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Haley B.J.,University of Maryland University College | Kokashvili T.,George Eliava Institute of Bacteriophages | Tskshvediani A.,George Eliava Institute of Bacteriophages | Janelidze N.,George Eliava Institute of Bacteriophages | And 14 more authors.
Frontiers in Microbiology | Year: 2014

Vibrio parahaemolyticus is a leading cause of seafood-related gastroenteritis and is also an autochthonous member of marine and estuarine environments worldwide. One-hundred seventy strains of V. parahaemolyticus were isolated from water and plankton samples collected along the Georgian coast of the Black Sea during 28 months of sample collection. All isolated strains were tested for presence of tlh, trh, and tdh. A subset of strains were serotyped and tested for additional factors and markers of pandemicity. Twenty-six serotypes, five of which are clinically relevant, were identified. Although all 170 isolates were negative for tdh, trh, and the Kanagawa Phenomenon, 7 possessed the GS-PCR sequence and 27 the 850 bp sequence of V. parahaemolyticus pandemic strains. The V. parahaemolyticus population in the Black Sea was estimated to be genomically heterogeneous by rep-PCR and the serodiversity observed did not correlate with rep-PCR genomic diversity. Statistical modeling was used to predict presence of V. parahaemolyticus as a function of water temperature, with strongest concordance observed for Green Cape site samples (Percent of total variance = 70, P < 0.001). Results demonstrate a diverse population of V. parahaemolyticus in the Black Sea, some of which carry pandemic markers, with increased water temperature correlated to an increase in abundance of V. parahaemolyticus. © 2014 Haley, Kokashvili, Tskshvediani, Janelidze, Mitaishvili, Grim, Constantin de Magny, Chen, Taviani, Eliashvili, Tediashvili, Whitehouse, Colwell and Huq.


Pirnay J.-P.,Queen Astrid Military Hospital | Blasdel B.G.,Catholic University of Leuven | Bretaudeau L.,Clean Cells SAS | Buckling A.,University of Exeter | And 34 more authors.
Pharmaceutical Research | Year: 2015

The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allowsa timely supplying of phage therapy products for 'personalized therapy' or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research. © 2015 The Author(s).


PubMed | Evergreen State College, George Eliava Institute of Bacteriophages, Foundation Medicine, Catholic University of Leuven and 2 more.
Type: | Journal: Journal of wound care | Year: 2016

Diabetic foot ulcer (DFU) infections are a growing public health problem, with increasing prevalence, poor response to antibiotics and bacterial resistance to traditional antimicrobials leading to increased morbidity and mortality. Bacteriophages (phages), the viruses that target specific bacteria, are one option for addressing bacterial infections, especially where antibiotics fail. Of particular value is a class of virulent staphylococcal phages that hit almost all Staphylococcus aureus, including most methicillin-resistant Staphylococcus aureus (MRSA) strains. Here we report a continuous case series assessing the effectiveness of treating infected and poorly vascularised toe ulcers with exposed bone, after failure of recommended antibiotic therapy, using topically applied Staphylococcus aureus-specific phage.This was a compassionate-use case series of nine patients with diabetes and poorly perfused toe ulcers containing culture-proven Staphylococcus aureus infected bone and soft tissue, who had responded poorly to recommended antibiotic therapy. Six representative cases are presented here. The only generally accepted other option in each case was toe amputation. Exposed portions of the infected phalanges were removed in three cases and left in place in two cases. One case presented as a micro-clot induced gangrene following vascular stenting. In this case, phage were used to prevent infection. The phage used was a commercially available fully sequenced preparation of staphylococcal phage Sb-1. Phage solution was applied topically to the ulcerations once weekly, following standard good wound care. The amount of phage solution applied varied from 0.1 to 0.5 cc depending on volume and area of the ulceration.All infections responded to the phage applications and the ulcers healed in an average of seven weeks with infected bone debridement. One ulcer, where vascularity was extremely poor and bone was not removed to preserve hallux function, required 18 weeks of treatment. In the case of the toe with the micro-clot gangrene, the toe was salvaged and healed in seven weeks without complications.Topical application of a staph mono-phage preparation can be used successfully to treat infected toe ulcerations with bone involvement, despite very poor vascularity and failure of antibiotic treatment. The success within this small series provides the groundwork for controlled clinical trials of staph phage for diabetic foot infections.


Friman V.-P.,University of Exeter | Friman V.-P.,University of York | Soanes-Brown D.,University of Exeter | Sierocinski P.,University of Exeter | And 9 more authors.
Journal of Evolutionary Biology | Year: 2016

Recent years have seen renewed interest in phage therapy - the use of viruses to specifically kill disease-causing bacteria - because of the alarming rise in antibiotic resistance. However, a major limitation of phage therapy is the ease at with bacteria can evolve resistance to phages. Here, we determined whether in vitro experimental coevolution can increase the efficiency of phage therapy by limiting the resistance evolution of intermittent and chronic cystic fibrosis Pseudomonas aeruginosa lung isolates to four different phages. We first pre-adapted all phage strains against all bacterial strains and then compared the efficacy of pre-adapted and nonadapted phages against ancestral bacterial strains. We found that evolved phages were more efficient in reducing bacterial densities than ancestral phages. This was primarily because only 50% of bacterial strains were able to evolve resistance to evolved phages, whereas all bacteria were able to evolve some level of resistance to ancestral phages. Although the rate of resistance evolution did not differ between intermittent and chronic isolates, it incurred a relatively higher growth cost for chronic isolates when measured in the absence of phages. This is likely to explain why evolved phages were more effective in reducing the densities of chronic isolates. Our data show that pathogen genotypes respond differently to phage pre-adaptation, and as a result, phage therapies might need to be individually adjusted for different patients. © 2016 European Society for Evolutionary Biology.


PubMed | U.S. Army, IRD Montpellier, University of Maryland University College, George Eliava Institute of Bacteriophages and University of Maryland College Park
Type: | Journal: Frontiers in microbiology | Year: 2014

Vibrio parahaemolyticus is a leading cause of seafood-related gastroenteritis and is also an autochthonous member of marine and estuarine environments worldwide. One-hundred seventy strains of V. parahaemolyticus were isolated from water and plankton samples collected along the Georgian coast of the Black Sea during 28 months of sample collection. All isolated strains were tested for presence of tlh, trh, and tdh. A subset of strains were serotyped and tested for additional factors and markers of pandemicity. Twenty-six serotypes, five of which are clinically relevant, were identified. Although all 170 isolates were negative for tdh, trh, and the Kanagawa Phenomenon, 7 possessed the GS-PCR sequence and 27 the 850 bp sequence of V. parahaemolyticus pandemic strains. The V. parahaemolyticus population in the Black Sea was estimated to be genomically heterogeneous by rep-PCR and the serodiversity observed did not correlate with rep-PCR genomic diversity. Statistical modeling was used to predict presence of V. parahaemolyticus as a function of water temperature, with strongest concordance observed for Green Cape site samples (Percent of total variance = 70, P < 0.001). Results demonstrate a diverse population of V. parahaemolyticus in the Black Sea, some of which carry pandemic markers, with increased water temperature correlated to an increase in abundance of V. parahaemolyticus.


Arbiol C.,French National Center for Scientific Research | Arbiol C.,Toulouse 1 University Capitole | Comeau A.M.,French National Center for Scientific Research | Comeau A.M.,Toulouse 1 University Capitole | And 5 more authors.
Genome Biology and Evolution | Year: 2010

Coliphage phi1, which was isolated for phage therapy in the Republic of Georgia, is closely related to the T-like myovirus RB49. The ∼ 275 open reading frames encoded by each phage have an average level of amino acid identity of 95.8%. RB49 lacks 7 phi1 genes while 10 phi1 genes are missing from RB49. Most of these unique genes encode functions without known homologs. Many of the insertion, deletion, and replacement events that distinguish the two phages are in the hyperplastic regions (HPRs) of their genomes. The HPRs are rich in both nonessential genes and small regulatory cassettes (promoterearly stem-loops [PeSLs]) composed of strong σ 70-like promoters and stem-loop structures, which are effective transcription terminators. Modular shuffling mediated by recombination between PeSLs has caused much of the sequence divergence between RB49 and phi1. We show that exchanges between nearby PeSLs can also create small circular DNAs that are apparently encapsidated by the virus. Such PeSL "mini-circles" may be important vectors for horizontal gene transfer. © The Author(s) 2010.


Rigvava S.,Ilia State University | Rigvava S.,George Eliava Institute of Bacteriophages | Tchgkonia I.,George Eliava Institute of Bacteriophages | Jgenti D.,George Eliava Institute of Bacteriophages | And 3 more authors.
Canadian Journal of Microbiology | Year: 2013

Enterococcus faecalis and Streptococcus mitis are common commensal inhabitants of the human gastrointestinal and genitourinary tracts. However, both species can be opportunistic pathogens and cause disease in nosocomial settings. These infections can be difficult to treat because of the frequency of antibiotic resistance among these strains. Bacteriophages are often suggested as an alternative therapeutic agent against these infections. In this study, E. faecalis and S. mitis strains were isolated from female patients with urinary tract infections. Bacteriophages active against these strains were isolated from sewage water from the Mtkvari River. Two phages, designated vB_EfaS_GEC-EfS_3 (Syphoviridae) and vB_SmM_GEC-SmitisM_2 (Myoviridae), were specific for E. faecalis and S. mitis, respectively. Each phage's growth patterns and adsorption rates were quantified. Sensitivity to ultraviolet light and temperature was determined, as was host range and serology. The S. mitis bacteriophage was found to be more resistant to ultraviolet light and exposure to high temperatures than the E. faecalis bacteriophage, despite having a much greater rate of replication. While each phage was able to infect a broad range of strains of the same species as the host species from which they were isolated, they were unable to infect other host species tested.


Skin and soft tissue infections (SSTIs) may represent a wide clinical spectrum from cellulitis to high-mortality associated necrotizing fasciitis. Limitations in therapy due to the multiple drug resistance, leads to increase in the morbidity and mortality rates, especially in complicated SSTIs such as diabetic foot, decubitus, and surgical wound infections. Therefore, alternative treatment strategies other than antibiotics are needed in appropriate clinical conditions. "Bacteriophage therapy", which is an old method and has been used as part of standard treatment in some countries such as Georgia and Russia, has again become popular worldwide. The aim of this study was to investigate the in vitro susceptibilities of multidrug-resistant (MDR) pathogens isolated from patients with complicated SSTIs, against standard bacteriophage (phage) cocktails. Six different ready-made phage preparations [Pyophage, Intestiphage, ENKO, SES, Fersisi and Staphylococcal Bacteriophage (Sb)] used in this study have been provided by C. Eliava Institute, Georgia. Because of the absence of ready-made phage preparations for Acinetobacter baumannii and Klebsiella pneumoniae, Φ1 -Φ7 and ΦKL1 - ΦKL3 phages were used provided from the same institute's phage library, respectively. Isolation and identification of the pathogens from abscess and wound samples of patients with SSTIs were performed by conventional methods and automatized VITEK®-2 (bioMerieux, ABD) system. Antimicrobial susceptibility testing was conducted complying CLSI standards' and the bacteria that were resistant to at least two different antibiotic groups were considered as MDR. Accordingly, a total of 33 isolates, nine of them were E.coli (8 ESBL and 1 ESBL + carbapenemase positive); nine were MDR P.aeruginosa; nine were MDR A.baumannii; three were methicillin-resistant Staphylococcus aureus (MRSA) and three were K.pneumoniae (1 ESBL, 1 carbapenemase and 1 ESBL + carbapenemase positive) were included in the study. The phage susceptibilities of the pathogens were performed by using spot test. In the study, 29 (87.9%) out of 33 MDR pathogens were found to be susceptible to at least one of the tested phage/phage preparations. All MRSA (3/3) strains were susceptible to ENKO, SES, Fersisi and Sb phage cocktails, while all A.baumannii isolates (9/9) were susceptible to Φ5 and Φ7 phages. However, two E.coli, one K. pneumoniae and one P.aeruginosa strains were resistant to the all phage preparations tested. Although the clinical use of phages has not been approved yet, except a few Eastern European countries, this study exhibits the potential use of the topical bacteriophage therapy in the treatment of complicated SSTIs caused by MDR pathogens with limited treatment options, such as diabetic foot, decubitus, and surgical wound infections.

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