CN101849947B - Composition of cefazedone sodium and tazobactam sodium and ratio of cefazedone sodium to tazobactam sodium - Google Patents
Composition of cefazedone sodium and tazobactam sodium and ratio of cefazedone sodium to tazobactam sodium Download PDFInfo
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- CN101849947B CN101849947B CN2010101137094A CN201010113709A CN101849947B CN 101849947 B CN101849947 B CN 101849947B CN 2010101137094 A CN2010101137094 A CN 2010101137094A CN 201010113709 A CN201010113709 A CN 201010113709A CN 101849947 B CN101849947 B CN 101849947B
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Abstract
The invention relates to a composition of cefazedone sodium and tazobactam sodium and a ratio of cefazedone sodium to tazobactam sodium, which are characterized in that: the composition consists of cefazedone sodium and tazobactam sodium in a weight ratio of 1:1-8:1. In infectious diseases caused by bacteria, bacteria which produce beta-lactamase are medicament-resistant to cefazedone to cause invalid treatment; and when the cefazedone sodium and tazobactam sodium are combined, the composition has high antibacterial activity on gram negative bacilli which produce the beta-lactamase and gram positive cocci. The composition is most sensitive to bacterial strains which are resistant to the cefazedone sodium, has strong antibacterial therapeutic effect, sufficient experimental evidences and obvious clinical antibacterial effect without adverse reaction.
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 sodium-tazobactam.
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): C18H14Cl2N5NaO5S3
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.
Sodium-tazobactam Tazobactam Sodium
The sodium-tazobactam chemical name: (2S, 3S, 5R)-and 3-methyl-7-oxo-3-(1H-1,2,3-triazole-1-ylmethyl)-4-sulfo--1-azabicyclo [3.2.0] heptane-2-carboxylic acid 4, the 4-dioxide
Molecular formula: C
10H
11N
4NaO
5S
Molecular weight: 322.27
Chemical structural formula:
Sodium-tazobactam is a kind of beta-lactamase inhibitor, and it is low to have toxicity, and good stability presses down advantages such as enzymatic activity is strong.Various types of beta-lactamases (particularly ultraphotic spectrum beta-lactamase) all there is irreversible inhibitory action.
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.Sodium-tazobactam (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 sodium-tazobactam 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 Tazobactam Sodium 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 Tazobactam Sodium 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 Tazobactam Sodium composition of sodium show that Refosporin (E.Merck). and sodium-tazobactam 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 sodium-tazobactam 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, cefazedone sodium/tazobactam sodium 1: 1-8: 1 all has good in-vitro antimicrobial than Refosporin (E.Merck).; The Refosporin (E.Merck). of 2: 1 proportionings+Tazobactam Sodium composition of sodium 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.
Specific embodiment:
Further set forth the present invention through embodiment below, but be not limited to the present invention.
Embodiment: different proportioning Refosporin (E.Merck) .s and sodium-tazobactam vitro antibacterial activity research material and method
1. test drug:
, (1) Refosporin (E.Merck). (Cefamandole Nafate): Xintai City, Shenzhen medicine company limited provides lot number 090702 to tire 89.1%.
(2) sodium-tazobactam (Tazobactam Sodium): Xintai City, Shenzhen medicine company limited 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 Tazobactam Sodium weight is given money as a gift with sodium-tazobactam and purely calculated by Tazobactam Sodium.
2. test proportioning:
(1) Refosporin (E.Merck).
(2) sodium-tazobactam
(2) Refosporin (E.Merck) .+sodium-tazobactam (1: 1)
(3) Refosporin (E.Merck) .+sodium-tazobactam (2: 1)
(4) Refosporin (E.Merck) .+sodium-tazobactam (4: 1)
(5) Refosporin (E.Merck) .+sodium-tazobactam (8: 1)
3. test strain:
3.1 reference culture: large intestine dust antibacterial ATCC25922, ATCC700603, staphylococcus aureus ATCC29213, ATCC25923, streptococcus pneumoniae ATCC49619.
3.2 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)
Bacterium all passes 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 10 by the examination bacteria suspension
4CFU.Measure the minimum inhibitory concentration of each antibacterials to various pathogenic bacterium.
The result
1. the cefazedone sodium/tazobactam sodium 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 sodium-tazobactam 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 16-256 doubly, MIC
90Value decline 4-128 doubly.
For MSSA (MSSA), add the antibacterial activity that sodium-tazobactam can obviously improve Refosporin (E.Merck)., MIC
50Value can descend 16-256 doubly, MIC
90Value decline 16-128 doubly.
Table 1. cefazedone sodium/tazobactam sodium is to the MIC result of the clinical separation pathogenic bacterium of 192 strains
2. the cefazedone sodium/tazobactam sodium 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 sodium-tazobactam 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 sodium-tazobactam has typical bactericidal action.
The cefazedone sodium/tazobactam sodium of the different proportionings of table 2 is to the MBC of the clinical separation pathogenic bacterium of 30 strains
3. killing curve result:
The cefazedone sodium/tazobactam sodium of four kinds of proportionings and Refosporin (E.Merck). single dose are seen Fig. 1～2 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) .+sodium-tazobactam to two strain No.119 and No.306 escherichia coli.When drug level is 8mg/L and 4mg/L; Refosporin (E.Merck) .+the sodium-tazobactam of 1: 1 proportioning can be respectively reduce to 0.31 and 0.1CFU/ml with 2 strain bacterium from 7.12CFU/ml at 24 hours, and 2: 1 proportioning can be respectively reduce to 0.23 and 0.22CFU/ml with 2 strain bacterium from 7.12CFU/ml at 24 hours.
Fig. 3,4 is for producing MSSA (MSSA) killing curve of beta-lactamase; Refosporin (E.Merck) .+the sodium-tazobactam of 1: 1 proportioning to the bactericidal action of No.337 and No.89 when concentration is 8mg/L and 4mg/L; Can this bacterium be reduced to 0.1 and 0.78CFU/ml by 7.12CFU/ml in 24 hours; Can this bacterium be reduced to 0.3 and 0.89CFU/ml in the Refosporin (E.Merck) .+sodium-tazobactam of 2: 1 proportionings 24 hours, be superior to 4: 1 and 8: 1 proportionings.
Fig. 1-4 sees Figure of description
4. to the influence factor of vitro antibacterial activity:
(1) as shown in table 3, the cefazedone sodium/tazobactam sodium 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 cefazedone sodium/tazobactam sodium of different proportionings.
Table 3 Refosporin (E.Merck) .+sodium-tazobactam 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) .+Tazobactam Sodiums does not have obviously influence in pH5.0～pH8.0 scope.
The influence of the MIC of table 4 Refosporin (E.Merck) .+sodium-tazobactam 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) .+sodium-tazobactam of four kinds of proportionings is not had.
Table 5. Refosporin (E.Merck) .+sodium-tazobactam human albumin's content is to the influence of MIC
Claims (1)
1. the pharmaceutical composition of anti-gram negative bacilli or GPC; It is characterized in that it is weight ratio 1: 1 or 2: 1 the Refosporin (E.Merck). and the compositions of sodium-tazobactam; Wherein Refosporin (E.Merck). weight is given money as a gift with Refosporin (E.Merck). and is purely calculated by cefazedone, and sodium-tazobactam weight is given money as a gift with sodium-tazobactam and purely calculated by Tazobactam Sodium.
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| WO2023039947A1 (en) * | 2021-09-18 | 2023-03-23 | 湘北威尔曼制药股份有限公司 | Pharmaceutical composition containing cefoperazone sodium and tazobactam sodium and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1729983A (en) * | 2005-06-20 | 2006-02-08 | 四川大学 | Pharmaceutical composition of cefadroxil and beta-lactamase inhibitor |
| CN1965838A (en) * | 2005-11-17 | 2007-05-23 | 李海超 | Pharmaceutical composition containing cefpiramide and beta-lactamase inhibitor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1729983A (en) * | 2005-06-20 | 2006-02-08 | 四川大学 | Pharmaceutical composition of cefadroxil and beta-lactamase inhibitor |
| CN1965838A (en) * | 2005-11-17 | 2007-05-23 | 李海超 | Pharmaceutical composition containing cefpiramide and beta-lactamase inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| 刘家健.头孢菌素类品种研发与生产现状探讨.《中国抗生素杂志》.2006,第31卷(第2期),100-106. * |
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