. A similar kind of regulation was observed in TNF-alpha and LPS-induced production, i.e. low production was significantly elevated, high strongly inhibited, and moderate only slightly affected. In summary, we demonstrated for the first time that effective phage therapy can normalize TNF-alpha serum levels and the production of TNF-alpha and IL-6 by blood cell cultures. [TOP OF PAGE]

  130. Bacteriophage therapy of bacterial infections: An update of our institute's experience. Weber-Dabrowska,B., Mulczyk,M., Gorski,A. (2000). Archivum Immunologiae et Therapiae Experimentalis 48:547-551. 1307 patients with suppurative bacterial infections caused by multidrug-resistant bacteria of different species were treated with specific bacteriophages (BP). BP therapy was highly effective; full recovery was noted in 1123 cases (85.9%). In 134 cases (10.9%) transient improvement was observed and only in 50 cases (3.8%) was BP treatment found to be ineffective. The results confirm the high effectiveness of BP therapy in combating bacterial infections which do not respond to treatment with the available antibiotics. [TOP OF PAGE]

  131. Viruses help fight bacteria that resist antibiotics. ??? (1999). The Patriot Ledger Quincy, MA 13(183?), 183? (News Section)-same? Scientists have harnessed nature's way of tackling antibiotic- resistant bacteria. An injection of a virus that attacks bacteria only has saved the life of a patient after all other drugs proved useless. The technique -- the use of bacteriophages, or bacteria-eaters -- was pioneered in the former Soviet Union at around the time of the discovery of much more swiftly effective antibiotics. Although penicillin and other such drugs changed medicine, one team in Tbilisi, Georgia, kept research in phages going to the present day. [TOP OF PAGE]

  132. Phage therapy: past history and future prospects. Carlton,R.M. (1999). Archivum Immunologii et Therapiae Experimentalis 47:267-274. Bacterial viruses (bacteriophages, also called "phages") can be robust antibacterial agents in vitro. However, their use as therapeutic agents, during a number of trials from the 1920s to the 1950s, was greatly handicapped by a number of factors. In part, there were certain limitations inherent in phage physiology (e. g. narrow host range, and rapid clearance from the body); in part there were technological limitations in the era (e.g. lysogeny not yet discovered); but the greatest limitation was the highly inadequate scientific methodologies used by practitioners at the time (e.g., their failure to conduct placebo-controlled studies, to remove endotoxins from the preparations, and to re-confirm phage viability after adding sterilizing agents to the preparations). In recent years, well-controlled animal models have demonstrated that phages can rescue animals from a variety of fatal infections, while non-controlled clinical reports published in Eastern Europe have shown that phages can be effective in treating drug-resistant infections in humans. This encouraging data, combined with the fact that drug-resistant bacteria have become a global crisis, have created a window of opportunity for phage therapy to be tested anew, this time using modem technologies and placebo-controlled designs. If successful, it can be used as a stand-alone therapy when bacteria are fully resistant to antibiotics, and as a valuable adjunct to antibiotics when the bacteria are still susceptible. [TOP OF PAGE]

  133. Eradication of Pseudomonas aeruginosa biofilm with bacteriophage. Ibrahim,I.J., Hanlon,G.W., Denyer,S.P. (1999). Abstracts of the General Meeting of the American Society for Microbiology 99, 445. [TOP OF PAGE]

  134. Biocontrol of Escherichia coli O157 with O157-specific bacteriophages. Kudva,I.T., Jelacic,S., Tarr,P.I., Youderian,P., Hovde,C.J. (1999). Appl. Environ. Microbiol. 65:3767-3773. Escherichia coli O157 antigen-specific bacteriophages were isolated and tested to determine their ability to lyse laboratory cultures of Escherichia coli O157:H7. A total of 53 bovine or ovine fecal samples were enriched for phage, and 5 of these samples were found to contain lytic phages that grow on E. coli O157:H7. Three bacteriophages, designated KH1, KH4, and KH5, were evaluated. At 37 or 4 degrees C, a mixture of these three O157-specific phages lysed all of the E. coli O157 cultures tested and none of the non-O157 E. coli or non-E. coli cultures tested. These results required culture aeration and a high multiplicity of infection. Without aeration, complete lysis of the bacterial cells occurred only after 5 days of incubation and only at 4 degrees C. Phage infection and plaque formation were influenced by the nature of the host cell O157 lipopolysaccharide (LPS). Strains that did not express the O157 antigen or expressed a truncated LPS were not susceptible to plaque formation or lysis by phage. In addition, strains that expressed abundant mid-range-molecular-weight LPS did not support plaque formation but were lysed in liquid culture. Virulent O157 antigen-specific phages could play a role in biocontrol of E. coli O157:H7 in animals and fresh foods without compromising the viability of other normal flora or food quality. [TOP OF PAGE]

  135. Bacteriophages: An altertnative to antibiotics? Lorch,A. (1999). Biotechnology and Development Monitor 39:14-17. Bacterial resistance to antibiotics has become a serious medical problem. Treatment with bacteriophages might pose an effective alternative that has long been known but has been ignored outside the former Soviet Union. The development of phage therapies exemplifies positive as well as negative implications for scientific development that is restricted in its access to the mainstream, English-language dominated scientific community. [TOP OF PAGE]

  136. Protective effects of bacteriophage on experimental Lactococcus garvieae infection in yellowtail. Nakai,T., Sugimoto,R., Park,K.-H., Matsuoka,S., Mori,K., Nishioka,T., Maruyama,K. (1999). Dis. Aquat. Org. 37:33-41. The present study describes the in vitro and in vivo survival of Lactococcus garvieae bacteriophages and the potential of the phage for controlling experimental L. garvieae infection in yellowtail. Anti-L. garvieae phages persisted well in various physicochemical (water temperature, salinity, pH) and biological (feed, serum and alimentary tract extracts of yellowtail) conditions, except for low acidity. In the in vivo, the phage PLgY-16 was detected in the spleens of yellowtail until 24 h after intraperitoneal (i.p.) injection, or the phage was recovered from the intestine of yellowtail 3 h after the oral administration of phage-impregnated feed but undetectable 10 h later. Simultaneous administration of live L. garvieae and phage enhanced recovery of the phage from the spleen or intestine. The survival rate was much higher in yellowtail that received i.p. injection of the phage after i.p. challenge with L. garvieae, compared with that of control fish without phage injection. When fish were i.p.-injected with phage at different hours after L. garvieae challenge, higher protective effects were demonstrated in fish that received phage treatment at the earlier time. Protection was also obtained in yellowtail receiving phage-impregnated feed, in which fish were challenged by an anal intubation with L. garvieae. Anal-intubated L. garvieae were detected constantly in the spleens of the control fish, while they were detected sporadically and disappeared from the phage-treated fish 48 h later. On the other hand, orally administered phage was detected at high plaque-forming units from the intestines and spleens of the phage-treated fish until 48 h later. These results indicate that intraperitoneally or orally administered anti-L. garvieae phage prevented fish from experimental L. garvieae infection, suggesting potential use of the phage for controlling the disease. [TOP OF PAGE]

  137. Prevention of Clostridium difficile-induced ileocecitis with bacteriophage. Ramesh,V., Fralick,J.A., Rolfe,R.D. (1999). Anaerobe 5:69-78. A bacteriophage specific for Clostridium difficile was examined for its ability to prevent ileocecitis in a hamster model. This species- and strain-specific bacteriophage was isolated from a lysogenic strain of C. difficile. Hamsters were maintained in sterile isolation cages to prevent the acquisition of C. difficile from the environment. Bicarbonate neutralization of gastric acidity was necessary for bacteriophage survival in the hamster's gastrointestinal tract. Bacteriophage recovery from the hamster cecum was 2 X 104 plaque forming units/mL of cecal contents 24 h after orogastric challenge with 108 plaque forming units/mL of bacteriophage. However, there was no bacteriophage recovery 48 h post challenge, indicating dissipation of bacteriophage from the hamster intestinal tract within this time frame. Twenty-four hours after being challenged with clindamycin, one group of hamsters was challenged with C. difficile followed by a single dose of bacteriophage (108 plaque forming units/mL). Two additional groups of hamsters received phage doses immediately after C. difficile challenge and subsequently thereafter every 8 h up to 48 and 72 h, respectively. The gastric acidity was neutralized with bicarbonate buffer preceding every bacteriophage treatment. Control animals that received only clindamycin and C. difficile died within 96 h after challenge while the majority of bacteriophage treated hamsters survived. Two weeks after stopping bacteriophage treatment, the surviving hamsters were rechallenged with clindamycin and C. diifficile. All the hamsters died within 96 h indicating susceptibility of the surviving hamsters to C. difficile disease in the absence of bacteriophage treatment. [TOP OF PAGE]

  138. Bacteriophage therapy of Clostridium difficile-associated intestinal disease in a hamster model. Rdamesh,V., Fralick,J.A., Rolfe,R.D. (1999). Miroecol. Anarobes[sic?] 5:69-??? [TOP OF PAGE]

  139. Hospital Horror. Sardar,Z. (1999). New Statesman , ??? Our hospitals are becoming hazardous places. One can go in with a curable illness and come out with an incurable one. The risk of being infected by a "superbug", bacterial infection that is resistant to antibiotic, is very real. It has always been possible to die from surgical infection, but the arrival of superbugs has increased this risk enormously. Within ten years most of these infections will not be treatable with antibiotics. ¶
    This crisis is solely due to overuse of antibiotics. We use antibiotics as a panacea for all illnesses, and doctors have become accustomed to prescribing them as blanket coverage for all complaints. Patients, too, think antibiotics are magic bullets and demand them for every flu of every season. Worse, we use antibacterial agents in household products such as washing-up liquid, bin liners and kitchen utensils. A recent essay in Nature shows how this domestic overuse is leading to resistant bacteria. For example, E coli, one of the most common causes of food poisoning, is developing resistance to triclosan, a common antibacterial agent. ¶ That is the bad news. The good news is that there is a relatively safe and easy cure for drug-resistant strains of infectious bacteria. It's called phage therapy. Bacteriophage, or "bacteria eaters", are viruses extracted from , raw sewage. They thrive wherever bacteria thrive -- in our bodies, waste products, rivers. Phage therapy has been freely available in the former communist world for decades. Even now, a dilapidated factory in Tblisi, Georgia, is producing supplies of bacteriophage under the most difficult conditions. And we in the west, having spent astronomical sums in a vain attempt to contain killer bugs, are beginning to think about learning from them. [TOP OF PAGE]

  140. Bacteriophage of Erwinia amylovora and their potential for biocontrol. Schnabel,E.L., Fernando,W.G.D., Meyer,M.P., Jones,A.I. (1999). pp. 649-653. In In Mornol,M.T. and Saygili,H. (eds.), Proceedings of the 8th International Workshop on Fire Blight. ISHS, Leuven, Belgium. [TOP OF PAGE]

  141. Characterization of a Vibrio parahaemolyticus phage isolated from marine. Yoon,S.O., Ju,S.A., Heo,M.S., Jung,C.R., Ju,J.W. (1999). Journal of the Korean Society for Microbiology 34:423-433. A novel bacteriophage, designated as VPP97, that infects the strains of Vibiro parahaemolyticus (hallophilic, Gram-negative bacterium) isolated most commonly from marine environments, has been discovered, and several of its properties have been determined. The plaques were clear and sized 0.6-1.0 mm in diameter. The virion forms a single band on 70% sucrose gradient and p1.50 CsCl gradient by sucrose gradient centrifugation and CsCl gradient centrifugation respectively. It has a hexagonal head and a relatively long tail, as shown by electron microscopy. Vibrio alginolyticus, Vibrio fluvialis and Vibrio furnissii were also sensitive to this phage It was almost totally inactivated at 70ºC and at pH below 5 or over 10. The nucleic acid of VPP97 is composed of DNA. The VPP97 had 9 specific structural proteins sized between 21.5 kDa and 97.4 kDa on SDS-PAGE. When V. parahaemolyticus cultures were treated with either phage VPP97 or one of the several antibiotics for 2 hours, the viable number of V. parahaemolyticus treated with the phage VPP97 is lower than that treated with chloramphenicol, erythromycin or penicillin, but not lower than that treated with tetracycline. Mice that have responded to the phage treatment revealed the lower numbers of V. parahaemolyticus in small intestine and less damage on small intestine compared to the untreated mice. Therefore, we suggest that the phage treatment appears effective to the infection by V. parahaemolyticus. [TOP OF PAGE]

  142. Ispol'zovanie adaptirovannogo sal'monelleznogo bakteriofaga v praktike lecheniia i profilaktiki nozokomial'nogo sal'monelleza [Practical use of adapted Salmonella bacteriophage for the treatment and prevention of nosocomial infections]. Akimkin,V.G., Bondarenko,V.M., Voroshilova,N.N., Darbeeva,O.S., Baiguzina,F.A. (1998). Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii 85-86. [TOP OF PAGE]

  143. Bacteriophages show promise as antimicrobial agents. Alisky,J., Iczkowski,K., Rapoport,A., Troitsky,N. (1998). J. Infect. 36:5-15. The emergence of antibiotic-resistant bacteria has prompted interest in alternatives to conventional drugs. One possible option is to use bacteriophages (phage) as antimicrobial agents. We have conducted a literature review of all Medline citations from 1966-1996 that dealt with the therapeutic use of phage. There were 27 papers from Poland, the Soviet Union, Britain and the U.S.A. The Polish and Soviets administered phage orally, topically or systemically to treat a wide variety of antibiotic-resistant pathogens in both adults and children. Infections included suppurative wound infections, gastroenteritis, sepsis, osteomyelitis, dermatitis, empyemas and pneumonia; pathogens included Staphylococcus, Streptococcus, Klebsiella, Escherichia, Proteus, Pseudomonas, Shigella and Salmonella spp. Overall, the Polish and Soviets reported success rates of 80-95% for phage therapy, with rare, reversible gastrointestinal or allergic side effects. However, efficacy of phage was determined almost exclusively by qualitative clinical assessment of patients, and details of dosages and clinical criteria were very sketchy. There were also six British reports describing controlled trials of phage in animal models (mice, guinea pigs and livestock), measuring survival rates and other objective criteria. All of the British studies raised phage against specific pathogens then used to create experimental infections. Demonstrable efficacy against Escherichia, Acinetobacter, Pseudomonas and Staphylococcus spp. was noted in these model systems. Two U.S. papers dealt with improving the bioavailability of phage. Phage is sequestered in the spleen and removed from circulation. This can be overcome by serial passage of phage through mice to isolate mutants that resist sequestration. In conclusion, bacteriophages may show promise for treating antibiotic resistant pathogens. To facilitate further progress, directions for future research are discussed and a directory of authors from the reviewed papers is provided. [TOP OF PAGE]

  144. Use of lytic bacteriophage for control of experimental Escherichia coli septicemia and meningitis in chickens and calves. Barrow,P., Lovell,M., Berchieri,A.jr. (1998). Clin. Diag. Lab. Immunol. 5:294-298. A lytic bacteriophage, which was previously isolated from sewage and which attaches to the K1 capsular antigen, has been used to prevent septicemia and a meningitis-like infection in chickens caused by a K1+ bacteremic strain of Escherichia coli. Protection was obtained even when administration of the phage was delayed until signs of disease appeared. The phage was able to multiply in the blood. In newly borne colostrum-deprived calves given the E. coli orally, intramuscular inoculation of phage delayed appearance of the bacterium in the blood and lengthened life span. With some provisos there is considerable potential for this approach to bacterial-disease therapy. [TOP OF PAGE]

  145. Biological control of bacterial blight of geranium with h-mutant bacteriophages. Harbaugh,B.K., Jones,J.B., Jackson,L.E., Somodi,G., Flaherty,J.E. (1998). Hortscience 33(3), 519. Bacterial blight, caused by Xanthomonas campestris pv. pelargonii (XCP), is considered the most serious disease of germaniums (Pelargonium x hortorum). A novel approach that uses bacteriophages (phaes, viruses that kill bacteria) for the biological control of geranium blight will be presented. Phages were once abandoned as biological control agents due to the emergence of bacterial mutants resistant to the phages employed. However, our approach utilizes a mixture of three to eight different phages including host-range mutants (H-mutants). H-mutants are spontaneously derived from their wild-type parent phages and lyse not only parent wild-type bacteria, but also phage-resistant mutants originating from parent bacteria. Two phages specific for XCP initially were isolated from soil samples from Florida and California. These phages produced virulent reactions in six of 30 XCP strains, and lysogenic reactions in 22 strains. After selection of these phages for increased virulence and additional phages were isolated from MN and UT, 17 phages were evaluated for sensitivity to 21 XCP strains from around the world. Four to 14 phages produced virulent reactions in the 21 XCP strains. Five phages produced virulent reactions in at least 17 XCP strains. A mixture of five phages tested against the 21 XCP strains produced virulent reactions for all 21 XCP strains. Geraniums in 10-cm pots were inoculated with XCP and placed on a greenhouse bench in the middle of 5 non-inoculated plants. After 2 weeks of daily spraying plants with a phage solution (109 pfu phage/ml) or water, there was a 71% reduction in the number of bacterial lesions on phage-treated plants. [TOP OF PAGE]

  146. …Spurs companies to study therapeutic uses. Holzman,D. (1998). ASM News 64:622-623. [TOP OF PAGE]

  147. Phage as antibacterial tool. Holzman,D. (1998). Genetic Engineering News 18(18), 1-48. [TOP OF PAGE]

  148. Reassessment of medicinal phage……. Holzman,D. (1998). ASM News 64:620-622. [TOP OF PAGE]

  149. Control of bacterial spot on tomato in the greehouse and field with bacteriophages. Jones,J.B., Somodi,G.C., Jackson,L.E., Harbaugh,B.K. (1998). Paper 5.2.14. Edinburgh, Scotland, 7th International Congress of Plant Pathology. [TOP OF PAGE]

  150. The hunt is on for new ways to overcome bacterial resistance. Knudson,M. (1998). Technology Review 100:22-30? Researchers from various pharmaceutical companies are employing high technology approaches to develop ways to address disease-causing microbes that mutate to resist conventional antibiotics. [TOP OF PAGE]

  151. Return of a killer. Koerner,B.I. (1998). U.S.News and World Report (November 2, 1998), 51-52. Phages may once again fight tough bacterial infections. [TOP OF PAGE]

  152. Bacteriophage genotypically modified to delay inactivations by the host defense system. Merril,C.R., Carlton,R.M., Adhya,S.L. (1998). Exponential Biotherapies, Inc. and The United States of America as represented by the Department of Health. 631427(5,811,093). 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 of a bacteriophage, 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]

  153. Antibacterial therapy with bacteriophage genotypically modified to delay inactivation by the host defense system together with an antibiotic. Merril,C.R., Carlton,R.M., Adhya,S.L. (1998). Exponential Biotherapies, Inc. and The United States of America as represented by the Department of Health. 464404(5,766,892). 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]

  154. Phage therapy. Soothill,J.S. (1998). J. Pharm. Pharmacol. 50:36 [TOP OF PAGE]

  155. Bacteriophage therapy and prophylaxis: Rediscovery and renewed assessment of potential. Barrow,P.A., Soothill,J.S. (1997). Trends Genet. 5:268-271. Bacteriophages were discovered 82 years ago. Claims for their use in the treatment of infections were not confirmed by early controlled trials, and the success of antibiotics superseded this potential use. However, recent studies have shown interesting therapeutic effects that warrant further investigation and development. [TOP OF PAGE]

  156. Infection and removal of L-forms of Listeria monocytogenes with bred bacteriophage. Hibma,A.M., Jassim,S.A., Griffiths,M.W. (1997). Int. J. Food Microbiol. 34:197-207. Phage breeding was employed to produce a bacteriophage (Listeria monocytogenes phage ATCC 23074-B1) which was specific for L-forms of L. monocytogenes. The bred phage was compared to its unbred parent for lytic activity and specificity. It was also tested for its ability to prevent L-form biofilm formation on stainless steel and compared with an organic acid (lactic) at L-form biofilm inactivation on stainless steel. The bred phage lysed only L-forms of L. monocytogenes in broth culture and only plaqued on L-form lawns. Likewise, the unbred phage performed similarly with classical cell-walled culture and lawns. The bred phage successfully inhibited L-form biofilm formation on stainless steel and was as successful as lactic acid (130 ppm) at inactivating pre-formed L-form biofilms. Both reduced viable cell numbers by 3-long cycles over a 6 h period. It appears that phage breeding technology may be an attractive alternative to chemical sanitizers which lack specificity and can be toxic. [TOP OF PAGE]

  157. [The study on biology of bacteriophages and their usage in the treatment of bacterial diseases and on the influence of different bacteriophages on cytokine production by leukocytes in human peripheral blood]. Kozminska,J., Weber-Dabrowska,B., Mulczyk,M. (1997). OTOLARYNGOLOGIA POLSKA 51 Suppl 25:195-198. The authors showed the examinations of the biology bacteriophages and using them in the treatment of the bacteriology infection and influence difference bacteriophages in producing cytokinins by leukocytes of human peripheral blood. [TOP OF PAGE]

  158. Antibacterial therapy with bacteriophage genotypically modified to delay inactivation by the host defense system. Merril,C.R., Carlton,R.M., Adhya,S.L. (1997). 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]

  159. Antibacterial therapy with bacteriophage genotypically modified to delay inactivation by the host defense system. Merril,C.R., Carlton,R.M., Adhya,S.L. (1997). Exponential Biotherapies, Inc. and The United States of America as represented by the Department of Health. 593269(5,688,501). 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]

  160. Control of Erwinia amylovora by mixtures of bacteriophage. Palmer,E.L., Fernando,W.G.D., Jones,A.L. (1997). Phytopathology 87(6 SUPPL.), S73-S74. A collection of bacteriophage specific to the fire blight pathogen Erwinia amylovora was isolated from dirt and leaf samples collected at orchards in Michigan and California in 1996. The most commonly encountered phage contains a 46 kb dsDNA genome, produces large clear plaques surrounded by expanding translucent haloes, and is similar to the phage PEa1 described by…. [TOP OF PAGE]

  161. Control of bacterial spot of tomato in transplant production using h-mutant bacteriophage and a hrp- strain of Xanthomonas campestris pv. vesicatoria. Somodi,G.C., Jones,J.B., Jackson,L.E. (1997). Phytopathology 87(6 SUPPL.), S92. Tomato transplants in planter flats were irrigated daily using backpack sprayers to simulate overhead imgation. Treatments included water, water and weekly applications of copper, water containing mixtures of several h-mutant phages specific to tomato race 3 of Xanfhomonas campestris pv. vesicaforia (Xcv), or a nonpathogenic hrp mutant of a Xcv T3 strain applied alone or in combination with phages. One week after transplanting, one seedling in the center of each flat was inoculated by infiltration with lo8 cfu/ml of a race T3 Xcv strain. Approximately 18 days after transplanting, the incidence of bacterial spot disease was determined for each flat. Disease incidence for the water treatment was 48%, compared to only 15% for phage-treated plants. Copper-treated plants had 44% disease incidence. Disease incidences for transplants treated with a nonpathogenic hrp- mutant applied alone or in combination with phages were 5.5% and 0.5%, respectively. [TOP OF PAGE]

  162. One infection cures another. Brown,P. (1996). New Scientist ???, ??? [TOP OF PAGE]

  163. Host-dependent modification/restriction and therapeutic potential of Pseudomonas phage. Gachechiladze,K.K., Adamia,R.S., Balardshishvili,N.S., Chanishvili,T.G., Kruger,D.H. (1996). Jerusalem (Israel). Xth International Congress of Virology. 1996.[TOP OF PAGE]

  164. Smaller fleas ... ad infinitum: therapeutic bacteriophage redux. Lederberg,J. (1996). Proc. Natl. Acad. Sci. USA 93:3167-3168. [TOP OF PAGE]

  165. Phage therapy revisited: the population biology of a bacterial infection and its treatment with bacteriophage and antibiotics. Levin,B.R., Bull,J.J. (1996). Am. Nat. 147:881-898. Phage therapy is the use of bacterial viruses (bacteriophage) to treat bacterial infections. It has been practiced sporadically on humans and domestic animals for nearly 75 yr. Nevertheless, phage therapy has remained outside the mainstream of modern medicine, presumably because of doubts about its efficacy, and possibly because it was eclipsed by antibiotics and other chemotherapeutic agents. In this report, we develop the study of phage therapy and antibiotic therapy as a population biological phenomenon-the dynamic interaction of bacteria with a predator (phage) or a toxic chemical (antibiotic) inside a host whose immune and other defenses also affect the interaction. Our goal is to identify the conditions under which phage and antibiotics can successfully control a bacterial infection and when they cannot. We review data published in the 1980s by H. Williams Smith and J. B. Huggins on the use of phage and antibiotics to control lethal, systemic infections of Escherichia coli in experimentally inoculated mice. We show that some of their observations can be accommodated by a quantitative model that invokes known or plausible assumptions about host defenses and the interactions of bacteria with phage and antibiotics; some observations remain unexplained by the model. Our analysis identifies several hypotheses about the population dynamics of phage and antibiotic therapy that can be tested experimentally. Included among these are hypotheses that account for variation in the efficacy of the different phages employed by Smith and Huggins and why, in their study, phages were more effective than antibiotics. [TOP OF PAGE]

  166. Long-circulating bacteriophage as antibacterial agents. Merril,C.R., Biswas,B., Carlton,R., Jensen,N.C., Creed,G.J., Zullo,S., Adhya,S. (1996). Proc. Natl. Acad. Sci. USA 93:3188-3192. The increased prevalence of multidrug-resistant bacterial pathogens motivated us to attempt to enhance the therapeutic efficacy of bacteriophages. The therapeutic application of phages as antibacterial agents was impeded by several factors: (i) the failure to recognize the relatively narrow host range of phages; (ii) the presence of toxins in crude phage lysates; and (iii) a lack of appreciation for the capacity of mammalian host defense systems, particularly the organs of the reticuloendothelial system, to remove phage particles from the circulatory system. In our studies involving bacteremic mice, the problem of the narrow host range of phage was dealt with by using selected bacterial strains and virulent phage specific for them. Toxin levels were diminished by purifying phage preparations. To reduce phage elimination by the host defense system, we developed a serial- passage technique in mice to select for phage mutants able to remain in the circulatory system for longer periods of time. By this approach we isolated long-circulating mutants of Escherichia coli phage lambda and of Salmonella typhimurium phage P22. We demonstrated that the long- circulating lambda mutants also have greater capability as antibacterial agents than the corresponding parental strain in animals infected with lethal doses of bacteria. Comparison of the parental and mutant lambda capsid proteins revealed that the relevant mutation altered the major phage head protein E. The use of toxin-free, bacteria-specific phage strains, combined with the serial-passage technique, may provide insights for developing phage into therapeutically effective antibacterial agents. [TOP OF PAGE]

  167. Bacteriophages of Pseudomonas solanacearum and their potential for biological control of potato bacterial wilt. Mosa,A.A., ABD El-Ghafar,N.Y., Othman,B.A. (1996). Zagazig J. Agric. Res. 23:1053-1063. The biological control of potato bacterial wilt by bacteriophage was studied. Bacteriophage (phages) of Ps. solanacearum was isolated from potato rhizospher soil from El-Twaila at El-Dakahlia governate using the enrichment technique. The most common phage produced circular 4-5 mm in diameter) plaques with a distinct translucent spreeding [sic] halo. The phages had a distinct host range among 44 bacterial isolates from five genera and nine species; the phages lysed only Ps. solanacearum. Thus, these phages could be used to readily differentiate potato isolates of Ps. solanacearum in Egypt. ¶ In greenhouse experiment, tuber seeds of potato cv. Daimont were treated by immersion in suspensions of the phage, virulent Ps. solanacearum, and a 1:1 mixture of phage plus Ps. solanacearum, directly before planting. Treatment of the phage plus Ps. solanacearum simultaneously caused a significant reduction in wild severity compared to the bacterial treatment alone. Tuber yield loss was also greatly reduced significantly. Populations of Ps. solanacearum were greatly reduced, while populations of phages were greatly increased, up to 90 days, in the rhizosphere of simultaneously inoculated treatment compared to single inoculations. This indicates that phage treatment could reduce and limit survival of Ps. solanacearum in soil. [TOP OF PAGE]

  168. The good virus. The use of bacteriophages to fight antibiotic-resistant bacterial diseases. Radetsky,P. (1996). Discover Magazine 17(11), 50-58. Interest in bacteriophage therapy is re-emerging as antibiotic resistance grows among bacterial diseases. Bacteriophage, viruses that can kill bacteria, were discovered by Felic d'Herelle in 1917. Bacteriophage therapy virtually ended with the discovery of antibiotics in the 1940s. [TOP OF PAGE]

  169. Interactions between a genetically marked Pseudomonas fluorescens strain and bacteriophage PHI-R2f in soil: Effects of nutrients, alginate encapsulation, and the wheat rhizosphere. Smit,E., Wolters,A.C., Lee,H., Trevors,J.T., van Elsas,J.D. (1996). Microb. Ecol. 31:125-140. The introduction of bacteriophages could potentially be used as a control method to limit the population size of engineered bacteria that have been introduced into soil. Hence, the ability of a species-specific phage, PHI-R2f, to infect and lyse its host, a Pseudomonas fluorescens PHI-R2f transposon Tn5 derivative, in soil, was studied. Control experiments in liquid media revealed that productive lysis of host cells by phage PHI-R2f occurred when cells were freely suspended, whereas cells present in alginate beads resisted lysis. The presence of nutrients enhanced the degree of lysis as well as the production of phage progeny, both with the suspended cells and with cells escaped from the alginate beads. Experiments in which host cells and phage PHI-R2f were introduced into two soils of different texture revealed that host cells were primarily lysed in the presence of added nutrients, and phage reached highest titres in these nutrient- amended soils. Encapsulation of the host cells in alginate beads inhibited lysis by the phage in soil. Populations of free host cells introduced into soil that colonized the rhizosphere of wheat were not substantially lysed by phage PHI-R2f. However, P. fluorescens R2f populations colonizing the rhizosphere after introduction in alginate beads were reduced in size by a factor of 1,000. Cells migrating from the alginate beads towards the roots may have been in a state of enhanced metabolic activity, allowing for phage PHI-R2f infection and cell lysis. [TOP OF PAGE]

  170. Viruses as biological control agents for blooms of marine phytoplankton. Suttle,C.A. (1996). pp. 71-76. In AnonymousProceedings of the Brown Tide Summit, 20-21 October, 1995. New York Sea Grant Institute???, [TOP OF PAGE]

  171. Pitting Microbe against Microbe. Talan,J. (1996). Newsday ???, ??? [TOP OF PAGE]

  172. Biological warfare: Scientists once again advocate pitting viruses against bacterial infections. Travis,J. (1996). Science News (149), 350-??? [TOP OF PAGE]

  173. Phagotherapy of nosocomial strains of P. aeruginosa, belonging to the o-groups. Gabisonia,T.G., others??? (1995). Georg. Med. News. (I suspect this is "Georgia Medical News" and I also suspect this is Georgia as in the former USSR) N.15:19-21. [TOP OF PAGE]

  174. A study on cyanophages inhibiting the growth of algae producing musty odor. Goto,Y., Kitayama,M. (1995). Water Supply 13:263-266. Recently blue-green algae have grown in large amount in the Lake Biwa. Authors have carried out a study on the cyanophages, which use Phormidium tenue (P. tenue), blue-green alga that produce musty odor in the Lake Biwa, as host and inhibit their growth. The samples used consisted of the surface-layer water in the Lake or the surface running water in Kizu River and Katsura River. A plate culture test by using the double-layered agar method was used in order to detect cyanophages, and the generation of plaque was observed. And, in order to confirm that the cyanophages inhibit the growth of P. tenue, authors also realized a liquid culture test, and observed the growth characteristics of the host. For the plate culture test, three samples presented the formation of plaque. In the liquid culture test, the growth of P. tenue was found to have been inhibited in the three samples. But for all these three samples, P. tenue was not completely killed; therefore, these cyanophages were believed to be temperate phages. By using these cyanophages is expected to be able to inhibit the growth of P. tenue alone without inhibiting the growth of other algae. [TOP OF PAGE]

  175. Biocontrol of bacterial blotch of the cultivated mushroom with lytic phages: Some practical considerations. Munsch,P., Olivier,J.M. (1995). pp. 595-602. In In Elliott,T.J. (ed.), Science and Cultivation of Edible Fungi, Vol. II: Proceedings of the 14th International Congress. Bacterial blotch is the most severe disease in mushroom farms: 10-15 % losses during crop, shelf life and cold storage. ¶ The causal agent is Pseudomonas tolaasii: it belongs to the biovar V of the Pseudomonads complex present in the mushroom bed. Pale cream spots appear on the caps (or on the stipe), they enlarge and become dark brown. The infection doesn't penetrate deeply but the mushroom become unmarketahle. ¶ Mainly practical problems occure [sic] on Agaricus bispoms strains, some others like A.bitorquis, A.campestris, even Pleurotus ostreatus, P.eryngi are susceptible. ¶ The bacteria produces an extracellular toxin "tolaasiine" (a lipodepsipeptide of 18 AA), which is able to disrupt membranes of bacterial, fungal, and still animal cells. ¶ The pathogen propagation and the disease severity are very dependent on relative humidity and T variations. Sciarid and Phorid flies, common vectors increase bacterial spoilage. Direct chemical control is limited, environmental control is not sufficient in case of severe disease incidence. ¶ Selection of less susceptible strains of A.hisponcs is promising (INRA Bordeaux). Biocontrol using an antagonistic bacteria ( 50 % efficiency) is available in Australia and U.K. The control Ievel has been increased by using a bacteriophage, TO1, isolated on diseased mushroom caps; the method is under experiment (INRA Bordeaux). ¶ Kinetics of lytic action has confirmed the TO1 virulence against P.tolaasii. Specifically of lytic action was tested with several strains of P.fluorescens, P..syringae, E.coli, Rhizobium, Erwinia,Bacillus pumilus and P.putida (known for triggering basidiome initiation). ¶ Efficiency of this control was proved in growing condilions: > 50% was noted when TO1 was sprayed onto casing soil. Variability among the pathogen population is on course; occurrence and frequency of lysogeny will be estimated. Variability among the control agent will be established in collaboration with P. and F. Grimont (Institut Pasteur). On the other hand, practical aspects are also considered: improving concentration and purification when large scale preparation of bacteriophages is required, combination of different viruses to prevent resistant bacteria. [TOP OF PAGE]

  176. [The efficacy of bacteriophage preparations in treating inflammatory urologic diseases]. [Russian]. Perepanova,T.S., Darbeeva,O.S., Kotliarova,G.A., Kondrat'eva,E.M., Maiskaia,L.M., Malysheva,V.F., Baiguzina,F.A., Grishkova,N.V. (1995). Urologiia i Nefrologiia 14-17. Urinary infection is the most commonly encountered hospital infection. Antibacterial therapy promotes selection and dissemination of polyresistant microorganism strains, development of intestinal dysbacteriosis, reduction of intestinal contamination resistance. Clinical and bacteriological efficacy of urinary infection treatment with bacteriophage preparations (pyocyanic, proteus, staphylococcal, coliphage, combined pyobacteriophage) was studied. Sensitivity of the infective agent phage isolated from urological patients was tested before treatment. The preparations were adapted to recently isolated agents from urological patients to raise phage sensitivity of the strains. A total of 293 strains were studied. Phage sensitivity made up 68.9%. Bacteriophage preparations were used both locally and orally in 46 patients with acute and chronic urogenital inflammation. Bacteriological efficacy amounted to 84%, clinical one to 92%. It is inferred that phagotherapy is effective and safe therapeutic modality in the treatment of urinary infection in monotherapy and in combination with antibiotics. [TOP OF PAGE]

  177. Pseudomonas aeruginosa bacteriophage in treatment of P. aeruginosa infetion in cystic fibrosis patients. Shabalova,I.A., Karpanov,N.I., Krylov,V.N., Sharibjanova,T.O., Akhverdijan,V.Z. (1995). 443. Zurich, Switzerland, International Cystic Fibrosis Association. Proceedings of IX International Cystic Fibrosis Congress. [TOP OF PAGE]

  178. Bacteriophage: A smart alternative to antibiotics? Dixon,B. (1994). pp. 190-192. In AnonymousThe Power Unseen. W.H.Freeman/Spektrum, Oxford, UK. [TOP OF PAGE]

  179. Rapid detection of Clavibacter toxicus and of its bacteriophage responsible for annual ryegrass toxicity in Australia and the effect of selected herbicides on toxin production. Kurtböke,D.I. (1994). Actinomycetes 5:31-39. Annual ryegrass toxicity bacterium, Clavibactertoxicus, was isolated from toxic ryegrass seeds and livestock feed by exposing the material to bacteriophages affecting plant pathogenic coryneform and saprophytic bacteria. Susceptibility to phages provided a selective means of reducing the cell numbers on isolation plates and hence facilitated the detection and isolation of C.toxicus. Plaque morphology, host range, and particle morphology of the phage isolated are described. Various concentration (20-400 mg/ml) of herbicides, commonly used in Western Australia, Simazine®, Glean®, Hoegrass®, Trifluralin® and Sertin®, were tested to determine their effects on the conversion rate of nontoxigenic C. toxicus strains into toxigenic derivatives by two different bacteriophages isolated from the toxic ryegrass seeds and livestock feed. The number of toxigenic strains increased when herbicide concentrations of 200 and 400 mg/ml were applied. [TOP OF PAGE]

  180. [Bacteriophage therapy in the treatment of recurrent subphrenic and subhepatic abscess with jejunal fistula after stomach resection]. [Polish]. Kwarcinski,W., Lazarkiewicz,B., Weber-Dabrowska,B., Rudnicki,J., Kaminski,K., Sciebura,M. (1994). Polski Tygodnik Lekarski 49:535 The case of recurrent subphrenic abscess with the jejunal fistula after stomach resection in 41-years old male is presented. In microbiological examination E. coli antibiotic-resisted was discovered. The bacteriophages were prepared and administered to the patient. The operation was performed without any antibiotics. During the whole stay at hospital the patient had got bacteriophages. He left the hospital in 33rd day of stay without any abscesses. [TOP OF PAGE]

  181. Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa. Soothill,J.S. (1994). Burns 20:209-211. Infection of split skin grafts in guinea-pigs by Pseudomonas aeruginosa 3719 destroys them, and bacteriophage BS24, lytic for strain 3719, protects the grafts. This supports the view that phage could be used to prevent infection of skin grafts applied to the contaminated wounds of burned patients. ["Demonstrated that destruction of small skin grafts to guinea pigs by P. aeruginosa could be prevented by the prophylactic application of phage. suggesting that phage could be used to prevent infection of skin graphs applied to contaminated wounds of burns patients." Quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  182. Xanthomonas campestris pv. pruni bacteriophages on peach trees and their potential use for biological control. Zaccardelli,M., Saccardi,A., Gambin,E., Minardi,P., Mazzucchi,U., Lemattre,M., Freigoun,S., Rudolph,K., Swings,J.G. (1994). Colloques de l'INRA 875-878. [TOP OF PAGE]

  183. Biological control of mushroom bacterial blotch with bacteriophages. Munsch,P., Olivier,J.M., Fritig,B., Legrand,M.E. (1993). 2nd International Conference of the European Foundation for Plant Pathology , 469. Bactcriel blotch is the most severe disease in mushroom farms: 10-15 % losses during crop, shelf life and cold storage. ¶ The causal agent is Pseudomonas tolaasii : it belongs to the biovar V of the Pseudomonads complex present in the mushroom bed. Pale cream spots appear on the caps (or on the stipe), they enlarge and become dark brown. The infection doesn't penetrate deeply but the mushroom become unmarketable. ¶ Mainly practical problems occure [sic] on Agaricus bispoms strains, some others like A.bitorques, A.campestris, even PIeurotus ostreatus, P.eryngi are susceptible. ¶ The bacteria produces an extracellular toxin "tolaasiine" (a lipodepsipeptide of 18 AA), which is able to disrupt membranes of bacterial, fungal, and still animial cells. ¶ 'The pathogen propagation and the disease severity are very dependent on relative humidity and To variations. Sciarid and Phorid flies, common vectors increase bacterial spoilage. Direct chemical control is limited, environmental control is not sufficient in case of severe disease incidence. ¶ Selection of less susceptible strains of A.bisporus is promising (INRA Bordeaux). Biocontrol using antagonistic bacteria ( 5O% efficiency) is available in Australia and U.K. The control level has been increased by using a bacteriophage, TO1, isolated on diseased mushroom caps; the method is under experiment (INRA Ilordeaux). ¶ Kinetics of lytic action has confirmed the TO1 virulence against P.tolaasii. Specificity of lytic action was tested with several strains of P.,f[uorescens, P.syringae, E.coli, Rhizobium, Erwinia, Bacillus pumilus and P.putida (known for triggering hasidiome initiation). ¶ Efficiency of this control was proved in growing conditions: >50% was noted when TO1 was sprayed onto casing soil. Variability among the pathogen population is on course; occurrence [sic] and frequency of lysogeny will be estimated. Variability among the control agent will be established in collaboration with P. and F. Grimont (Institiit Pasteur). On the other hand, practical aspects are also considered: improving concentration and purification when large scale preparation of bacteriophages is required, combination of different viruses to prevent resistant bacteria. [TOP OF PAGE]

  184. Bacteriophagotherapy and enterosorbtion in treatment of sepsis of newborns caused by gram-negative bacteria. Pavlenishvili,I., Tsertsvadze,T. (1993). Pren. Neon. Infect. 11:104-??? [TOP OF PAGE]

  185. Phage coating of soybean seed reduces nodulation by indigenous soil bradyrhizobia. Basit,H.A., Angle,J.S., Salem,S., Gewaily,E.M. (1992). Can. J. Microbiol. 38:1264-1269. Inoculation of soybean with Bradyrhizobium japonicum is often unsuccessful owing to the failure of inoculum strains to nodulate soybeans (Glycine max (L.) Merr.) in the presence of indigenous strains of rhizobia in soil. Previous studies have shown that it is possible to reduce nodulation with indigenous strains of rhizobia by amending the soil with a bacteriophage specific for the indigenous strain. The objective of the current study was to determine whether the coating of seed with phage affected nodule occupancy and soybean growth. A phage specific for B. japonicum USDA 469 and a symbiotically superior strain of rhizobium (B. japonicum USDA 110) were coated together onto soybean seed and planted into both greenhouse and field soil previously inoculated with B. japonicum USDA 469. The phage coated onto seed reduced nodulation by B. japonicum USDA 469 to 48% occupancy, compared with 64% for the untreated control value. Nodulation by the superior inoculum strain was increased from 48 to 82% occupancy by coating seed with the homologous phage and B. japonicum USDA 110. The rate of nitrogenase activity (on a per plant basis) was increased by coating seed with the phage and B. japonicum USDA 110. No other plant or symbiotic parameters were affected by phage coating of seed. These results indicate that the nodulation of soybeans can be significantly affected by the coating of seed with phage specific for undesirable strains of rhizobia in soil and the concurrent coating of seed with desirable strains of rhizobia. [TOP OF PAGE]

  186. [Immunobiological properties and therapeutic effectiveness of preparations from Klebsiella bacteriophages]. [Russian]. Bogovazova,G.G., Voroshilova,N.N., Bondarenko,V.M., Gorbatkova,G.A., Afanas'eva, EV, Kazakova,T.B., Smirnov,V.D., Mamleeva,A.G., Glukharev,I., Erastova,E.I. (1992). Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii 30-33. The purified preparations of Klebsiella bacteriophages, viz. the monovalent preparation of K. pneumoniae bacteriophage and the polyvalent bacteriophage preparation for the treatment of infections caused by K. ozaenae, K. rhinoscleromatis scleromatis and K. pneumoniae sensu lato, have been obtained. The bacteriophage preparations have proved to be nontoxic and safe for laboratory animals after the intraperitoneal injection of these preparations followed by the pathomorphological study of the internal organs of the animals. The clinical study of the newly developed bacteriophage preparations in the course of the treatment of purulent inflammatory diseases in 109 patients has revealed that the preparations are not reactogenic and exhibit sufficient effectiveness in the therapy of ozena, rhinoscleroma and Klebsiella infections with different localization of the infectious process. [TOP OF PAGE]

  187. Use of polyvalent phage for reduction of streptomycetes on soil dilution plates. Kurtböke,D.I., Chen,C.F., Williams,S.T. (1992). J. Appl. Bacteriol. 72:103-111. An isolation method was developed in which prior to inoculation soil suspensions were exposed to suspensions of polyvalent phage isolated to Streptomyces spp. The phage susceptibility of streptomycetes provided a selective means of reducing streptomycetes on isolation plates subsequent to inoculation, and this reduction was persistent after long incubation periods. The efficiency and applicability of the method developed were checked with different samples from a range of sources. The increased chances of development of other genera after the reduction of streptomycetes on soil dilution plates were assessed. [TOP OF PAGE]

  188. Characteristics and diffusion in the rabbit of a phage for Escherichia coli 0103. Attempts to use this phage for therapy. Reynaud,A., Cloastre,L., Bernard,J., Laveran,H., Ackermann,H.W., Licois,D., Joly,B. (1992). Vet Microbiol 30:203-212. A bacteriophage for Escherichia coli 0103 was isolated during a study on E. coli diarrhoea in intensive breeding units of rabbits. The phage had an isometric head and a short tail and resembled coliphage N4 (Podoviridae). It had a very narrow host range and seemed to be specific for serogroup 0103, suggesting that it might be used for preliminary identification of E. coli strains of this serogroup instead of the usual slide agglutination. In view of its possible use as a therapeutic phage, we investigated its dissemination in rabbit organs after oral administration. The phage persisted in the spleen for at least 12 days. However, in vivo studies showed that this phage and a mixture of more virulent phages for E. coli 0103 were ineffective in preventing disease in rabbits inoculated with an enteropathogenic strain of E. coli 0103. [TOP OF PAGE]

  189. Treatment of experimental infections of mice with bacteriophages. Soothill,J.S. (1992). J. Med. Microbiol. 37:258-262. Bacteriophages for Acinetobacter baumanii, Pseudomonas aeruginosa and Staphylococcus aureus were tested in experimental infections of mice to investigate their potential for the treatment of infections of man. As few as 10(2) particles of an acinetobacter phage protected mice against 5 LD50 (1 x 10(8)) of a virulent strain of A. baumanii, and phage was demonstrated to have multiplied in the mice. A pseudomonas phage protected mice against 5 LD50 of a virulent strain of P. aeruginosa, with a PD50 of 1.2 x 10(7) particles. A staphylococcal phage failed to protect mice infected with a strain of S. aureus. These studies support the view that bacteriophages could be useful in the treatment of human infections caused by antibiotic-resistant strains of bacteria. [TOP OF PAGE]

  190. The activity in the chicken alimentary tract of bacteriophages lytic for Salmonella typhimurium. Berchieri,A.jr., Lovell,M.A., Barrow,P.A. (1991). Res. Microbiol. 142:541-549. Bacteriophages lytic for Salmonella typhimurium were isolated in considerable numbers from chickens experimentally infected with S. typhimurium, and in much lower numbers from the chicken feed. Lytic phages were also regularly isolated from human sewerage systems. One of these was used to inoculate S. typhimurium--infected two day-old chickens orally and via the feed. The phage took longer to establish in the caeca than did the Salmonella and it disappeared when the caecal S. typhimurium counts fell to 10(6) CFU/ml. No neutralizing antibodies to the phage were detected in the serum of these chickens. In a second experiment, five of 30 chickens similarly infected with S. typhimurium were inoculated with the phage. Within 3 days, the phage was isolated from 72% of the "in-contact" birds. A second phage, isolated from sewage, when inoculated into newly-hatched chickens simultaneously with any of 3 strains of S. typhimurium, produced a considerable reduction in mortality in the birds. This effect was only produced by inoculation of high concentrations of phage (greater than 10(10) PFU/ml). The phage produced reductions in the viable numbers of S. typhimurium in the crop, small intestine and caeca for up to 12 h after inoculation, with smaller reductions in bacterial numbers in the liver at 24 and 48 h after infection. ["Extended work on veterinary diarrhoea to Salmonella in poultry. . . Fewer chicks died . . . when . . . phages were given orally soon after the bacteria were administered." Quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  191. Effektivnost' bakteriofaga Klebsiella pneumoniae pri terapii eksperimental'noi klebsielleznoi infektsii.[The efficacy of Klebsiella pneumoniae bacteriophage in the therapy of experimental Klebsiella infection]. [Russian]. Bogovazova,G.G., Voroshilova,N.N., Bondarenko,V.M. (1991). Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii 4:5-8. The effectiveness of specific phage therapy was studied on Klebsiella experimental sepsis in noninbred white mice, caused by the intraperitoneal injection of K. pneumoniae highly virulent strain K2 5055 into the animals. For treatment, Klebsiella polyvalent bacteriophage administered on day 2 after the infection of the animals with Klebsiella was used. The study revealed that bacteriophage could be detected in the blood and internal organs of the animals within 24 hours irrespective of the route of its administration: intraperitoneal, intravenous or intranasal. The bacteriophage preparation, introduced intraperitoneally, was shown to be effective in the treatment of generalized Klebsiella infection. One daily intraperitoneal injection of Klebsiella bacteriophage for 15-20 days proved to be the optimum scheme of treatment. In contrast to chemotherapeutic preparations, bacteriophages had no effect on normal microflora and did not aggravate dysbiotic disturbances. For this reason, bacteriophages may become one of alternative antimicrobial remedies, selectively affecting infective agents. [TOP OF PAGE]

  192. Process for retarding bacterial growth in cheese. Day,C.A., Holton,B.W. (1991). Microbial Development Ltd. 350215(5,006,347). England. The present invention discloses the use of bacteriophages for controlling unwanted fermentation of cheese by bacteria. [TOP OF PAGE]

  193. Host-controlled modificaiton and restriction as a criterion of evaluating the therapeutical potential of Pseudomonas phage. Gachechiladze,K.K., Balardshishvili,N.S., Adamia,R.S., Chanishvili,T.G., Kruger,D.H. (1991). J. Basic Microbiol. 31:101-106. [TOP OF PAGE]

  194. Experimental control of bacterial blotch by bacteriophages. Munsch,P., OLIVIER,J.L., Houdeau,G. (1991). pp. 389-396. In In Maher,M.J. (ed.), Mushroom Science. Rotterdam, Netherlands. Recent experimentations have confirmed the efficiency of a biological control of bacterial blotch (agent Pseudomonas tolaasii) using specific bacteriophages ; as previously reported by GuillaumBs et al. (1988). More information has been collected including TEN observation of the phages, kinetic of lytic action, specificity ... The more efficient virus is a typical "T type" phage without any lytic effect on Pseudomonas putida. P.fluorescens sensus stricto and other. This selected phage has been used for biological control under experimental conditions (bags filled with 4 Kg of spawned compost each), alone or mixed with an antagonistic bacteria (P. fluorescens) previously described (Olivier and Guillaumis. 1981). In these medium scale experiments, a 70% reduction of the crop losses can be achieved with the phages sprayed on the casing soil. Different problems have to be solved before going through larger experiments; possibility of lysogeny, resistance of P.tolaasii to phages, validity under other environmental conditions, effect on Pseudomonas involved in the browning process during shelf-life. [TOP OF PAGE]

  195. The virus that eats bacteria. Radetsky,P. (1991). pp. 74-88. In AnonymousThe Invisible Invaders: The Story of the Emerging Age of Viruses. Little Brown & Company, Boston. [TOP OF PAGE]

  196. The combined use of specific phages and antibiotics in different infectious allergoses. Sakandelidze,V.M. (1991). Vrach. Delo 3:60-63. [TOP OF PAGE]

  197. Pathomorphological evaluation of therapeutic effect of mycophages in tuberculosis. Zemskova,Z.S., Dorozhkova,I.R. (1991). Probl. Tuberk. 11:63-66. [TOP OF PAGE]

  198. Bacteriophage therapy of pseudomonas burn wound sepsis. Abdul-Hassan,H.S., El-Tahan,A., Massoud,B., Gommaa,R. (1990). Annals of the Mediterranean Burn Club 3, 4:262-264. [TOP OF PAGE]

  199. Control of soft rot Erwinias with bacteriophages [Abstract]. Eayre,C.G., Concelmo,D.E., Bartz,J.A. (1990). Phytopathology 80(10), 994. Bacteriophages of Erwinia carotovora subsp. Carotovora were isolated from lake water by a standard enrichment technique. At least 16 different phages were identified based on host range against 71 strains of soft rot erwinias. One phage caused plaques in lawns of at least one strain of each of the three major soft rot erwinas [sic], e.g., E. c. atroseptica, E. c. carotovora, and E. chrysanthemi. Certain phages infected up to 65% of strains of E. c. carotovora. However, none of the phages caused plaques in lawns of E. herbicola. Bacterial soft rot in slices of potato tubers was prevented when [sic] 12 l of 106 cfu E. c. carotovora/ml. When the concentration of the inoculum was 10-fold greater, some decay occurred, but lesion diameters were reduced by the bacteriophage. [TOP OF PAGE]

  200. Inability of a bacteriophage pool to control beef spoilage. Greer,G.G., Dilts,B.D. (1990). Int. J. Food Microbiol. 10:331-342. The biological control of beef spoilage, with a bacteriophage (phage) pool, was evaluated under simulated retail conditions. A pool of seven phages was selected with the potential to lyse 78% of 86 Pseudomonas test strains. Subsequent host range studies with 1023 pseudomonads from three meat species (beef, pork, lamb) and five abattoirs showed that 585 (57.2%) isolates were susceptible to the phage pool. Depending on bacterial origin, bacterial sensitivity to lysis by the phage pool varied from 25 to 72%. When added to ribeye steaks, the phage pool produced a significant reduction in Pseudomonas growth but this was not sufficient to produce any significant effect upon the retail shelf life of beefj. The inability of phages to control beef spoilage was not attributed to a loss of phage virulence since sufficient densities (log pfu/cm2 - 5 to 6) of virulent phage could be re-isolated from beef, 14 days after treatment. It was concluded that the efficacy of the current phage pool was limited by a narrow range of specificity. [TOP OF PAGE]

  201. Use of bacteriophages and antibiotics for prevention of acute postoperative empyema in chronic suppurative lung diseases. Kaczkowski,H., Weber-Dabrowska,B., Dabrowski,M., Zdrojweicz,Z., Cwioro,F. (1990). Wiad. Lek. 43:136-141. [TOP OF PAGE]

  202. Bacteriophages and their therapeutic-prophylactic use. Chernomordick,A.B. (1989). Med. Sestra. 6:44-47. [TOP OF PAGE]

  203. Bacteriophage prevention and control of harmful plant bacteria US PATENT-4828999. MAY 9 1989. Jackson,L.E. (1989). 887348(4,828,999). For preventing or controlling bacterial harm to plants, as by disease or ice nucleation, a bateriophage composition of matter containing one or more viral h mutants specific to amutant of the bacteria concerned is produced and applied to seed, soil or soil supplements, plants, or plant materials that have been exposed to or are contaiminated with or infected by bacerial disease, or to growing plants subject to ice nucleation or other bacterial harm. The invention is concerned with the composition and with the method of producing and using same. [TOP OF PAGE]

  204. [Phagotherapy of postoperative suppurative-inflammatory complications in patients with neoplasms]. [Russian]. Kochetkova,V.A., Mamontov,A.S., Moskovtseva,R.L., Erastova,E.I., Trofimov,E.I., Popov,M.I., Dzhubalieva,S.K. (1989). Sovetskaia Meditsina 23-26. The authors assess the efficacy of phage therapy ofsuppurative and inflammatory complications in oncological patients. A clinical and laboratory analysis has involved 131 patients whose etiotropic therapy consisted of bacteriophages (65 patients) and antibiotics (66). Medicinal phages, manufactured by the Tbilisi Research Institute for Vaccines and Sera, have been administered according to 3 schemes: (1) parallel with antibiotics, (2) after long ineffective antibiotic therapy, (3) phages alone starting from the onset of the purulent complication. The preparations have been prescribed with due consideration for the isolated microflora sensitivity. Incorporation of phages in combined therapy of infectious complications has yielded positive results in 81.5% of cases, whereas antibiotics have proved effective in but 60.6%. The efficacy of phage therapy depends on the type of pyoinflammatory complications (the results are the best in the management of wound infections), the microflora pattern of the purulent foci (phages are the most effective with a corresponding monoinfection), characteristics of the therapeutic phages proper (Pseudomonas aeruginosa phage is characterized by the highest therapeutic activity, as compared to staphylococcal and other phages). [TOP OF PAGE]

  205. Control of microbiofouling using bacteriophage 2. Detection of phages and fundamental study of their lytic effect on fouling bacteria. Sakaguchi,I., Shinshima,K., Kawaratani,K., Sugai,O. (1989). Denryoku Chuo Kenkyusho Hokoku 1-32. Microbiofouling of condenser tubes of thermal power plants markedly reduces cooling efficiency. Recently a method for controlling microbiofouling using bacteriophages has been receiving consideration. In this paper, studies of the ecological relationship between fouling bacteria and phages, and the lytic activity of phages to fouling bacteria are reported. With thirty cultures of the isolated fouling bacteria from microbial film on glass substratum immersed in flowing seawater at Sendai Bay in north Japan, we carried out the detection and isolation of phages lysing the bacteria from seawater from October 1987 to December 1988 about once per month. The results obtained were as follows: Seventeen cultures were sensitive to phages and were found to belong to Pseudomonas (12 strains), Acinetobacter - Achromobacter (3 strains), Vibrio (1 strain) and Flavobacterium (1 strain). Eighteen strains of phages were isolated. A high frequency of phage incidence was observed with the cultures of rapid growing bacteria. But, for cultures of slow growing bacteria, phages were rarely isolated. Under different M.O.I.(multiplicity of infection), the lytic activity of phage to host bacteria was studied. At M.O.I. higher than 0.1, the phage could effectively lyse host bacteria after 5-7 hr of infection. At M.O.I. lower than 0.01, the low level of bacteria concentration was maintained with only slight increase until 48 hr after infection. Various filamentous bacteria were commonly found as predominant species in condenser tube microbiofouling communities. However we were unable to grow the filamentous bacteria in the standard culture medium used in these experiments. Development of culture methods is necessary in order to develop control methods for filamentous bacteria. [TOP OF PAGE]

  206. Improvement of the biocontrol of Pseudomonas tolaasii using bacteriophages associated with an antagonistic bacterium. Guillaumes,J., Houdeau,G., Germain,R., Olivier,J.M. (1988). Bull. OEPP 18:77-82. Improvement of the biocontrol of Pseudomonas tolaasii using bacteriophages associated with an antagonistic bacterium. No chemical control of mushroom bacterial blotch, due to Pseudomonas tolaasii, is available today. Biocontrol using an antagonistic strain of Pseudomonas fluorescens decreases losses with an efficiency of 30-60%, but this is insufficient in practice and so an improvement of the method is required. Among different possibilities, we have studied the use of lytic bacteriophages. Several phages were purified from diseased mushroom caps. Their selectivity was tested using many saprophytic and pathogenic bacteria isolated from different ecosystems. We selected phages strongly aggressive in P. tolaasii and only moderately so in the P. fluorescens strain used for biocontrol. In this way it should be possible to build up a strategy for protecting the casing soil by spraying a mixture of antagonistic bacteria and phages. The first experiments showed that the effects of the antagonistic bacteria and of the phages were additive. The decrease in symptoms was highly significant (> 80%). However, several points have to be resolved before application on a larger scale can be envisaged. Questions also arise on the effect of bacteriophages on the natural population dynamics of Pseudomonas spp. useful or pathogenic to mushrooms. [TOP OF PAGE]

  207. The efficacy of phages in the prevention of the destruction of pig skin in vitro by Pseudomonas aeruginosa. Soothill,J.S., Lawrence,J.C., Ayliffe,G.A.J. (1988). Med. Sci. Res. 16:1287-1288. [TOP OF PAGE]

  208. Method and compositions for use in the treatment of fireblight. Vedamuthu,E.R., Vidaver,A.K. (1988). Microlife Technics, Inc. 920754(4,783,406). Sarasota, FL. A method and compositions for the treatment of fireblight disease in plants are described. The compositions include a phage for Erwinia amylovora which produces fireblight and an enzyme produced by the phage which depolymerizes a polysaccharide produced by Erwinia amylovora which is the cause of the fireblight disease. Purified enzyme preparations are described. [TOP OF PAGE]

  209. Bacteriophage treatment of suppurative skin infections. Cislo,M., Dabrowski,M., Weber-Dabrowska,B., Woyton,A. (1987). Archivum Immunologii et Therapiae Experimentalis 35:175-183. The study material comprised 31 patients with chronic suppurative infections of the skin caused by Pseudomonas, Staphylococcus, Klebsiella, Proteus and Escherichia. Within 2-16 weeks of the treatment, an improvement of the general state was observed as well as suppression of the local inflammation, purification of a wound from the suppurative and necrotic content, faster healing of the ulcers and fully negative results of the bacteriologic tests. In 16 cases, an outstanding therapeutic effect was obtained, in 7 cases marked improvement was reported and in 2 a transitory improvement was reported. In 7 patients the treatment was abandoned due to the lack of improvement (1 case) or development of side effects (6 cases). The results obtained provide evidence for the high effectiveness of phage therapy in the treatment of suppurative skin infections. [TOP OF PAGE]

  210. Bacteriophage therapy. Dixon,B. (1987). British Medical Journal Clinical Research Ed . 294:1168 [TOP OF PAGE]

  211. Immunogenic effect of bacteriophage in patients subjected to phage therapy. Kucharewicz-Krukowska,A., Slopek,S. (1987). Archivum Immunologii et Therapiae Experimentalis 35:553-561. Fifty seven cases of bacterial infections subjected to phage therapy were tested for a production of antibodies against the applied bacteriophages. Monoinfections confirmed in 40 patients were caused in majority of cases by pyogenic Staphylococci (29 cases) and rarely by Gram-negative bacteria: Klebsiella, Escherichia, Proteus and Pseudomonas (11 cases). Polyinfections caused by the above types of bacteria were recorded in 17 cases. The titer of neutralizing and hemagglutinating antibodies was determined before phage therapy, in the 10th day and in some cases in the 21st day of its course. The effect of natural and immune antibodies on the final result of therapy was analyzed. [TOP OF PAGE]

  212. Immunogenic effects of bacteriophage in patients subjected to phage therapy. Kucharzewicz-Krukowska,A., Slopek,S. (1987). Arch. Immunol. Ther. Exp. 35:553-561. [TOP OF PAGE]

  213. Results of bacteriophage treatment of suppurative bacterial infections in the years 1981-1986. Slopek,S., Weber-Dabrowska,B., Dabrowski,M., Kucharewicz-Krukowska,A. (1987). Arch. Immunol. Ther. Exp. 35:569-583. In the years 1981-1986 bacteriophage therapy was applied in 550 cases (100 treated in 1986) of suppurative bacterial infections. Positive results were obtained in 508 cases (92.4%). In 38 cases (6.9%) a transient improvement was observed and in 4 cases (0.7%) phage treatment proved ineffective. Considering that majority of patients (518 cases, 94.2%) were resistant to antibiotic treatment, the results of phage therapy may be regarded as favorable. [TOP OF PAGE]

  214. The control of experimental Escherichia coli diarrhoea in calves by means of bacteriophages. Smith,H.W., Huggins,M.B., Shaw,K.M. (1987). J. Gen. Microbiol. 133:1111-1126. Seven phages highly active in vitro and in vivo against one or other of seven bovine enteropathogenic strains of Escherichia coli belonging to six different serotypes were isolated from sewage. Severe experimentally induced E. coli diarrhoea in calves could be cured by a single dose of 10(5) phage organisms. It could be prevented by doses as low as 10(2), by spraying the litter in the calf rooms with aqueous phage suspensions or simply by keeping the calves in uncleaned rooms previously occupied by calves whose E. coli infections had been treated with phage. Microbiological examinations of calves used in these experiments revealed that the phage organisms multiplied rapidly and profusely after gaining entry to the E. coli-infected small intestine, quickly reducing the E. coli to numbers that were virtually harmless. The only phage-resistant E. coli that emerged in the studies on calves infected with one or other of the seven E. coli strains were K-. These organisms were much less virulent than the K+ organisms from which they were derived and did not present a serious problem in calves given adequate amounts of colostrum. Infections produced by oral inoculation of a mixture of six strains of the E. coli could be controlled by administration of a pool of the six phages that were active against them but, in general, the control was less complete than that observed in the single-strain infections. K+ phage-resistant bacteria emerged in some of the calves used in these mixed infections and they were as virulent as their parent organisms; evidence from in vitro studies suggested that they might have arisen by genetic transfer between organisms of the different infecting strains. Infections produced by these K+ mutants and their parents could be controlled by the use of mutant phages derived from phages that were active on their parents. During the experiments with mixed E. coli infection, an extraneous phage active against one of the six E. coli strains suddenly appeared in calves kept in the same rooms. Microbiological examinations revealed that this phage was effectively controlling the multiplication of organisms of that particular strain of E. coli in the small intestines of the calves. [TOP OF PAGE]

  215. Method and compositions for use in the treatment of fireblight. Vedamuthu,E.R., Vidaver,A.K. (1987). Microlife Technics, Inc. 662065(4,678,750). Sarasota, FL. A method and compositions for the treatment of fireblight disease in plants are described. The compositions include a phage for Erwinia amylovora which produces fireblight and an enzyme produced by the phage which depolymerizes a polysaccharide produced by Erwinia amylovora which is the cause of the fireblight disease. Purified enzyme preparations are described. [TOP OF PAGE]

  216. Studies on bacteriophage penetration in patients subjected to phage therapy. Weber-Dabrowska,B., Dabrowski,M., Slopek,S. (1987). Archivum Immunologii et Therapiae Experimentalis 35:563-568. Two healthy volunteers and 56 patients with suppurative bacterial infections were tested for penetration of oral administered bacteriophage to the blood circulation system and urinary tract. In the blood and urine samples collected from patients before phage therapy application, no presence of "wild phages" was confirmed. Examination performed on the 10th day of phage therapy revealed the presence of bacteriophages in 47 of 56 blood samples tested; positive result of examination was obtained in 9 cases of 26 urine samples. [TOP OF PAGE]

  217. The epizootic of milkfish vibriosis and its biological control by bacteriophage AS10. Wu,J.L., Chao,W.J. (1987). In Kou,K.S., Wu,J.L., Hsu,Y.L., Chen,S.N., Tung,M.C., Liao,I.C., and Chung,H.Y. (eds.), The Memoir of Virology and Pharmacology in Fish Disease. 3. Taipei. The bacteriophage which infect and lyse Vibrio anguillarum , the pathogen of milkfish vibriosis, was isolated from the overwintering ponds and was named AS10. AS10 had wide spectrum of host range by showing 100% of the virulence in 18 strains of V. anguillarum isolated from the Taiwan area. The optimal stable salinity range of AS10 is 15-45%. By exposing to ultraviolet irradiation, the loss of AS10 infectivity is linearly correlated with U.V. fluence. The pathogenicity of V. anguillarum was almost completely eliminated after 4 h. by AS10 infection at an M. O. I.-1. In the field trial, it is proved that the vibriosis can be inhibited by AS10 application in milkfish overwintering ponds. [TOP OF PAGE]

  218. Predatory Myxobacteria: Lytic Mechanisms and Prospects as Biological Control Agents for Cyanobacteria (Blue-Green Algae). Lake Restoration: Protection and Mangement. Burnham,J.C., Fraleigh,P. (1986). U.S.EPA Symposium Volume EP-A4401/583001, 249-256. To control problem growths of primary producers in lakes and ponds, especially blooms of blue-green algae and high densities of macrophytes, a diversity of methods have been proposed and are used. However, absent in this repertoire are methods of biological control analogous to those that have been successful in terrestrial ecosystems. Presented here is a discussion of studies that suggest that myx- obacterial predation may be useful in biological control of blue-green algae in aquatic ecosystems. algae and high densities of macrophytes, a diversity of methods have been proposed and are used. However, absent in this repertoire are methods of biological control analogous to those that have been successful in terrestrial ecosystems. Presented here is a discussion of studies that suggest that myxobacterial predation may be useful in biological control of blue-green algae in aquatic ecosystems. [TOP OF PAGE]

  219. Bacteriophage control of beef spoilage. Greer,G.G. (1986). J. Food Prot. 49:104-??? [TOP OF PAGE]

  220. Homologous bacteriophage control of Pseudomonas growth and beef spoilage. Greer,G.G. (1986). J. Food Prot. 49:104-109. The effects of homologous bacteriophages upon growth of a beef spoilage pseudomonad and the retail case life of beef were examined under conditions of simulated retail display. Initial studies with an aqueous extract of beef muscle showed Pseudomonas growth was significantly limited by phages for up to 3 d at 7 degrees C. Subsequently, it was shown that the treatment of Pseudomonas-inoculated steaks with high titer phage lysates (108 PFU/ml) resulted in a 1- to 2-log reduction in the level of bacterial contamination and a 2-log increase in phage numbers after 4 d of retail display. These changes were accompanied by a marked decrease in steak surface discoloration and a concurrent improvement in retail acceptance. Steak case life was positively correlated with phage concentration within the range of 10 to 108 PFU/ml. At the highest concentration of phages tested (108 PFU/ml) steak case life was significantly increased from 1.6 to 2.9 d. It was concluded that phages could multiply on the steak surface and have the potential for the biological control of beef spoilage. [TOP OF PAGE]

  221. Efficiency of preventive treatment by phage preparations of children's hospital salmonellosis. Kilnadze,G.P., Gadua,M.M., Tsereteli,E.V., Mchedlidze,L.S., Birkadze,T.V. (1986). pp. 41-44. In In Kiknadze,G.P. (ed.), Intestinal Infections. Sovetskaya Meditsina, Tbilisis, Georgia. [TOP OF PAGE]

  222. Constraints on the coevolution of bacteria and virulent phage: A model, some experiments, and predictions for natural communities. Lenski,R.E., Levin,B.R. (1985). Am. Nat. 125:585-602. One view of the coevolution of parasites and their hosts is that of a gene-for-gene arms race between host defenses and parasite counterdefences. We have incorporated mutations into a model of the ecological interactions between bacteria and virulent phage to determine rates of mutation that would be consistent with this scenario. The model assumes an open habitat (e.g., a chemostat) in which virulent phage and sensitive bacteria can coexist. Equilibrium densities of bacteria and phage are inversely proportional to the efficiency with which phage irreversibly adsorb to their hosts. The absolute rate at which mutations appear is proportional to the product of habitat size, population density, rate of increase, and mutation rate. ¶ The bacterium Escherichia coli B readily evolved resistance to virulent phage T4 in our chemostat experiments. Approximately 100 h was required for the appearance, establishment, and attainment of a resourse-limited population of these T4-resistant mutants; this time period is close to that predicted from the model when the parameters of the model are estimated independently. No hostrange phage T4 mutants appeared, yet the phage persisted even after the resistant bacteria had become resource-limited. We hypothesized that the failure to observe corresponding phage mutants indicates mutational constraints on the coevolutionary potential of this phage. We also hypothesized that the persistence of the wild-type phage indicates the presence of a minority population of sensitive bacteria that persists because of selective constraints which produce a competitive disadvantage for resistant baceria under resource-limiting conditions. Both of these hypotheses were verified. Host-range T4 mutants occurred at a rate on the order of 10-12 or less, and could not be expected in the chemostats for several years. T4-sensitive and -resistant bacteria had very nearly the same exponential growth rates, but at steady state the latter had approximately a 50% disadvantage. ¶ We also examined the interactions of E. coli B and virulent phages T2, T5, and T7 for evidence of selective and mutational constraints on the bacteria and phage, respectively. Under the conditions of our experiments, T2-resistant and T7-resistant (but not T4-resistant) bacteria also had clear competitive disadvantages to sensitive bacteria udner resource-limiting conditions. We were able to isolate T2 and T7 (but not T5) host-range mutants. Even with T2 and T7, however, we could not select indefinitely for host-range mutants active against higher-order resistant bacteria. This general asymmetry in the coevolutionary potential of bacteria and phage occurs becuase mutations conferring resistance may arise by either the loss or alteration of gene function, while host-range mutations depend on specific alterations of gene function. ¶ These constraints preclude observing endless arms races between baceria and virulent phage. Instead, because of the asymmetry in coevolutionary potential of these hosts and parasites, we anticipated that natural communities of coliform bacteria and virulent coliphage are dominated by bacterial clones resistant to all co-occurring virulent phage. If virulent pahge to which the dominant clones are sensitive should appear, then bacteria will either rapidly evolve resistance or be replaced by existing clones resistant to the phage. Thus, the role of virulent phage in structuring communities of bacteria is seen as important in determining clonal composition but uninportant in determining bacterial densities. [TOP OF PAGE]

  223. Bacteria and phage: A model system for the study of the ecology and co-evolution of hosts and parasites. Levin,B.R., Lenski,R.E. (1985). pp. 227-242. In In Rollinson,D. and Anderson,R.M. (eds.), Ecology and Genetics of Host-Parasite Interactions. Academic Press, London. The results are reviewed of theoretical and experimental investigations of the population biology of bacteria and bacteriophage, emphasizing those apsects of general interest in the study of host-parasite ecology and evolution. ¶ 1) Existence conditions: the conditions are considered udner which phage can invade bacterial populations and will stably co-exist with these hosts. Particular emphasis is given to the effects of phage resistant bacterial clones on these communities, and hypotheses are presented to account for the observation that experimental populations of bacteria and virulent phage are more stable than anticipated from theory. ¶ 2) Co-evolution: The nature and effects of selection on the interacting populations of bacteria and phage are examined. Evidence is presented that the resulting co-evolution is a constrained process, rather than the indefinite gene-for-gene arms race previously postulated. ¶ 3) Latency: Temperate bacteriophage are analogous to the latent virusses of eukaryotes. We critically discuss three classes of hypotheses for the ecological conditions and selective pressures responsible for the evolution and maintenance of temperate (as opposed to virulent) modes of phage reproduction. ¶ 4) Immunity: Bacterial restriction-modification systems are similar to the immune systems of higher organisms. The hypothesis is considered that restriction-modification systems evolved nad are maintained for the defence against phage infection and we speculate on the effects of this type of immune system on the population dynamics of bacteria and phage. ¶ 5) Coda: This review is concluded with a brief consideration of the use of phage for the biological control of bacteria. [TOP OF PAGE]

  224. Large-scale production of pruniphage for biocontrol of prunus bacterial spot disease in field. Randhawa,P.S., Civerolo,E.L. (1985). Phytopathology 75(11), 1328. High titre phage lysates (1011 – 1012 pfu/ml) were prepared by incubating Xanthomonas campestris pv. Pruni (Xcp) and pruniphage in nutrient glucose sodium chloride broth for 24 h. Pruniphage was purified by precipitation from lysates adjusted to 7.5% polyethylene glycol (PEG) and 0.5 M sodium chloride. Crude phage lysates diluted in tap water and containing 107 to 109 pfu/ml reduced bacterial spot disease on apricot fruits but lysates in which infectivity was neutralized with anti-phage serum were ineffective. Partially purified phage in tap water reduced bacterial spot disease on foliage of commercial peach trees at two of four selected locations. On young symptomless leaves on phage-treated peach trees 42-50% of the Xcp population was prunihpage resistant and different in plasmid DNA content from the phage propagating strains. [TOP OF PAGE]

  225. Results of bacteriophage treatment of suppurative bacterial infections. V. Evaluation of the results obtained in children. Slopek,S., Kucharewicz-Krukowska,A., Weber-Dabrowska,B., Dabrowski,M. (1985). Archivum Immunologii et Therapiae Experimentalis 33:241-259. The results of phage therapy applied in 114 cases of suppurative bacterial infections in children were analyzed. Positive therapeutic results were obtained in 109 (95.6%) cases. The results confirmed great effectiveness of bacteriophages in the treatment of septic infections, spontaneous or postoperative, caused by pyogenic Staphylococci, Klebsiella, Escherichia, Proteus and Pseudomonas bacteria. [TOP OF PAGE]

  226. Results of bacteriophage treatment of suppurative bacterial infections. VI. Analysis of treatment of suppurative staphylococcal infections. Slopek,S., Kucharewicz-Krukowska,A., Weber-Dabrowska,B., Dabrowski,M. (1985). Archivum Immunologii et Therapiae Experimentalis 33:261-273. Analysis of phage therapy results was carried out on 273 cases of spontaneous and postoperative septic staphylococcal infections. The treatment appeared effective in 254 (93.0%) cases. Detailed analysis of the results obtained in particular disease categories revealed that staphylococcal bacteriophages may be efficiently applied in the treatment of suppurative staphylococcal infections resistant to antibiotics. [TOP OF PAGE]

  227. Results of bacteriophage treatment of suppurative bacterial infections. IV. Evaluation of results obtained in 370 cases. Slopek,S., Kucharewicz-Krukowska,A., Weber-Dabrowska,B., Dabrowski,M. (1985). Arch. Immunol. Ther. Exp. 33:219-240. [TOP OF PAGE]

  228. [Experience with bacteriophage therapy in nonspecific suppurative lung diseases]. [Russian]. Timoshchuk,I.I., Natsiashvili,E.I., Chanishvili,T.G., Meladze,G.D. (1985). Grudnaia Khirurgiia 11-13. [TOP OF PAGE]

  229. Preventive effectiveness of dried polyvalent Shigella bacteriophage in organized collective groups. Anpilov,L.I., Prokudin,A.A. (1984). Voenno-Med. Zh. 5:39-40. [TOP OF PAGE]

  230. Attack of the phages. Dixon,B. (1984). Science 84 , 66-69. [TOP OF PAGE]

  231. The use of a lytic bacteriophage to remove Rhizobium trifolii from protoplast culture of Trifolium repens. Graves,D.A., Beck,R.W. (1984). Plant Sci. Lett. 34:385-389. A lytic rhizobiophage was isolated and used to remove non-internalized Rhizobium trifolii from protoplast cultures of Trifolium repens following treatment of bacteria and protoplasts with polyethylene glycol. The phage was shown to kill R. trifolii in plant cell culture media. The lytic phage served as an alternative to the use of antibiotics for the removal of external contaminating R. trifolii in protoplast cultures. [TOP OF PAGE]

  232. Psychrotropic bacteriophages for beef spoilage bacteria. Greer,G.G. (1984). Journal of Food Protection 47, 822. The objectives of this study were to isolate, purify and characterize virulent bacteriophages for beef spoilage bacteria. Thirty-eight phages, lytic for 1 or more of 37 Pseudomonas strains and 21 phages lytic for 1 or more of 16 Brocothrix thermosphacta strains, were successfully isolated from spoiled rib steaks. The psychotrophy of the B. thermosphacta phages was demonstrated by an increase in plaque size and plating efficiency as incubation temperatures were decreased from 25 to 1ºC. Electron microscopy of two homologous B. thermosphacta phages showed the virions consist of hexagonal heads and tails ranging in total length from 210 to 280 nm. On the basis of differential susceptibility to phage lysis a phage typing scheme was established which would provide a sensitive means of distinguishing different strains of beef spoilage bacteria. In addition, phages resulted in a pronounced inhibition of bacterial growth in a culture medium prepared from an aqueous extract of homogenized beef muscle. Phages may provide a unique method for biological control of beef spoilage. [TOP OF PAGE]

  233. Control of microbiofouling formed on the heat exchanger by bacteriophage. Kaminura,K., Araki,M. (1984). pp. 40-46. In AnonymousProceedings of the Pacific Congress on Marine Technology (Honolulu, Hawaii). The surface of the heat exchangers using natural seawater is usually covered with the microbial films formed by the attachment and growth of marine bacteria during their operation. The formation of the microbial film lowers the total heat transfer coefficient because of its low thermal-conductivity and then leads to the decrease of the efficiency of the heat exchanger system. In the OTEC system which utilizes the small temperature difference between warm surface water and cold depth water as energy source, it becomes important to control the marine microbiofouling. This report, discusses the isolation and characterization of marine bacteriophages which lyse fouling bacteria and the application of bacteriophages to controlling a marine microbiofouling. [TOP OF PAGE]

  234. Mucoid conversion by phages of Pseudomonas aeruginosa strains from patients with cystic fibrosis. Miller,R.V., Renta Rubero,J.R. (1984). J. Clin. Microbiol. 19:717-??? [TOP OF PAGE]

  235. Inhibition of Xanthomonas campestris pathovar pruni by bacteria and pruniphage on detached peach leaves. Randhawa,P.S., Civerolo,E.L. (1984). Phytopathology 74(7), 864. Inhibition of Xanthomonas campestris pv pruni (X. pruni) by bacteria isolated from apricot and peach leaves and a pruniphage was studied on young detached leaves of greenhouse grown peaches. Detached leaves were washed with 70% ethanol for 1 min and placed on 0.5% water agar with their adaxial side up. Suspensions of test bacteria (A600=0.1) or pruniphage (2x10-2x109) were mixed with suspension of X. pruni (1x108 cfu/ml) in 1:1 ratio and placed on 100 sites on 5 leaves @ 5 ul/site. After incubation for 0 and 120 hr at 25C under 16 hr photoperiod, leaves were assayed for surface and internal population of X. pruni. Four of 47 bacterial strains reduced surface population and 6 reduced internal population by 95% or more. Pruniphage at pfu/cfu ratio of 2 reduced surface as well as internal population by more than 95%. [TOP OF PAGE]

  236. [Bacteriophages and phage therapy in pediatric practice]. [Review] [21 refs] [Russian]. Samsygina,G.A., Boni,E.G. (1984). Pediatriia 67-70. [TOP OF PAGE]

  237. Results of bacteriophage treatment of suppurative bacterial infections. III. Detailed evaluation of the results obtained in further 150 cases. Slopek,S., Durlakowa,I., Weber-Dabrowska,B., Dabrowski,M., Kucharewicz-Krukowska,A. (1984). Archivum Immunologii et Therapiae Experimentalis 32:317-335. The results of phage therapy applied in further 150 cases of suppurative bacterial infections were analyzed. Positive therapeutic results were obtained in 137 cases (91.3%). The results obtained confirmed the previous findings on great effectiveness of bacteriophages in the treatment of septic infections, spontaneous or postoperative, caused by pyo genic Staphylococci, Klebsiella, Escherichia, Proteus and Pseudomonas. [TOP OF PAGE]

  238. Phage therapy. Anonymous (1983). Lancet 2(8362):1287-1288. [TOP OF PAGE]

  239. Viral Control of Nuisance Cyanobacteria (Blue-Green Algae). II. Cyanophage Strains, Stability on Phages and Hosts, and Effects of Environmental Factors on Phage-Host Interactions. Desjardins,P.R., Olson,G.B. (1983). California Water Resource Center, University of California, Davis, CA.Differentiation of phage strains in the AS cyanophage group was accomplished. Studies on Anabaena cyanophages (A-1 , A-4, and AN-lo), which originally were received from Russia, demonstrated that the A-4 preparation was actually a mixture of a lytic (AN-10) phage and a temperate (A-4) phage. An additional strain of Anabaena variabilis was shown to be a host of all three phages in the group. ¶ Antiserum to the LPP-1 cyanophage with a relatively high titer was prepared for later use in cyanophage detection. Storage by simply freezing in culture media permitted some cyanobacterial species to survive for several months. Failure of other species to survive under identical conditions indicates a need for additional research in this area. The adverse effects of freezing on virion structure and infectivity were characterized for the AS-1 and LPP-1 cyanophages. ¶ Bloom concentrations of Plectonema boryanum were established in outdoor pond facilities. Some control of this cyanobacterial species was effected with the LPP-1 cyanophage. Results suggest that the cyanophage is most effective when present before the bloom develops. ¶ Studies on the effect of temperature on the growth cycle of AS-1 cyanophage demonstrated that the length of the cycle varied inversely with temperature in the range 25-36°C. The importance of light quality in the growth cycle of this cyanophage has also been shown. Of special significance is the finding that the red/far red light ratio can greatly influence the yield of AS-1 in Anacystis niduIans. [TOP OF PAGE]

  240. Cyanophage: Histroy and likelihood as a control. Desjardins,P.R. (1983). pp. 242-248. In AnonymousLake Restoration, Protection, and Management. Environmental Protection Agency, Washington, D.C. It has been 20 years since the first cyanophage was discovered. Since then additional cyanophages and strains that infect both unicellular and filamentous cyanobacteria have been found. Cyanophages are similar to other bacteriophages in many physical, chemical and biological characteristics, but dif- fer from them in their requirement of light for absorption to their hosts and their dependence upon the photosynthetic activity of their hosts for their replication. Light quality and the ratio of red to far- red light affect virus replication. Cyanophages play a distinctive role in the ecology of their hosts and probably are effecting some natural control. Certain factors (development of resistant host strains, specific ion requirements, environmental factors and lysogeny) may affect the potential of the cyanophages to control their hosts, but these have not been conclusively shown to completely destroy this potential. There is much need for additional research on the experimental control of nuisance species in natural water bodies. Preliminary studies suggest that the phages may be more effective in preventing blooms than in eliminating one already formed. An integrated approach involving several biological techniques is recommended for control of nuisance populations of cyanobacteria. [TOP OF PAGE]

  241. Use of UV-irradiated bacteriophage T6 to kill extracellular bacteria in tissue culture infectivity assays. Shaw,D.R., Maurelli,A.T., Goguen,J.D., Straley,S.C., Curtiss,R.I. (1983). J. Immunol. Meth. 56:75-83. We have utilized 'lysis from without' mediated by UV-inactivated bacteriophage T6 to eliminate extracellular bacteria in experiments measuring the internalization, intracellular survival and replication of Yersinia pestis within mouse peritoneal macrophages and of Shigella flexneri within a human intestinal epithelial cell line. The technique we describe has the following characteristics: (a) bacterial killing is complete within 15 min at 37 degrees C, with a greater than 10(3)-fold reduction in colony-forming units (CFU); (b) bacteria within cultured mammalian cells are protected from killing by UV-inactivated T6; (c) the mammalian cells are not observably affected by exposure to UV-inactivated T6. This technique has several advantages over the use of antibiotics to eliminate extracellular bacteria and is potentially widely applicable in studies of the interactions between pathogenic bacteria and host phagocytic cells as well as other target tissues. [TOP OF PAGE]

  242. Results of bacteriophage treatment of suppurative bacterial infections. I. General evaluation of the results. Slopek,S., Durlakova,I., Weber-Dabrowska,B., Kucharewicz-Krukowska,A., Dabrowski,M., Bisikiewicz,R. (1983). Arch. Immunol. Ther. Exp. 31:267-??? [TOP OF PAGE]

  243. Results of bacteriophage treatment of suppurative bacterial infections. II. Detailed evalulation of the results. Slopek,S., Durlakova,I., Weber-Dabrowska,B., Kucharewicz-Krukowska,A., Dabrowski,M., Bisikiewicz,R. (1983). Arch. Immunol. Ther. Exp. 31:293-??? [TOP OF PAGE]

  244. Effectiveness of phages in treating experimental Escherichia coli diarrhoea in calves, piglets and lambs. Smith,H.W., Huggins,M.B. (1983). J. Gen. Microbiol. 129:2659-2675. A mixture of two phages, B44/1 and B44/2, protected calves against a potentially lethal oral infection with an O9:K30,99 enteropathogenic strain of Escherichia coli, called B44, when given before, but not after, the onset of diarrhoea; a mixture in which phage B44/3 was replaced by phage B44/3 was effective after the onset of diarrhoea. Calves that responded to phage treatment had much lower numbers of E. coli B44 in their alimentary tract than untreated calves. Usually, high numbers of phage B44/1 and rather lower numbers of phage B44/2 or B44/3 were present in the alimentary tract of these animals. At death, most calves that had not responded to treatment with phages B44/1 and B44/2 had high numbers of mutants of E. coli B44 resistant to phage B44/1 in their small intestine. Phage-treated calves that survived E. coli infection continued to excrete phage in their faeces, at least until the numbers of E. coli B44 also excreted were low. The phages survived longer than E. coli B44 in faecal samples taken from phage-treated calves and exposed to the atmosphere in an unheated animal house. Calves inoculated orally with faecal samples from phage-treated calves that contained sufficient E. coli B44 to cause a lethal infection remained healthy. A mixture of two phages, P433/1 and P433/2, and phage P433/1 alone cured diarrhoea in piglets caused by an O20:K101,987P strain of E. coli called P433. The numbers of the infecting bacteria and phages in the alimentary tract of the piglets resembled those in the calves. Another phage given to lambs 8 h after they were infected with an O8:K85,99 enteropathogenic strain of E. coli, called S13, reduced the numbers of these organisms in the alimentary tract and had an ameliorating effect on the course of the disease. No phage-resistant mutants of E. coli S13 were isolated from the lambs. The only mutants of E. coli B44 and P433 that emerged in the calves and piglets were K30- or K101- and resistant to phage B44/1 or P433/1 respectively; those tested were much less virulent than their parent strains. [TOP OF PAGE]

  245. Psychotrophic bacteriophages for beef spoilage pseudomonads. Greer,G.G. (1982). J. Food Prot. 45:1318-1325. Psychrotrophic bacteriophages for beef spoilage pseudomonads.A total of 40 beef spoilage pseudomonads was used as bacterial hosts for the isolation of psychrotrophic bacteriophages (phages) from spoiled rib steaks. Thirty-eight homologous phages, lytic for 25 of these hosts, were isolated and purified. An additional 12 bacterial isolates were susceptible to heterologous phage lysis and only 3 of the bacteria examined were resistant to lysis by any of the phage tested. On the basis of heterologous cross-sensitivity to phages, the meat-borne Pseudomonas strains and 4 identified ATCC Pseudomonas hosts were differentiated into 37 distinct phage lysotypes. Pseudomonas phages inhibit bacterial growth in tryptic soy broth by significantly extending the lag phase under psychrotrophic conditions ( C). The incubation of bacteria with phages resulted in the selection of phage resistant bacterial mutants. [TOP OF PAGE]

  246. Teh efficacy of staphylococcal bacteriophage in treatment of purulent diseases of lungs and pleura. Meladze,G.D., Mebuke,M.G., Chkhetia,N.S., Kiknadze,N.I., Koguashvili,G.G., Timoshuk,I.I., Larionova,N.G., Vasadze,G.K. (1982). Grudnaia Khirurgiia 1:53-56. [TOP OF PAGE]

  247. Successful treatment of experimental Escherichia coli infections in mice using phage: Its general superiority over antibiotics. Smith,H.W., Huggins,M.B. (1982). J. Gen. Microbiol. 128:307-318. Anti-K 1 phages were more active in vitro and in vivo against an 018:K1:H7 ColV+ Escherichia coli strain, designated MW, than were other phages. A single intramuscular dose of one anti-K1 phage was more effective than multiple intramuscular does of tetracycline, ampicillin, chloramphenicol, or trimethoprim plus sulphafurazole in curing mice of a potentially lethal intramuscularly or intracerebrally induced infection of MW; it was at least as effective as multiple intramuscular doses of streptomycin. When MW and the phage were inoculated into different gastrocnemius muscles of the same mice, a rapid reduction in numbers of MW organisms occurred in the MW-inoculated muscle and in other tissues; the numbers of phage particles in the MW-inoculated muscle increased rapidly and greatly. MW failed to proliferate in the brains of intracerebrally infected mice that had been inoculated intramuscularly with the phage at the same time; many more phage particles were found in the brains of these mice than in other sites. The few phage-resistant mutants of MW found in the phage-treated mich were K1-; previous studies had shown such mutants to be of greatly reduced virulence. The phage administered intramuscularly 3-5 d before challenge with a potentially lethal intramuscularly induced infection of MW was protective, the protective effect varying between phage propagated on different bacterial. [TOP OF PAGE]

  248. Cyanophages--are they potential biological control agents of nuisance blue-green algae? Desjardins,P.R. (1981). E-81-7, 198-229. Pacific Grove, California. Proc.Workshop Algal Manage.Control. 1980.[TOP OF PAGE]

  249. Estudos sobre um bacteriophago isolado de Xanthomonas campestris II. Seu emprego no controle de X. campestris e X. campestris vesicatoria [Studies on a bacteriophage isolated from Xanthomonas campestris II. Its use in the control of X. campestris and X. campestris vesicatoria]. Filho,A.B., Kimati,H. (1981). Summa Phytopathol. 7:35-43. The phage described can be used successfully, at least under greenhouse conditions, in the control of the cabbage disease caused by X. campestris and the pepper disease caused by X. vesicatoria. For both diseases the most efficient treatment was simultaneous inoculation with the phage and bacteria. The symptoms were reduced in 99.83% for X. campestris and 99.02% for X. vesicatoria. [TOP OF PAGE]

  250. Experience in the therapeutic use of bacteriophage preparations in suppurative surgical infections. Peremitina,L.D., Berillo,E.A., Khvoles,A.G. (1981). Zh. Mikrobiol. Epidemiol. Immunobiol. 9:109-110. [TOP OF PAGE]

  251. Therapy of experimental tuberculosis in guinea pigs with mycobacterial phages DS-6A, GR-21 T, My-327. Sula,L., Sulova,J., Stolcpartova,M. (1981). Czechoslovak Medicine 4:209-214. Guinea pigs, weighing 250-350 g, were infected with approximately 5,000 of live germs M- tuberculosis H 37 Rv grown 10 days in deep culture of liquid semisynthetic medium according to Sula. The infection was performed subcutaneously in inquinal region. For the therapy following phages were used: DS-6A, GR-21/T, My-327 injected twice a week subcutaneously in the dose of 10(6)/1 ml of live particles for 10 weeks. The therapeutic effect was expressed by spleen and hilus index. Out of the phages used, phage DS-6A had the highest therapeutic effect with mean spleen index of 0.19, corresponding approximately to the spleen index reached with the most effective tuberculostaticum INH. The exact explanation of the phage therapeutic effect in given experimental conditions, when the phages are not applied locally in order to gain the direct contact with infectious antigens, is not known. It is suggested that there presumably exists an interaction between the released phage nucleic acid and the nucleic acid synthesis needed for the growth of mycobacteria in vivo. [TOP OF PAGE]

  252. Korrektsiia disbakterioza kishechnika biologicheskimi preparatami u bol'nykh ostrymi leiozami. [Correction of intestinal dysbacteriosis with biological preparations in acute leukemia]. Tolkachera,T.Y., Abakumova,E.M., Martynova,V.A., Golosova,T.V. (1981). Problemy Germatologii i Perelivaniia Krovi 26:29-33. [TOP OF PAGE]

  253. Biological Control of Fish Bacterial Pathogen, Aeromonas hydrophila by Bacteriophage AH 1. Wu,J.L., Lin,H.M., Jan,L., Hsu,Y.L., Chang,L.H. (1981). Fish Pathol. 15:271-276. The usefulness of the bacteriophages as a biological control agent for cultured fish diseases is discussed. The authors have initiated the isolation of bacteriophages to infect Aeromonas hydrophila which is the pathogen of eel's red-fin disease. Among the eight isolated bacteriophages, AH1 has strongest bacteria-lysis ability. Therefore, AH1 was selected as the experimental model system for the study of biological control of diseases. The one-step growth curve showed that AH1 started to form phage particles after 50 min of infection and completed at 100 min with a burst size of 160. One AH1-infected A. hydrophila can produce 160 phage particles. In order to test the loss of pathogenecity of A. hydrophila after AH1 infection, the AH1-infected bacteria were injected to loach Misgurnus anguillicaudatus . After 3 infection of AH1, the A. hydrophila had completely lost its infectivity and mortality in the injected loaches. [TOP OF PAGE]

  254. Investigation of the effect of Brucella-phage on the course of experimental infection with Brucella abortus. Corbel,M.J., Morris,J.A. (1980). Br. Vet. J. 136:278-??? [TOP OF PAGE]

  255. Ecology of Streptococcus faecium bacteriophage in chicken gut. Houghton,S.B., Fuller,R. (1980). Appl. Environ. Microbiol. 39:1054-1058. The interaction in the chick gut between Streptococcus faecium and its phage was examined. In conventional chicks, large numbers of S. faecium and phage were found in the cecum and smaller numbers were found in the anterior gut. In gnotobiotic chicks associated with S. faecium SY1 and its phage, there was no marked effect on bacterial numbers, but resistance to the phage rapidly developed. Depression of chick growth caused by S. faecium strain SY1 was partially reversed by its phage. [TOP OF PAGE]

  256. Use of bacteriophages and antibiotics for prevention of acute postoperative empyema in chronic suppurative lung diseases. Ioseliani,G.D., Meladze,G.D., Chkhetiia,N.S., Mebuke,M.G., Kiknadze,N.I. (1980). Grudnaia Khirurgiia 6:63-67. [TOP OF PAGE]

  257. Bacteriophage therapy of septic complications of orthopaedic surgery. Lang,G.P., Kehr,P., Mathevon,H., Clavert,J.M., Sejourne,P., Pointu,J. (1979). Rev. Chir. Orthop. Reparatrice Appar. Mot. 1:33-37. [TOP OF PAGE]

  258. Evaluation of efficacy of the use of E. coli-Proteus bacteriophage in intestinal dysbacteriosis in premature infants. Litvinova,A.M., Chtetsova,V.M., Kavtreva,I.G. (1979). Vopr. Okhr. Materin. Det. 9:42-44. [TOP OF PAGE]

  259. Données actuelles sur les applications thérapeutiques des bactériophages. Vieu,J.-F., Guillermet,F., Minck,R., Nicolle,P. (1979). Bull. Acad. Natl. Med. 163:61 [TOP OF PAGE]

  260. Viral Control of blue-green algae. Desjardins,P.R., Barkley,M.B., Swiecki,S.A., West,S.N. (1978). California Water Resource Center, University of California, [TOP OF PAGE]

  261. Traitement d'une endocardite à Serratia par les bactériophages. Grimont,P.-A.D., Grimont,F., Lacut,J.-Y., Issanchou,A.-M., Aubertin,J. (1978). Nouv. Presse Med. 7:2251-??? [TOP OF PAGE]

  262. Decontamination of bacterial infection of monolayer cultures with a specific bacteriophage. Riche,P.H., Vic,P., Humeau,C., Vanneraeau,H., Vlahovitch,B., Sentein,P. (1978). In Vitro 14:935-??? [TOP OF PAGE]

  263. Succession of Streptococcus bovis strains with differing bacteriophage sensitivities in the rumens of two fistulated sheep. Iverson,W.G., Millis,N.F. (1977). Appl. Environ. Microbiol. 33:810-813. The bacteriophage sensitivity of the Streptococcus bovis population resident in the ruments of two fistulated sheep was monitored for 112 days. During this time, three changes in the bacteriophage sensivity of S. bovis occurred in the absence of detectable bacteriophages. Identical changes in bacteriophage sensitivity occurred simultaneously in both animals and, except for the relatively short periods of changeover in phage sensitivity, the S. bovis population in the rumens of the two sheep was homogeneous with respect to phage sensitivity. [TOP OF PAGE]

  264. Recovery and susceptibility pattern of faecal streptococci bacteriophages. Saleh,F.A. (1977). Water Res. 11:403-409. [TOP OF PAGE]

  265. [Experience with treating complicated forms of abscessing pneumonia in children]. [Russian]. Pipiia,V.I., Eteriia,G.P., Gotua,T.P., Volobuev,V.I., Katsarava,V.S. (1976). Vestnik Khirurgii Imeni i - i - Grekova 117:64-68. Under observation were 157 patients with different forms of abscessing pneumonias. Pleural complicaitons were noted in 113 patients (about 60%). The complex treatment was employed in all patients (intensive antibacterial therapy, immunotherapy, bacteriophage, administration of protein preparations, vitamin-therapy, fresh blood transfusion, artery system and by means of percutaneous catheterization of th subclavian vein. The results of the treatment are described. [TOP OF PAGE]

  266. Prospects for control of phytopathogenic bacteria by bacteriophage and bacteriocins. Vidaver,A.K. (1976). Ann. Rev. Phytopathol. 14:451-465. [TOP OF PAGE]

  267. Topley and Wilson's Principles of Bacteriology and Immunity. Wilson,G.S., Miles,A.A. (1975). p.1634-1636. Edward Arnold, London.[TOP OF PAGE]

  268. The occurrence of bacteriophages in the rumen and their influence on rumen bacterial population. Orpin,C.G., Munn,E.A. (1974). Experimentia 30:1018-1020. [TOP OF PAGE]

  269. Use of combined phages in suppurative-inflammatory diseases. Sakandelidze,V.M., Meipariani,A.N. (1974). Zh. Mikrobiol. Epidemiol. Immunobiol. 6:135-136. [TOP OF PAGE]

  270. [Materials on the study of bacteriophage therapy of deep forms of staphyloderma]. [Russian]. Vartapetov,A.I. (1974). Vestnik Dermatologii i Venerologii 8-11. [TOP OF PAGE]

  271. Effects of homologous bacteriophage on growth of Pseudomonas fragi in milk. Ellis,D.E., Whitman,P.A., Marshall,R.T. (1973). Appl. Microbiol. 25:24-25. [TOP OF PAGE]

  272. Characteristics of Erwinia amylovora bacteriophage and its possible role in the epidemiology of fire blight. Erskine,J.M. (1973). Can. J. Microbiol. 19:837-845. Bacteriophage (S1) of Erwinia amylovara, isolated from soil at the base of fire-blight-infected trees, was characterized by small, clear plaques on E. amylovara strain PR1 and hazy plaques of the same size on closely related, yellow, saprophytic bacterium, Y, which was isolated together with PR1 from the diseased trees. Phage S1 plated with optimal efficiency at 10C on PR1 and at 28C on Y was relatively unstable to storage temperatures typical of summer and to ultraviolet (UV) irradiation, and lysogenized Y but not PR1. Pathogenicity tests in pear slices demonstrated that symptom development was (i) delayed when mixtures of either PR1 and phage S1 or PR1 and Y were inoculated, (ii) delayed when a culture of a phage-resistant mutant of PR1 was inoculated, and (iii) prevented from appearing at all when PR1 and the lysogenic from of Y, Y (S1), were inoculated together. Strains Y was easily lysogenized and Y (S1) released phage spontaneously and after UV irradiation. It is suggested that the yellow saprophyte, which is invariably isolated from fruit trees with E. amylovora, may frequently occur in its lyogenic form in nature and serve as a reservoir of phage which may exert some influence on the occurrence and severity of fire-blight disease. [TOP OF PAGE]

  273. The fate of bacteriophage lambda in non-immune germ-free mice. Geier,M.R., Trigg,M.E., Merril,C.R. (1973). Nature 246:221-223. [no abstract]. [TOP OF PAGE]

  274. Interaction between bacteria and bacteriophages on plant surfaces and in plant tissues. Civerolo,E.L. (1972). pp. 25-37. In AnonymousPlant Pathogenic Bacteria 1971. The Netherlands. The ecological role of phages of bacteria associated with plants in nature has not yet been dearly established. Poor nodulation of several leguminous plants has been attributed to lysis of Rhizobium species by phages in root nodules and soil. In several cases phages of phytopathogenic bacteria have been associated with naturally infected and diseased tissues. Experimentally, phages can reduce infection of various tissues by several phytopathogenic bacteria; presumably these phages interact with their bacterial hosts at infection sites on plant surfaces or within plant tissue. In relation to plant disease, phages may be effective only in protecting tissue from infection rather than by eradicating the pathogen. ¶ At high temperatures, Xanthomonas phaseoli phages attack Xanthomonas and Pseudomonas species which are resistant at lower temperatures. Therefore, in addition to other factors, halo blight and brown spot diseases of bean, caused by P. phaseolicola and P. syrinpae, respectively, may be more prevalent at low temperatures because of resistance of these bacteria to phage at or below 22°C. ¶ Retardation of crown gall development after absorption of Agrobacterium tumejaciens phage PB2-A by tomato plants was attributed to blockage of the bacterial attachment site or to reduction of viable bacterial cells at the wound site. [TOP OF PAGE]

  275. Retardation of crown gall enlargement after bacteriophage treatment. Boyd,R.J., Hildebrant,A.C., Allen,O.N. (1971). Pl. Dis. Reptr. 55:145-148. Tomato plants absorbed within 3 hours after root immersion a bacteriophage lysate of Agrobacterium tumefaciens strain B2-A containing 109-1010 particles per ml. Lysate-treated plants repotted in soil showed wilting and leaf necrosis, but recovered after 2 weeks. The phage was detected at 168 hours after lysate absorption in leaves, stems, and roots and at 336 hours in the stems and roots. Enlargement of tomato stem galls was retarded only when wounded plants absorbed lysate for 12 hours prior to bacterial inoculation. The average gall weight from plants that absorbed a viable phage-containing lysate was 28% of that from plants that were inoculated with strain B2-A only. [TOP OF PAGE]

  276. Biological agents which cause lysis of blue-green algae. Shilo,M. (1971). Vehr. Int. Verein. Limnol. 19:206-213. [TOP OF PAGE]

  277. Algal viruses-eutrophication control potential. Jackson,D., Sladecek,V. (1970). Yale Sci. 44:16-21. [TOP OF PAGE]

  278. Use of staphylococcal bacteriophage for therapeutic and preventive purposes. Proskurov,V.A. (1970). Zh. Mikrobiol. Epidemiol. Immunobiol. 2:104-107. [TOP OF PAGE]

  279. Phage treatment for severe burns. Shera,G. (1970). Br. Med. 1:568-??? [TOP OF PAGE]

  280. A study of the therapeutic effect of bacteriophage agents in a complex treatment of suppurative surgical diseases. Zhukov-Verezhnikov,N.N., Peremitina,L.D., Berillo,E.A., Komissarov,V.P., Bardymov,V.M., Khvoles,A.G., Ugryumov,L.B. (1970). Sov. Med. 12:64-66. [TOP OF PAGE]

  281. Inhibition of bacterial spot of peach foliage by Xanthomonas pruni bacteriophage. Civerolo,E.L., Kiel,H.L. (1969). Phytopathology 59:1966-1967. The use of bacteriophages for control of plant diseases caused by phytopathogenic bacteria was reviewed by Okabe & Goto (4). Keil & Wilson (3) reported of Elberta peach seedlings from infection by X. pruni (E.F.Sm.) Dows. Leaf infection was significantly reduced when the phage was mixed with a suspension of X. pruni inoculum, or when the phage was applied as a spray and allowed to dry before inoculation with X. pruni (3). The present study confirms and extends their results. [TOP OF PAGE]

  282. Die bakteriophagie in der Therapie und Prophylaxe der Infektionskranheiten. Mazácek,M., Petera,A., Mach,J. (1969). Zentralbl. Bakteriol. Parasienkd. Infektionskr. Hyg. Abt. 1 Orig. Reihe A 211:385-??? [TOP OF PAGE]

  283. Felix d'Herelle and bacteriophage therapy. Peitzman,S.J. (1969). Transactions and Studies of the College of Physicians of Philadelphia 37:115-123. [TOP OF PAGE]

  284. [Assumptions for successful therapy using staphylococcal phage lysates]. [German]. Pillich,J., Vymola,F., Buda,J. (1969). Zentralblatt Fur Bakteriologie, Parasitenkunde, Infektionskrankheiten Und Hygiene - 1 - Abt - Medizinisch-Hygienische Bakteriologie, Virusforschung Und Parasitologie - Originale 210:377-381. [TOP OF PAGE]

  285. [Further data on the association of bacteriophage with antibiotic therapy for the purpose of sterilizing carriers of dysentery bacilli]. [French]. Zilisteanu,C., Mintzer-Morgenstern,L., Ionesco,H., Ionesco-Dorohoi,T. (1969). Archives Roumaines de Pathologie Experimentales et de Microbiologie 28:1073-1080. [TOP OF PAGE]

  286. Prevenative value of dried dysentery bacteriophage. Babalova,E.G., Katsitadze,K.T., Sakvarelidze,L.A., Imnaishvili,N.S., Sharashidze,T.G., Badashvili,V.A., Kiknadze,G.P., Meipariani,A.N., Gendzekhadze,N.D., Machavariani,E.V., Gogoberidze,K.L., Gozalov,E.I., Dekanosidze,N.G. (1968). Zh. Mikrobiol. Epidemiol. Immunobiol. 2:143-145. [TOP OF PAGE]

  287. Studies on protection of Klebsiella pneumonia -infected mouse with phage. Ha,T.-Y. (1968). Journal of Korean Modern Medicine 8:395-??? [TOP OF PAGE]

  288. [Effectiveness of phage therapy in experimental proteus infection]. [Russian]. Matusis,Z.E., Mel'nikov,V.D., Gerasimov,A. (1967). Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii 44:100-103. [TOP OF PAGE]

  289. [Lytic activity of the bacteriophage used in planned phage therapy in children's institutions in Perm in 1963-1965]. [Russian]. Smirnova,N.P. (1967). Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii 44:136-137. [TOP OF PAGE]

  290. Etude du phénomène des lyses et cultures alternées de Staphylococcus aureus Twort par le phage homologue. Zekam-Tchendjeu,J. (1967). Pharm. Paris. [TOP OF PAGE]

  291. Bacteriophage therapy in infective childhood asthma. Wittig,H.J., Raffetto,J.F., Bason,R. (1966). J. Am. Med. Assoc. 196:435 [TOP OF PAGE]

  292. [Association of bacteriophage with antibiotic therapy for the sterilization of carriers of dysentery bacilli]. [French]. Zilisteanu,C., Filotti,A., Mintzer-Morgenstern,L., Ghyka,G. (1965). Archives Roumaines de Pathologie Experimentales et de Microbiologie 24:1021-1028. [TOP OF PAGE]

  293. Control of algae with viruses. Safferman,R.S., Morris,M.E. (1964). J. Am. Water Works Assoc. 56:1217-1224. [TOP OF PAGE]

  294. Topley and Wilson's Principles of Bacteriology and Immunity. Wilson,G.S., Miles,A.A. (1964). Williams and Wilkins, Baltimore.[no abstract]. [TOP OF PAGE]

  295. Control of peach bacterial spot by Xanthomonas pruni bacteriophage [abstract]. Keil,H.L., Wilson,R.A. (1963). Phytopathology 53, 746-747. [TOP OF PAGE]

  296. Bacteriophages of plant pathogens. Okabe,N., Goto,M. (1963). Ann. Rev. Phytopathol. 1:397-418. Studies on bacteriophages have advanced markedly in recent years, especially the study of phages related to medical bacteriology. We are not as well informed as yet on the phages in relation to plant diseases, especially in relation to basic research of their nature.

    However, a number of interesting papers concerning the phages of plant pathogens have been published in recent years. Many phages act specifically on definite host bacteria. Some of them have been applied as useful tools in many diverse studies such as the identification of bacterial species, the differentiation of strains of bacterial species, the detection of pathogens hibernating in fields or no plants, the counting of bacterial density, and the forecasting of disease development. Since interesting results worthy of our attention are now accumulating, we would like to introduce them together with our present knowledge. [TOP OF PAGE]

  297. ??? Salmon,G., Symonds,M. (1963). J. Med. Soc. 60:188-193. [TOP OF PAGE]

  298. Treatment and prophylaxis of cholera with bacteriophage. Sayamov,R.M. (1963). Bull. W. H. O. 28:361-??? [TOP OF PAGE]

  299. Molecular Biology of Bacterial Viruses. Stent,G. (1963). WH Freeman and Co., San Francisco, CA.[TOP OF PAGE]

  300. Die therapeutische Anwendung von Bakteriophagen unter besonderer Berücksichtigung des Typhus and Paratypus B. Clajus,W. (1959). Zentralbl. Bakteriol. Parasitenkd. Infektionskr. Hyg. Atb. 1 Ref. 170:427-??? [TOP OF PAGE]

  301. Cholera. Pollitzer,R. (1959). World Health Organization, ["The World Health Organization came to the conclusion that, with the success of tetracycline therapy, there did not seem any reason why investigation into phage therapy should continue." --- Quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  302. A study of the action of bacteriophage on some diseases of tomato and cabbage. Gutermuth,C. (1958). Kent State University. The purpose of the research undertaken was to make a study of the action of bacteriophage on some bacterial diseases of tomato and cabbage. The diseases investigated were Bacterial Canker of Tomato, produced by the organism Corynebacterium michiganense; Brown Rot of Tomato, produced by the organism Pseudomonas solanacearum; and Black Rot of Cabbage, produced by the organisms Xanthomonas campestris. As stated more fully later in the chapter on materials and methods, the write was especially interested in the individual treatment rather than the mass treatment of plants in this experimentation. [TOP OF PAGE]

  303. Fate of bacteriophage particles induced into mice by various routes. Keller,R., Engley,F.B. (1958). Proc. Soc. Exp. Biol. Med. 98:577-??? [TOP OF PAGE]

  304. The acquired resistance of Staphylococcus aureus to bacteriophage. Lowbury,E.J.L., Hood,A.M. (1953). J. Gen. Microbiol. 9:524-535. To test the capacity of different staphylococci to acquire resistance to bacteriophage in vitro, twenty phages were grown on solid medium and in fluid medium wiht their propagating strains of Staphylococcus aureus, different phage types and patterns being represented. ¶ Resistant secondary growth never appeared among staphylococci of the 3A group and often appeared among members of the 6/47 group. Some members of the 29/52 group acquired resistance readily, and others never became resistant. Cross-resistance to other phages was commonly acquired. Secondary growth was shown to be resistant or sensitive to thephage, or to yield a mixture of resistant and sensitive colonies. ¶ With the exception of propagating strain PS 69, all staphylococci which became resistant to phage acquired lysogenicity for the sensitive parent strain. All but one of the staphylococci which had acquired resistance to a phage appeared to be capable of absorbing that phage. A substance which caused non-specific inhibition of phage lysis on agar medium was present in phage lysates of a staphylococcus that had shown sensitive secondary growth. These results are discussed with reference to phage typing and to the possibilities of therapy by phage. [TOP OF PAGE]

  305. [title fragment in Japanese] Bacillus carotovorous Jones Bacteriophage [title fragment in Japanese] [text of manuscript is in Japanese]. Miyake,I., Hamada,M. (1952). Ann.Phytopathol.Soc.Jpn. 16, 181. [TOP OF PAGE]

  306. Bacteriophages attacking Pseudomonas taba????? and P. angulatum. Fulton,R.W. (1950). Phytopathology 40:936-949. [TOP OF PAGE]

  307. The Bacteriophage: A Historical and Critical Survey of 25 Years Research. Flu,P.C. (1946). Universitaire Pers Leiden, Leiden.[TOP OF PAGE]

  308. Le Bactériophage: Sa Nature et son Emploi Thérapeutique. Steinmann,J. (1946). [TOP OF PAGE]

  309. Bacteriophage therapy in bacillary dysentery. Boyd,J.S.K., Portnoy,B. (1944). Trans. R. Soc. Trop. Med. Hyg. 37:243-262. ["Some well controlled studies (on bacteriophage therapy), both experimental and clinical, produced results that were negative or where the observed effects were not regarded as useful." Quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  310. Phage therapy in diarrhœa and dysentery. Compton,A. (1944). Lancet 2:192-193. [TOP OF PAGE]

  311. The multiplication of bacteriophage in vivo and its protective effects against experimental infection with Shigella dysenteria. Dobus,R.J., Straus,J.H., Pierce,C. (1943). J. Exp. Med. 20:161-168. [TOP OF PAGE]

  312. The multiplication of bacteriophage in vivo and its protective effects against an experimental infection with Shigella dysenteriae. Dubos,R.J., Straus,J.H., Pierce,C. (1943). J. Exp. Med. 78(20?):161-168. ["Inocultated mice intracerebrally with 106 colony-forming units (cfu) of Shigella dysenteriae, which resulted in an acute cerebritis and meningitis followed by death of 8/8 mice within 2-5 days. Simultaneous intraperitoneal inoculation with 109 plaque-forming units (pfu) of an unpurified phage suspension produced 6/8 animals, while inoculation with a lower dose (105 pfu) protected 2/8 mice. There was evidence that the phages had multiplied in situ in the brain and had crossed the blood-brain barrier as a result of the bacterial infection." Quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  313. Bacteriophagy in the developing chick embryo. Rakieten,T.L., Rakieten,M.L. (1943). J. Bacteriol. 45:477-484. [TOP OF PAGE]

  314. Protective action of VI bacteriophage in Eberthella typhi infections in mice. Ward,W.E. (1943). J. Infect. Dis. 72:172-176. Mice were infected, by use of he mucin technic, with strains of Eberthella typhi in the Vi phase. Blood stream invasion occurred within an hour following injection. It was possible to protect more than 90% of infected mice when intravenous specific bacteriophage treatment was instituted within 4 hours following infection. Nontreated mice and mice treated with nonspecific bacteriophage showed a mortality approaching 100%. ¶ Titrations on the heart blood from specifically treated animals showed an increase in bacteriophage concentration over a period of several hours with detectable phage present for more than 60 hours. Bacteriophage disappeared in a very few hours from the blood of infected miced treated with bacteriophage not active for the infecting strain. ¶ Treated mice were healthy carriers of the infecting organisms for about one month after infection. However, in many cases these organisms were in the degraded or W form. [TOP OF PAGE]

  315. Treatment of wounds with bacteriophages. Pokrovskaya,M.P., Kaganova,L.C., Morosenko,M.A., Bulgakova,A.G., Skatsenko,E.E. (1942). State Publishing House "Medgiv", Moscow, USSR.[TOP OF PAGE]

  316. Effect of bacteriophage in experimental staphylococcal septicemia in rabbits. Bronfenbrenner,J.J., Sulkin,S.E. (1941). J. Bacteriol. 41:61 The present experiments were undertaken to evaluate the validity of the reports of successful bacteriophage therapy in clinical staphylococcal infections. Rabbits were infection by the intravenous introduction of staphylococci of varying degrees of virulence and were submitted to therapy with bacteriophage propagated on each of the respective strains of the organisms. While no definite therapeutic effect was attained in any instance, the use of bacteriophage propagated on the invasive staphylococcus prolonged and increased the severity of the course of the infection irrespective of the degree of virulence of the infecting organism. [TOP OF PAGE]

  317. Use of bacteriophage for freeing protozoal cultures of contaminating bacteria (isolation of Leptospira icterohaemorrhagiae from mixed infections in guinea-pigs). DeMonte,A.J.H., Gupta,S.K. (1941). Indian Med. Gaz. 76:154-??? [TOP OF PAGE]

  318. The bacteriophage: Its nature and its therapeutic use (I). Krueger,A.P., Scribner,E.J. (1941). J. Am. Med. Assoc. 116:2160-2167. [TOP OF PAGE]

  319. The bacteriophage: Its nature and its therapeutic use (II). Krueger,A.P., Scribner,E.J. (1941). J. Am. Med. Assoc. 116:2269-2277. [TOP OF PAGE]

  320. ??? Kawamura,A. (1940). Sci. Bull. Fac. Agr. Kyushu Univ. 9:148-156. [TOP OF PAGE]

  321. Bacteriophage therapy. II. Prophylactic and therapeutic effect of bacteriopahge and of antivirus in experimental infections of the eye. Bronfenbrenner,J.J., Sulkin,E. (1939). J. Infect. Dis. 65:58-??? [TOP OF PAGE]

  322. Bacteriophage therapy. III. On the nature of the deleterious effect of the local application of staphylococcus bacteriophage. Bronfenbrenner,J.J., Sulkin,E. (1939). J. Infect. Dis. 65:64-??? [TOP OF PAGE]

  323. The inactivation of "pure line" phages by bacterial extracts and the loss of phage types in vivo. Rakieten,M.L., Rakieten,T.L. (1938). Yale J. Biol. Med. 10:191-208. [TOP OF PAGE]

  324. The effect of an anti-Vi bacteriophage on typhoid infection in mice. Asheshov,I.N., Wilson,J., Topley,W.W.C. (1937). Lancet 1:319-320. ["Showed some protection against different bacterial infections in animals given very large doses of phage." Quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  325. ??? Kent,G.C. (1937). Phytopathology 27:871-902. [TOP OF PAGE]

  326. ??? Vinogradova,M.O.S., Pershina-Mansireva,M.S.G. (1937). Bull. Exptl. Biol. Med. URSS 4:275-278. [TOP OF PAGE]

  327. Bacteriophage and antivirus therapy of localized experimental infections with staphylococcus. Bronfenbrenner,J.J., Sulkin,S.E. (1936). J. Bacteriol. 31:56 [TOP OF PAGE]

  328. The bacteriophage in relation to Salmonella pullora infection in the domestic fowl. Pyle,N.J. (1936). J. Bacteriol. 12:245-261. The purpose of this work has been first to study the intestinal contents, fluids and tissues from the domestic fowl, and to locate and identify in these materials a bacteriophage, lytic for Salmonella pullora (Bacterium pullorum Rettger). ¶ Secondly, methods have been employed for increasing the lytic activity of the avian bacteriophage in vitro, to the end of using it as a therapeutic reagent in avian therapeutics. ¶ From the data presented and the observations made, the following conclusions appear to be justified. ¶ 1. Tissues of the domestic fowl do contain bacteriophages causing lysis of various strains of Salmonella pullora. ¶ 2. Up to the present time, although these avian "phages" are lytic for Salmonella pullora, it has not been demonstrated that they are specific for this organism. ¶ 3. When agar slant cultures of Salmonella pullora are treated with liquid cultures of these avian bacteriophages which are lytic for Salmonella pullora, watery, moth-eaten or pellucid areas are demonstrated. This fact, together with the demonstration of the transmission of bacteriophagy for Salmonella pullora in series would indicate that the transmissible bacteriolysis is a living ultra-microscopic entity. These reactions of the avian bacteriophage are characteristic of d'Herelle's "Bacteriophagum Intestinale." ¶ 4. Although the bacteriophages isolated and studied have demonstrated marked bacteriolysis in vitro, the evidence from animal experiments does not indicate that as now prepared and used that they have much therapeutic effect in freeing the bird's body of infection. ¶ 5. Bacteriophages actively bacteriolytic for Salmonella pullora have been isolated from domestic fowls showing a high agglutinative titre for this organism. ["Some well controlled studies (on bacteriophage therapy), both experimental and clinical, produced results that were negative or where the observed effects were not regarded as useful." Quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  329. A bacteriophage in relation to Stewart's disease of corn. Thomas,R.C. (1935). Phytopathology 25:371-372. [TOP OF PAGE]

  330. The bacteriophages. Burnet,F.M. (1934). Biol. Rev. Cambridge Phil. Soc. 9:332-350. [TOP OF PAGE]

  331. Bacteriophage therapy: Review of the principles and results of the use of bacteriophage in the treatment of infections (I). Eaton,M.D., Bayne-Jones,S. (1934). J. Am. Med. Assoc. 103:1769-1776. [TOP OF PAGE]

  332. Bacteriophage therapy: Review of the principles and results of the use of bacteriophage in the treatment of infections (III). Eaton,M.D., Bayne-Jones,S. (1934). J. Am. Med. Assoc. 103:1934-1939. [TOP OF PAGE]

  333. Bacteriophage therapy: Review of the principles and results of the use of bacteriophage in the treatment of infections (II). Eaton,M.D., Bayne-Jones,S. (1934). J. Am. Med. Assoc. 103:1847-1853. [TOP OF PAGE]

  334. Inactivation of antistreptococcus bacteriophage by animal fluids. Evans,A.C. (1933). Public Health Report 48:411-426. [TOP OF PAGE]

  335. Badteriophage therapy. Stout,B.E. (1933). Neruol. Neurochir. Pol. 3:693-698. [TOP OF PAGE]

  336. Studies on commercial bacteriophage products. Straub,M.E., Applebaum,M. (1933). J. Am. Med. Assoc. 100:110-113. [TOP OF PAGE]

  337. Relationship of bacteriophage to the natural and experimental diseases of laboratory animals. Colvin,M.G. (1932). J. Infect. Dis. 51:17-29. ["Some well controlled studies (on bacteriophage therapy), both experimental and clinical, produced results that were negative or where the observed effects were not regarded as useful." Quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  338. Baceriophage in clinical medicine. Larkum,N.W. (1932). J. Lab. Clin. Med. 17:675-680. [TOP OF PAGE]

  339. Bacteriophage in the Treatment and Prevention of Cholera. Morison,J. (1932). H.K. Lewis, ["Early (phage therapy) studies were poor and uncontrolled. For example, in one trial, claims for benefit in cholera were based on the administration of phage to all inhabitants of villages who had diarrhoea and, in another trial, on simply pouring an undisclosed amount of phage down the village well and assessing the number of cases subjectively." quoted from Barrow & Soothill, 1997]. [TOP OF PAGE]

  340. Bacteriophage in the treatment of plague. Naidu,B.P.B., Avari,C.R. (1932). Indian J. Med. Res. 19:737-748. [TOP OF PAGE]

  341. The effect of bacteriophagy and hemotytic streptococci upon protoplasma (Paramecium). Rakieten,M.L. (1932). Yale Journal of Biology and Medicine 4, 746. Paramecia served as biological test-tubes, by first rendering them bacteriologically sterile, and then placing them in environments containing bacteria and bacteriophage. Sterile paramecia which have ingested staphylococci may be cleared of these bacteria when a small amount of a powerful bacteriophage is added to the medium containing the protozoa. When sterile paramecia are allowed to remain in the medium containing bacteriophage no evicience that the animals retained this substance in their protoplasm is obtained. The reaction between bacteria and bacteriophage does not have any observable effect on paramecium either in vivo, or in the medium surrounding them. ¶ Sterile paramecia are not affected either by the autolysates or toxic products of hemolytic streptococci. In this respect they serve no purpose as biological indicators in differentiating hemolytic streptococci. [TOP OF PAGE]

  342. Staphylococcus aureus meningitis: treatment with specific bacteriophage. Schless,R.A. (1932). Am. J. Dis. Child. 44:813-822. [TOP OF PAGE]

  343. The kinetics of the bacterium-bacteriophage reaction. Krueger,A.P., Northrop,J.H. (1931). J. Gen. Physiol. 14:223-??? [TOP OF PAGE]

  344. Investigations on bacilliary dysentery in infants, with special reference to the bacteriophage phenomena. Burnet,F.M., McKie,M., Wood,I.J. (1930). Medical Journal of Australia 2:71-78. [TOP OF PAGE]

  345. The Bacteriophage and its Clinical Application. d'Herelle,F., Smith,G.H. (1930). p.165-243. Charles C. Thomas, Publisher, Springfield, Illinois.[TOP OF PAGE]

  346. ??? Muncie,J.H., Patel,M.K. (1930). Phytopathology 20:289-305. [TOP OF PAGE]

  347. Use of bacteriophage filtrates in treatment of suppurative conditions: report of 300 cases. Rice,T.B. (1930). American Journal of Medical Science 179:345-360. [TOP OF PAGE]

  348. Influence of bacteriophage on Bacterium tumefaciens, and some potential studies of filtrates. Brown,N.A., Quirk,A. (1929). J. Agr. Res. 39:503-530. While making potentiometer studies of the juices of 50 different species of healthy plants as compared with the juices of tumors produced on the plants by Bacterium tumefaciens Sm. and Town., the junior writer was impressed by the frequent reversal of the relative magnitudes of the pH values in the various juices after they had oxidized from one to five days. It was observed that whereas the juice of the normal sugar beet immediately after crushing might be pH 5.9 and that of the crushed tumor 6.3, in two days the juice of the normal sugar beet would be 6.2 and that of the tumor 4.8. It occurred to her that this oxidized tumor juice might influence the organism producing the tumor and that bp growing the organism in a suitable medium, along with the oxidized tumor juice which had reversed its pH relative to the pH of the normal juice, there might be obtained a culture that had lost its power to infect. ¶ Two cultures of Bacterium tumefaciens were accordingly exposed to different dilutions of the oxidized juice from crushed Ricinus tumors, and after the cultures had been incubated for a few days young Ricinus plants were inoculated with them. At the same time other Ricinus plants were inoculated with control cultures. Although neither treated culture became inactivated as was expected, one produced more rapidly forming and larger tumors and the other more slowly forming and smaller tumors than the controls. Recognizing that something besides oxidation with accompanying pH change had entered into these results, and believing that it was the principle of bacteriophagy, the junior writer began the work which developed into the joint investigation here reported. [TOP OF PAGE]

  349. Choudhury, Morison (1929). Indian Med. Gazette 64:[TOP OF PAGE]

  350. Virus diseases of bacteria -- bacteriophagy. Bronfenbrenner,J.J. (1928). pp. 373-414. In In Rivers and T.F. (eds.), Filterable Viruses. Williams & Wilkins, Baltimore, MD. The inclusion of bacteriophagy or transmissible lysis of bacteria, frequently called the Twort-dHerelle phenomenon, in a discussion of filterable virus diseases may be opposed by certain workers. The fact, however, that d'Herelle believes the phenomenon to be a disease of bacteria produced by an autonomous, ultramicroscopic, corpuscular virus is sufficient reason for including a discussion of it in a book on filterable viruses. Many of the author's ideas are not in agreement with those of d'Herelle. Nevertheless, at the present time ample justification exists for considering bacteriophagy, particularly in view of the general remarks concerning filterable viruses in Chapter I. [This is a wonderful and critical review of the first decade or so of phage literature - STA]. [TOP OF PAGE]

  351. ??? Kauffman,F. (1928). Z. Krebsforsch. 28:109-120. [TOP OF PAGE]

  352. Bacteria in relation to plant diseases. Link,G.K. (1928). pp. 590-606. In In Jordan,E.O. and Falk,I.S. (eds.), The Newer Knowledge of Bacteriology and Immunology. University of Chicago Press, Chicago. "The phenomenon of a transmissible lytic principle (bacteriophage) has been reported by a few investigators as occurring in the plant field. This interesting but highly controversial subject has however been merely touched, and more work will have to be done before any definite conclusions can be drawn. Gerretsen and Sack, and Söhngen and Gryns report isolations of lytic principles from nodules, roots, and stems, but not from leaves of leguminous plants bearing nodules, the lytic principle being specific for the bacteria of the plants in question; also from garden and field soil, but not from heath or forest soil. Mallmann and Hemstreet report the recovery of an inhibitory substance from cabbage decayed by fluorescent organisms, but did not demonstrate lysis. Following their work, Coons and Kotila report the recovery of a lytic principle from rotted carrots, from soil, and from river water which in low dilutions inhibited growth and in higher dilutions lysed B. carotovorus, B. atrosepticus, and Bact. tumefaciens. They report loss of mobility, malformation, and agglutination as characteristics of cultures treated with the lytic principle, agglutination being the first evidence of change in the organisms. Kotila and Coons also report isolation of a lytic principle from B. atrosepticus which when placed on potato tubers prevents the rotting normally caused by this organism. They venture the suggestion that this principle is responsible for the rapid decline of B. atrosepticus in the soil." (p. 601). [TOP OF PAGE]

  353. Bacteriophage and plant cancer. Israilsky,W.P. (1927). Centr. Bakteriol. Parasitenk. 71:302-311. [TOP OF PAGE]

  354. Arrowsmith. Lewis,S. (1926). Signet Classics, New York.[TOP OF PAGE]

  355. D'Herelle's bacteriophage in relation to plant parasites. Moore,E.S. (1926). South Afr. J. Sci. 23:306-??? [TOP OF PAGE]

  356. Investigations on the blackleg disease of potato. Kotila,J.E., Coons,G.H. (1925). Michigan Agr. Exper. Sta. Tech. Bull. 67:[TOP OF PAGE]

  357. Über therapeutische Versuche mit bakteriophagem Lysin bei Kindern und Saüglingen. Munter,H., Boenheim,C. (1925). Zeitschr. F. Kinderheilk. 39:388-??? [TOP OF PAGE]

  358. La traitment des dysentéries bacillaires par le bactériophage. da Costa Cruz,J. (1924). Compt. Med. Rend. Soc. Biol. 91:845-??? [TOP OF PAGE]

  359. Traitement spécifique de la fiévre typhoïde. Le Blaye,R. (1924). p. 87-??? In Poitiers (???) (ed.), Méd. de al Vienne. Poitiers (???), [TOP OF PAGE]

  360. The therapeutic value of bacteriophage in the treatment of bacillary dysentery. Spence,R.C., McKinley,E.B. (1924). Southern M. J. 17:563-??? [TOP OF PAGE]

  361. O bacteriophago en therapeutica. da Costa Cruz,J. (1923). Brazil-med 37:298-??? [TOP OF PAGE]

  362. Le bactériophage dans le traitment de la fièvre typhoïde. Beckerich,A., Hauduroy,P. (1922). Compt. Rend. Soc. Biol. 86:168-??? [TOP OF PAGE]

  363. The Bacteriophage: Its Role in Immunity. d'Herelle,F. (1922). Williams and Wilkins Co./Waverly Press, Baltimore.[TOP OF PAGE]

  364. The bacteriolysant therapy of bacillary dysentery in children. Therapeutic application of bacteriolysants; d'Herelle's phenomenom. Davison,W.C. (1922). AmJ. Dis. Child. 23:531-??? [TOP OF PAGE]

  365. Essais de thérapeutique au moyen du bactériophage. Bruynoghe,R., Maisin,J. (1921). Compt. Rend. Soc. Biol. 85:1120-1121. [TOP OF PAGE]

  366. Le microbe bactériophage, agent d'immunité dans la peste et la barbone. d'Herelle,F. (1921). C. R. Acad. Sci. Ser. D 172:99-?? [TOP OF PAGE]

  367. Le bactériophage: Son rôle dans l'immunité. d'Herelle,F. (1921). Presse Méd. 29:463-??? [TOP OF PAGE]

  368. d'Herelleschen Phänomen. Otto,R., Munter,H. (1921). Deutsche Med. Wchschr. 47:1579-??? [TOP OF PAGE]

  369. L'action bacericide des Eaux de la Jumma et du Gange sur le vibrion du cholera. Hankin,E.H. (1896). Ann. de l'Inst. Pasteur 10:511-??? [TOP OF PAGE]

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