Method for overcoming gentamycin resistance in methicillin-resistant s. aureus strains

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to clinical microbiology and antimicrobial chemotherapy, and concerns developing and creating new combinations providing potentiating bactericidal action and effectively inhibiting the purulent infection caused by methicillin-resistant S. aureus by using two classes of compounds possessing the essentially different mechanism of antimicrobial action.

EFFECT: developing and creating the new combinations providing potentiating bactericidal action and effectively inhibiting the purulent infection.

2 dwg, 6 tbl

 

The invention relates to medicine, namely to clinical Microbiology and antimicrobial chemotherapy, and relates to the development and creation of new combinations that provide potentiation of bactericidal action and an effective suppression of suppurative infections caused by methicillinresistant staphylococci, through the use of two classes of compounds, possessing a fundamentally different mechanism of antimicrobial action.

The growth of antibiotic resistance in bacteria is a serious, global problem. Known currently more than 30 species of staphylococci main clinical significance of Staphylococcus aureus and Staphylococcus epidermidis. The most difficult to treat are infections caused by methicillin-resistant staphylococci S. aureus (MRSA) and S. epidermidis (MRSE). The high prevalence of MRSA and prevalence is constantly increasing, while methicillinresistant pathogens cause the infection not only in hospitalized patients and medical staff, but also among the General population [B. C. Herold, Immergluck L. C., M. C. Maranan, Lauderdal S. D., Gaskin, R. E., Boyle-Vavra S. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. // J. of Am.Medical Association 1998. - 279. - R. 593-8].

Modern drugs with strong antistaphylococcal action of linezolid, daptomycin, tigecyclin, Otley�expect a high cost which limits their wide use. Glikopeptidnykh antibiotics (vancomycin, teicoplanin) in all countries of the world to date remain the drugs of choice for infections caused by strains of MRSA and MRSE. However, many authors have noted a decrease in the effectiveness of vancomycin in antibiotic therapy of infections caused methicillinresistant staphylococci, in vitro sensitive to vancomycin [Howden V. R., Davies, J. K., Johnson P. D. R., Stinear T. P, M. L. Grayson Reduced vancomycin susceptibility in staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev 2010; 3: 99-139]. Teicoplanin so far not registered in the Russian Federation. This determines the need to develop new antibiotics, and new approaches to solving this problem. Development of new antibacterial drugs requires enormous time and costs and is not necessarily an effective way of dealing with resistant pathogens such as bacteria possess the ability to develop resistance to new drugs. In this regard, another way of solving the problem may be finding effective combinations of already known drugs with synergistic activity against microbial pathogens.

Synergy is the increase of bactericidal action of antibiotics in �x joint application. An example is the combination of the drugs prevent the synthesis of cell walls, and aminoglycosides. Drugs that suppress the formation of the cell wall (penicillin, ampicillin, vancomycin) against enterococci at best have a slow bactericidal effect. Aminoglycosides act on these organisms only bacteriostatic. The combination of a drug that suppresses the synthesis of cell walls, and facilitates aminoglycoside penetration of the latter into bacterial cells and leads to rapid death of the bacteria. These drugs synergize are also active against Staphylococcus spp.

Gentamicin, the drug of the group of aminoglycosides, against Staphylococcus possesses bactericidal action, however methicillinresistant strains are often characterized by associative resistant to this antibiotic. The mechanism of action is associated with inhibition of the ribosomal 30S subunits. Proven synergistic effect with the combination of gentamicin with penicillin against streptococci and enterococci. In addition, the good performance shown by the combination of gentamicin and vancomycin in the treatment of endocarditis caused by S. aureus [T. Le, A. S. Bayer Combination antibiotic therapy for infective endocarditis. // Clin. Infect. Dis. 2003. - V. 36. - R. 615-21]. In another study in patients with bacteremia due to MSSA, combined t�therapy gentamicin and vancomycin reduced the duration of bacteremia, but did not improve the treatment outcome [Korzeniowski, O., Sande, M. A., Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. // Ann. Intern. Med. - 1982. - V. 97. - P. - 496-503.]. Despite improved antimicrobial effectiveness, a combination of vancomycin and gentamicin cannot be recommended for widespread use because it has undesirable effects, namely the increase nephrotoxicity and ototoxicity [Rybak, M. J., Abate BJ, Kang S. L., M. J. Ruffing, S. A. Lerner, G. L. Drusano Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. // Antimicrob. Agents. Chemother. - 1999. - V. 43.- P. 1549-55]. In the instruction on medical application of gentamycin there were clear indications that avoid the simultaneous and/or sequential systemic or topical use of other neuro - and/or nephrotoxic means, such as cisplatin, cephaloridine, aminoglycoside antibiotics, polymyxin b, colistin, vancomycin.

The known method of overcoming the antibiotic resistance of bacteria, including frequent administration of antimicrobial agents used in high doses, greatly exceeding the minimum ingibiruyuscyeye concentration [Aguado-Garcia J. M., Martín-Herrero je, Lumbreras-Bermejo S. Bacterial resistance and as the pharmacodynamics prescribing antibiotics in respiratory infections. // Enferm. Infecc. Microbiol. Clin., 2004, V. 22, №4, P. 230-237]. The use of this method is limited by the danger to exceed the daily dose of the antibiotic recommended by �instrukcia on medical use of the drug, with the increase in the incidence of adverse effects.

Another known method of overcoming drug resistance in bacteria is the use of antibiotics in combination with inhibitors of the bacterial enzymes. For example, in order to overcome beta-lactamase resistance were developed specific inhibitors of beta-lactamases: clavulanic acid (clavulanate, sulbactam and tazobactam [S. Friese Prophylaxin in gynaecological surgery: a prospective randomized comparision between single dose profilaxis with amoxicillin clavulanate and the combination of cefuroxime and metronidazole. // Antimicrob. Chemother. - 1989.- V. 24, Suppl. V. - P. 213-6]. On this basis created a combination of drugs containing aminopenicillins or cephalosporin antibiotic and one of the inhibitors of beta-lactamases (amoxicillin/clavulanate, ampicillin/sulbactam, cefoperazone/sulbactam, tikarcillin/clavulanate). The disadvantage of this method is that these combinations of drugs to overcome resistance microbes, caused only by the production of beta-lactamases, and are not active against methicillinresistant staphylococci.

As a prototype adopted a method of overcoming drug resistance in bacteria, including the combined use of two antibiotics with different mechanisms of action: penicillin and streptomycin, gentamicin and ampicillin [Navashin S. M. and Fomin, I. P. �national antibiotic therapy. Guide., 4-e Izd., revised and enlarged extra - M.: Medicine, 2002, 496 PP.]. The disadvantage of the prototype is the lack of activity of these combinations against strains of staphylococci resistant to methicillin.

Ineffective or potentially harmful available antimicrobial drugs in the treatment of severe forms of purulent infection, makes you turn to alternative drugs, including dioxidine.

Dioxidine (state registration number 82/1265/6)-derived di-N-oxide quinoxaline: 1,4 Di-N-oxide 2,3 bis(hydroxymethyl) quinoxaline. Characterized by high chemotherapeutic activity in vivo (survival rate of 80-100%, sterilizing effect, "morphological" recovery) to model infections with similar pathogenesis to pathological processes in humans and caused by strains of aerobic bacteria that are resistant (including multidrug-resistant) to drugs of other classes, including strains and methicillinsensitive staphylococci. Dioxidine applies to products with bactericidal action type. In the basis of mechanism of action dioksidina is damage to the DNA biosynthesis microbial cells with impaired structure in the nucleus already at action subinhibitory concentrations. Activity dioksidina is significantly increased under conditions of anaerobiosis, and the magnitude of the IPC in this case can be reduci�cies in 8-128 times [Padejskij E. N. Antibacterial drug dioxidine: peculiarities of biological action, and significance in the treatment of various forms of purulent infection. // Infection in surgery. - 2001, No. 5. - S. 150-5]. Increased activity under anaerobic conditions is characteristic of all derivatives of di-N-oxide quinoxaline with antimicrobial activity and is not described for other classes of antimicrobials. This is the fundamental difference between the mechanism of action dioksidina from the mechanism of action of other antimicrobial agents. In terms of anaerobiosis, including in the infected organism, dioxidine (and other di-N-oxide) activates free radical processes by inducing the formation of so-called reactive oxygen species [W. Suter, Russelet A., F. Knusel Mode of action of quindoxin and substituted quinoxaline-di-N-oxides on Escherichia coli. // Agents Chemother. - 1978. - V. 13(5). - P. 770-83].

Dioxidine not accumulates in the kidneys with the re-introductions [Padejskij E. N., Shipilova, L. D., L. I. Budanov Pharmacokinetics dioksidina, the penetration of the drug in organs and tissues after a single and repeated administration. // Chem. Pharm. log. - 1983. - N 6 - P 667-71], making it a combination with gentamicin safer than vancomycin and gentamicin.

The technical result of the invention is to enhance the action of gentamicin using system allowed for the use of chemotherapy dioxidine, which provides potentiation bactericide�wow effect in relation methicillinresistant strains of staphylococci. This combination effectively suppresses purulent infection but does not cause amplification of nephrotoxicity, which occurs in the appointment of gentamicin combined with vancomycin, as dioxidine does not cause changes in glomerular and tubular system of the kidney.

The result of the invention is achieved due to the synergistic interaction subinhibitory concentrations of components used, namely gentamicin and dioksidina. Dioxidine disrupts the synthesis of DNA from microbial cells, which provides the potentiation of the bactericidal effect subinhibitory concentrations of the components used due to the synergistic interaction.

In the tables below:

Table 1: scheme 96-well plates to evaluate the effect of combinations of two antimicrobial agents using the "chess Board" in relation to the culture of the clinical MRSA strain 8074. In the table marked (here and below):

"+" - growth of the test culture in a cell;

"-" - absence of visible growth.

Table 2: scheme 96-well plates to evaluate the effect of combinations of two antimicrobial agents using the "chess Board" in relation to the culture of the clinical MRSA strain 8785.

Table 3: scheme 96-well plates to evaluate the effect of combinations of two antimicrobial agents using the "chess Board" in relation to the culture of the reference strain MSS ATS.

Table 4: scheme 96-well plates to evaluate the effect of combinations of two antimicrobial agents using the "chess Board" in relation to the culture of the reference strain MSSA ADS.

Table 5: MIC Values (ág/ml) and calculated a FIC and FIX index for the tested strains (data from two parallel experiments).

Table 6: results of the determination of microbial number (lg CFU/ml) S. aureus (on the example of a clinical strain of MRSA 8785). In table 6 indicated: dio - dioxidine; Gen - gentamicin; MIC values (in combination) on the results to identify synergies using the "checkerboard": MICK dioksidina - 2.5 ág/ml; MIC of gentamicin and 1.25 mg/ml.

In the figures presented:

Fig. 1: Isobologram for Staphylococcus aureus based on the results of the evaluation of the action of combinations of antimicrobial agents gentamicin and dioksidina method "chessboard".

Fig. 2. Graphic representation of synergism subinhibitory concentrations of gentamicin and dioksidina in relation to clinical methicillinresistant S. aureus strain 8785.

To confirm the synergistic interaction of gentamicin with dioksidina against strains of S. aureus were carried out in vitro experiments to determine antimicrobial activity of combinations of these drugs in various concentrations in relation to methicillin-resistant and sensitive isolates with �characterized by resistance to gentamicin.

Synergism was studied using the method of "chessboard" [Berenbaum M. C. A method for testing for synergy with any number of agents. // J. Infect. Dis. - 1978. - V. 137. - P. 122-130] against 4 strains of staphylococci: reference strains of MSSA ADS 25923 and ATSS 6538, clinical isolates of MRSA 8074 and 8785 isolated from patients with documented infection the surgical field after a hip replacement, showing resistance to gentamicin. All analyses were performed in duplicate, in parallel on two 96-well microplates.

To assess the interaction of antibiotics used fractional inhibition index (FIX - the fractional inhibitory index), which was calculated by the formula:

FIX=FIC (antibiotic) + FIC (second antibiotic),

where FIC (fractional inhibitory concentrations) of the fractional inhibitory concentration of the studied antibiotic, which was calculated as the ratio between the MIC of antibiotic in combination with MICK one antibiotic.

The calculation results FIX to identify drug interactions are interpreted according to the scale [Takashi Sugita, Mami Tajima, Tomonobu Ito et al. Antifungal activities of tacrolimus and azole agents against the eleven currently accepted malassezia species. // J. Clin. Microbiol. - 2005. - V. 43. - P. 2824-9]:

<0,5 synergism

0,5-4 indifference

>4 antagonism

For the evaluation of synergies in each cell 96-well plates were added 50 microliters (μl) nutrient control unit�Iona Mueller-Hinton (MHB). Gentamicin was titrated twice serially along the axis of ordinates (Y) concentrations starting from 2400 to 0 μg/ml, the second antimicrobial agent (dioxidine) was titrated along the x-axis (X) at concentrations starting from 2500 to 0 μg/ml in accordance with the submitted scheme tablets (PL. 1-4). Inoculum prepared for each culture in sterile isotonic, with a density of microbial suspensions, corresponding to 0.5 McFarland. In each cell 96-well microplates made of 100 µl of inoculum and placed the tablet for incubation in a thermostat at 37°C for 18 h. At MIC (µg/ml) had the lowest concentration of an antimicrobial agent, which was not observed for visible growth of a microorganism.

In accordance with the results presented in diagrams A, B, C and D 96-well microplates for the tested strains of S. aureus were calculated the coefficients of FIX (tab.5), which in all cases were less than 0.5, which is typical for synergistic effects of drugs. The FIC values, also calculated on the basis of the experimental results, was used to build isobologram (Fig.1), concave in nature which also argues in favor of a synergistic interaction of gentamicin and dioksidina.

Confirm by using the "checkerboard" potentiation of gentamicin in combination with dioksidina against meticillin�sistently Staphylococcus evaluate the synergies of these antimicrobial agents was performed by the method of kinetic curves loss/growth of bacteria.

Comparative evaluation of the effects of different concentrations of the individual drugs and their combinations was based on the death kinetics of Staphylococcus as a result of the action of drugs. For this assessment used the measurements of the numbers of CFU/ml in set periods of time and built kinetic curves the death of microorganisms. The slope of the kinetic curve is a measure of the rate of death of microorganisms.

Synergism was defined as a decrease in CFU in 100 or more times or 2 Lg after 24 h in combination, when compared with an individual of the most active antimicrobial component and as a 100-fold decrease in CFU compared to the initial inoculum.

Potentiation (additivity), or indifference, defined as less than a 10-fold change in CFU counts at 24 h under the action of the combination compared with SOME action when the most fastest individual (antimicrobial) component.

Antagonism was defined as 100 or more times the increase in the number of CFU at 24 h under the action of the combination compared with the most active individual component.

To study the activity of antimicrobial agents gentamicin and dioksidina, each individually, and their combination in sub-MIC concentrations, designed curves loss/growth of a culture of Staphylococcus aureus in parallel; the test-culture were incubated with a solution of�mi antimicrobials:

1. Gentamicin, individually: at concentrations of 1.25 μg/ml (MIC); 0,313 mg/ml (1/MIC).

2. Dioxidine, individually, at a concentration of 2.5 μg/ml (MIC); of 0.625 µg/ml (1/MIC).

3. The combination of the two agents: MIC+MIC, MIC+1/MIC (each agent).

4. Nutritional MHB without antibiotic to determine the control OP.

Data were expressed as Lg CFU/ml in each time period: from Lg in the number of surviving colony forming units (CFU/ml). Method of inhibition of culture across time was performed using the technique of microdesmidae in MHB, in 96-well microplates. The test strain was tested against each antimicrobial agent (gentamicin and dioksidina) individually and in combination. From isolated colonies of the test strains were prepared suspension to the turbidity standard of 0.5 McFarland with subsequent dilution to a concentration of 105CFU/ml in 10 ml medium MHB containing the appropriate concentration of antimicrobial agents. The tubes were incubated at 37°C. Sampling was performed at 0 h, 2 h, 6 h and 24 h. the CFU counts at 0 h and 24 h were used for the determination of synergy.

The study showed similar results for all tested strains. Here are the results of the evaluation of antimicrobial activity of the investigated drugs against clinical S. aureus strain 8785.

According to the results presented in table. 6 the combination of gentamicin and dioksidina in subinhibitory concentrations of 1.25 μg/ml and 2.5 µg/ml, respectively demonstrates synergy in terms of strain And MRS 8785, resistant to gentamicin; synergism is also confirmed by the kinetics of death of the test strain under the influence of the action of the combination of gentamicin and dioksidina in concentrations of 1.25 and 2.5 µg/ml, respectively, which is reflected in the character of the curve "1D+1D" in Fig. 2. At time point 24 h under the action of this combination demonstrated a reduction of SOME 2.5 lg on when compared with an individual of the most active antimicrobial component - dioxydinum at a concentration of 2.5 μg/ml and more than 100-fold decrease in CFU compared to the initial inoculum.

Thus, the inventive combination of gentamicin and dioksidina provides the potentiation of the bactericidal activity of gentamicin due to the ability dioksidina to inhibit DNA microbial cells and increase the bactericidal activity under anaerobic conditions. These advantages allow the use of the combination for the treatment of infections caused by multidrug-resistant staphylococcal flora.

The list of references

1. Herold, B. C., L. C. Immergluck, M. C. Maranan, Lauderdal S. D., Gaskin, R. E., Boyle-Vavra S. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. // J. of Am. Medical Association 1998. - 279. - P. 593-8.

2. Howden, B. P., Davies, J. K., Johnson P. D. R., Stinear T. P, M. L. Grayson Reduced vancomycin susceptibility in staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev 2010; 3:99-139.

3. Le T., A. S. Bayer Combination anibiotic therapy for infective endocarditis. // Clin. Infect. Dis. 2003. - V. 36. - R. 615-21].

4. Korzeniowski O., M. A. Sande Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. // Ann. Intern. Med. - 1982. - V. 97. -P. - 496-503.

5. Rybak, M. J., Abate BJ, Kang S. L., M. J. Ruffing, S. A. Lerner, G. L. Drusano Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. // Antimicrob. Agents. Chemother. - 1999. - V. 43. - P. 1549-55.

6. Aguado-Garcia J. M., Martin-Herrero J. E., Lumbreras-Bermejo C. Bacterial resistance and as the pharmacodynamics prescribing antibiotics in respiratory infections. // Enferm. Infecc. Microbiol. Clin., 2004, V. 22, №4, P. 230-7.

7. Friese S. Prophylaxin in gynaecological surgery: a prospective randomized comparision between single dose profilaxis with amoxicillin clavulanate and the combination of cefuroxime and metronidazole. // Antimicrob. Chemother. - 1989. - V. 24, Suppl. V. - P. 213-6.

8. Navashin CM. and Fomina I. P. Rational antibiotic therapy. Guide., 4-e Izd., Rev. and add., M, Medicine, 2002, 496 S.

9. Padejskij E. N. Antibacterial drug dioxidine: peculiarities of biological action, and significance in the treatment of various forms of purulent infection. // Infection in surgery. - 2001, No. 5. - S. 150-5.

10. Suter W., Russelet A., F. Knusel Mode of action of quindoxin and substituted quinoxaline-di-N-oxides on Escherichia coli. // Agents Chemother. - 1978. - V. 13(5). - P. 770-83.

11. Padejskij E. H., Shipilova, L. D., L. I. Budanov Pharmacokinetics dioksidina, the penetration of the drug in organs and tissues after a single and repeated administration. // Chem. Pharm. log. - 1983. - N 6 - P 667-71.

12. Berenbaum M. With A method for testing for synergy with any number of agents. // J. Infect. Dis. - 1978. - V. 137. - P. 122-130

13. Takashi Sugita, Mami Tajima, Tomonobu Ito et al. Antifungal activities of acrolimus and azole agents against the eleven currently accepted malassezia species. // J. Clin. Microbiol. - 2005. - V. 43. - P. 2824-9.

Table 5
StrainsGentamicinDioxidineFIX
MICKMICK for the combinationFICMICKMICK for the combinationFIC
MRSA 8074
Experience 14,81,20,251561,220,0070,26
Experience 24,81,20,251562,440,0160,27
MRSA 8785
Experience 1 1,20,251560,610,0040,25
Experience 24,81,20,251562,440,0160,27
The MSSA ADS 25923
Experience 10,0290,00090.031 inch392,440,0620,09
Experience 20,0150,00050,034392,440,0620,10
The MSSA ADS 6538
Experience 10,0290,00370,12739,060,610,0160,14
Experience 2/td> 0,0150,00090,0639,062,440,0620,12

Table 6
Time (h)Control growthGene MICGene MICDio MICDio MICGene MICGene MICGene MICGene MIC + dio MIC
05,86,06,25,96,05,95,75,15,8
26,46,56,56,66,66,46,46,46,4
6 8,17,58,06,97,15,77,87,87,9
248,38,08,16,07,93,58,07,38,1

The way to overcome resistance to gentamicin in methicillinresistant strains of stafilokok, including a combined introduction of antimicrobial agents, characterized in that gentamicin combined with drug dioxidine in subinhibitory concentrations of 1.25 μg/ml and 2.5 µg/ml, respectively.



 

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9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to dentistry. A method for the conservative treatment of parodontium involves applying a treatment wrap prepared of zinc oxide and zinc sulphate; applying the treatment wrap is preceded by a multiple irrigation of parodontium tissues with butol solution; the treatment wrap is prepared by adding zinc oxide powder and zinc sulphate powder into butol solution and mixing them to pasty consistency; dental tissues from the vestibular and oral surfaces in the neck region are covered with a gauze drain of the diameter of 1-4mm saturated with butol solution; parodentium and dental tissues covered with the gauze drain saturated with butol solution is coated with the treatment wrap.

EFFECT: using the method enables achieving optimum diffusion of the therapeutic preparation in the parodontium tissue and its prolonged effect on parodontal tissues, with providing haemostatic effect and adequate anti-inflammatory action.

2 ex

FIELD: medicine.

SUBSTANCE: inventions refers to medicine, namely to pulmonology, and can be used for treating a pulmonary disorder in a patient. That is ensured by administering an effective dose of the nebulised liposomal amikacin formulation of 100 to 2,500 mg daily within the cycle of treatment, which involves the period of administration from 15 to 75 days and the following withdrawal period from 15 to 75 days. The cycle of treatment repeats at least twice.

EFFECT: invention provides improving the pulmonary function, which is supported for at least 15 days after the termination of treatment, and increasing the one-second forced expiratory volume (FEV1).

28 cl, 16 tbl, 11 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents dermatological cream, intended for local treatment of bacterial skin infections and for healing wounds associated with them, which contains framycetin sulfate and biopolymer, included into cream base, which contains at least one substance from each of the following groups: preservative, primary and secondary emulsifier, selected from the group which contains ketostearyl alcohol, ketomacrogol 1000, polysorbate-80 and Span-80; paraffin as wax-like product, cosolvent, selected from the group, including propylene glycol, hexylene glycol and polyethylene glycol-400; nitric acid or lactic acid and water, with said biopolymer preferably being chitosan.

EFFECT: invention provides higher therapeutic effect.

8 cl, 10 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention represents an antimicrobial agent for preventing an implant-associated infection containing gentamicin sulphate 0.96 g, dioxidine 1.0 g, medium-molecular-weight medical collidone (molecular weight 30000D) 10.0 g, distilled water up to 100.0 ml.

EFFECT: extending the range of products preventing the developing implant-associated infection and prevents preserving the antimicrobial activity of the tissues surrounding the implantation area.

2 cl, 1 ex, 3 tbl

FIELD: veterinary medicine.

SUBSTANCE: method comprises administering an agent containing gentamicin, gamavit, sodium benzoate, potassium sorbate and propylene glycol. The agent is used in intrauterine mode 2 times a day for 7-10 days at a dose of 5-10 ml to cat and 10-20 ml to dog.

EFFECT: method comprises high therapeutic efficacy in endometritis of cats and dogs.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns a simplified capsular form of clofazimine, containing clofazimine, bee wax, soya bean lecithin, butylhydroxy toluene, soya bean oil, gelatine, glycerol, sorbitol, methylparabene, propylparabene, titanium dioxide, brown chocolate and purified water with preserving high efficacy.

EFFECT: simplifying the form.

4 tbl, 3 ex

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