Synthèse et Bibliographie de Bactériophages

Je soutiens dans la mesure de mes moyens l'initiative "PLOS", qui consiste à promouvoir la "gratuité" de l'accès à la science. A l'ère de l'Internet, pourquoi continuer à payer pour des revues qui ne font rien d'autre que de diffuser une information? Autant qu'elle soit gratuite dès l'origine... Depuis le 1er octobre 2003, une revue gratuite est mise en ligne.

Synthèse

Les cinquante dernières années ont montré que nous ne pourrons jamais gagner la bataille contre les bactéries. Tout au plus ferons-nous pencher la balance de notre côté à l'aide de bactériophages. A. Sulakvelidze.

Article dans cette bibliographie Phrases clés, commentaires
Dave Cullen, "New-age therapy, or a return to the past?"  cullin.doc
Wired Magazine 11.10 
How Ravenous Soviet Viruses Will Save the World; Richard Martin (rmartin@7dogs.com), http://www.wired.com/wired/archive/11.10/phages.html,
Comment Sulakvelidze a travaillé aux USA avec une société de capital-risque, au départ en collaboration avec la Géorgie. Puis, la société changeant de directeur, ce dernier décide qu'on ne pourra obtenir d'accord avec la FDA que si la production de phage à lieu aux USA : Harlingten's Phage Therapeutics coupe les ponts avec Eliava.
Sulakvelidze et Moris se retire alors de cette entreprise et se consacrent à leur propre boïte (Intralytix, qui vit encore, alors que Phage Therapeutics a coulé). Ils réoriente leurs activité vers le traitement des animaux, moins contraignant législativement.

Les chercheurs d'Eliava s'opposent à la recherche de phage génétiquement modifiés : les phages naturels ont subis d'énormes pressions de sélection, et représenteraient un compromis optimal entre survie, spécificité et efficacité...

Nature 425, 225 (18 September 2003);
  Drug companies snub antibiotics as pipeline threatens to run dry
  Tom Clarke

+ commentaire de phage-group / G. W. Riedel)
Symposium "Phage therapy as it applies to food public health bacteriology.", Chicago, 14/07/03 .

Les compagnies pharmaceutiques diminuent leur activité de recherche dans le domaine des antibiotiques : -10% publication; 2 molécules soumises à la F.D.A. cette année; réorientation des effort vers les traitements des maladies chroniques

Raisons : résistances inévitables (20% des infections traitées à l'hopital) surtout avec le temps; un patient guéri est un client en moins; les nouvelles molécules sont peu rentabilisées, car gardées sous le coude par les praticiens pour les cas exceptionnels.

Les antibiotiques seraient des "médicaments sociaux" selon l'industrie, dont la découverte reposerait sur les pouvoir public...

Commentaire annexé :
8.000 canadiens meurent annuellement d'infections hospitalières. 40.000 nord-Américains décèdent prématurément infections résistantes; 56.000 amputations annuelles suite aux infections diabétiques intraitables.

Colère sur le délai pour qu'une méthode appliquée depuis 70 ans en Géorgie nécessite 10 ans d'étude avant son usage en Occident, induisant la perte de 360.000 vies aux States pendant cette période.
"There is only one thing more stupid then dying in the name of hubris and that is to let people die in the name of hubris" (hubris = orgueil)

Treatment of experimental infections of mice with bacteriophages

Soothill JS. Department of Infection, Medical School, Edgbaston, Birmingham.
J Med Microbiol 1992 Oct;37(4):258-61

Dynamics of success and failure in phage and antibiotic therapy in experimental infections

J J. Bull,1 Bruce R. Levin,2 Terry DeRouin,2 Nina Walker,2 and Craig A. Bloch3
BMC Microbiol. 2002; 2 (1): 35

Confirmation d'expérience antérieure sur des souris. Modélisation de l'apparition de résistance et d'évolution de la population bactérienne infectante. Prédiction de cette évolution in vivo à partir de tests in vitro.
Des bactériophages contre les infections streptococciques
Nelson, Proc Natl Acad Sci USA 2001; 7: 4107-12

Dr Alain Hagège
Des bactériophages peuvent éradiquer le portage de streptocoques pathogènes du groupe A sans détruire la flore normale de la membrane muqueuse. Les bactériophages sont des virus qui infectent seulement les bactéries et sécrètent des enzymes qui détruisent la membrane cellulaire de ces bactéries (et à chaque bactérie son bactériophage). Une de ces enzymes protège les souris de l´infection streptococcique. Une nouvelle voie thérapeutique en infectiologie semble avoir été ouverte.

Cette note a été transmise sur le site egora.fr le lundi 26 mars 2001, et le plus intéressant : il n'y a eu aucune réaction sur le site! J'ai constaté le même phénomène sur une liste de discussion de cadre infirmier ... Incompréhension? Incrédulité?

Rechercher les coordonnées du Dr Hagège.

Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa

Soothill J S    Department of Infection, Medical School, Birmingham, UK

BURNS  (1994 Jun),  20(3),  209-11

Results of bacteriophage treatment of suppurative bacterial infections in the years 1981-1986

Slopek S; Weber-Dabrowska B; Dabrowski M; Kucharewicz-Krukowska A    Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw 

ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1987),  35(5),  569-83.

Bacteriophage therapy of septic complications of orthopaedic surgery

Lang G; Kehr P; Mathevon H; Clavert J M; Sejourne P; Pointu J

REVUE DE CHIRURGIE ORTHOPEDIQUE ET REPARATRICE DE L APPAREIL MOTEUR  (1979 Jan-Feb),  65(1),  33-7.

Bacteriophage Therapy

Alexander Sulakvelidze, Zemphira Alavidze, and  J. Glenn Morris Jr.

Antimicrobial Agents and Chemotherapy, March 2001, p. 649-659, Vol. 45, No. 3 2001

Entretien 30/06/2003 La "phage-thérapie est un vieux serpent de mer, que j'ai étudié il y a 20 ans. Il faut se méfier des études / publications biaisées, faussement nouvelles. Si c'était vraiment efficace, les pragmatiques anglo-saxons auraient bondi dessus. Il y a au moins une contre-étude aux résultats négatifs (essais sur des lapins, 1992, Raynaud et Laveran).
Pubmed donne un petit nombre de résultats avec bacteriophage/legionella. Problème d'adaptation rapide de la bactérie au phage, in vitro.
Pbm d'immunisation au phage (mais à la bactérie aussi...), et inactivation.
Pbm avec un cocktail de phages : inactivation d'opérons bactériens (?), intégration de fragments viraux au patrimoine bactérien (?). Un phage inadapté serait-il détruit par l'organisme humain avant d'être "digéré" par une bactérie baignant dans la lymphe ou le plasma?
Adapté pour des traitements de crise, plutôt du milieu externe.
Les surfaces sont maintenant choisies pour être facilement nettoyées, supportant les produits chimiques. La contamination se fait plutôt par humain, ou portage initial. Quant au traitement des pseudomonas, compte tenu de la variété au sein de l'espèce, difficulté de sélectionner les germes néfastes à l'homme.

A faire:
Petite étude pour TFE d'E-IDE : traiter l'eau entrerait-il dans le travail d'hygiène IDE? Soumettre le sujet à ma référente pédagogique. S'informer plus étroitement des exigences du nouveau TFE.
Contacter le centre de référence en Legionella pour obtenir des infos (et plus?) sur leurs bacteriophages.
Un cocktail actualisé de phages utilisé pour une désinfection de l'environnement d'un patient contaminé entre-t-il dans la classe des désinfectants, des antibiotiques ... quelle législation, quelles normes devrait-il satisfaire? 

New insights into the possible role of bacteriophages in host defense and disease

Andrzej Gorski,1,2 Krystyna Dabrowska,1 Kinga Switala-Jeleń,1 Maria Nowaczyk,2 Beata Weber-Dabrowska,1 Janusz Boratynski,1 Joanna Wietrzyk,1 and Adam Opolski1
Med Immunol. 2003; 2 (1): 2

Certains phages reconnaissent des récepteurs cellulaires (intégrines betâ-3) et en cela inhiberaient certaines réactions inflammatoires ou métastatiques.

 

Bibliographie

Recherches de phages pour Legionnella Pneumophila sérotype A : pas de phage à Legionnelles décrites à B.E.G.

Recherches sur les phages de pseudomonas

Pseudomonas AND ( putida OR aeruginosa ) AND (bacteriophage OR phage) AND selection

Characterization of Pseudomonas aeruginosa Bacteriophage UNL-1, a Bacterial Virus with a Novel UV-A-Inducible DNA Damage Reactivation Phenotype

Julie J. Shaffer,1 Lisa M. Jacobsen,1 John O. Schrader...

Applied and Environmental Microbiology, June 1999, p. 2606-2613, Vol. 65, No. 6

Full article 

Prevalence of Broad-Host-Range Lytic Bacteriophages of Sphaerotilus natans, Escherichia coli, and Pseudomonas aeruginosa

Ellen C. Jensen,

Appl Environ Microbiol, February 1998, p. 575-580, Vol. 64, No. 2

Full article 

Liste des phages connus de Pseudomonas

The first bacteriophage known to science was the Bacteriophagum intestinale described by  ...

Elevated Abundance of Bacteriophage Infecting Bacteria in Soil

Kevin E. Ashelford, Martin J. Day, and John C. Fry*
Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3TL, United Kingdom
1 October 2002

Here we report the first direct counts of soil bacteriophage and show that substantial populations of these viruses exist in soil (grand mean = 1.5 x 107 g-1), at least 350-fold more than the highest numbers estimated from traditional viable plaque counts. Adding pure cultures of a Serratia phage to soil showed that the direct counting methods with electron microscopy developed here underestimated the added phage populations by at least eightfold. So, assuming natural phages were similarly underestimated, virus numbers in soil averaged 1.5 x 108 g-1, which is equivalent to 4% of the total population of bacteria. This high abundance was to some extent confirmed by hybridizing colonies grown on Serratia and Pseudomonas selective media with cocktails of phage infecting these bacteria. This showed that 8.9 and 3.9%, respectively, hybridized with colonies from the two media and confirmed the presence of phage DNA sequences in the cultivable fraction of the natural population. Thus, soil phage, like their aquatic counterparts, are likely to be important in controlling bacterial populations and mediating gene transfer in soil.

* Corresponding author. Mailing address: Cardiff School of Biosciences, Cardiff University, Main Building, Park Place, P.O. Box 915, Cardiff CF10 3TL, United Kingdom. Phone: 44 29 2087 4190. Fax: 44 29 2087 4305. E-mail: fry@cardiff.ac.uk.

Antagonistic coevolution between a bacterium and a bacteriophage.

Buckling A, Rainey PB.
Department of Plant Sciences, University of Oxford, Oxford OX1 3RB, UK. bssagjb@bath.ac.uk
Proc R Soc Lond B Biol Sci 2002 May 7;269(1494):931-6

Antagonistic coevolution between hosts and parasites is believed to play a pivotal role in host and parasite population dynamics, the evolutionary maintenance of sex and the evolution of parasite virulence. Furthermore, antagonistic coevolution is believed to be responsible for rapid differentiation of both hosts and parasites between geographically structured populations. Yet empirical evidence for host-parasite antagonistic coevolution, and its impact on between-population genetic divergence, is limited. Here we demonstrate a long-term arms race between the infectivity of a viral parasite (bacteriophage; phage) and the resistance of its bacterial host. Coevolution was largely driven by directional selection, with hosts becoming resistant to a wider range of parasite genotypes and parasites infective to a wider range of host genotypes. Coevolution followed divergent trajectories between replicate communities despite establishment with isogenic bacteria and phage, and resulted in bacteria adapted to their own, compared with other, phage

Treatment of experimental infections of mice with bacteriophages.

Soothill JS.
Department of Infection, Medical School, Edgbaston, Birmingham.
J Med Microbiol 1992 Oct;37(4):258-61

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.

Dynamics of success and failure in phage and antibiotic therapy in experimental infections

J J. Bull,1 Bruce R. Levin,2 Terry DeRouin,2 Nina Walker,2 and Craig A. Bloch3
BMC Microbiol. 2002; 2 (1): 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.

full article.

Treatment of post-burns bacterial infections by bacteriophages, specifically ubiquitous Pseudomonas spp. notoriously resistant to antibiotics.

Ahmad SI.
Med Hypotheses 2002 Apr;58(4):327-31
Department of Life Sciences, Nottingham Trent University, Nottingham, England. Shamim.ahmad@ntu.ac.uk

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. Copyright 2002 Elsevier Science Ltd. All rights reserved.

Nature 425, 225 (18 September 2003);
  Drug companies snub antibiotics as pipeline threatens to run dry
  TOM CLARKE

  [CHICAGO] Major drug companies are pulling out of antibiotic
  development - and their timing couldn't be worse, a leading meeting on
  infectious disease was told this week.

  Speakers at the 43rd Interscience Conference on Antimicrobial Agents
  and Chemotherapy in Chicago said that many firms, such as Roche and
  Eli Lilly, are turning away from antibiotics to concentrate on
  treatments for chronic illness instead.

  Yet the need for new drugs has never been greater. Resistance to
  antibiotics is growing - 20% of infections in US hospitals involve
  multidrug-resistant bacteria, reports the Food and Drug Administration
  (FDA). Moreover, the pipeline of new antibiotics is running dry: the
  FDA has approved just two this year.

  "There's unequivocal evidence that antimicrobial research is on a
  steep downward slope," said John Edwards, head of policy at the
  Infectious Diseases Society of America. Recent scares over diseases
  such as anthrax have served as a reminder that it is impossible to
  predict when new anti- infectious agents will be needed.

  The retreat was palpable at the meeting. There were 10% fewer
  presentations of new drug candidates than last year, and a slump in
  attendees from industry. "Attendance is down, the number of new
  antimicrobial agents is down," said Barbara Murray of the University
  of Texas Medical School in Houston, chair of the meeting's programme
  committee.

  Big drug companies are in the financial doldrums, and antibiotics
  research is easy to cut, said Steven Projan, who directs such work at
  Wyeth's facility in Pearl River, New York. Natural selection makes
  resistance inevitable, rendering any antibiotic less profitable over
  time. New drugs that combat resistant bacteria are often held in
  reserve by doctors to treat only the most stubborn infections - so
  they aren't big earners. And unlike drugs for chronic illnesses such
  as heart disease, antibiotics cure people, eliminating their customers.

  The shift away from infectious diseases could have lasting effects on
  antibiotic research in academia, warned microbiologist Stuart Levy of
  Tufts University School of Medicine in Boston, Massachusetts. Jobs for
  microbiologists in the drug industry are becoming rarer, he said, as
  is industry funding for basic microbiology.


  Levy suggested that antibiotics be subjected to lighter regulation and
  given more public-research funds, to reflect the fact that infectious
  diseases place a burden on society. "These are societal drugs," he argued.


  But Martin Sprinkslee, vice-president of product development with
  Bayer in West Haven, Connecticut, admitted that the industry's pleas
  for special treatment may receive little sympathy. "There is a
  perception that the industry has made unethically high returns on
  sales in the past," he said.

Date: Sat, 20 Sep 2003 20:18:07 -0400
   From: "G.W. \(Bill\) Riedel" <briedel@magma.ca>; yahoogroupes
Subject: Re: Drug companies snub antibiotics Nature Magazine

On July 14, 2003, I was in Chicago where I had organized and was co-moderating a symposium entitled, "Phage therapy as it applies to food public health bacteriology." Four scientists, representing academia, phage therapy innovators and government, discussed the current scientific knowledge as it relates to this technology, which uses very highly specific viruses, the bacteriophages, to eliminate bacteria and has great potential for curing antibiotic-resistant bacterial superbug infections even when treatment with antibiotics fails. Additionally, phage therapy is a natural, green and sustainable technology, which in addition to medical applications, can be used to remove bacteria from various environmental situations, including bio-terrorist threats.

In early August the media provided extensive coverage of a newly published study indicating that an estimated 8,000 Canadians die each year from hospital infections and the author of the study was quoted as saying that the current situation regarding hospital infections is a tragedy. A few weeks later there was further coverage of an outbreak of antibiotic-resistant bacterial infections in an Ottawa hospital. Other information indicates that 40,000 North Americans die yearly from antibiotic-resistant infections and that 56,000 foot amputations are done yearly on diabetics for untreatable infections. However, if we consider that many of these infections can be treated/cured by currently available phage therapy technology from Eastern Europe, then in my humble opinion, this becomes a crime against humanity! For a recent, concise overview on phage therapy entitled, "Stalin's Forgotten Cure" (Science, vol 298, October 25, 2002, pp 728-731) the reader is encouraged to go to ( http://www.phage-biotech.com/images/Science-phagetherapy.pdf ) .

Some North Americans have opted to travel to Georgia, Eastern Europe, for phage therapy treatment: Alfred Gertler, a Canadian, travelled to Tbilisi, Georgia to get phage medicine treatment for a foot infection not responding to antibiotics - ( http://www.cbsnews.com/stories/2002/09/19/48hours/main522596.shtml ); Fred Bledsoe, is a US citizen from Fort Wayne, Indiana and after stepping on a nail, his wound became infected. After 10 weeks of unsuccessful treatment in hospital he faced amputation; however, he opted to travel to Tbilisi, Georgia for successful phage therapy treatment ( http://seattletimes.nwsource.com/html/nationworld/134619088_phage21.html ) .

Since seniors and young children are at elevated risk from such infections, I would recommend that any individual who is bugged by antibiotic-resistant superbug infections click http://www.phage-therapy.com . This is a new website of the Bacteriophage Institute in Tbilisi, Georgia and it provides information useful for anyone needing such treatment and contemplating a trip to Georgia to get it.

It should also be noted that Health Canada and the Department of National Defence have programs (re)inventing phage therapy for Canadian applications; however, the antibiotic-resistant superbug crisis is clearly upon us now and as Canadians we cannot afford to wait for 10 or 20 years before this technology has been mapleleafed because, if it is illustrated that Polish research showing 90% cure is correct, then the funerals of 360,000 North Americans could have been delayed and 504,000 amputations could have been avoided if it takes 10 years to approve phage therapy for legal use in North America. We should demand that we benefit from the work carried out on phage therapy in Georgia during the past 70 years, especially since a Canadian-born scientist discovered phage therapy and was involved in some of the early research in Georgia. The technology should be imported to Canada/North America by arranging medical and scientific technology exchanges, as well as using imported phage therapy products on an emergency and/or compassionate basis until Canadian/North maerican companies and/or hospitals can produce bacteriophages for use to treat antibiotic-resistant bacterial infections. There is only one thing more stupid then dying in the name of hubris and that is to let people die in the name of hubris (orgueil).

Dépistage du portage des Bactéries Multi-Résistantes

Ducki S., Conroy M.-C., Bollaert P.-E., Weber M., Blesch M.-F.

Hygiène et Médecine Hospitalière N°51 pp 7-11 (2002)

L'étude porte sur des patients hospitalisés plus de 7 jours en réanimation, et se fait depuis des écouvillonnage rectaux (BGN) et des deux narines (SARM). 12% des hospitalisés portaient des BMR après environ 20 (35)jours dont SARM (BMR), dont 20% à l'admission (sont 80% de SARM). 50% des patients "propres" à l'arrivée se sont faits coloniser au cours du séjour.
L'incidence d'infection à SARM monte à 15% chez les porteurs de SARM; 25% pour les BGN.
Les trois facteurs de gravité sont : l'implantation de cathéter, le nombre de journées de ventilation assistée, l'intubation, .
Les trois facteurs de risque sont : importante durée d'hospitalisation, antibiothérapie le mois précédant, provenance d'une autre institution.

Article scanné.

Comment prévenir les légionelloses hospitalières

Bernard Banga.

Décision Santé N°187 pp 14-18 (2002)

Article scanné.

THE ISOLATION OF T-EVEN PHAGES

Stephen T. Abedon

A much modified version of this piece can be found in the
June, 2000, issue of the journal Genetics under the title
"The Murky Origin of Snow White and Her T-Even Dwarfs

Web article.

Effect of phage therapy on the turnover and function of peripheral neutrophils

Weber-Dabrowska, Beata; Zimecki, Michal; Mulczyk, Marian; Gorski, Andrzej

FEMS Immunology and Medical Microbiology (2002), 34(2), 135-138 CODEN: FIMIEV; ISSN: 0928-8244

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 detd. the levels of circulating neutrophils and their precursors before therapy, after 3 wk of therapy, and at a distant time interval (3 mo) following the beginning of therapy.  In addn., 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, vs. 61.4).  This value dropped further in patients after 3 mo 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, vs. 3.8).  After 3 wk of the therapy and after 3 mo, the levels of neutrophil precursors were significantly higher (mean 4.8 and 4.9, resp.) than in control donors.  The phagocytic index was lower in patients before therapy than in control donors (mean 66.3, vs. 70.1) and decreased further after 3 wk of therapy (mean 59.0) and after 3 mo (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.

Overcoming the phage replication threshold: A mathematical model with implications for phage therapy.

Kasman, Laura M.; Kasman, Alex; Westwater, Caroline; Dolan, Joseph; Schmidt, Michael G.; Norris, James S.

Journal of Virology  (2002),  76(11),  5557-5564.  CODEN: JOVIAM  ISSN:0022-538X.  CAN 137:106313  AN 2002:375476    CAPLUS

Prior observations of phage-host systems in vitro have led to the conclusion that susceptible host cell populations must reach a crit. d. before phage replication can occur.  Such a replication threshold d. would have broad implications for the therapeutic use of phage.  In this report, we demonstrate exptl. 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 soln.  This result leads us to conclude that the frequently used measure of multiplicity of infection (MOI), computed as the ratio of the no. of phage to the no. of cells, is generally inappropriate for situations in which cell concns. are less than 107/mL.  In its place, we propose an alternative measure, MOIactual, that takes into account the cell concn. 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 concns.  In addn., the concept of MOIactual allows us to write simple formulas for computing practical quantities, such as the no. of phage sufficient to infect 99.99% of host cells at arbitrary concns.

Minimum bacterial density for bacteriophage replication:  implications for significance of bacteriophages in natural ecosystems.

Wiggins, Bruce A.; Alexander, Martin.    Dep. Agron.,  Cornell Univ.,  Ithaca,  NY,  USA.

Appl. Environ. Microbiol.  (1985),  49(1),  19-23.  CODEN: AEMIDF  ISSN: 0099-2240.  Journal  written in English.    CAN 102:92753    AN 1985:92753    CAPLUS

Bacteriophage 80a did not increase in no. in cultures contg. <1.0 ´ 104-1.5 ´ 104 colony-forming units (CFU) of Staphylococcus aureus/mL (threshold level for replication), but bacteriophage replication did occur when the no. of bacteria exceeded this d., either initially or as a result of host cell multiplication.  The min. d. of an asporogenous strain of Bacillus subtilis required for an increase in the no. of bacteriophage SPb cI was .apprx.3 ´ 104 CFU/mL.  The threshold d. of Escherichia coli for the multiplication of bacteriophage T4 was about 7 ´ 103 CFU/mL.  In the presence of montmorillonite, bacteriophage T4 did not increase in no. until the E. coli population was >104 CFU/mL.  The mineralization of glucose was not affected in E. coli cultures inoculated with a low no. of bacteriophage T4, but it could not be detected in cultures inoculated with a large no. of phage.  The nos. of bacteriophage T4 and bacteriophage that lyses Pseudomonas putida declined rapidly after being added to lake water or sewage.  Thus, bacteriophages may not affect the no. or activity of bacteria in environments where the d. of the host species is below the host cell threshold of .apprx.104 CFU/mL.

Some physical-chemical and biological properties of the rod-shaped coliphage M13.

Salivar, William O.; Tzagoloff, Helen; Pratt, David.

Univ. of Wisconsin,  Madison,    Virology  (1964),  24(3),  359-71.  Journal  written in English.    CAN 62:10630    AN 1965:10630    CAPLUS

The bacteriophage M13 differs widely from most other phages of Escherichia coli in its structure and method of release from infected cells.  The phage is a slender flexible rod about 8000 A. in length, contg. single-stranded DNA with the base compn. of thymine 36%, adenine 23, cytosine 20, and guanine 21.  The DNA sediments with an S value of 24 at 20° in 0.25M NaCl + 0.015M Na citrate.  The phage bands in a CsCl gradient at the very low d. of 1.29 g./cc.  The phage structure is such that M13 is highly resistant to heating and stable to a variety of mech. stresses.  It is not affected by trypsin or DNase, but is inactivated by the proteolytic enzyme Nagarse.  Cells infected with either the wild-type M13 phage or clear or turbid plaque types mutants do not lyse but release progeny phage while continuing to grow and divide.  The growth rates of uninfected cultures and those infected with the 3 types of phage are in the order: uninfected > turbid > wild type > clear.  These differences in growth rate probably account for the differences in turbidity between wild type and mutant plaques.  The growth rates of infected cultures are neg. correlated with the numbers of phage produced per cell per generation.  M13 resembles the E. coli phages fl and fd in all phys.-chem. and biol. characteristics for which information is available.  By serological tests, the 3 phages are very closely related but are definitely not identical.  28 references

Understanding bacteriophage therapy as a density-dependent kinetic process.

Payne, Robert J. H.; Jansen, Vincent A. A.    Department of Zoology,  University of Oxford,  Oxford,  UK.

Journal of Theoretical Biology  (2001),  208(1),  37-48.  CODEN: JTBIAP  ISSN: 0022-5193.  Journal  written in English.    CAN 135:101991    AN 2001:115994    CAPLUS

Studies of bacteriophage as therapeutic agents have had mixed and unpredictable outcomes.  The authors argue that interpretation of these apparently paradoxical results requires appreciation of various d.-dependent threshold effects.  The authors use a math. 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 formulas dependent on biol. meaningful parameters; exptl. measurement of the parameters will be a prerequisite of application of the model to particular study systems.  Such modeling can point to which aspects of phage biol. might most fruitfully be engineered to enhance the viability of bacteriophage therapy.  (c) 2001 Academic Press.

Long-circulating bacteriophage as antibacterial agents.

Merril, Carl R.; Biswas, Biswajit; Carlton, Richard; Jensen, Nicole C.; Creed, G. Joseph; Zullo, Steve; Adhya, Sankar.    Lab. Biochem. Genetics,  Natl. Inst. Mental Health Neurosci. Cent. at Saint Elizabeths,  Washington,  DC,  USA.

Proceedings of the National Academy of Sciences of the United States of America  (1996),  93(8),  3188-92.  CODEN: PNASA6  ISSN: 0027-8424.  Journal  written in English.    CAN 124:306642    AN 1996:241102    CAPLUS

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 prepns.  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 l and of Salmonella typhimurium phage P22.  We demonstrated that the long-circulating l mutants also have greater capability as antibacterial agents than the corresponding parental strain in animals infected with LDs of bacteria.  Comparison of the parental and mutant l 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.

New insights into the possible role of bacteriophages in host defense and disease

Med Immunol. 2003; 2 (1): 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 β3 integrins (primarily αIIbβ3). Therefore, phages could bind β3+ 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 β3 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 β3 blockade (e.g., anti-metastatic activity).

Implication of the hypothesis
If, indeed, phages can modify functions of β3+ 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.

full article.

Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa.

Soothill J S    Department of Infection, Medical School, Birmingham, UK

BURNS  (1994 Jun),  20(3),  209-11.  Journal code: 8913178.  ISSN:0305-4179.  ENGLAND: United Kingdom  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 94331130 PubMed ID 8054131 AN 94331130    MEDLINE

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

Use of lytic bacteriophage for control of experimental Escherichia coli septicemia and meningitis in chickens and calves.

Barrow P; Lovell M; Berchieri A Jr    Institute for Animal Health, Compton Laboratory, Berkshire, United Kingdom.  Paul.Barrow@bbsrc.ac.uk

CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY  (1998 May),  5(3),  294-8.  Journal code: 9421292.  ISSN:1071-412X.  United States  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 98267016 PubMed ID 9605979 AN 1998267016    MEDLINE

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.

Results of bacteriophage treatment of suppurative bacterial infections in the years 1981-1986.

Slopek S; Weber-Dabrowska B; Dabrowski M; Kucharewicz-Krukowska A    Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw

ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1987),  35(5),  569-83.  Journal code: 0114365.  ISSN:0004-069X.  Poland  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 88339529 PubMed ID 3455647 AN 88339529    MEDLINE

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.

Bacteriophages: Potential treatment for bacterial infections

Duckworth, Donna H.; Gulig, Paul A.

BioDrugs (2002), 16(1), 57-62 CODEN: BIDRF4; ISSN: 1173-8804

Phage therapy in terms of bacteriophage genetics: hopes, prospects, safety, limitations.

Krylov, V. N.    State Research Institute for Genetics and Selection of Industrial Microorganisms,  Moscow,  Russia.

Russian Journal of Genetics (Translation of Genetika (Moscow, Russian Federation))  (2001),  37(7),  715-730.  CODEN: RJGEEQ  ISSN: 1022-7954.  Journal; General Review  written in English.    CAN 135:352167    AN 2001:580704    CAPLUS

A review with refs.  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 harmless phage therapy.

Phylogeny of the major head and tail genes of the wide-ranging T4-type bacteriophages.

Tetart, Francoise; Desplats, Carine; Kutateladze, Mzia; Monod, Caroline; Ackermann, Hans-Wolfgang; Krisch, H. M.    Laboratoire de Microbiologie et Genetique Moleculaire du CNRS,  Toulouse,  Fr.

Journal of Bacteriology  (2001),  183(1),  358-366.  CODEN: JOBAAY  ISSN: 0021-9193.  Journal  written in English.    CAN 135:87794    AN 2001:11565    CAPLUS

We examd. a no. of bacteriophages with T4-type morphol. that propagate in different genera of enterobacteria, Aeromonas, Burkholderia, and Vibrio.  Most of these phages had a prolate icosahedral head, a contractile tail, and a genome size that was similar to that of T4.  A few of them had more elongated heads and larger genomes.  All these phages are phylogenetically related, since they each had sequences homologous to the capsid gene (gene 23), tail sheath gene (gene 18), and tail tube gene (gene 19) of T4.  On the basis of the sequence comparison of their virion genes, the T4-type phages can be classified into three subgroups with increasing divergence from T4: the T-evens, pseudoT-evens, and schizoT-evens.  In general, the phages that infect closely related host species have virion genes that are phylogenetically closer to each other than those of phages that infect distantly related hosts.  However, some of the phages appear to be chimeras, indicating that, at least occasionally, some genetic shuffling has occurred between the different T4-type subgroups.  The compilation of a no. of gene 23 sequences reveals a pattern of conserved motifs sepd. by sequences that differ in the T4-type subgroups.  Such variable patches in the gene 23 sequences may det. the size of the virion head and consequently the viral genome length.  This sequence anal. provides mol. evidence that phages related to T4 are widespread in the biosphere and diverged from a common ancestor in acquiring the ability to infect different host bacteria and to occupy new ecol. niches.

Phages and their application against drug-resistant bacteria.

Chanishvili, N.; Chanishvili, T.; Tediashvili, M.; Barrow, P. A.    George Eliava Institute of Bacteriophage, Microbiology and Virology,  Georgian Academy of Sciences,  Tbilisi,  Georgia.

Journal of Chemical Technology & Biotechnology  (2001),  76(7),  689-699.  CODEN: JCTBED  ISSN: 0268-2575.  Journal; General Review  written in English.    CAN 135:239000    AN 2001:512148    CAPLUS

A review with 69 refs.  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, Microbiol. and Virol. 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 yr, 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 no. 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 concd. the minds of the western world on the potential for infectious disease control that bacteriophage offer, a procedure that is biol. more acceptable than antibiotic use and which has been in use for several decades already.

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 Lawrence; Sosnowska Danuta; Miltner Elizabeth; Chacon Ofelia; Wagner Dirk; McGarvey Jeffery; Barletta Raul G; Bermudez Luiz E    Med-America Research, Whitestone, New York, USA

JOURNAL OF INFECTIOUS DISEASES  (2002 Oct 15),  186(8),  1155-60.  Journal code: 0413675.  ISSN:0022-1899.  United States  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 22242178 PubMed ID 12355367 AN 2002493512    In-process for MEDLINE

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. avium-infected, 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.

Effective phage therapy is associated with normalization of cytokine production by blood cell cultures.

Weber-Dabrowska B; Zimecki M; Mulczyk M    Laboratory of Bacteriophages, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw.  secret@immuno.iitd.pan.wroc.pl

ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (2000),  48(1),  31-7.  Journal code: 0114365.  ISSN:0004-069X.  Poland  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 20185304 PubMed ID 10722229 AN 2000185304    MEDLINE

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.

Results of bacteriophage treatment of suppurative bacterial infections in the years 1981-1986.

Slopek S; Weber-Dabrowska B; Dabrowski M; Kucharewicz-Krukowska A    Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw 

ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1987),  35(5),  569-83.  Journal code: 0114365.  ISSN:0004-069X.  Poland  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 88339529 PubMed ID 3455647 AN 88339529    MEDLINE

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.

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    ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1985),  33(2),  261-73.  Journal code: 0114365.  ISSN:0004-069X.  Poland  (CLINICAL TRIAL); Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 86102500 PubMed ID 2935117 AN 86102500    MEDLINE

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.

Results of bacteriophage treatment of suppurative bacterial infections. IV. Evaluation of the results obtained in 370 cases.

Slopek S; Kucharewicz-Krukowska A; Weber-Dabrowska B; Dabrowski M    ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1985),  33(2),  219-40.  Journal code: 0114365.  ISSN:0004-069X.  Poland  (CLINICAL TRIAL); Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 86102498 PubMed ID 2935115 AN 86102498    MEDLINE

The results of phage therapy applied in 370 cases of suppurative bacterial infections were analyzed. Positive therapeutic results were obtained in 342 (92.4%) cases. The results obtained confirmed the previous findings on great effectiveness of bacteriophages in the treatment of septic infections, spontaneous or postoperative, caused by pyogenic Staphylococci, Klebsiella, Escherichia, Proteus and Pseudomonas bacteria.

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    ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1984),  32(3),  317-35.  Journal code: 0114365.  ISSN:0004-069X.  Poland  (CLINICAL TRIAL); Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 85121316 PubMed ID 6395825 AN 85121316    MEDLINE

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.

Results of bacteriophage treatment of suppurative bacterial infections. II. Detailed evaluation of the results.

Slopek S; Durlakowa I; Weber-Dabrowska B; Kucharewicz-Krukowska A; Dabrowski M; Bisikiewicz R    ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1983),  31(3),  293-327.  Journal code: 0114365.  ISSN:0004-069X.  Poland  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 84078908 PubMed ID 6651485 AN 84078908    MEDLINE

The results of treatment with specific bacteriophages of 184 nosologic units diagnosed in 138 cases as septic bacterial infections, presented in the first part of this report, were submitted to detailed analysis. The results obtained revealed that phage therapy may be successfully applied in the treatment of septic infections induced by Staphylococcus, Klebsiella, Escherichia, Proteus and Pseudomonas as well as of the digestive system infections induced by Shigella and Salmonella. They also widened the scope of phage therapy application.

Full Article

Studies on bacteriophage penetration in patients subjected to phage therapy.

Weber-Dabrowska B; Dabrowski M; Slopek S    Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw

ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1987),  35(5),  563-8.  Journal code: 0114365.  ISSN:0004-069X.  Poland  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 88339528 PubMed ID 3332066 AN 88339528    MEDLINE

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.

Immunogenic effect of bacteriophage in patients subjected to phage therapy.

Kucharewicz-Krukowska A; Slopek S    Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw

ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS  (1987),  35(5),  553-61.  Journal code: 0114365.  ISSN:0004-069X.  Poland  Journal; Article; (JOURNAL ARTICLE)  written in English.    DN 88339527 PubMed ID 3455646 AN 88339527    MEDLINE

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.

Bacteriophage therapy of septic complications of orthopaedic surgery

Lang G; Kehr P; Mathevon H; Clavert J M; Sejourne P; Pointu J

REVUE DE CHIRURGIE ORTHOPEDIQUE ET REPARATRICE DE L APPAREIL MOTEUR  (1979 Jan-Feb),  65(1),  33-7.  Journal code: 1272427.  ISSN:0035-1040.  France  Journal; Article; (JOURNAL ARTICLE)  written in French.    DN 79202649 PubMed ID 156386 AN 79202649    MEDLINE

Seven septic cases have been treated by bacteriophage; two infections after insertion of a hip prosthesis, two septic arthritis of the knee, one osteomyelitis of the tibia, one septic non-union of the femur and one septic complication following Harrington rodding. Only specific phages were used in association with several types of surgical procedure. The technique of treatment is described. All cases were long-term infections with resistant organisms. Results were good in five, fair in one and one case was a failure. It is concluded that phage therapy may be helpful in the treatment of long-term infections.

Bacteriophages: Evolution of the majority

HENDRIX Roger W.

Theoretical population biology : (Print). [ Theor. popul. biol. : (Print). ] 2002 , vol. 61 , no 4 , pp. 471 - 480

The dsDNA-tailed bacteriophages are probably the largest evolving group in the Biosphere and they are arguably very ancient. Comparative examination of genomes indicates that the hallmark of phage evolution is horizontal exchange of sequences. This is accomplished, first, by rampant non-homologous recombination between different genomes and, second, by reassortment of the variant sequences so created through homologous recombination. The comparative analysis suggests mechanisms by which new genes can be added to phage genomes and by which genes with novel functions may be assembled from parts. Horizontal exchange of sequences occurs most frequently among closely related phages, but it also extends across the entire global population at lower frequency. Bacteriophages also have probable ancestral connections with viruses of eukaryotes and archaea.

Bacteriophage Therapy

Alexander Sulakvelidze, Zemphira Alavidze, and  J. Glenn Morris Jr.

Antimicrobial Agents and Chemotherapy, March 2001, p. 649-659, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.649-659.
2001

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

TABLE 1.   Some of the major human phage therapy studies performed in Poland and the former Soviet 
TABLE 2.   Comparison of the prophylactic and/or therapeutic use of phages and antibiotics
TABLE 3.   Some of the problems with early therapeutic phage research...
full article

Use of Genetically Engineered Phage To Deliver Antimicrobial Agents to Bacteria: an Alternative Therapy for Treatment of Bacterial Infections

Antimicrobial Agents and Chemotherapy, April 2003, p. 1301-1307, Vol. 47, No. 4

Caroline Westwater*, Laura M. Kasman, David A. Schofield, Phillip A. Werner, Joseph W. Dolan, Michael G. Schmidt, and James S. Norris

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Medical University of South Carolina, BSB-201, 173 Ashley Avenue, Charleston, SC 29403. Phone: (843) 792-7703. Fax: (843) 792-2464. E-mail: westwatc@musc.edu.

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.

Phage Therapy of Local and Systemic Disease Caused by Vibrio vulnificus in Iron-Dextran-Treated Mice

Karen E. Cerveny,1 Angelo DePaola,2 Donna H. Duckworth,1 and Paul A. Gulig1*

  Infection and Immunity, November 2002, p. 6251-6262, Vol. 70, No. 11

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, Box 100266, College of Medicine, University of Florida, Gainesville, FL 32610-0266. Phone: (352) 392-0050. Fax: (352) 392-3133. E-mail: gulig@ufl.edu.

  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.

Coevolution of Bacteriophage PP01 and Escherichia coli O157:H7 in Continuous Culture

Katsunori Mizoguchi, Masatomo Morita, Curt R. Fischer, Masatoshi Yoichi, Yasunori Tanji,* and Hajime Unno

  Applied and Environmental Microbiology, January 2003, p. 170-176, Vol. 69, No. 1
* Corresponding author. Mailing address: Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan. Phone: 81-45-924-5763. Fax: 81-45-924-5818. E-mail: ytanji@bio.titech.ac.jp

 The interaction between Escherichia coli O157:H7 and its specific bacteriophage PP01 was investigated in chemostat continuous culture. Following the addition of bacteriophage PP01, E. coli O157:H7 cell lysis was observed by over 4 orders of magnitude at a dilution rate of 0.876 h-1 and by 3 orders of magnitude at a lower dilution rate (0.327 h-1). However, the appearance of a series of phage-resistant E. coli isolates, which showed a low efficiency of plating against bacteriophage PP01, led to an increase in the cell concentration in the culture. The colony shape, outer membrane protein expression, and lipopolysaccharide production of each escape mutant were compared. Cessation of major outer membrane protein OmpC production and alteration of lipopolysaccharide composition enabled E. coli O157:H7 to escape PP01 infection. One of the escape mutants of E. coli O157:H7 which formed a mucoid colony (Mu) on Luria-Bertani agar appeared 56 h postincubation at a dilution rate of 0.867 h-1 and persisted until the end of the experiment (200 h). Mu mutant cells could coexist with bacteriophage PP01 in batch culture. Concentrations of the Mu cells and bacteriophage PP01 increased together. The appearance of mutant phage, which showed a different host range among the O157:H7 escape mutants than wild-type PP01, was also detected in the chemostat culture. Thus, coevolution of phage and E. coli O157:H7 proceeded as a mutual arms race in chemostat continuous culture.


Glossaire

Arber Werner 
Microbiologiste suisse (néà Gränichen en 1929).
Professeur à l'université de Bâle depuis 1971,Werner Arber s'est livré à des études de biologie moléculaire sur les bactériophages (virus), réussissant finalement à démontrer l'existence, dans certaines souches bactériennes, d'enzymes capables de modifier (enzymes de modification) ou de scinder en des sites spécifiques (enzymes de restriction) l'ADN des bactériophages qui parasitent ces organismes. Sans cette découverte, le génie génétique n'aurait jamais existé. Elle met en effet à la disposition des expérimentateurs une panoplie sans cesse croissante d'outils permettant d'isoler et de manipuler des gènes afin de réaliser des modifications dirigées de l'ADN. Cette découverte a valu à Arber le prix Nobel de médecine et de physiologie de 1978, qu'il a partagé avec Daniel Nathans et Hamilton Smith.
BGN
Bacille Gram Négatif. GBN multi-résistantes : entérobactéries sécrétrices de B-lactamase ou de céphalosporinase; Pseudomonas et Acinetobacter résistants à l'imipénem...; Streptomonas maltophila résistant à n'importe quel ATB.
SARM
Staphylococcus aureus résistant à la méticilline.