CN102274218B - Faropenem sodium and sulbactam sodium combined medicine - Google Patents
Faropenem sodium and sulbactam sodium combined medicine Download PDFInfo
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- CN102274218B CN102274218B CN 201110168700 CN201110168700A CN102274218B CN 102274218 B CN102274218 B CN 102274218B CN 201110168700 CN201110168700 CN 201110168700 CN 201110168700 A CN201110168700 A CN 201110168700A CN 102274218 B CN102274218 B CN 102274218B
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- sodium
- faropenem
- sulbactam
- sulbactam sodium
- acinetobacter bauamnnii
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- 229960000379 faropenem Drugs 0.000 title claims abstract description 77
- NKZMPZCWBSWAOX-IBTYICNHSA-M Sulbactam sodium Chemical compound [Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)N2C(=O)C[C@H]21 NKZMPZCWBSWAOX-IBTYICNHSA-M 0.000 title claims abstract description 67
- 229960000614 sulbactam sodium Drugs 0.000 title claims abstract description 67
- MOGICMVNWAUWMK-HIXRZVNASA-L disodium;(5r,6s)-6-[(1r)-1-hydroxyethyl]-7-oxo-3-[(2r)-oxolan-2-yl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].S([C@@H]1[C@H](C(N1C=1C([O-])=O)=O)[C@H](O)C)C=1[C@H]1CCCO1.S([C@@H]1[C@H](C(N1C=1C([O-])=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 MOGICMVNWAUWMK-HIXRZVNASA-L 0.000 title claims abstract description 64
- 239000003814 drug Substances 0.000 title claims abstract description 45
- 208000015181 infectious disease Diseases 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims description 7
- 201000009906 Meningitis Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 3
- 208000013223 septicemia Diseases 0.000 claims description 3
- 230000002485 urinary effect Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 25
- 229940079593 drug Drugs 0.000 abstract description 10
- 208000035473 Communicable disease Diseases 0.000 abstract description 9
- 241000588626 Acinetobacter baumannii Species 0.000 abstract description 6
- 206010059866 Drug resistance Diseases 0.000 abstract description 5
- 230000002195 synergetic effect Effects 0.000 abstract 1
- 241000589291 Acinetobacter Species 0.000 description 38
- 241000894006 Bacteria Species 0.000 description 27
- 239000007788 liquid Substances 0.000 description 14
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- 241000699670 Mus sp. Species 0.000 description 13
- 231100000668 minimum lethal dose Toxicity 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 230000001580 bacterial effect Effects 0.000 description 9
- 229960005256 sulbactam Drugs 0.000 description 9
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 9
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 description 8
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 8
- 229960004682 cefoperazone Drugs 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 7
- 229940088710 antibiotic agent Drugs 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 6
- 230000035945 sensitivity Effects 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- HGGAKXAHAYOLDJ-YZJVMBJSSA-N faropenem Chemical compound S([C@@H]1C(C(N1C=1C(O)=O)=O)C(O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-YZJVMBJSSA-N 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000003906 pulsed field gel electrophoresis Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 4
- 229960002182 imipenem Drugs 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 3
- 206010011409 Cross infection Diseases 0.000 description 3
- 229940041011 carbapenems Drugs 0.000 description 3
- 230000002427 irreversible effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 235000013372 meat Nutrition 0.000 description 3
- 235000014347 soups Nutrition 0.000 description 3
- LITBAYYWXZOHAW-XDZRHBBOSA-N (2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]hept Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 LITBAYYWXZOHAW-XDZRHBBOSA-N 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 206010029803 Nosocomial infection Diseases 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
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- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 description 2
- 229940104641 piperacillin / tazobactam Drugs 0.000 description 2
- 229960005264 piperacillin sodium Drugs 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
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- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 description 2
- FKENQMMABCRJMK-UHFFFAOYSA-N 3,3-dimethyl-4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=S1(=O)C(C)(C)C(C(O)=O)N2C(=O)CC21 FKENQMMABCRJMK-UHFFFAOYSA-N 0.000 description 1
- 241000588624 Acinetobacter calcoaceticus Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
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- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
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- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
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- 150000002961 penems Chemical class 0.000 description 1
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 1
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- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a combined medicine, specifically, provides a faropenem sodium and sulbactam sodium combined medicine used for treating infectious diseases caused by acinetobacter baumannii. The invention further provides use of the faropenem sodium and sulbactam sodium combined medicine used for treating infectious diseases caused by acinetobacter baumannii. The faropenem sodium and sulbactam sodium combined medicine provided by the invention has synergistic and accumulatively antibacterial actions on acinetobacter baumannii (including multi-drug resistant acinetobacter baumannii) and can be used for curing clinical infection caused by drug resistance acinetobacter baumannii.
Description
Technical field
The invention provides a kind of combination medicine, specifically, provide a kind of combination medicine that Acinetobacter bauamnnii causes the Faropenem sodium/sulbactam sodium of infectious disease that is used for the treatment of.Belong to medical technical field.
Background technology
Carbapenem antibiotics is the class antibiotic that antimicrobial spectrum is the widest so far, antibacterial activity is very strong, but along with being widely used of carbapenems, Acinetobacter bauamnnii increases year by year to the antibiotic resistant rate of carbapenems.And in case to Carbapenem-resistant, just mean that existing common broad-spectrum antibacterials are to its many inefficacies.
Acinetobacter bauamnnii (Acinetobacter baumanii) is non-fermentation gram-negative bacteria, is distributed widely in nature and the hospital environment, and be conditioned pathogen.The large absolutely number of the acinetobacter calcoaceticus that is separated in the clinical samples is Acinetobacter bauamnnii, and the infection that other strain causes is more rare.Identify Acinetobacter bauamnnii: 16sRNA, 23sRNA, 51-like-OXA.
In recent years, increased year by year by the nosocomial infection that Acinetobacter bauamnnii causes, a plurality of countries have reported a lot of hospital infection outbreak of epidemic by its initiation in succession, cause global extensive concern.Acinetobacter bauamnnii can cause serious even infection lethal such as breathing pneumonia, septicemia, urinary system infection, meningitis, ratio in Nosocomial Infection Pathogens increases very fast, clinically the Acinetobacter bauamnnii of drug resistance is not had the specific treatment medicine.
In to the monitoring of the bacterial resistance in 3 years of the whole America 2005-2007, find, gram-negative bacteria sensitivity to each antibacterials in these 3 years is comparatively stable, the sensitivity that has only Acinetobacter bauamnnii has downward trend year by year, and drug resistance, multidrug resistant rate be constantly to rise, and its Acinetobacter bauamnnii ratio that accounts for whole clinical separation rises to 30.8% by 6.3%.The carbapenems medicine is the choice drug for the treatment of Acinetobacter bauamnnii severe infection, but the carbapenem multiple antibiotic resistant strain is occurring all over the world successively in recent years, from Spain to Norway, alarming multidrug resistant Acinetobacter bauamnnii " invasion " phenomenon has appearred, popular in the wound soldier who stays Afghanistan and Iraq U.S. army and the British army, cause serious public health problem, the Acinetobacter bauamnnii that Iraq U.S. army takes back is popular in the U.S..
Faropenem sodium, English name: Faropenem sodium, chemical name: (5R, 6S)-6-[(1R)-1-ethoxy]-the 7-oxidation-3-[(2R)-the 2-tetrahydrofuran base]-4-thia-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid list sodium salt.Faropenem sodium is a kind of penems antibiotics clinically.
Sulbactam sodium (sulbactam) has another name called sulbactam, sulbactam sodium, Sulbactam Sodium.Chemical name: (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium-4,4-dioxide.Sulbactam sodium is irreversible competitive beta-lactamase inhibitor, the beta-lactamase that Grain-positive and negative bacterium (except bacillus pyocyaneus) are produced all has inhibitory action, occur to make enzyme deactivation after the irreversible reaction with enzyme, inhibitor can not make the activity of enzyme be restored after removing.With the beta-lactamase that produces very strong irreversible competitive inhibition is arranged.
Summary of the invention
One of the object of the invention is to provide the combination medicine of a kind of faropenem and sulbactam.Technical solution of the present invention is as follows:
The invention provides a kind of combination medicine, it comprises faropenem or its officinal salt or its solvate and sulbactam or its officinal salt or its solvate and randomly can comprise one or more pharmaceutically suitable carrier.
As preferably, the invention provides a kind of combination medicine, it is characterized in that this combination medicine comprises the pharmaceutical composition that contains Faropenem sodium and sulbactam sodium and randomly unite one or more pharmaceutically suitable carrier.
Combination medicine described above, the weight ratio that it is characterized in that Faropenem sodium and sulbactam sodium is 1: 0.25～1: 12, preferred 1: 4～1: 12 more preferably is 1: 0.25,1: 1,1: 2,1: 4,1: 8 or 1: 12.
As another purpose of the present invention, provide the purposes of Faropenem sodium and sulbactam sodium combination medicine.
Specifically:
Faropenem or its officinal salt or its solvate and sulbactam or its officinal salt or its solvate cause purposes in the medicament of infectious disease at preparation treatment Acinetobacter bauamnnii.
As preferably, Faropenem sodium and sulbactam sodium cause purposes in the medicament of infectious disease at preparation treatment Acinetobacter bauamnnii.
Specifically, Faropenem sodium is for the preparation of causing purposes in the medicament of infectious disease with the sulbactam sodium administration with the treatment Acinetobacter bauamnnii.
Specifically, sulbactam sodium is for the preparation of causing purposes in the medicament of infectious disease with the Faropenem sodium administration with the treatment Acinetobacter bauamnnii.
Preferably, purposes described above, wherein the weight ratio of Faropenem sodium and sulbactam sodium is 1: 0.25～1: 12, preferred 1: 4～1: 12 more preferably is 1: 0.25,1: 1,1: 2,1: 4,1: 8 or 1: 12.
Purposes described above, wherein said Acinetobacter bauamnnii cause that infectious disease is selected from breathing pneumonia, septicemia, urinary system infection, meningitis etc.
As the another goal of the invention of the present invention, a kind of patient pack that comprises be used to the apparatus of the unit dose of measuring is provided, this patient pack comprises Faropenem sodium and sulbactam sodium and the apparatus that helps use the present invention combination medicine described above.
The present invention studies unexpectedly discovery, the infectious disease that Faropenem sodium and sulbactam sodium combination medicine cause Acinetobacter bauamnnii has collaborative and cumulative antibacterial action, particularly strain also has well collaborative and cumulative antibacterial action to the multidrug resistant Acinetobacter bauamnnii, can be used to cure clinically because the clinical infection that the multidrug resistant Acinetobacter bauamnnii causes.
Embodiment of the invention experiment has been used from 109 strain imipenem-resistant bacterial strains of outpatient service isolation identification and has all been carried bla
OXA-51Gene, blaoxa-
51The group gene is the natural intrinsic gene of Acinetobacter bauamnnii chromosome, and antibacterial shows as the sensitivity to beta-lactam antibiotic.The Acinetobacter bauamnnii of experiment is not only to imipenem-resistant, also selected simultaneously simultaneously Faropenem sodium, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, Sulbactam/Cefoperazone (1: 1), ciprofloxacin resistance are used Faropenem sodium/sulbactam sodium composition in these Resistant strains.Show that by the in vitro activity to 6 kinds of variable concentrations mass ratioes (1: 0.25,1: 1,1: 2,1: 4,1: 8,1: 12) Faropenem sodium/sulbactam sodium drug combination can significantly improve the imipenem-resistant bacterial strain is all carried bla
OXA-51The sensitivity of the Acinetobacter bauamnnii of gene has clear and definite and strong antibacterial activity.Faropenem sodium all has stronger bactericidal action from the different proportionings of sulbactam sodium, and 1: 0.25 to 1: 12 proportioning all significantly is better than the independent medication of Faropenem sodium to the bactericidal action of Acinetobacter bauamnnii.In vitro tests is the result show, Faropenem sodium/sulbactam sodium 1: 0.25-1: 12 all have stronger vitro antibacterial activity than Faropenem sodium list medicine.
The specific embodiment
Further set forth the present invention below by embodiment, but and in the present invention protected perhaps scope be construed as limiting.
Embodiment 1: Faropenem sodium/sulbactam sodium in vitro activity
One, materials and methods
1. test drug:
(1) Faropenem sodium (Faropenem): the new Pharmaceutical production in capital, Zhejiang, lot number DK67-1012281, content 91.6%.
(2) sulbactam sodium (Sulbactam sodium SBT): lot number 0430-200002, available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Following ratio proportioning by weight, wherein Faropenem sodium weight is with the Faropenem sodium pure calculating of giving money as a gift, sulbactam sodium weight is given money as a gift with sulbactam sodium and is purely calculated by sulbactam.
2. test proportioning:
(1) Faropenem sodium
(2) sulbactam sodium
(3) Faropenem sodium+sulbactam sodium (1: 0.25)
(4) Faropenem sodium+sulbactam sodium (1: 1)
(5) Faropenem sodium+sulbactam sodium (1: 2)
(6) Faropenem sodium+sulbactam sodium (1: 4)
(7) Faropenem sodium+sulbactam sodium (1: 8)
(8) Faropenem sodium+sulbactam sodium (1: 12)
3. test strain:
This experiment has been used from 109 strain imipenem-resistant bacterial strains of outpatient service isolation identification and has all been carried bla
OXA-51Gene, blaoxa-
51The group gene is the natural intrinsic gene of Acinetobacter bauamnnii chromosome, and antibacterial shows as the sensitivity to beta-lactam antibiotic.The Bao Man bacillus of this 109 strain is simultaneously to Faropenem sodium, piperacillin, piperacillin/Tazobactam Sodium (1: 1), cefoperazone, Sulbactam/Cefoperazone (1: 1), ciprofloxacin also drug resistance, belong to the multidrug resistant Acinetobacter bauamnnii, the Quality Control bacterium is escherichia coli ATCC25922 and Pseudomonas aeruginosa ATCC27853.Bacterial strain is available from attached Shengjing city hospital of Chinese Medical Sciences University.
4. reagent and instrument
M-H meat soup and M-H agar (French Biomerieux SA); Taq archaeal dna polymerase, dNTPs, DNA Maker DL2000, ApaI enzyme (TaKaRa company); Calorstat (Chongqing four reaches company), pulsed field gel electrophoresis instrument (Biorad company); Gel imaging system (genome company), than turbid instrument (French Biomerieux SA), PCR instrument (U.S. Eppendorf company).
5. method
The plate doubling dilution 5.1 in-vitro antibacterial medicine drug sensitive detection is adopted international standards.Measure each antibacterials to the minimum inhibitory concentration (M IC) of various pathogenic bacterium.Critical concentration by U.S.'s laboratory and clinical criteria institute (CILS) regulation in 2009, judge every strain bacterium to the sensitivity of antibacterials, obtain antibacterial responsive rate (S%), the intermediary of the various antibacterials measured led (I%) and resistant rate (R%).Wherein antibacterial is judged to be drug resistance to imipenum MIC 〉=16.
5.2 pulsed field gel electrophoresis (pulsed-field gel electrophoresis, PFGE) boiling method extracts bacteria total DNA.Genomic DNA is inserted in 1% agarose gel in 0.5mol/L tromethane-ethylenediaminetetraacetic acid (Tris-EDTA) after using the ApaI enzyme action, uses 6V/cm pulsed field gel electrophoresis instrument to detect.The burst length scope continues 24h at 5.0-8.0s.Then the gel ethidium bromide staining is observed under uviol lamp and the film making retention.
5.3OXA enzyme gene test: detect 4 groups of OXA enzyme genes with the PCR method.PCR reaction system volume 20 μ L, the PCR condition: 94 ℃ of denaturation 5min, 94 ℃ of degeneration 25s, 56 ℃ of annealing 40s, 72 ℃ are extended 50s, and after 30 circulations, 72 ℃ are extended 6min again.The PCR product is made Preliminary Identification with 1.5% agarose gel electrophoresis and Ethidum Eremide dyeing.The PCR primer is given birth to worker engineering company by Shanghai and is synthesized.PCR product electrophoresis is cut glue and is carried out checking order behind the purification.Sequence among sequencing result and the GenBank is compared, determine the product type.
6. to the influence factor of vitro antibacterial activity
(1) bacterial load impact
Measure four kinds of matching method faropenem/sulbactam sodium to the different bacterium amounts (10 of test bacterium with the plate doubling dilution
4, 10
5, 10
6, 10
7CFU/ml) on the impact of MIC value.
(2) impact of Medium's PH Value
Measure 6 kinds of matching method faropenem/sulbactam sodium to the impact on the MIC value under different pH condition of test bacterium with the plate doubling dilution.
(3) impact of serum albumin content
Measure 6 kinds of matching method faropenem/sulbactam sodium with the plate doubling dilution test bacterium is observed serum albumin content to the impact of MIC value in different serum-concentration (25%, 50%, 75%) and the culture medium that does not contain serum.
Two, result
1. Faropenem sodium/sulbactam sodium is to the antibacterial activity in vitro of Acinetobacter bauamnnii
The results are shown in Table 1.
Table 1. antibacterial activity in vitro
2. to the influence factor of vitro antibacterial activity:
(1) as shown in table 2, the Faropenem sodium/sulbactam sodium of different proportionings is respectively 10 at bacterial load
4, 10
5, 10
6With 10
7During CFU/ml, to Acinetobacter bauamnnii MIC value.Illustrate that bacterial load is 10
4～10
7CFU/ml has no significant effect the MIC value of the anti-Acinetobacter bauamnnii of Faropenem sodium/sulbactam sodium of different proportionings.
Table 2. Faropenem sodium+sulbactam sodium is on the impact of Acinetobacter bauamnnii inoculum concentration
(2) as seen from Table 3, the MIC value to Acinetobacter bauamnnii of 6 kinds of matching method faropenem+sulbactams has no significant effect in pH5.0～pH 8.0 scopes.
Table 3. Faropenem sodium+sulbactam sodium under different pH MIC on the impact of Acinetobacter bauamnnii
(3) human albumin's content in the culture medium, anti-Acinetobacter bauamnnii effect has no significant effect result such as table 4 to the Faropenem sodium+sulbactam sodium of 6 kinds of proportionings.
Table 4. Faropenem sodium+sulbactam sodium human albumin's content is on the impact of Acinetobacter bauamnnii MIC
Embodiment 2: the vivo bacteria corrosion action research of Faropenem sodium/sulbactam sodium
Faropenem sodium and sulbactam sodium be (1: 1) by weight, and (1: 2), (1: 4), the combination medicine of (1: 8) or (1: 12) has significant antibacterial therapy effect to the mice that infects.
1 tested medicine
Faropenem sodium (Faropenem): the fixed intelligent Pharmaceutical Technology Co., Ltd in Guangzhou provides the new Pharmaceutical production in capital, Zhejiang, lot number DK67-1012281, content 91.6%.
Sulbactam sodium, lot number: 0430-200002 is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
White mice, Kunming kind, body weight 18～22g, male and female half and half.Chinese Medical Sciences University belongs to the second laboratory animal room of hospital to be provided.The quality certification number, the Liao Dynasty is real moving for word 031.Random packet, 10 every group, male and female half and half.If 7 dosage groups, the equal Intraperitoneal injection 3 * 10 of each Mus
-5MLD bacterium liquid 0.5ml.Calculate ED with bacteriumization probit
50(each medicine)
The preparation of 2 medicines
Be mixed with desired concn with 0.9% sodium chloride fluid injection.
1, Faropenem sodium (single dose) 2, sulbactam sodium (single dose)
3, Faropenem sodium+sulbactam sodium (1: 1) 4, Faropenem sodium+sulbactam sodium (1: 2)
5, Faropenem sodium+sulbactam sodium (1: 4) 6, Faropenem sodium+sulbactam sodium (1: 8)
7, Faropenem sodium+sulbactam sodium (1: 12)
Observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage, different with bacterial strain, but be the minimum lethal dose (MLD) that causes mice 100% death.Adopt the low ratio serial dilution, two are faced mutually dosage group dose-difference i value and are 0.1-0.15.The maximum dose level of the title dose=medicinal liquid of giving * mice average weight ÷ administration volume * volumetric flask volume ÷ tires. and observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage.
3 infectious bacterias and bacterium amount
Incubated overnight bacterium liquid transferred species in M-H meat soup, is cultivated 18h for 35 ℃, be experiment bacterium stock solution.Bacterium stock solution is suitably diluted, be diluted to the required final concentration of infection animal with 5% high activity dried yeast liquid.This concentration is different according to different strains, but is the minimum lethal dose (MLD. that causes mice 100% death
MLD bacterium liquid processed: total amount=0.5ml * test Mus number; 10 Mus of each dosage group awarded medicinal liquid (0.5ml/ gavage) in 1 hour behind every mouse infection 0.5ml MLD bacterium liquid.
4 experimental results
See Table 5.
The different matching method faropenem/sulbactam sodium of table 5. are to the protective effect of Acinetobacter bauamnnii infecting mouse
Compare with the Faropenem sodium single dose ※ ※ P＜0.001
As shown in table 5, Faropenem sodium/sulbactam sodium (1: 2,1: 4,1: 8,1: 12) obviously is better than the Faropenem sodium single dose to the protective effect of Acinetobacter bauamnnii abdominal cavity infection mice.
Embodiment 3: the comparative study to the Acinetobacter bauamnnii antibacterial action of faropenem/sulbactam and Sulbactam/Cefoperazone
Faropenem sodium and sulbactam sodium be (1: 1) by weight, and (1: 2), (1: 4), the combination medicine of (1: 8) or (1: 12) has significant antibacterial therapy effect to the mice that infects.
1. tested medicine
Faropenem sodium (Faropenem): the new Pharmaceutical production in capital, Zhejiang, lot number DK67-1012281, content 91.6%.Cefoperazone+sulbactam sodium (1: 1), the fixed intelligent Pharmaceutical Technology Co., Ltd in Guangzhou provides.
Sulbactam sodium, lot number: 0430-200002 is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
White mice, Kunming kind, body weight 18～22g, male and female half and half.Chinese Medical Sciences University belongs to the second laboratory animal room of hospital to be provided.The quality certification number, the Liao Dynasty is real moving for word 031.Random packet, 10 every group, male and female half and half.If 2 dosage groups, the equal Intraperitoneal injection 3 * 10 of each Mus
-5MLD bacterium liquid 0.5ml.Calculate ED with bacteriumization probit
50(each medicine)
2. medicine preparation
Faropenem sodium+sulbactam sodium (1: 1); Cefoperazone+sulbactam sodium (1: 1) is mixed with desired concn with 0.9% sodium chloride fluid injection.
Observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage, different with bacterial strain, but be the minimum lethal dose (MLD) that causes mice 100% death.Adopt the low ratio serial dilution, two are faced mutually dosage group dose-difference i value and are 0.1-0.15.The maximum dose level of the title dose=medicinal liquid of giving * mice average weight ÷ administration volume * volumetric flask volume ÷ tires. and observe dead mouse number after 7 days, draw the upper limit and the lower limit of trial drug dosage.
3. infectious bacteria and bacterium amount
Incubated overnight bacterium liquid transferred species in M-H meat soup, is cultivated 18h for 35 ℃, be experiment bacterium stock solution.Bacterium stock solution is suitably diluted, be diluted to the required final concentration of infection animal with 5% high activity dried yeast liquid.This concentration is different according to different strains, but is the minimum lethal dose (MLD) that causes mice 100% death.
MLD bacterium liquid processed: total amount=0.5ml * test Mus number; 10 Mus of each dosage group awarded medicinal liquid (0.5ml/ gavage) in 1 hour behind every mouse infection 0.5ml MLD bacterium liquid.
5 experimental results
See Table 6.
The different matching method faropenem/sulbactam sodium of table 6. are to the protective effect of Bao acinetobacter mice
※P＜0.001
As shown in table 6, Faropenem sodium/sulbactam sodium (1: 1) obviously is better than cefoperazone+sulbactam sodium (1: 1) dosage to the protective effect of Acinetobacter bauamnnii abdominal cavity infection mice.
Claims (3)
1. combination medicine, it is characterized in that this combination medicine comprises the pharmaceutical composition that contains Faropenem sodium and sulbactam sodium and randomly unite one or more pharmaceutically suitable carrier, wherein, the weight ratio of Faropenem sodium and sulbactam sodium is 1: 1,1: 2 or 1: 4～1: 12.
Faropenem sodium and sulbactam sodium the preparation anti-Acinetobacter bauamnnii medicine in purposes, wherein, the weight ratio of Faropenem sodium and sulbactam sodium is 1: 1,1: 2 or 1: 4～1: 12.
3. purposes according to claim 2, wherein said medicine are used for breathing pneumonia, septicemia, urinary system infection or meningitis.
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| 徐浩等.法罗培南钠片治疗细菌性呼吸道感染疗效及体外抗菌活性研究.《淮海医药》.2009,第27卷(第5期),p.396表2. * |
| 果茵茵等.鲍氏不动杆菌的药物治疗进展.《中华医院感染学杂志》.2010,第20卷(第17期),p.2717左栏第4段. * |
| 褚少朋等.舒巴坦单剂对鲍曼不动杆菌的体外抑菌活性研究.《临床检验杂志》.2004,第22卷(第5期),摘要. * |
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