KR102086462B1 - Antibiotics complex composition for veterinary treatment of multiple respiratory diseases - Google Patents

Abstract

The present invention relates to a complex antibiotic composition for veterinary treatment of complex respiratory diseases. More specifically, the present invention relates to a composite antibiotic composition for veterinary treatment of respiratory diseases accompanied with E. coli or Salmonella infection, which is composed mainly of ceftquinom, lincomycin and butaphosphane, and chlorpheniramine maleate as a minor component.

Description

Antibiotic complex composition for veterinary treatment of multiple respiratory diseases

The present invention relates to a complex antibiotic composition for veterinary treatment of complex respiratory diseases. More specifically, the present invention relates to a composite antibiotic composition for veterinary treatment of respiratory diseases accompanied with E. coli or Salmonella infection, which is composed mainly of ceftquinom, lincomycin and butaphosphane, and chlorpheniramine maleate as a minor component.

In pigs, digestive diseases caused by Escherichia coli ( E. coli ) are common, the incidence of edema is increasing, and diarrhea caused by Salmonella typhimurium is also increasing. Weaning stress also causes Pasteurella multocida to overgrow in the upper respiratory tract, leading to Actinobacillus pleuropneumoniae and multiple respiratory diseases. In addition, the incidence of sepsis and arthritis caused by Streptococcus suis is increasing.

Looking at the infection strain and its symptoms of the bacterial infection disease are as follows.

Pleural pneumonia is an infection caused by Actinobacillus pleuropneumoniae . Acute type of fever develops at high temperature of 41.5 ℃. It causes symptoms such as anorexia, anorexia, dyspnea and cough. Can cause atrophy. In addition, the chronic form may be accompanied by mild fever, intermittent coughing, loss of appetite, decreased activity, arthritis, endocarditis and edema. Examples of antibiotics for treating pleural pneumonia include ampicillin, cephalosporin, colistin, and gentamicin.

Pasteurella pneumonia is a disease caused by Pasteurella multocida , which is normally incubated in the upper respiratory tract of pigs, and when bacteria become less resistant due to stress or unsanitary management such as long distance transport or severe temperature changes. It develops explosively. Severe cough, runny nose, high fever and anorexia findings can occur, and infected pigs can cause atrophy even if they die and recover within five to six days. It is caused by a secondary infection following mycoplasma pneumonia, influenza, pleural pneumonia rather than a single infection, and antibiotics for treating Pasteurella pneumonia include ampicillin, ceftiofur, enlofloxacin, and tolathromycin. have.

Streptococcus suis is a disease caused by Streptococcus suis , which causes arthritis, meningitis, endocarditis, and umbilitis in piglets, and MMA (endometritis, mastitis, and non-irritation) and arthritis in piglets. have. Streptococcal infections can also lead to sepsis and systemic infection to cause arthritis, meningitis and endocarditis.

Escherichia coli infections are diseases caused by E. coli and usually occur with diarrhea, edema or other pathogens and occur in the form of sepsis. E. coli infections, a symptom of diarrhea, have no fever but weakness due to lethargy, dehydration, and nutrient deterioration. Causes death by the back. Antibiotics for the treatment of E. coli infections include amoxacillin / clavulanic acid, fluoroquinolone, cephalosporin, apramycin, ceftiofer, neomycin, and trimethoprim.

Swine Salmonella disease is a sudden chronic digestive disease of pigs caused by the genus Salmonella, with sepsis and diarrhea as the main symptom, usually in young pigs 2 to 4 months of age. Mortality from sepsis is high and acute sepsis is caused by infection with Salmonella cholerasus or Salmonella typhisuis strains, and acute chronic enteritis develops with Salmonella typhimurium, Salmonella enteritidis and Salmonella derby strains. Antibiotics for treating swine Salmonella disease include ampicillin, gentamicin sulfate, amoxacillin and the like.

The synergistic effect of various antibiotic antibiotics for animals was tested for veterinary treatment of complex respiratory diseases such as pleural pneumonia, Pasteurella pneumonia and streptococcal infection with pig Escherichia coli or Salmonella infection as described above.

Cefquinome is a cephalosporin-based fourth-generation antibiotic developed by Bryskir in 1994 and the first commercial veterinary antibiotic available from Intervet under the trade name Cobactan. Mechanisms of action inhibit bacterial cell wall synthesis and antagonize the action of penicillin binding proteins and binding cell wall enzymes in the cell membrane. It has a wide range of antibiotic effects on Gram-negative and Gram-positive bacteria, very high sensitivity to P. haemolytica and high antibacterial activity against Streptococcus bacteria. It also exhibits high antimicrobial activity against bacteria of the genus Pseudomonas and Proteus.

Lincomycin is obtained from Streptomyces lincolnensis protease and acts on 50S ribosomes in bacterial cells to block RNA-dependent protein synthesis, thereby inhibiting bacterial growth and proliferation. It has high sensitivity to Gram-positive bacteria and Mycoplasma strains.

Accordingly, the present inventors measured the antimicrobial activity of ceftquinom and lincomycin complex antibiotic composition to develop a complex antibiotic composition for treating complex respiratory diseases caused by Pasteurella pneumococcal pneumoniae, pleural pneumococcal, and the like.

Cefquinom and lincomycin complex antibiotic composition used in the present invention showed a high antimicrobial activity synergistic effect, especially against Pasteurella pneumoniae. In addition, it showed an excellent antimicrobial activity synergistic effect against pleural pneumonia. However, E. coli strains showed no significant synergy except for some strains.

Therefore, the complex antibiotic composition of the present invention further includes butaphosphane useful for stress reduction for effective symptom relief of an infectious disease, thereby preventing E. coli or Salmonella infection of the complex antibiotic composition mainly composed of ceftquinom, lincomycin and butaphosphane. The synergistic effect of veterinary treatment with accompanying respiratory disease was measured.

Butaphosphan is a source of organic phosphorus that improves metabolism and muscle activity in the body of animals. Butaphosphane lowers the concentration of cortisol to reduce the stress of metabolic reactions and increases insulin concentration to improve glucose transport in cells. Accordingly, butaphosphane is to be included as a main component in the ceftquinom and lincomycin complex antibiotic composition of the present invention for the stress reducing effect.

Meanwhile, chlorpheniramine maleate, an antihistamine, is included as a side ingredient. Chlorfeniramine maleate competitively antagonizes histamine to H1-receptors located in the gastrointestinal respiratory tract and thus exhibits an antihistamine effect, thereby alleviating the symptoms of complex respiratory diseases, and thus including it as a minor component in the complex antibiotic composition of the present invention.

Accordingly, the present inventors measured the synergistic effect of various antibiotics for veterinary treatment of complex respiratory diseases such as pleural pneumonia, Pasteurella pneumonia and streptococcal infection with pig Escherichia coli or Salmonella infection.

Through this, the present invention is completed by developing a complex antibiotic composition for veterinary treatment of respiratory diseases accompanied with E. coli or Salmonella infection, which is mainly composed of ceftquinom, lincomycin and butaphosphane of the present invention, and chloreniramine maleate as a minor component. It is done.

The problem to be solved by the present invention is to measure the synergistic effect of various combination antibiotics for veterinary treatment of complex respiratory diseases such as pleural pneumonia, Pasteurella pneumonia and streptococcal infection with pig Escherichia coli or Salmonella infection It was a good thing. This is to develop a complex antibiotic composition for the veterinary treatment of respiratory diseases accompanied with E. coli or Salmonella infection, the main component of the present invention, cefequinome, lincomycin and butaphosphane and chlorpheniramine maleate as a minor component.

An object of the present invention is a combined antibiotic for veterinary treatment of a complex respiratory disease comprising 5 to 6 parts by weight of lincomycin, 0.8 to 5.0 parts by weight butaphosphane and 0.2 to 0.3 parts by weight of chlorpheniramine maleate per 1 part by weight of ceftquinom. It is to provide a composition.

In this case, the complex respiratory disease is characterized by complex respiratory diseases such as pleural pneumonia, Pasteurella pneumonia and streptococcal infection accompanied by E. coli or Salmonella infection.

The complex respiratory disease is also infected from Pasteurella multocida , Actinobacillus pleuropneumoniae or Streptococcus suis and from respiratory disease infected with E. coli or Salmonella spp. Characterized in that it is a complex respiratory disease accompanied by digestive diseases.

Meanwhile, the complex antibiotic composition for veterinary treatment of the complex respiratory disease is 20 mg (titer) of ceftquinom powder injection (component 1) and 100-120 mg (titer) of lincomycin, 16-100 mg butaphosphane and 4 ~. 6 mg (titer) of chlorpheniramine maleate is prepared by dissolving 1 ml of liquid injection (component 2) in an injectable solution, and is characterized by administering a mixed dissolution preparation during use.

Meanwhile, the complex antibiotic composition for veterinary treatment of the complex respiratory disease is characterized in that 0.5 ~ 1.5 ml per 10 kg of pig body weight is administered once a day by intramuscular injection.

The effects of the present invention are the cefequinome and lincomycin of the present invention, which show an antimicrobial potency effect for the veterinary treatment of complex respiratory diseases such as pleural pneumonia, Pasteurella pneumonia and streptococcal infection with pig Escherichia coli or Salmonella infection. And it provides a complex antibiotic composition for veterinary treatment of respiratory diseases accompanied with E. coli or Salmonella infection, the main component of butaphosphane and chlorpheniramine maleate.

The present invention relates to a composite antibiotic composition for veterinary treatment of a complex respiratory disease comprising 5 to 6 parts by weight of lincomycin, 0.8 to 5.0 parts by weight butaphosphane, and 0.2 to 0.3 parts by weight of chlorpheniramine maleate per 1 part by weight of ceftquinom. It is about.

In this case, the composite respiratory disease is a complex of respiratory diseases such as pleuropneumonia, wave stew Pasteurella pneumoniae and Streptococcus infections accompanied by E. coli or Salmonella infection also the composite respiratory disease wave stew Pasteurella pneumoniae (Pasteurella multocida), pleural pneumoniae (Actinobacillus pleuropneumoniae Or respiratory diseases infected from Streptococcus suis and digestive diseases infected from E. coli or Salmonella spp. Strains.

Hereinafter, the present invention will be described in more detail.

In order to develop the complex antibiotic composition for veterinary treatment of the complex respiratory disease, pathogenella pneumococcal, pleural pneumococcus (APP), type 1, type 2, type 5, Streptococcus, E. coli (K99, K88ab, Antibiotics highly sensitive to K88ac) are selected by MIC measurement.

Cefquinome and Ceftiofur were compared with susceptibility by MIC test using the pathogen as a specimen. As a test method for MIC measurement, a liquid medium microdilution method using a 96 well plate was used.

Table 1 is a table showing the MIC measurement data for each strain strain of ceftquinom and ceftiofer.

Strain (Unit: ㎍ / ml) Chefquinom Sefthiopher Remarks Pasteurella pneumococcal 0.0125 0.016 Outdoor separator Pleural pneumococcal type 1 0.008 0.008 Outdoor separator Pleural pneumococcal type 2 0.0313 0.004 Outdoor separator Pleural pneumococcal type 5 0.016 0.008 Outdoor separator Streptococcus 0.004 0.008 Outdoor separator Escherichia coli (K99) 0.0625 0.5 Outdoor separator Escherichia coli (K88ab) 0.0625 0.5 Outdoor separator Escherichia coli (K88ac) 0.0625 0.25 Outdoor separator Salmonella Typhimurium 0.125 One Outdoor separator

Cefquinome showed lower MIC values than Cefthiofer for Pasteurella pneumoniae, Streptococcus, E. coli and Salmonella. Therefore, it was confirmed that ceftquinom showed higher susceptibility to Pasteurella pneumococci, Streptococci, E. coli and Salmonella.

Therefore, ceftquinom was selected as the main antibiotic of the complex antibiotic composition for veterinary treatment of the complex respiratory disease of the present invention. In addition, in order to develop a complex antibiotic composition for veterinary treatment of complex respiratory diseases, a complex antibiotic composition of Cefquinom (C) and Lincomycin (L) was prepared, and each unit antibiotic minimum inhibitor concentration (MIC) and complex antibiotic were prepared in the sample strain. The split inhibition concentration (FIC) index of is measured.

Mutual antibiotic activity synergy of the combined antibiotic composition of ceftquinom (C) and lincomycin (L) is assessed through the FIC index. If the FIC index is less than 0.6, the synergy is shown. If the FIC index is 0.6 or 2, the additive effect is shown. If the FIC index is greater than 2, the antagonism is shown.

The FIC index of ceftquinom (C) and lincomycin (L) is calculated as the sum of the MIC values of the CIC (sephquinom) / sequinquinom and MIC values of the lincomycin / rincomycin when used in combination.

When the combination of ceftquinom (C) and lincomycin (L) was used to determine the synergistic effect on the antimicrobial activity of the sample strain was measured FIC index for each content of each sample strain. Table 2 is a table showing the FIC measurement data for each of the ceftquinom and lincomycin sample strain.

Strain (Unit: ㎍ / ml) Chefquinom
(C) Lincomycin
(L) C + L Complex Antibiotic Composition C L FIC Translate Pasteurella pneumococcal 4 32 0.5 14 0.525 Increase Pleural pneumococcal
Type 1 0.008 16 0.003 8 0.531 Increase Pleural pneumococcal
Type 2 0.008 32 0.00025 16 0.531 Increase Pleural pneumococcal
5 type 0.016 16 0.007 8 0.9 store Chain
coccus 0.0625 1024 0.0313 64 0.513 Increase Escherichia coli
(K99) 0.0625 1024 0.0625 64 1.063 store Escherichia coli
(K88ab) 0.0625 1024 0.0313 512 1.001 store Escherichia coli
(K88ac) 0.0625 512 0.008 256 0.628 store

As shown in Table 2, the combined antibiotic composition of ceftquinom (C) and lincomycin (L) of the present invention shows a synergistic effect of the combined antibiotic composition in Pasteurella pneumoniae, pleural pneumococci type 1 and type 2, streptococci. It was.

However, the combined antibiotic composition of the present invention did not show a synergistic effect in pleural pneumococcal type 5, E. coli K99, E. coli K88ab, E. coli K88ac, and showed only ordinary additive effects.

Therefore, the composite antibiotic composition of the present invention was confirmed to be an effective antibiotic composition showing a synergistic effect on the composite respiratory disease caused by infection of Pasteurella pneumoniae, pleural pneumococcal type 1 and type 2, Streptococcus.

Meanwhile, cefequinom, lincomycin and butaphosphane are the main components of the complex antibiotic composition of the present invention for effective symptom relief of infectious diseases caused by strains that do not exhibit synergistic effects such as pleural pneumococcal type 5, E. coli K99, E. coli K88ab, and E. coli K88ac. The chlorpheniramine maleate is further included in the combined antibiotic composition.

Therefore, the combined antibiotic composition for veterinary treatment of the complex respiratory disease is 20 mg (titer) of ceftquinom powder injection (component 1) and 100-120 mg (titer) of lincomycin, 16-100 mg butaphosphane and 4 ~. 1 ml of liquid injection (component 2) in which 6 mg (titer) of chlorpheniramine maleate is dissolved in an injectable solution is prepared, and then mixed and dissolved in preparation for administration.

The composite antibiotic composition of the present invention is prepared from the component 1 of the powder injection and the component 2 of the liquid injection, and is then used by mixing and dissolving the component 1 of the powder injection in the component 2 of the liquid injection for stability in the injection solution of cephquinom sulfate. In order to prevent deterioration, the ceftquinom sulfate is powdered and prepared as component 1, and then mixed and dissolved in preparation for use.

In addition, the complex antibiotic composition for veterinary treatment of the complex respiratory disease is administered 0.5 ~ 1.5 ml per 10 kg of pig body weight once daily intramuscular injection.

Meanwhile, the complex antibiotic composition for veterinary treatment of the composite respiratory disease of the present invention may be easily carried out by a person having ordinary skill in the art, and may be used as an animal injection, powder, liquid or granule for veterinary treatment. It can be formulated into a tablet.

In the case of veterinary injectables and oral solutions for the purpose of veterinary treatment, a pharmaceutically acceptable carrier is a pyrrolidone solvent or N, N-dimethylamide, N, N-dimethylformamide, DMSO, acetone, glycerol Foam, N-methyl-2-pyrrolidone, 2-pyrrolidone, ethyl oleate, ethanol, isopropanol, 1,2-propanediol, glycerin, benzyl alcohol, dimethylisosorbet, triacetin, glyco ether, Propylene glycol, polyethylene glycol having an average molecular weight of about 200 to about 600, triacetin, lidocaine, propylene glycol dicaprylate, medium chain triglycerides, aluminum stearate and the like can be used.

As antioxidants, ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, tocopherol, butylated hydroxyanasol, sodium monothioglycerol and the like can be used, and as a preservative, methyl p-hydroxybenzoate (methylparaben), propyl It can be formulated with p-hydroxybenzoate (propylparaben), thimerosal, benzalkonium chloride, phenol, cresol, paraoxymethylbenzoate and the like.

In addition, in the case of animal powders and granules for the purpose of veterinary treatment, vitamins, glucose, lactose and other sugars, starch or various powders and liquid enzymes can be formulated in an appropriate amount.

In addition, the administration of the complex antibiotic composition for veterinary treatment of the complex respiratory disease according to the present invention is usually administered by intramuscular injection as an injection, in the case of a liquid, orally or mixed with drinking water, and powders and granules are used in drinking water and feed. Administered in combination.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples do not limit the scope of the present invention.

Preparation Example Preparation of Complex Antibiotic Composition for Veterinary Treatment of Complex Respiratory Disease of the Present Invention

A 1 ml liquid injection (component 2) was prepared by dissolving 20 mg of cefequinom sulfate powder injection (component 1), 110 mg of lincomycin hydrochloride hydrate, 20 mg of butaphosphane, and 5 mg of chlorpheniramine maleate in an appropriate amount of an injection. After use, mixed and dissolved together to prepare a composite antibiotic composition.

Preparation Example 1 Preparation of Antibiotic Composition for Veterinary Treatment of Complex Respiratory Disease (Without Lincomycin)

1 mg liquid injection (component 2) is prepared by dissolving 50 mg of cephquinom sulfate powder injection (component 1), 20 mg butaphosphane and 5 mg chlorpheniramine maleate in an appropriate amount of injectable solution. An antibiotic composition is prepared.

Preparation Example 2 Preparation of Antibiotic Composition for Veterinary Treatment of Combined Respiratory Disease (butaphosphane not added)

1 mg of liquid injection (component 2) prepared by dissolving 20 mg of sephquinom sulfate powder injection (component 1), 110 mg of lincomycin hydrochloride hydrate and 5 mg of chlorpheniramine maleate in an appropriate amount of injectable solution is mixed and dissolved together. The complex antibiotic composition is prepared.

Example 1 Efficacy test using piglets (body weight 20 kg)

Thirty test piglets weighing 20 ㅁ 5 kg are divided into six groups of five animals. One control group was not infected with pathogens, and each of the four test groups had 5 ml (2 ×) of Pasteurella pneumococci (test group 1), pleural pneumococci (APP) (test group 2) and streptococci (test group 3), respectively. 10 ⁹ / ml) is transmitted through the nasal cavity, and E. coli (test group 4) and Salmonella strains (test group 5) are infected by oral administration of 5 ml (2 x 10 ⁹ / ml), respectively.

On the day when the increase in body temperature and respiratory abnormalities were observed, the antibiotic composition for veterinary treatment of the composite respiratory disease prepared in Preparation Examples and Comparative Examples 1 and 2 was 0.5 mg / 10 Kg body weight. Inject the muscle once a day. Three days after injection, the piglets of test groups 1 to 5 and the control group are judged for treatment of respiratory diseases through body temperature measurement and nasal sampling. For comparative judgment, it is indicated as +2 when respiratory disease is treated, +1 when symptoms improve, 0 when no symptoms change, and -1 when symptoms worsen. The results are shown in Table 3.

Control Test group 1 Test group 2 Test group 3 Test group 4 Test group 5 Preparation Example 0 +2 +2 +2 +2 +2 Comparative Example 1 0 +1 0 +1 +1 +1 Comparative Example 2 0 +1 +1 +2 +1 +1

As shown in Table 3, in the case of the combined antibiotic composition for veterinary treatment of the composite respiratory disease prepared in the preparation examples of the present invention, test group 1 infected with Pasteurella pneumoniae, test group 2 infected with pleural pneumococcal, and streptococcal infection Excellent therapeutic effect was shown in both group 3, test group 4 infected with E. coli and test group 5 infected with Salmonella strains.

Meanwhile, the antibiotic composition prepared in Comparative Example 1, in which lincomycin contained in the complex antibiotic composition for veterinary treatment of the present invention, was replaced with ceftquinom, showed the lowest therapeutic effect. In test group 2 infected with pleural pneumococci, complex respiratory disease was not treated, test group 1 infected with Pasteurella pneumoniae, test group 3 infected with Streptococcus, test group 4 infected with E. coli and test group 5 infected with Salmonella spp. Only improvement in symptoms was measured. Therefore, none of the test groups 1 to 5 effectively treated the complex respiratory disease.

Meanwhile, the antibiotic composition prepared in Comparative Example 2, which excludes butaphosphane from the composite antibiotic composition for veterinary treatment of the composite respiratory disease, effectively treated the complex respiratory disease in test group 3 infected with Streptococcus. Only improvement of symptoms was measured in test group 1 infected with pneumococcal, test group 2 infected with pleural pneumococcal, test group 4 infected with E. coli and test group 5 infected with Salmonella spp.

Therefore, it was confirmed that the complex antibiotic composition for veterinary treatment of the complex respiratory disease of the present invention is a very effective therapeutic agent for treating the complex respiratory disease caused by Pasteurella pneumococcal, pleural pneumococcal (APP), Streptococcus, Escherichia coli and Salmonella strains.

Example 2 Visual pathology examination test of pigs

Pigs used in Test Groups 1 to 5 in Example 1 were then bred for 11 days, after which euthanasia was performed on the heads of the lungs, and gross pathology examination was performed. Pulmonary pneumonitis and pleural pneumonia with mesenteric exudate were observed in the lungs of the control group who received only vaccination and no treatment. The lung lesion index showed only 10% of the lungs. Porcine lungs considered to be treated (+2 points) showed some Pasteurella pneumonia, but overall lung condition was good.

Therefore, when the respiratory disease is treated by administering the complex antibiotic composition for the veterinary treatment of the composite respiratory disease prepared in the preparation of the present invention, there are some individuals showing some Pasteurella pneumonia in the lungs of all the pigs. The condition was good. However, the test group administered with the antibiotic composition prepared in Comparative Examples 1 and 2 did not exhibit sufficient lung treatment status.

Claims (5)

In the composite antibiotic composition for veterinary treatment of the complex respiratory disease comprising 5 to 6 parts by weight of lincomycin, 0.8 to 5.0 parts by weight butaphosphane and 0.2 to 0.3 parts by weight chlorpheniramine maleate per 1 part by weight of ceftquinom,
The complex respiratory disease is a complex antibiotic composition for veterinary treatment, characterized in that the complex respiratory diseases such as pleural pneumonia, Pasteurella pneumonia and streptococcal infection with E. coli or Salmonella infection.
delete The method of claim 1, wherein the respiratory disease complex is waves stew Pasteurella pneumoniae (Pasteurella multocida), pleural pneumoniae (Actinobacillus pleuropneumoniae), or Streptococcus (Streptococcus suis) and respiratory disease from infected E. coli (E. coli), or genus Salmonella (Salmonella spp .) for veterinary treatment composite antibiotic composition characterized in that the composite respiratory diseases accompanied by digestive diseases from the infected strain.
According to claim 1, wherein the combined antibiotic composition for veterinary treatment of the complex respiratory disease is 20 mg (titer) of ceftquinom powder injection (component 1) and 100-120 mg (titer) of lincomycin, 16-100 mg buta A composite antibiotic for veterinary treatment, which is prepared by preparing 1 ml of liquid injection (component 2) in which phosphane and 4-6 mg (titer) of chlorpheniramine maleate are dissolved in an injectable solution. Composition.
[Claim 5] The complex antibiotic composition for veterinary treatment according to claim 4, wherein the complex antibiotic composition for veterinary treatment for complex respiratory disease is administered 0.5 to 1.5 ml per 10 kg of pig body weight once daily.