CN101912402B - Composition of cefazedone sodium sterile and clavulanate potassium and proportion thereof - Google Patents
Composition of cefazedone sodium sterile and clavulanate potassium and proportion thereof Download PDFInfo
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- CN101912402B CN101912402B CN2010101403317A CN201010140331A CN101912402B CN 101912402 B CN101912402 B CN 101912402B CN 2010101403317 A CN2010101403317 A CN 2010101403317A CN 201010140331 A CN201010140331 A CN 201010140331A CN 101912402 B CN101912402 B CN 101912402B
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Abstract
The invention relates to a composition of cefazedone sodium sterile and clavulanate potassium and a proportion thereof. The composition is characterized by consisting of cefazedone sodium sterile and clavulanate potassium in a weight ratio of 1:1-8:1. In infectious diseases caused by bacteria, certain bacteria generate beta-lactamase which has medicament resistance to cefazedone, so the treatment is not effective. After the cefazedone sodium sterile and the clavulanate potassium are applied in combination, different proportions of the composition have different and relatively strong antibacterial activities to gram negative bacilli and gram positive coccus which generates beta-lactamase. Tests show that the composition is sensitive to the bacteria strain generating beta-lactamase, so that the antibiotic action of the cefazedone sodium sterile can be increased by times and the enzyme-generating strain is restored to be sensitive to the cefazedone sodium sterile. The test bases are enough; the clinical antibacterial effect is clear; and the happening of adverse reactions is not increased.
Description
Invention field
The invention belongs to medical technical field, relate to the compositions and the proportioning thereof of a kind of antibiotic Refosporin (E.Merck). and clavulanate potassium.
Background information
Cefazedone
English name: Cefazedone Sodium
Chemical name:
(6R, 7R)-7-(2-(3,5-two chloro-4-oxo-1 (4H)-pyridine radicals) acetylamino)-3-(((5-methyl isophthalic acid, 3,4-sulfur diazole-2-yl) sulfur) methyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-its chemical structural formula of 2-sodium formate:
Structural formula:
Molecular formula (Molecular Formula): C18H14C12N5NaO5S3
Molecular weight (Molecular Weight): 570.43
1. pharmacology
Cefazedone is a kind of semisynthetic first generation cephalosporin, is the cephalosporin derivant, and is similar with other cephalosporins medicine, through influencing the bacteria cell wall biosynthesis, thereby plays antibacterial action.Cefazedone except that the enterococcus of sensitivity and staphylococcus aureus are had efficient, also effective to escherichia coli, the kerekou pneumonia diphtheria of sensitivity, but to producing the negative bacillus and the positive coccus drug resistance of beta-lactamase.
2. toxicity
Acute toxicity LD50 (mg/kg): mice and rat intravenous injection are respectively 6800 (6139-7532) and 4225 (3920-4552); Mice and rat muscle injection are all＞10000; Beasle dog intravenous injection＞4000.
Long term toxicity test: the maximal non-toxic property dosage of the rat administered intramuscular in June and the convalescent repeat administration toxicity test in 6 weeks is 100mg/kg.
The maximal non-toxic property dosage of beasle dog cefazedone 4 all intravenous administrations and 8 all convalescent repeat administration toxicity tests is 180mg/kg.
3. pharmacokinetics
Blood level: the quiet notes of the 10 routine Refosporin (E.Merck). 1g (tiring) of health adult, the concentration meansigma methods is to be 3.87 μ g/mL behind 144.38 μ g/mL, the 6h in 5 fens bleeding from anus of administration, the blood level half-life is about 1.64h.
Metabolism and drainage: Refosporin (E.Merck). is not in vivo by metabolism, and antibacterial activity is the medicine original shape, and most of drainage from urine.The quiet notes of the 10 routine Refosporin (E.Merck). 1g (tiring) of health adult, average recovery rate is 76.09% in the urine of 6h.
4. indication
Respiratory tract infection such as bronchitis, pneumonia, pharyngolaryngitis, urinary tract infection, cholangitis and peritonitis, female genital tract infections such as endometritis, septicemia, skin soft-tissue infection, bone and the infection of joint etc.
5. usage and dosage
Adopt intravenous administration.Gram positive bacteria is infected: every day dosage 1-2g, divide 2 or 3 administrations.Gram-negative bacteria is infected: every day dosage 3-4g, divide 2 or 3 administrations.To moderate to severe infection: every day, maximum dosage can reach 6g.
Clavulanate potassium Potassium clavulanate
Clavulanate potassium is claimed clavulanic acid again
Structural formula:
Molecular formula: C
8H
8KNO
58KNO
5
Molecular weight: 237.25
Clavulanate potassium is the blue or green enzyme alkanes of the irreversible wide spectrum oxygen of an a kind of competitiveness beta-lactamase inhibitor; These article antibacterial action very a little less than, press down the enzyme effect but have strong effect wide-spectrum, unite with beta-lactam antibiotic; Process the enzyme inhibitor combination formulations; Can be at protection in varying degrees and the beta-lactam antibiotic of its associating not by the beta-lactam enzyme-deactivating, thus the anti-effect of producing the enzyme fastbacteria of this antibiotic improved, improve clinical efficacy.It is that it combines with beta-lactamase that clavulanate potassium presses down enzyme mechanism, the performance competitive inhibition.Beta-lactam carboxyl position through in the clavulanate potassium molecular structure makes the beta-lactamase acetylation, and this step reaction is very similar with the reaction that beta-lactam antibiotic took place that beta-lactamase combines with it.Contact with beta-lactamase like benzylpenicillin, enzyme is also by the beta-lactam carboxyl position acetylation of benzylpenicillin, but the very fast hydrolysis of this acetylated enzyme discharges organized enzyme with benzylpenicillin hydrolysis deactivation.Then hydrolysis is very slow for the acetylated enzyme that beta-lactamase and clavulanate potassium form; Make it to discharge organized enzyme very soon; Thereby in fact this beta-lactamase is temporarily suppressed by enzyme inhibitor; Thereby the effect substrate beta-lactam antibiotic of having protected enzyme makes it still have antibacterial action to general product enzyme fastbacteria not by the enzyme hydrolysis deactivation.
At present because the irrational application of antibiotics causes the Grain-positive bacillus increasing to the drug resistance of cephalo-type.Domestic and international up-to-date bacterial resistance monitoring result shows, 1-4 is risen respectively for the antibiotics resistant rate, special first generation cephalosporin, because unstable to the negative bacillus beta-lactamase, the resistant rate of positive bacteria is very high, and clinical practice descends significantly.Clavulanate potassium (sulbactam) is a kind of wide spectrum beta-lactamase inhibitor, and is stronger to the inhibitory action of wide spectrum enzyme, and ultra wide spectrum enzyme is also had certain effect.With the two associating,, have stable and the enhancing antimicrobial susceptibility to gram negative bacilli through the enzyme effect that presses down of beta-lactamase inhibitor; Stronger antibacterial activity is arranged, the antimicrobial spectrum expanded range to producing the beta-lactamase GPC simultaneously.
Summary of the invention
The object of the invention: be to provide better compositions of a kind of antibacterial effect and proportioning thereof, after Refosporin (E.Merck). and clavulanate potassium Combined application, gram negative bacilli and the GPC that produces beta-lactamase produced stronger antibacterial activity.
Cefazedone is a first generation cephalosporin, and sterilizing power is strong, but gram negative bacilli to the beta-lactamase less stable, and the main resistance mechanism of enterobacteriaceae lactobacteriaceae is for producing beta-lactamase.Many drug resistance monitoring results show that the escherichia coli, Klebsiella Pneumoniae and the Bacillus proteus that separate from the patient that is in hospital have reached 76.2%, 57.5% and 34.6% to the second generation cephalosporin resistant rate, before 10 years, increase 10-20 percentage point.The beta-lactamase inhibitor clavulanate potassium can suppress the activity of wide spectrum enzyme and ultra wide spectrum enzyme, overcomes bacterial resistance through inhibitory enzyme, recovers the antibacterials effect.Therefore, antibacterial to the Refosporin (E.Merck). drug resistance after, the compositions of Refosporin (E.Merck). and clavulanate potassium solves its drug resistance problem specially, has expanded its antibiotic curative effect.
Refosporin (E.Merck). in clinical practice for many years, respiratory tract infection such as tracheitis, pneumonia, pharyngolaryngitis, urinary tract infection, cholangitis and peritonitis, female genital tract infections such as endometritis.Septicemia, skin soft-tissue infection, bone and the infection of joint etc.
Developing this product, also meet the current policy that clinical antibacterials are used by turns of implementing in the world, increase the selectivity of clinical antibiotics, is significant.
Through to 4 kinds of variable concentrations mass ratioes (1: 1; 2: 1; 4: 1,8: 1) the vitro antibacterial activity research carried out of Refosporin (E.Merck). and clavulanate potassium compositions show that Refosporin (E.Merck). and clavulanate potassium Combined application can significantly improve the sensitivity of Refosporin (E.Merck). to gram negative bacilli.
The also stronger antibacterial activity of GPC to the beta-lactamase that produces.
The Refosporin (E.Merck). and the clavulanate potassium of different proportionings all have bigger bactericidal action, and the proportioning of 1: 1 and 2: 1 obviously is superior to the independent medication of Refosporin (E.Merck). to the bactericidal action of GPC.
Result of the test shows, Refosporin (E.Merck) ./clavulanate potassium 1: 1-8: 1 all has good in-vitro antimicrobial than Refosporin (E.Merck).; The Refosporin (E.Merck). of 2: 1 proportionings+clavulanate potassium compositions has stronger vitro antibacterial activity, and is suitable with 1: 1 proportioning, and 1: 1-8: which is more reasonable for 1 proportioning, can compare diversity through clinical efficacy in the clinical trial afterwards.
Description of drawings:
Fig. 1 is the killing curve figure of Refosporin (E.Merck) .+sodium-tazobactam to the No.137 escherichia coli
Fig. 2 is the killing curve figure of Refosporin (E.Merck) .+sodium-tazobactam to the No.97 escherichia coli
Fig. 3 is the killing curve figure of Refosporin (E.Merck) .+sodium-tazobactam to MSSA No.235
Fig. 4 Refosporin (E.Merck) .+sodium-tazobactam is to the killing curve figure of MSSA No.176
Specific embodiment:
The present invention further sets forth through following embodiment, but is not limited to the present invention.
Embodiment: different proportioning Refosporin (E.Merck) .s and the research of clavulanate potassium vitro antibacterial activity
Materials and methods
1. test drug:
(1) Refosporin (E.Merck). (Cefamandole Nafate): Beijing Lianmu Medical Technology Development Co., Ltd. provides lot number 090604 to tire 89.1%.
(2) clavulanate potassium (Potassium clavulanate): Beijing Lianmu Medical Technology Development Co., Ltd. provides, and lot number 0481-9801 tires: 93.7%.Available from Nat'l Pharmaceutical & Biological Products Control Institute
Following ratio proportioning is calculated by weight, and wherein Refosporin (E.Merck). weight is given money as a gift with Refosporin (E.Merck). and purely calculated by cefazedone, and clavulanate potassium weight is given money as a gift with clavulanate potassium and purely calculated by clavulanic acid.
2. test proportioning:
(1) Refosporin (E.Merck).
(2) clavulanate potassium
(2) Refosporin (E.Merck) .+clavulanate potassium (1: 1)
(3) Refosporin (E.Merck) .+clavulanate potassium (2: 1)
(4) Refosporin (E.Merck) .+clavulanate potassium (4: 1)
(5) Refosporin (E.Merck) .+clavulanate potassium (8: 1)
3. test strain:
3.1 reference culture: large intestine dust antibacterial ATCC25922, ATCC700603, staphylococcus aureus ATCC29213, ATCC25923, streptococcus pneumoniae ATCC49619.
3.23.2 produce 165 strains of beta-lactamase gram-negative bacteria, measure whether produce enzyme with nitrocefin:
Escherichia coli Escherichia coli (49 strain)
Klebsiella Pneumoniae Klebsiella peumoniae (38 strain)
Moraxelle catarrhalis moraxella catarrhalis (32 strain)
Proteus mirabilis Proteus mirabilis (26 strain)
Hemophilus influenza Haemophilus influenzae (20 strain)
3.3 produce 27 strains of beta-lactamase gram positive bacteria:
MSSA MSSA (27 strain)
All bacterium all pass through dull and stereotyped commentaries on classics branch alive before test pure, is used for test with new fresh thalli.Each experiment all uses reference culture as sensitive experiment Quality Control bacterium; Use the plate that does not contain antibacterials as the test strain growth control.
4. culture medium and incubation conditions
Staphylococcus and enterobacteriaceae lactobacteriaceae are hatched 16-20h for 35 ℃ in the M-H culture medium; Streptococcus on blood meida (in the M-H culture medium add 5% defiber Sanguis caprae seu ovis process), 35 ℃ of 5%CO
2Environment (CO
2Incubator) hatches 20-24h in.
5. minimum inhibitory concentration (MIC) is measured
Employing standard plate doubling dilution.Antibacterials are measured concentration range 256-0.016mg/L.With the inoculation of multiple spot inoculation appearance, every some inoculum concentration is 104CFU by the examination bacteria suspension.Measure the minimum inhibitory concentration of each antibacterials to various pathogenic bacterium.
The result
1. Refosporin (E.Merck) ./the clavulanate potassium of different proportionings is to MIC result's (table 1) of the clinical separation pathogenic bacterium of 192 strains
From table 1, can find out,, add the antibacterial activity that clavulanate potassium can obviously improve Refosporin (E.Merck)., MIC for the escherichia coli, Klebsiella Pneumoniae, moraxelle catarrhalis and the proteus mirabilis that produce beta-lactamase
50Value can descend 4-256 doubly, MIC
90Value decline 4-256 doubly.
For MSSA (MSSA), add the antibacterial activity that clavulanate potassium can obviously improve Refosporin (E.Merck)., MIC
50Value can descend 16-128 doubly, MIC
90Value decline 16-64 doubly.
Table 1. Refosporin (E.Merck) ./clavulanate potassium is to the MIC result of the clinical separation pathogenic bacterium of 192 strains
2. Refosporin (E.Merck) ./the clavulanate potassium of different proportionings is to MBC result's (table 2) of the clinical separation pathogenic bacterium of 30 strains
MBC result shows; The Refosporin (E.Merck). of 4 kinds of different proportionings and clavulanate potassium are to MBC/MIC≤2 of escherichia coli and moraxelle catarrhalis times; To MBC/MIC≤4 of staphylococcus aureus times, explain that the compositions of Refosporin (E.Merck). and clavulanate potassium has typical bactericidal action.
Refosporin (E.Merck) ./the clavulanate potassium of the different proportionings of table 2 is to the MBC of the clinical separation pathogenic bacterium of 30 strains
3. killing curve result:
Refosporin (E.Merck) ./the clavulanate potassium of four kinds of proportionings and Refosporin (E.Merck). single dose are seen Fig. 1～4 to the killing curve of the 4 strain clinical isolates such as escherichia coli No.97 of product beta-lactamase.
Fig. 1,2 is the killing curve of Refosporin (E.Merck) .+clavulanate potassium to two strain escherichia coli No.137 and No.97.When drug level is 8mg/L and 4mg/L; Refosporin (E.Merck) .+the clavulanate potassium of 1: 1 proportioning can be respectively reduce to 0.9 and 0.99CFU/ml with 2 strain bacterium from 6.57CFU/ml at 24 hours, and 2: 1 proportioning can be respectively reduce to 1.09 and 1.21CFU/ml with 2 strain bacterium from 6.57CFU/ml at 24 hours.
Fig. 3,4 is for producing MSSA (MSSA) killing curve of beta-lactamase; Refosporin (E.Merck) .+the clavulanate potassium of 1: 1 proportioning to the bactericidal action of No.235 and No.176 when concentration is 8mg/L and 4mg/L; Can this bacterium be reduced to 0.5 and 0.71CFU/ml by 6.57CFU/ml in 24 hours; Can this bacterium be reduced to 0.65 and 0.98CFU/ml in the Refosporin (E.Merck) .+clavulanate potassium of 2: 1 proportionings 24 hours, be superior to 4: 1 and 8: 1 proportionings.
4. to the influence factor of vitro antibacterial activity:
(1) as shown in table 3, the Refosporin (E.Merck) ./clavulanate potassium of different proportionings is respectively 10 at bacterial load
4, 10
5, 10
6With 10
7During CFU/ml, to the MIC value of escherichia coli, Klebsiella Pneumoniae and MSSA.Explain that bacterial load is 10
4～10
7CFU/ml does not have obviously influence to the MIC value of the anti-3 kinds of bacterium of Refosporin (E.Merck) ./clavulanate potassium of different proportionings.
Table 3 Refosporin (E.Merck) .+clavulanate potassium is to the influence of bacterial load
(2) visible from table 4, the MIC value to escherichia coli, moraxelle catarrhalis, MSSA of four kinds of proportioning Refosporin (E.Merck) .+clavulanate potassium does not have obviously influence in pH5.0～pH8.0 scope.
The influence of the MIC of table 4 Refosporin (E.Merck) .+clavulanate potassium under different pH
(3) human albumin's content in the culture medium, the appreciable impact (table 5) that the outer antibacterial action of the Refosporin (E.Merck) .+clavulanate potassium of four kinds of proportionings is not had.
Table 5. Refosporin (E.Merck) .+clavulanate potassium human albumin's content is to the influence of MIC
Claims (1)
1. the compositions of Refosporin (E.Merck). and clavulanate potassium it is characterized in that it and be made up of Refosporin (E.Merck). and clavulanate potassium, and the weight ratio of described Refosporin (E.Merck). and clavulanate potassium is 1: 1 or 2: 1.
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Non-Patent Citations (2)
| Title |
|---|
| D. T. ROGERS,A. D. RUSSELL.Combinations of Clavulanic Acid and other P-lactam Antibiotics against Strains of Pseudom onas aeruginosa, Serratia marcescens and other Bacteriaitm.《Journal of Applied Bacteriology》.1980,第49卷(第1期),111-118. * |
| D.T.ROGERS，A.D.RUSSELL.CombinationsofClavulanicAcidandotherP-lactamAntibioticsagainstStrainsofPseudomonasaeruginosa Serratia marcescens and other Bacteriaitm.《Journal of Applied Bacteriology》.1980 |
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Assignee: Shenzhen Wanyuan Pharmaceutical Co., Ltd. Assignor: Suntay Pharma Co., Ltd. Contract record no.: 2012440020098 Denomination of invention: Composition of cefazedone sodium sterile and clavulanate potassium and proportion thereof License type: Exclusive License Open date: 20101215 Record date: 20120508 |
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