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Bacteriophages for Treatment Cow Metritis and Endometritis

#G-1037


Prolonged Acting, High Effective Bacteriophage Preparation for Treatment of Cow Metritis and Endometritis

Tech Area / Field

  • AGR-VTH/Vaccines and Theraupetics/Agriculture
  • BIO-MIB/Microbiology/Biotechnology

Status
3 Approved without Funding

Registration date
11.06.2003

Leading Institute
Georgian Academy of Sciences / Institute of Bacteriophage, Microbiology and Virology, Georgia, Tbilisi

Collaborators

  • The Evergreen State College, USA, MD, Washington

Project summary

Wide and often groundless application in veterinary medicine of antibiotics and chemical preparations, especially those with a wide spectrum of action, has promoted the general spread of bacteria with natural and acquired resistance. In addition, intense antibiotic therapy is accompanied by a number of complications, including alterations of immune reactivity and the development of secondary infections induced by conditionally-pathogenic microorganisms.

Considering the probability of complications due to the application of antibiotics, interest in the use of phage preparations for this purpose has greatly increased worldwide. This interest is enhanced by a number of positive properties of the phages. These include the possibility of high specificity towards the pathogenic agents while sparing the regular flora of the animal, their lytic capability against antibiotic-resistant strains and, most important, their safety for the animals and environment (they are naturally occurring bactericides). It should also be noted that virulent bacteriophages are bactericidal whereas most antibiotics are only bacteriostatic.

It is known that following calving, the uterus of over 90% of all dairy cows becomes contaminated with bacteria. Some of these bacteria are harmful and others are not. When harmful bacteria are present, the uterus may become infected. If these infections cause only mild changes in the superficial layers of the uterus, it is termed endometritis. However, in some instances, severe infections that involve all the tissue layers of the uterus develop and this condition is called metritis. Metritis often involves the accumulation of fluid within the uterus and suppression of the estrous cycle. While few animals die from uterine infections, there is often a negative effect on fertility, milk production and overall health of the cow. The most important organism involved in pathologic postpartum uterine infections (metritis and endometritis) are Pseudomonas spp, streptococci and staphylococci, E.coli (various serovars), and P.vulgaris etc.

Treatment of this disease in cows is currently executed by using antibiotics such as oxitetracyclin, gentamycin, penicillin, lincomycin, and streptomycin. However, their action on the microorganisms often is inefficient because the metritis and endometritis inducing strains happen to be multi-drug-resistant. In addition, the high doses of antibiotics deteriorate the normal micro-flora of the cows and negatively influence the milk quality.

Considering all of these problems, we propose a Project in which a specific polyvalent bacteriophage cocktail will be utilized as an anti-bacterial agent against the various conditionally-pathogenic bacteria which may induce cow metritis and endometritis (S.pyogenes, S.zooepidemicus, S.aureus, P.aeruginosa, E.coli, P.vulgaris or other microorganisms, isolated during our research, which induce cow metritis and endometritis These bacteriophages will be impregnated into biodegradable polymeric matrices to prolong their action in the localized affected areas and thus increase effectiveness. For therapeutic purposes, only virulent bacteriophages with a reasonably wide spectrum of lytic action must be chosen. The collection needs to include a variety of phages against staphylococci, streptococci, enteric bacilli, pyocyanic bacilli, E. coli, and proteus. It is essential to investigate their major and auxiliary taxonomic properties, such as plaque morphology, nucleocapsid structure, serological relationships, incidence of bacterial mutation to resistance against the given phage clone, and cross-resistance of the phage-resistant host mutants against the various other phage clones in the cocktail.

The Laboratory of Microbiology and Taxonomy of Phages of the G.Eliava Institute of Bacteriophagy, Microbiology and Virology IBMV, under the supervision of Prof. T.Gabisonia has already established a substantial collection of separate phages against S.agalacticae, S.pyogenes, S.aureus, E.coli (various serovars), P.aeruginosa and P.vulgaris which will have been adapted on the strains isolated from the cow metritis and endometritis.

Treatment of the above mention diseases is frequently complicated by the development of connective tissue pathology induced by the inflammatory process – fibroses and various hypertrophied degenerations, which counteract efficient action of both medicinal preparations and elements of the immune system of the organism. Sometimes, restoration of the tissues occurs following elimination of the bacteria however, with development of the scar tissues. With an aim to avoid the above pathologies, careful application of hyaluronidase, an enzyme degrading the main component of connective tissue – hyaluronic acid – may be advised. There are indications that appropriate use of this enzyme promotes tissue restoration without scarring, facilitating resorption of solutions and oxidizing metabolites that have infiltrated into the tissues, entry of the phage preparations and of immune system components into the chronic and acute foci, and healing of endometrium.

At the same time, some of the microorganisms participating in metritis pathogenesis have capsules that contain hyaluronic acid and are important virulence factors (e.g. A and C group streptococci). The hyaluronidase enzyme, depleting these capsules, increases efficiency of the phage preparations. The medicinal effect is thus based on both increased permeability to the medicinal preparations and decreased resistance of the microorganisms against the phage preparations and phagocytosis. We therefore intend to investigate the application of microbial hyaluronidase in combination with our phage preparations to increase treatment efficiency in cow metritis and endometritis.

To further enhance the effectiveness and ease of administration of our preparation, it will be applied in a proven sustained release form. The matrix involves original biodegradable polymers that have already been fully tested and approved for similar uses for human applications in the form of Phage Bioderm and Phage Biodent, patented by the Research Center for Medical Polymers and Biomaterials. The bacteriophage/biodegradable polymer composite, in the form of a fine powder with and without the hyaluronidase, will be suspended in saline to produce a localized, sustained-release drug that can easily be administered into the uterus by syringe or bonus.

The construction of the proposed highly efficient phage preparation against the pathogenic agents of cow metritis and endometritis will involve the following major steps (involving 11 tasks listed in Paragraph 4 (Scope of Activities) below):

1. Creation of a more extensive collection of the conditionally-pathogenic strains (S.zooepidemicus, S.pyogenes, S.aureus, E.coli (various serovars), P.aeruginosa, P.vulgaris, etc.), which circulate in the farms and induce metritis and endometritis.

2. Isolation, purification and concentration of a number of virulent phage clones and determination of the activity and action ranges of the various phages.

3. Investigation of their major taxonomic features (plaque morphology, nucleocapsids’ morphology, antigenic composition, mutation frequency of the host to resistance, etc.) and assessment of optimal combinations of the phages for general application against cow metritis and endometritis.

4. The production of a highly purified preparation of staphylococcal hyaluronidase.

5. The selection of the specific solvent and biodegradable polymer for obtaining biocomposites able to effectively sustain and release this phage and enzyme combination, including study of the interaction of the different components of the complex preparation.

6. The study of the kinetics of release of the bacteriophages and hyaluronidase from the powdered biocomposite suspended in saline.

7. Short-term study of the effectiveness of the new biocomposite preparation for treatment of metritis and endometritis in diary cattle.


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