WO2002076483A2

WO2002076483A2 - Bacteriophage preparation

Info

Publication number: WO2002076483A2
Application number: PCT/EP2002/003464
Authority: WO
Inventors: Nodar A. Danelia
Original assignee: Danelia Nodar A
Priority date: 2001-03-28
Filing date: 2002-03-27
Publication date: 2002-10-03
Also published as: AU2002304792A1; DE10115310A1; WO2002076483A3

Abstract

The invention relates to a composition comprising bacteriophages and endotoxins and to a medicament that contains such a composition. The invention further relates to the use of said medicament for treating bacterial diseases, fungal infections and/or inflammations. The inventive composition can also be used as cleaning agent or/and disinfectant.

Description

Bacteriophage preparation

description

The present invention relates to a composition comprising bacteriophages and endotoxins and a medicament which contains such a composition and the use of this medicament for combating bacterial diseases and / or inflammation. The composition according to the invention can also be used as a cleaning agent and / or disinfectant.

In recent years, resistance has been increasingly observed in many pathogenic microorganisms, such as bacteria. Bacteria such as staphylococci, streptococci, pneumococci and the like. increasingly develop resistance to conventional antibiotics. It is particularly problematic that the bacteria often not only develop resistance to a specific antibiotic, but also become resistant to a large number of very different antibiotics. This multi-resistance means that infections caused by multi-resistant pathogenic microorganisms can no longer be treated with many known antibiotics, and even untreatability with antibiotics. As a result, infections that could be combated with conventional antibiotics prior to the appearance of resistance or multi-resistance of bacteria can no longer be treated with antibiotics and, in the worst case, lead to the death of the patient. For example, it has been shown that even when antibiotics are used in chemotherapy, the bacterial inflammation that occurs during chemotherapy is increasingly difficult or impossible to combat due to multi-resistance of the bacteria. Multi-resistance of bacteria has already been observed with many known classes of antibiotics, for example carbohydrate antibiotics, macrocyclic lactones, cienones, amino acid antibiotics, peptide antibiotics, N-containing heterocyclic antibiotics, O-containing heterocyclic antibiotics, alicyclic antibiotics and aromatic antibiotics.

In order to be able to fight resistant or multi-resistant bacteria, new classes of antibiotics are constantly being developed. However, the development of new antibiotics is laborious and time-consuming and there is a fear that pathogenic microorganisms will sooner or later also develop resistance or multi-resistance to newly discovered antibiotics.

Multi-resistant bacteria in hospitals represent a particularly big problem, with the occurrence of resistant or multi-resistant bacteria being observed particularly often here, and infections with such bacteria, if they cannot be treated immediately, further weaken the patient.

DE 1 98 28 596 A1 describes a medicament for the treatment of bacterial diseases which contains polyvalent bacteriophages as an active ingredient. Polyvalent bacteriophages are able to lyse different strains of bacteria, regardless of whether these bacteria are resistant to antibiotics or multi-resistant. In this way, an effective control of resistant bacterial strains is possible.

WO 98/51 31 8 describes pharmaceutical compositions which comprise a self-replicating agent against a heterologous pathogenic organism, for example bacteriophages which are specifically directed against a certain heterologous pathogenic organism. EP 0 41 4 304 describes aqueous antibacterial compositions for controlling unwanted bacteria which contain a nonionic surface-active agent, a neutral salt and bacteriophages.

An object of the invention was to provide new compositions which, in particular, have an improved action in the treatment of pathogenic organisms.

According to the invention, this object is achieved by a composition comprising

(a) bacteriophages and

(b) endotoxin.

Bacteriophages, often also called phages, are viruses which infect bacteria and in particular viruses which specifically infect bacteria, ie do not infect the host, for example a mammal and in particular a human being. Infection of bacteria or other pathogenic microorganisms by virulent phages leads to the lytic cycle and thus ultimately to the lysis and destruction of the bacteria. The lytic cycle begins with the adsorption of the phage to the bacterial cell. The phage or its nucleic acids penetrate the host bacterium and cause its synthetic machinery to synthesize phage-specific proteins and nucleic acids. Phage-specific proteins are, for example, early proteins, such as regulator proteins and catalytic proteins, and late proteins, such as capsid proteins and lysozyme. After the assembly of new phages (virions) from proteins and nucleic acids, the bacterial cell wall is dissolved with the help of the lysozyme (lysis) and the new phages are released. In addition to the lytic cycle, phage infection via the lysogenic pathway is also possible. Endotoxins are bacterial toxins which, in contrast to exotoxins, are not excreted by living bacteria, but are only released by autolysis. Examples of endotoxins are the heat-stable lipopolysaccharide (LPS) fraction of the cell membrane anchored in the outer membrane of gram-negative bacteria. Lipopolysaccharides consist of lipid A, the core polysaccharide, and an O-specific chain, lipid A being responsible for the toxic effects of lipopolysaccharides. Endotoxins can be found in all Enterobacteriaceae, e.g. Salmonella (typhoid), Shigella (Ruhr) and many other gram-negative germs. In a broader sense, protein toxins of Gram-negative bacteria located in the cytoplasm are also referred to as endotoxins, such as, for example, toxins from Vibrio cholerae (cholera toxin), the bacteriocins (eg Colicine) or the gamma-endotoxins formed by Bacillus thuringiensis, which are polypeptide crystals.

It has now surprisingly been found that the combined administration of bacteriophages and endotoxins achieves a cooperating and possibly even synergistic effect, in particular in wound healing. This is attributed to the fact that many inflammatory diseases, such as the diabetic foot, are based on three processes, namely a change in the vessels, a change in nerve conduction and an infection. The infection can be combated by administering bacteriophages, which triggers the overall healing process. It has now been found that the additional presence of endotoxins has a positive effect on the overall healing process. This positive effect may be due to the immunostimulatory properties of endotoxins. Endotoxins stimulate mediators, especially cytokines, of the immune system. One consequence of this is the production of interleukin-1 and kachectin (tumor necrosis factor). So far, however, it has been assumed that the immunostimulating effect of endotoxins has adverse effects on a patient's organism, such as an increase in temperature (fever) and numerous other pathophysiological effects, and even an irreversible endotoxin shock can occur if high doses of endotoxins are released. For this reason, endotoxins have so far been undesirable in pharmaceutical compositions, such as for controlling bacteria. Since it was assumed that endotoxins are rather harmful and at least unimportant for the success of a cure, only endotoxin-free preparations have so far been considered for use.

In contrast, it has now surprisingly been found that endotoxins in combination with bacteriophages have a positive effect on the healing success.

The composition according to the invention preferably has at least 10 ⁵ , in particular at least 10 ⁶ , more preferably at least 10 ⁷ and preferably up to 10 ¹⁰ , more preferably up to ¹⁰ ⁹ and most preferably up to ¹⁰ ⁸ bacteriophages per ml total volume of the composition. It is also possible to provide concentrate compositions which have a higher proportion of bacteriophages, for example up to 10 ²⁰ bacteriophages per ml total volume. Furthermore, it can be advantageous for some applications to use compositions which have a lower bacteriophage content, for example at least 10, at least 100 or at least 1,000 bacteriophages per ml of total volume.

The compositions according to the invention furthermore preferably contain at least 0.05 ng, in particular at least 5 ng and more preferably at least 10 ng endotoxin per ml total volume of the composition. The endotoxin content can be of any size, but is preferably up to 100,000 ng, more preferably up to 10,000 ng and most preferably up to 1000 ng per ml total volume of the composition. The endotoxin content can be detected in a sample, for example, using the Limulus amoebocyte lysate test.

The composition according to the invention can contain specific monovalent phages which are able to infect and lyse only a specific type of bacteria. However, the composition according to the invention is preferably active against several bacteria at the same time, for example by containing several different monovalent bacteriophages and / or containing one or more polyvalent bacteriophages. Polyvalent bacteriophages are able to infect and lyse different types of bacteria.

Bacteriophages are preferred which can infect or lyse one or more of the following types of bacteria: Enterobacteriaceae, e.g. the representatives Proteus, in particular P. vulgaris, Salmonealla, Yersinia, in particular Y. pestis, Enterocolitica (Enterocolitiden), Vibrio, Enterobacter, Escherichia, in particular E.coli, Micorococcaceae, Staphylococci, in particular S. aureus, S. epidermidis and others.

Further examples of phages which can be used according to the invention are lysteriaphages, in particular Listeriaphagen A51 1, B054, Klebsiellaphagen, in particular Klebsiellaphagen K1 1, Klebsieila pneumonia bacteriophages, staphylococcus phages, in particular staphylococcus phages from group II, yeast LA virus, ScVL1, KVLa virus, ScVL1 Killer virus, Chlamydiaphagen such as Chp 1 (Storey et al., Gen. Virol. 70 (1,989), 1321-1327), Bacillus phages such as phi 20 (Inal et al., Curr. Microbiol. 32 (1,996 ) 1 71 -1 75), CP ₅₄ (Mol. Mikrobiol., Virosol. 1 37 (1 989) 14-1 9) and Tg ₁₃ ant (Mol. Gen. Mikrobiol. 55 (1 991), 28-31) , Salmonella phages, in particular of type 4 and type 8 (Zentralbl. Bacteriol. 285 (1 997), 379-388) and phages 1 3a, 14b, 23, 8 and 2 (Singer et al., Avian, Dis. 36 (1 992) 324-333) and Vibriocholeraphagen, in particular Vibriocholeraphage 01 39.

In particular, phages are used which are able to infect and possibly lyse one of the following hosts: Listeriae, Klebsiellae, streptococci, staphylococci, pneumococci, Moraxellae, Legionellae, Vibrio, Edwardsiellae, Yersiniae, Escherichiae, Haemophilus influenza, Proteus , Salmonaellae, Chlamydiae, Aeromonas salmonicida, Renibacterium salmoninarum, Candida albicans, Leishmania, Anthrax, Trichomonas vaginalis, Giardia lamblia, Cryptosporidium parvum, Plasmodium falciparum, Entamoeba histolytica, Trypocystos carambiosiiensei, Trenseocanis cariniii. Examples of special bacteria from these classes, which are preferably infected, are Listeriae monocytogenesor, Klebsielle (K.) ozaenae, K. rhinoscleromatis scleromatis, K. pneumoniae, Staphylococcus aureus, Yersinia ruckeri, Renibacterium salmoninaram, Vibrio anguillarum, Vibrio chonicida, Vibrio chonicae, Vibrio , Vibrio viscosus, Edwardsieila ictalari but also mushrooms, such as Candida, for example Yeast Candida albicans, Candida guillermondii, Candida krusei, Candida parapsilosis, Candida pseudotropicalis, Candida pulcerrima, Candida stellatoidea, Candida tropicalis, Syringospora albicans, dermatophyte fungi, Trichophyton rubrum, T. schoenleini, T. mentagureumytes . verrucosum, T.interdigitalis, Empidermophtyton floccosum, Microsporum audouini, M. canis, M. gypseum, Mycophyta, Mycota, Eumycetes, Mycetes, Archi-, Phyco-, Asco- and Basidiomycetes, Adelomycetes, Deuteromycetes, saprophothores, saprophytophoree Emmonsia species or protozoa, such as Leishmania, and also chlamydia, such as Chlamydia pneumoniae, Chlamydia trachomatis and Chlamydia psittaci, Moraxella catarrhalis and Salmonella enteritides.

The composition according to the invention can contain bacteriophages of the virulent type and / or the lysogenic type. A composition is particularly preferred which contains bacteriophages, for example as a mixture or as multivalent bacteriophages, which are capable of infecting and lysing at least staphylococcus, streptococcus, E. coli, Pseudomonas and Proteus.

Bacteriophages which are active against Klebsiella, Enterococcus and / or Acinetobacter bacteria are also preferred.

Another preferred composition, which is also referred to as IntestiPhag, includes salmonelosephages, staphylococcus phages,

Streptococcus phage and proteus phage. Another preferred composition called Coli-Proteus comprises a mixture of

E.coliphagen and Proteusphagen and is e.g. used for entercolitis or colpitis. Further preferred compositions in human medicine include phages against streptococci, staphylococci, Escherichia coli,

Pseudomonas aeruginosa, Proteus, Acinetobacter and Klebsiela or against

Staphylococci, Streptococci, Escherichia coli, Pseudomonas aeruginosa and Proteus or against Staphylococci and Escherichia coli or against

Proteus and Escherichia coli or against Pseudomonas au. The above mixtures are particularly suitable for use in human medicine. For use in veterinary medicine, intestiphag,

Yersiniaphag and Salmonellephag preferred.

While it is possible to use genetically modified bacteriophages, wild-type bacteriophages are preferably used according to the invention.

Since the control mechanism of pathogenic organisms of bacteriophages differs fundamentally from that of antibiotics, infection and lysis occur regardless of whether the representatives of a bacterial strain have developed resistance or multi-resistance to antibiotics. Furthermore, it was found that bacteriophages and in particular the composition according to the invention are also effective against fungi and in particular against fungal attack if the phages are selected appropriately.

In addition to the ingredients mentioned, bacteriophages and endotroxin, the composition according to the invention can contain other ingredients, in particular a carrier or solvent, such as water or a salt solution, in particular a physiological saline solution. In addition, it is also possible to add further active ingredients to the composition in order to achieve a further improvement in effectiveness for certain applications or formulation auxiliaries to achieve a consistency and / or quality suitable for a proposed application.

Since bacteriophages have specificity for heterologous, especially pathogenic, microorganisms while keeping the host of such microorganisms, e.g. a person who does not infect, the composition according to the invention is particularly suitable as a medicament. The invention therefore furthermore comprises a medicament which comprises a composition according to the invention containing bacteriophages and endotoxin.

The medicament is particularly intended for the treatment of vertebrates such as birds, fish and mammals, preferably for the treatment of humans. It can therefore be used both in human medicine and in veterinary medicine.

With the medicament according to the invention or the pharmaceutical composition according to the invention, a positive effect on the overall healing process of many bacterial or inflammatory diseases can be achieved, even if bacteria or other pathogenic microorganisms are involved which are compared to conventional ones Antibiotics have developed resistance or multi-resistance. In addition, the medicament according to the invention can be successfully used for the treatment of fungal attack and / or fungal diseases.

The medicament according to the invention can be used both as an outpatient and as an inpatient in hospitals, it being particularly advantageous in the latter case in particular because of the multi-resistant bacteria in hospitals. The drug is suitable for use in intensive care and transplantation medicine as well as for symptomatic treatments.

Since bacteriophages, in particular of the virulent type, use the infected bacterial cell to produce a large number of other effective bacteriophages, the bacteria can be effectively combated by further penetration of the released bacteriophages into other bacterial cells and lysis thereof, thereby enhancing the desired bacterial control is achieved in the presence of bacteria to be controlled.

The medicament according to the invention is suitable both for treatment and for the prophylaxis of bacterial diseases or inflammation or fungal diseases, in particular on account of the very low associated side effects. Due to the mechanism of action, which involves a multiplication of the active bacteriophages only when an infection of the host with a corresponding bacterium or fungus occurs, it is possible to administer prophylactically small amounts of bacteriophages and endotoxins which do not damage the host organism, but which do occur when bacteria or fungi to be combated can be multiplied in a short time. In acute infections, the administration of high doses of bacteriophages is possible because these selectively lyse the pathogenic microorganism without harming the host organism, for example a mammal. The medicament according to the invention can be formulated for various applications, for example for topical, intravenous, intestinal, oral, rectal, intramuscular, subcutaneous or intraperitoneal use. The medicament according to the invention is preferably formulated for external use, for example as a rinse, irrigation, bandage or tamponing, or for topical use, for example for use under the skin, for use in an inner cavity or for intramuscular use.

Both applications against fungal and / or infectious diseases are external applications, for example as an ointment, gel or solution, and oral applications, for example incorporated into a toothpaste or as a solution for gargling.

The respective concentration of bacteriophages and endotoxin can be adapted to the intended application. For example, drugs for topical use preferably contain at least 10 ng endotoxin, while drugs intended for intravenous administration preferably contain 0.05 ng to 0.1 ng endotoxin.

The type of formulation can also be adapted to the intended type of application. The medicament according to the invention can be formulated, for example, as a solution, as a spray, as a rinsing liquid, as an injection, as a dragee, capsule, etc., depending on the carrier substances, both solid, liquid and gel-like formulations are possible.

The treatment of a patient with the medicament according to the invention is generally carried out over a period of about 3 to 7 days, with a noticeable effect being recognizable after 24 hours in most cases. The dose depends on the type of disease and application, but usually comprises one or more, for example up to three times, administration of the drug per day. For topical Applications can be applied, for example, to compresses impregnated with the medicament according to the invention. In the case of large wounds, continuous dropwise application can also be advantageous.

The medicament according to the invention optionally contains pharmaceutically suitable auxiliaries and / or carriers. It preferably contains water, a saline solution, in particular a saline solution or a soda solution. A physiological saline solution, for example a phosphate-buffered physiological saline solution with a pH of 7 to 7.8, preferably of 7.3 to 7.5, is particularly preferably used as the carrier.

The medicament according to the invention preferably has a local antibacterial effect and can be used for wound cleaning of pus.

In addition to the active substances mentioned bacteriophages and endotoxin, the medicament according to the invention can contain further active substances, each of which can be adapted to the disease to be treated and the form of use. For example, the medicament according to the invention can additionally have conventional antibiotics, immunrepressants or / and cytostatics.

The medicament according to the invention is particularly suitable for the treatment and / or prophylaxis of bacterial and / or inflammatory diseases, such as erysipelas, nasal-upper lip furuncles, otitis externa, perichondritis of the auricles, otitis media, mastoiditis, septal abscess, sinusitis acuta purulenta, nosocomial sinusitis, orbital Complications of sinusitis, rhinogenic brain abscess, floor of the mouth, tonsilitis, peritonsillar abscess, endocarditis prophylaxis in ENT surgery, pharyngitis, epiglotis, rhynopharyngitis, laryngitis, tracheitis, bacterial ENT infections, anthrax, diabetic foot ulcers, epidermophytiasis Decubitus, burns, chronic wounds, osteomyelitis, skin diseases, chronic dermatitis, especially of the hands and feet, contact dermatitis, housewife eczema, pompholyx, psoriasis, puster eruptions, skin abscess, boils, carbuncles, sycosis, other dermatitis, intestinal diseases, bacterial urinary tract infections, bacterial infections and chronic cystitis, prostatitis, bacterial urogenital tract infections, vaginal infections, bacterial infections, po sttra uma tischer O ste iti s, ch ro n is cher O steo mye l iti s, infectious osteoarthritis, bone defects with fistula, knee joint sensation or / and TEP- Relaxation on infection.

The treatment and / or prophylaxis of pneumonia, tuberculosis, malaria, leishmaniasis and gonorrhea is of particular importance, since many people worldwide are affected by these diseases.

For use in urology, oral administration is preferred, the phages diffusing into the blood and urine and excreted in the urine, so that urological and nephrological diseases can be successfully treated. In the case of infectious diseases, preference is given to external applications, for example in the form of an ointment, a gel or a solution, or oral applications, for example in the form of a toothpaste or for gargling.

The medicament according to the invention is particularly preferably used for the treatment of diabetic ulcers, in particular diabetic foot. For the treatment of the diabetic foot, solutions, for example as a spray or in the form of soaked compresses, are preferably applied to the infected areas. An amount of about 20 to 40 ml of composition containing at least 10 ⁵ bacteriophages per ml and at least 5 ng endotoxin is usually sufficient for this type of application. Pneumonia caused by pneumococci, meningitis and intestinal diseases are also preferred.

Sepsis can also be successfully treated by intravenous administration of the medicament according to the invention.

Fungal diseases that can be controlled include e.g. chronic dermatitis, especially on the hands and feet, epidermophytia, such as microsporum, trichophyton or epidermophyton, tinea capitis, T. corporis, T. pedis, T. unguium (onychomycosis), candidiasis, tinea versicolor, mycoses (e.g. histoplasmosis, coccidioidomycosis) Tinea cruris, candidiasis, endo- or systemic mycoses, mycosis, endogenous mycosis, exogenous mycosis, blasto-, coccidioido-, chromomycosis, histoplasmosis, nocardiosis, sporotrichosis, dermatomycosis, pneumo-, entermycoses, chromo-, madura-, keloid- blasto- , Phyco-, blasto-, coccidioidomycosis, South American blastomycosis, pheomycotic cyst, rhinosporidiosis, sporotrichosis, adiaspiromycosis, cladosporiosis, histoplasmosis.

The medicinal product according to the invention is characterized in particular by the following advantageous properties:

larger settlements of microorganisms can be lysed;

Reproduction with appropriate microflora; - specific lytic activity; strains resistant to antibiotics can also be lysed; there is the possibility of expanding the lytic spectrum

(e.g. in connection with phagoresistant strains)

Selection; - relatively low frequency of development of phargoresistant

microorganisms; Possibility of using several phages and also combining them together with other medicinal products

preparations;

Possibility of an application combination with antibiotics, the treatment, for example, with the invention

Medicament can be started and completed with antibiotics, treatment with antibiotics can be started and, if antibiotic resistance is formed or is established, can be completed with the medicament according to the invention or the treatment can be carried out simultaneously with the medicament and antibiotics according to the invention; no known side effects; Harmlessness to the host; - there is no age limit.

Because of the advantages mentioned, the medicament according to the invention can be used with great success for treatment, prophylaxis and / or sanitation.

The medicament according to the invention provides successful protection against infection by bacteriophages, a reduced risk of postoperative wound infections, an avoidance of infection-related longer periods of stay, low costs in short-term use, no side effects and no elicitation of allergy with a broad coverage of pathogens, for example coverage of the commonly occurring basic strains.

In addition to being used as a medicament, the composition according to the invention can also be used in other areas in which combating bacteria or pathogenic microorganisms is desired. The invention therefore also includes the use of the composition according to the invention as a cleaning or / and disinfectant. It has been found that a composition which contains bacteriophages and endotoxins can also be used for disinfecting rooms, surfaces and / or devices, in particular for disinfecting in hospitals and / or pharmaceutical practices. When used as a cleaning agent and / or disinfectant, the advantage of bacteriophages over conventional antibiotics, namely the possibility of combating antibiotic-resistant microorganisms, has a particularly good effect. In particular, hospital pathogens can often no longer be controlled using conventional disinfectants or antibiotics, but can be killed using the compositions according to the invention. When used as a cleaning agent and / or disinfectant, in addition to the bacteriophages and endotoxins, the composition preferably contains only water, a sodium chloride or sodium carbonate solution, in particular a physiological sodium chloride solution.

The compositions according to the invention can be obtained by combining a bacteriophage preparation which is obtained in a conventional manner as described in the prior art (e.g. in DE 1 98 28 569 A1) and a composition containing endotoxin.

However, a composition which already contains bacteriophages and endotoxins is preferably formed immediately during production. For this purpose, bacterial strains, which are also to be combated later, are infected with the corresponding phages and kept under conditions in which a complete lysis of the bacterial strains is achieved. ^{'Subsequently,} filtration of Phagolysate is carried out under conditions in which the bacteriophages and endotoxins remain in the recovered fraction, while undesirable components and bacteria residues are separated. Such separation can be done, for example, by filtration with a filter with a pore diameter of at least 0.3 μm, more preferably at least 0.4 μm and up to 3 μm, more preferably up to 2 μm and particularly preferably up to 1.5 μm, for example with a 0.45 μm or a 1.2 μm pore filter through which the desired components can penetrate bacteriophages and endotoxins. A combination preparation produced in this way can be used directly without further purification or isolation of the bacteriophages.

The invention is further illustrated by the following examples.

Examples

Example 1 Preparation for Manufacturing

Phage breeds and bacterial strains were used as raw materials for the preparation.

First, bacterial strains are isolated from patients who have the relevant ethnological disease. Then there is a

Selection or screening of bacterial strains or phages for the preparation of the preparations.

The bacterial strains or phages are checked morphologically, serologically and biochemically once a quarter.

Bacterial strains or phages that do not match morphologically, serologically or biochemically are discarded. The bacterial strains or phages are stored in a dry environment or on appropriate liquid or solid nutrient media. The phages can be separated (extracted) from the environment (waste water, water reservoir) and from inflammable exudate, pus or faeces. The phagoras must contain virulent phages that can completely lyse the corresponding bacterial strains. Be isolated phages tested for sensitivity to microbes. In the case of weak sensitivity, phages can be enriched by phage passage (adaptation) in the presence of bacterial strains. After sufficient activity, mother phages (starting phages) are transferred sterile to vessels and stored at + 2 to 10 ° C.

Example 2 Production of a combination preparation containing

Bacteriophages and endotoxins

Mother phages are obtained in a nutrient medium as in Example 1 and the corresponding bacterial strains are mixed together, the aim being a complete lysis of the bacterial strains. Complete lysis is determined experimentally. The incubation of the culture is e.g. at 37 ° C for 1 6 to 1 8 hours, during which time total lysis is achieved. Only bacterial strains without phages serve as controls. The cultures without complete lysis are discarded. The desired constituents, in particular phages and endotoxins, are then removed by removing unwanted constituents of the phagolysates, e.g. obtained by filtration through a filter with a pore diameter of 0.45 μm. The preparation can be filled and used directly without further cleaning steps, the preparation preferably being filled into ampoules. If desired, the manufactured preparations can be checked.

Each batch of preparations is checked and quantified and certified for physical properties, sterility, toxicity, biological activity, in particular bacteriophage and endotoxin content as well as exotoxin content.

Example 3

Exemplary embodiments Example 3.1

Application and rinsing In the event of an injury to the oral mucosa, the tongue and / or the lips, the preparation prepared according to Example 2 is used locally in the form of the application and as a rinse. The rinsing is carried out several times a day, advantageously after thorough cleaning of the wound area with 3 to 5% sodium hydrogen carbonate. The application of the mucous membrane is advantageously carried out using the liquid preparation prepared according to Example 2 and 0.5% novocaine solution (for example 1 ml 0.5% novocaine + 3 ml preparation according to the invention). The application is carried out every day until the pathological focus is liquidated, the duration of each treatment being 5 to 10 minutes.

3.2 Wetting / irrigation of a pus wound

After a surgical procedure, the wound treated with 3 to 5% sodium hydrogen carbonate is watered with 3 to 5 ml of the preparation prepared according to Example 2, depending on the extent of the damaged tissue, and a drainage with tampons is left in the wound, which are soaked with the combination preparation according to the invention , Watering the wound and inserting the tampons into the wound is repeated for 3 to 6 days.

For irrigation of a pus wound, the preparation prepared according to Example 2 can be used successfully in the form of a spray. Irrigation of a pus wound with a spray has the advantage over tampons that no additional dressing is required and that parts of the wound that cannot be reached with a tampon are also treated with the spray.

3.3 Internal cavity application

In the case of abscesses, the preparation prepared according to Example 2 can be punctured into the inner cavity of the pus after the pus has been aspirated be filled in. The quantity of preparation introduced is advantageously somewhat less than the quantity of pus sucked out.

3.4 Use in the form of inhalation If the inflammatory and pus processes in the nasopharynx are severe, complications such as pneumonia or pulmonary destruction are not uncommon. In such a case, inhalation with the preparation prepared according to Example 2 is successfully used, atomization being carried out using a conventional inhaler. For this purpose, the preparation is placed in an inhalation glass and the electric heater is heated to a temperature of 36 to 38 ° C. The duration of the inhalation is usually 5 to 10 minutes, 5 ml of the preparation according to the invention being used. A course of treatment typically involves 10 inhalations, with about 3 inhalations per day.

Claims

Expectations

1. A composition comprising (a) bacteriophages and

(b) endotoxin.

2. Composition according to claim 1, so that it is at least 10 ⁵ , in particular at least 10 ⁶

Contains bacteriophages per ml of total volume of the composition.

3. Composition according to claim 1 or 2, so that it contains at least 0.05 ng, in particular at least 10 ng endotoxin per ml total volume of the composition.

4. A composition according to any one of the preceding claims, that it contains wild type bacteriophages.

5. Composition according to one of the preceding claims, d a d u rc h g e ke n n ze i c h n et that it contains bacteriophages of the monovalent type, bacteriophages of the polyvalent type and / or mixtures of bacteriophages of the polyvalent and / or the monovalent type.

6. Composition according to one of the preceding claims, so that it contains water or / and a salt solution, in particular a saline solution, as a carrier.

7. Medicament containing a composition according to any one of claims 1 to 6, optionally together with pharmaceutically suitable auxiliaries and / or carriers.

8. Medicament according to claim 7 for topical, intravenous, oral, rectal, intramuscular, subcutaneous, intraperetonal or intestinal administration.

9. Medicament according to claim 7 or 8, d a d u rc h g e ke n n ze i c h n et that it contains as a carrier a physiological saline.

10. Use of a composition according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prophylaxis of bacterial diseases, fungal attack or / and

Inflammation.

11. Use according to claim 10 for the manufacture of a medicament for the treatment and / or prophylaxis of pneumonia, tuberculosis, malaria, leishmaniasis, gonorrhea, erysipelas, nasal

Upper lip furunculus, otitis externa, perichondritis of the auricles, otitis media, mastoiditis, septal abscess, sinusitis acuta purulenta, nosocomial sinusitis, orbital complications of sinusitis, rhinogenic brain abscess, floor of the mouth, tonsilitis, peritonsillar abscess, endocarditis prophylaxis, endocarditis prophylaxis

Pharyngitis, epiglotis, rhynopharyngitis, laryngitis, tracheitis, bacterial ENT infections, anthrax, epidermophytia, diabetic foot, decubitus, burns, chronic wounds, osteomyelitis, skin diseases, chronic dermatitis, skin abscess, boils, other carbondelitis, syterkitis, sy

Intestinal diseases, bacterial urinary tract infections, acute and chronic cystitis, prostatitis, bacterial Urogenital tract infections, vaginal infections, bacterial infections, post-traumatic osteitis, chronic osteomyelitis, infectious osteoarthritis, bone defects with fistula, knee joint sensation or / and TEP loosening in the event of an infection.

1 2. Use according to claim 1 1 in diabetic foot.

1 3. Use of a composition according to one of claims 1 to 6 as a cleaning or / and disinfectant.

14. Use of a composition according to any one of claims 1 to 6 as a diagnostic agent.

1 5. Use according to claim 14 for the diagnosis of bacterial diseases, fungal attack and / or inflammation.