Treatment of topical and systemic bacterial infections

Abstract

Bacteriophage covalently attached to a carrier particle with an average diameter of from 0.1 microns to 15 microns, are used in topical treatment of bacterial infection. Bacteriophage covalently attached to a carrier particle of average diameter 7 microns or less are used in systemic treatment of bacterial infection. A plurality of bacteriophages lytic against different bacterial strains gives wide antibacterial activity. A combination therapy comprises administration of antibiotic and bacteriophage covalently attached to a carrier particle.

Description

FIELD OF THE INVENTION[0001]The present invention relates to compositions and methods for treatment of bacterial infections in mammals, especially in humans. In particular, the present invention relates to treatment of topical bacterial infections and systemic bacterial infections.BACKGROUND TO THE INVENTION[0002]In recent years, as resistance to conventional antibiotics has continued to grow and the application of chemical biocides becomes increasingly unacceptable on environmental grounds, attention has turned to alternative methods for control of bacterial infection.[0003]One promising approach involves the application of bacteriophages, being naturally occurring ubiquitous viruses that are harmless to humans, animals, plants and fish but lethal for bacteria. Bacteriophages are specific and will infect only particular bacterial types, with several sanitation products now on the market against pathogens such as Salmonella and Listeria. [0004]Bacteriophages have specific actions ag...

AI Technical Summary

Benefits of technology

[0064]Advantages of the invention, attributable to one or more embodiments thereof, include increased activity, especially after medium to long term storage, resulting in increased product shelf-life. Similarly, an advantage of the invention is the increased resistance to heat of covalently immobilised bacteriophage included in products of the invention. Use of such heat-resistant bacteriophage simplifies the production and sterilisation process and thus makes compounding such preparations more efficient. Skin treatments can avoid harsh chemicals such as salicylic acid and benzoyl peroxide. Particle size is optionally small and can provide smooth feeling topical treatments. For systemic treatments, the achievement of systemic efficacy in the short term but also after many days post injection demonstrates long term retention of activity, including activity effectively stored in vivo on particles retained internally. Decreased clearance of phage on particles compared to free phage further prolongs the effectiveness of the therapy. Combining the specificity of bacteriophages to target antibiotic resistant strains of bacteria with the wider specificity of antibiotics may overcome known problems of antibiotic resistance, both in individual instances of use and in the environmental distribution of bacteria by providing a selection against particular resistance mechanisms.

[0065]Antibody responses to free phage are known from the prior art. In addition, it is appreciated in the art that using repeated doses of free bacteriophage will increase the likelihood of the production of neutralising antibodies which will be detrimental to the use of bacteriophage as an effective invasive therapy. According to the present invention, use of covalently immobilised bacteriophage has the surprising advantage of absent or very low stimulation of an antibody response. This is borne out in specific examples. Further, long term stability of immobilised preparations compared to free phage enables reduction in both the dose per administration and the number or frequency of administrations, leading to a further reduction in the immune response, if any, to the therapy. Immobilised bacteriophage may not generate an antibody response due to the fact there is little or no antigenic material on the surface of e.g. beads or microspheres to which phage is attached. This observation and the resultant advantage is unexpected and surprising. Using a human dose of, say 107 to 1010 PFU (compare this with 109 PFU of free phage used in the mouse prior art) is thus unlikely to produce an immune response even after repeated doses.

[0066]In specific embodiments of the invention, described in examples below, it is also found that phage immobilised onto particles are retained in the body, in active form, for long periods of time, by retention e.g. in the liver. Particles bearing active (i.e. infective) phage were detectable in the liver of animals 14 days after systemic injection. This provides a prolonged effect of the systemic treatment as blood circulating through the liver brings bacteria into contact with these trapped, active phage. The antibacterial activity is hence of unexpected and surprisingly long duration.

[0067]Phage may be separately neutralized by complement. Again, in separate specific testing of the invention, we have shown that surprisingly the immobilized phage is not neutralized by complement—whereas free phage is. This is a further and separate benefit of the uses and therapies of the invention.

[0068]The invention is now illustrated in specific embodiments with reference to the accompanying drawings, in which

[0069]FIG. 1 shows the survival of phage in phage-containing formulations of the invention in storage;

Problems solved by technology

In recent years, as resistance to conventional antibiotics has continued to grow and the application of chemical biocides becomes increasingly unacceptable on environmental grounds, attention has turned to alternative methods for control of bacterial infection.

Antibiotics have wider specificity and are therefore useful for non-targeted interventions and emergency use, but suffer from resistant strain emergence with use.

Topical infections such as acne and impetigo may be treatable with bacteriophage as an alternative to existing products that are regarded as inefficient: some hospital handwashes have been proposed that contain bacteriophage K but have not been widely pursued; many acne treatments are known but most include active agents such as salicylic acid and benzoyl peroxide known to damage the skin.

One general problem with bacteriophage therapy, identified e.g. in the “Bacteriophage Therapy” minireview by Sulakvelidze et al, Antimicrobial Agents and Chemotherapy, March 2001, pp 649-659 is the absence of demonstration of efficacy of such preparations.

Indeed, in the prior art mentioned above no working formulations or proof of principle are provided.

Other problems identified by Sulakvelidze et al include the risk that rapid clearance of phage from the human body will reduce or negate possible effects, production of anti-phage antibodies in the patient, poor stability of phage in the body, the narrow host range of phages and insufficient purity of phage preparations.

It does not disclose the use of beads of any other size.

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