CN102475703A - Anti-Acinetobacter baumannii drug combination and application thereof - Google Patents
Anti-Acinetobacter baumannii drug combination and application thereof Download PDFInfo
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- CN102475703A CN102475703A CN2010105685562A CN201010568556A CN102475703A CN 102475703 A CN102475703 A CN 102475703A CN 2010105685562 A CN2010105685562 A CN 2010105685562A CN 201010568556 A CN201010568556 A CN 201010568556A CN 102475703 A CN102475703 A CN 102475703A
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Abstract
The invention provides an anti-Acinetobacter baumannii drug combination and an application thereof. The drug combination contains meropenem and sulbactam with the weight ratio of meropenem to sulbactam being 1:2-4. The invention is designed by a checkerboard method. The synergetic antibacterial effect of the combined use of meropenem and sulbactam to carbapenems sensitive and drug resistant Acinetobacter baumannii is found by broth microdilution detection. As shown in the test result, no matter meropenem drug resistant strain or meropenem sensitive strains, most of them show a synergetic and partly synergetic effect to the combined use of meropenem and sulbactam and the strains which show a synergetic effect account for 25%.
Description
Technical field
The present invention relates to a kind of medical composition and its use, be specifically related to a kind of medical composition and its use of anti-Acinetobacter bauamnnii.
Background technology
Acinetobacter bauamnnii is the important pathogenic bacteria that causes nosocomial infection, and the treatment that the multidrug resistant Acinetobacter bauamnnii infects has become clinical a great problem.Anti-pseudomonas carbapenem antibiotic is the main medicine that treatment multidrug resistant Acinetobacter bauamnnii infects like imipenum, meropenem.But, have report to point out that (carbapenem-resistant Acinetobacter baumannii, CRAB) wide-scale distribution has worldwide caused serious public health problem to carbapenem antibiotic drug resistance Acinetobacter bauamnnii.And the clinical selectable antibiotic that is used to treat CRAB is very limited, and antibacterials newly developed are also not satisfactory for the antibacterial activity of such drug resistance Acinetobacter bauamnnii.Therefore, reasonably the existing antibacterials of utilization are only more actual coping strategy.
Sulbactam is except well-known beta-lactam enzyme inhibition; It also can act on the PBP2 of Acinetobacter bauamnnii; Thereby bring into play inherent antibacterial action (Corbella X, Ariza J, Ardanuy C; Vuelta M; Tubau F, Sora M, et al.Efficacy of sulbactam alone and in combination with ampicillin in nosocomial infections caused by multiresistant Acinetobacter baumannii.J Antimicrob Chemother.1998 Dec; 42 (6): 793-802), lower and intermediary leads higherly but CRAB is to the responsive rate of sulbactam, and (Wang is multiple to have limited the use of sulbactam; Zhu Demei, Hu Fupin, Chinese CHINET bacterial drug resistance monitoring in 2008; China infects and the chemotherapy magazine, 2009 Dec, 9 (5): 321-29).
Research shows that Combined application has synergistic antibacterials and might become the outlet of capturing an above-mentioned difficult problem.Several retrospective study results have affirmed to unite and have used beta-lactam class and the beta lactamase restrainer antibacterial action to the multidrug resistant acinetobacter calcoaceticus that they have reduced the nephrotoxicity of mortality rate and medicine.Several results of in vitro studies have shown that antibiotic such as sulbactam and cefepime, amikacin, rifampicin unite use, can strengthen the antibacterial activity to Acinetobacter bauamnnii, but activity are still very limited.
Summary of the invention
Therefore, the purpose of this invention is to provide a kind of pharmaceutical composition of anti-Acinetobacter bauamnnii increased activity, thereby can more effectively prevent and/or treat the infectious disease that causes by Acinetobacter bauamnnii.
Be used to realize that the technical scheme of above-mentioned purpose is following:
A kind of pharmaceutical composition of anti-Acinetobacter bauamnnii wherein comprises meropenem and sulbactam, and the weight ratio of meropenem and sulbactam can be 1: 2-4.
Specifically, it is 1 that this pharmaceutical composition can comprise weight ratio: the meropenem of 2-4 and sulbactam, best weight ratio is 1: 4.This pharmaceutical composition can also comprise pharmaceutically acceptable carrier and/or excipient; This pharmaceutical composition can be sucked agent for being selected from injection, freeze-dried powder, tablet, capsule, the dosage form of drop pill.
The present invention also provides the purposes of aforementioned pharmaceutical compositions in the medicine of the anti-Acinetobacter bauamnnii of preparation.
The present invention further provides aforementioned pharmaceutical compositions to prevent and/or treat the purposes in the medicine of the disease that Acinetobacter bauamnnii causes in preparation.
For such use, Acinetobacter bauamnnii can be preferably the drug-fast Acinetobacter bauamnnii of carbapenem antibiotic for responsive Acinetobacter bauamnnii of carbapenem antibiotic and/or the drug-fast Acinetobacter bauamnnii of carbapenem antibiotic.
Above-mentioned disease is specially infection; Be preferably in respirator dependency pneumonia, septicemia, urinary tract infection and the wound infection one or more.
Acinetobacter bauamnnii is to cause nosocomial infection, the especially important pathogen of respirator dependency pneumonia, septicemia, urinary tract infection, wound infection etc.Resist antibiotic ability thereby Acinetobacter bauamnnii possesses from the pathogen acquisition drug resistant gene of other kinds, it finally can form the multidrug resistant Acinetobacter bauamnnii, and this has proposed a difficult problem for the medication of clinical experience property.Its indomitable survival ability on the armarium surface especially in environment makes Acinetobacter bauamnnii serious day by day to the threat of nosocomial infection in addition.Chinese CHINET bacterial drug resistance Monitoring Data in 2008 show Acinetobacter bauamnnii to the resistant rate of imipenum and meropenem for being respectively 48.1% and 49.3%, to the resistant rate of amikacin, minocycline, cefepime, ciprofloxacin etc. all 50%～70%.Many bibliographical informations in the worldwide multidrug resistant Acinetobacter bauamnnii send out popular.
The present invention uses the chessboard method design, and micro-broth dilution method has assessed meropenem and sulbactam is united the synergetic antibacterial effect of use to carbapenems sensitivity and drug-fast Acinetobacter bauamnnii.The present invention has selected the responsive and drug-fast Acinetobacter bauamnnii of clinical isolating meropenem, so that the interaction of meropenem and sulbactam Combined application is described better.Chessboard method meropenem sensitive strain associating drug sensitive test result shows: synergism is 24.4% (10/41), and part is collaborative to be 68.3% (28/41), and summation action is 7.3% (3/41), and irrelevant and antagonism is 0%; And meropenem Resistant strain associating drug sensitive test result shows: synergism is 27.5% (11/40), and part is collaborative to be 40% (16/40), and summation action is 25% (10/40), and irrelevant is 7.5% (3/40), and there is antagonism in no bacterial strain.Can find out by these results; No matter be meropenem Resistant strain or meropenem sensitive strain; Wherein great majority use for uniting of meropenem and sulbactam and show collaborative and part synergism, wherein show as synergistic (promptly two kinds of medicine MIC values all drop to original below 1/4) and account for 25%.In addition, it should be noted that all not have in the meropenem Resistant strain of being tested and the meropenem sensitive strain and show as antagonism.
The existing experiment in vitro result of foreign study shows that imipenum associating amikacin, An Bianxilin sulbactam associating amikacin show antibacterial action collaborative or that part is collaborative to Acinetobacter bauamnnii, but its experimental strain number has only 14 strains.Carlos etc. have tested the clinical isolating Acinetobacter bauamnnii of 48 strains; Wherein the ratio of imipenum Resistant strain is 22.9%; Its meropenem and the demonstration of sulbactam associating drug sensitivity tests are worked in coordination with the part synergism and are respectively 29.2% and 47.9%; Account for the experimental strain larger proportion, more consistent with result of study of the present invention.But exist 3 strains to show as the bacterial strain of antagonism in this experimental result, maximum ∑ FIC reaches 8, and the present invention does not find this type of bacterial strain.Usefulness time killing curves such as Ko have proved the synergetic antibacterial effect of meropenem associating sulbactam to a strain Acinetobacter bauamnnii.This shows that meropenem associating sulbactam exists collaborative and part synergism for the motionless bacterial strain of part Bao Man.Although being 1: 1 the meropenem and the synergism of sulbactam, weight ratio is disclosed; But compared with prior art; Advantage of the present invention is: with weight ratio is 1: meropenem and the sulbactam of 2-4 are united use, the antagonistic strain that does not show as, and the experiment bacterial strain uses therefor is wider.Particularly; Object of study comprises responsive Acinetobacter bauamnnii of 41 strain meropenems and 40 strain meropenem drug resistance Acinetobacter bauamnniis; Respectively its result is carried out statistical analysis, find no matter be first, all show similarly and work in coordination with, partly work in coordination with or summation action in meropenem sensitivity or meropenem drug resistance group; In our experiment, do not find that the two has antagonism.(table 1 and table 3 can be used for explaining the problems referred to above)
There is inherent antibacterial activity in sulbactam to Acinetobacter bauamnnii, and has research report sulbactam effective to the drug-fast Acinetobacter bauamnnii bacterial strain of fraction carbapenem antibiotic.In vitro study and zoopery confirm that for the sulbactam sensitive strain sulbactam list usefulness or associating cefoperazone are close to the antibacterial ability and the carbapenem antibiotic of Acinetobacter bauamnnii.Clinical research also proves, respirator dependency pneumonia, bacteremia that sulbactam/beta-lactam antibiotic therapeutic alliance multidrug resistant Acinetobacter bauamnnii causes, and its usefulness is similar with carbapenem antibiotic.A retrospective study result shows the bacteremia that carbapenem antibiotic associating ampicillin/sulbactam causes with treatment multidrug resistant Acinetobacter bauamnnii, and its effect is superior to carbapenems list medicine and carbapenems associating amikacin.Though experiment in vitro can not be explained clinical effectiveness fully; But result of the test of the present invention has been pointed out the therapeutic scheme of sulbactam associating meropenem once more; Can be used as one of selection of treatment multidrug resistant Acinetobacter bauamnnii; This measure also can reduce the dosage that clinical carbapenems uses, to delay the drug-fast development of carbapenems serious day by day in the gram negative bacilli.
The specific embodiment
Below in conjunction with the specific embodiment the present invention is further described in detail, the embodiment that provides has been merely and has illustrated the present invention, rather than in order to limit scope of the present invention.
Embodiment 1
1, material
(1) experimental strain: (be collected in China 19 tame hospitals from the Acinetobacter bauamnnii of preserving; Time: the responsive Acinetobacter bauamnnii of picked at random 40 strain meropenem drug resistances and 41 strain meropenems year JIUYUE in January, 2005 to 2009); All be accredited as calcium acetate-Acinetobacter bauamnnii complex again, identify kind by region sequence order-checking between 16S-23S rRNA again through the VITEK GNI of Biomerieux SA.The Quality Control bacterial strain is ATCC25922.
(2) main agents and instrument: meropenem (Shenzhen City Haibin Pharmaceutical Co., Ltd, lot number: 20090903.In anhydride, actual content: 87.0%); Sulbactam (Shenzhen City Haibin Pharmaceutical Co., Ltd, lot number: 0030009072.In anhydride, actual content: 89.3%).Polymyxin E, ampicillin/sulbactam, piperacillin/tazobactam, 3 kinds of antibacterials Etest bars are Sweden AB Biodisk Company products.Cefepime, ceftazidime, piperacillin, amikacin, gentamycin, ciprofloxacin, the minocycline scraps of paper adopt the OXOID scraps of paper.
2, method
(1) determination of drug sensitivity: meropenem and sulbactam list medicine minimal inhibitory concentration (MIC) pH-value determination pH scope according to each bacterial strain are diluted to a series of concentration with antibacterials with the contrast on 96 empty flat boards of sterilization of cation adjustment MH meat soup, and every hole dilute liquid medicine is 100 μ L.Grow in the dull and stereotyped fresh bacterium colony of MH with the inoculating loop picking and place normal saline, adjustment turbidity to 0.5 Maxwell turbidity is inoculated 5 μ L to the hole with 1: 10 dilution back of MH meat soup.CLSI guide in 2009 is followed in trace meat soup dilution test method and interpretation as a result.Cefepime, ceftazidime, piperacillin, amikacin, gentamycin, ciprofloxacin, minocycline adopt disk diffusion method to measure drug susceptibility; Polymyxin E, ampicillin/sulbactam, piperacillin/tazobactam, 3 kinds of antibacterials adopt Etest to measure the MIC value.Scraps of paper diffusion test method is followed CLSI 2009 guides, and disk diffusion method result and MIC result judge according to CLSI 2009.
(2) chessboard method is measured the associating susceptibility: two kinds of medicines dilute in 96 orifice plate files and line respectively by micro-broth dilution method; Every hole adds meropenem medicinal liquid 50 μ L and sulbactam medicinal liquid 50 μ L; Dilution factor confirms the MIC value result of meropenem and sulbactam according to each bacterial strain, finally obtain two kinds of medicines from maximum concentration for 2 times of its MIC to 1/32 the various combination of least concentration for its MIC.And box out with plate and to do the MIC pH-value determination pH of single medicine trace meat soup.Inoculation is diluted to the bacterium liquid 5 μ L of 0.5 Maxwell turbidity with the MH meat soup of 1: 10 ratio, and final bacterial concentration is 5 * 10
5CFU/ml.Hatched observed result 24 hours for 35 ℃.
(3) the antibacterial index of part (∑ FIC) calculates and interpretation standard
∑ FIC=MIC meropenem associating/MIC meropenem list medicine+MIC sulbactam associating/MIC sulbactam list medicine
∑ FIC≤0.5 is a synergism, and 0.5＜∑ FIC＜1 is the part synergism, and ∑ FIC=1 is a summation action, and 1＜∑ FIC＜4 are irrelevant effect, and ∑ FIC>=4 are antagonism.
3, result
(1) drug sensitivity tests: meropenem and sulbactam list medicine are seen table 1 to the MIC value scope result of the Acinetobacter bauamnnii of 40 strain meropenem drug resistances and 41 strain Metros sensitivity.
Table 1 81 strain Acinetobacter bauamnnii meropenems and sulbactam list medicine MIC value result (μ g/ml)
The Acinetobacter bauamnnii of 40 strain meropenem drug resistances and 41 strain Metros sensitivity is seen table 2 to the drug susceptibility result of other antibacterials.
10 kinds of antibacterials of table 2 are to the sensitivity of Acinetobacter bauamnnii
(2) associating drug sensitivity tests: chessboard method is measured meropenem and sulbactam coupling, and that 40 strain meropenem drug resistances and the responsive Acinetobacter bauamnnii of 41 strain meropenems are united drug sensitivity tests and ∑ FIC maximum and minima is as shown in table 3.Meropenem and sulbactam coupling show as collaborative collaborative with part to meropenem sensitive strain majority, proportion is respectively 24.4% and 68.3%, and promptly the ∑ FIC of most bacterial strains is less than 1.It is close with the meropenem sensitive strain that meropenem and sulbactam coupling show as collaborative bacterial strain number to the meropenem Resistant strain, and ratio is 27.5%, and part is worked in coordination with and the bacterial strain ratio difference 40% and 25% of addition but show as.The meropenem drug resistance does not all have the bacterial strain that shows as antagonism with responsive Acinetobacter bauamnnii to meropenem and sulbactam associating.
Table 3 81 strain Acinetobacter bauamnnii meropenems and sulbactam synergy result and FIC value
Best proportioning is confirmed through the symphyogenetic result of the different proportionings with sulbactam of meropenem.Measure the result according to chessboard method; Synergy shows as totally 11 strains of collaborative bacterial strain to meropenem drug resistance Acinetobacter bauamnnii to the meropenem sulbactam; The MIC value result of its different proportioning meropenem sulbactam combination formulations shows; Along with the raising sulbactam MIC of meropenem concentration has downward trend, the raising meropenem MIC along with sulbactam concentration has downward trend (seeing table 4) equally.
According to the result in the table 4, the MIC value result of 5 kinds of proportioning meropenem sulbactam combination formulations (4: 1,2: 1,1: 1,1: 2 and 1: 4) shows, sulbactam content raises then that meropenem MIC50, MIC90 reduce in the combination formulations, and vice versa.Meropenem sulbactam ratio is 1: 2 o'clock, and the meropenem MIC value of experimental strain is minimum, and its MIC50 and MIC90 are respectively 16 μ g/ml and 32 μ g/ml.For guaranteeing effect of drugs, should guarantee as far as possible that its drug ratios relation is 1: 2 to 1: 4, wherein 1: 4 optimum.
Claims (8)
1. the pharmaceutical composition of an anti-Acinetobacter bauamnnii wherein comprises meropenem and sulbactam, and the weight ratio of meropenem and sulbactam is 1: 2-4.
2. pharmaceutical composition according to claim 1, wherein, the weight ratio of meropenem and sulbactam is 1: 4.
3. pharmaceutical composition according to claim 1 and 2, wherein, said pharmaceutical composition also comprises pharmaceutically acceptable carrier and/or excipient.
4. according to each described pharmaceutical composition in the claim 1 to 3, wherein, said pharmaceutical composition is sucked agent for being selected from injection, freeze-dried powder, tablet, capsule, the dosage form of drop pill.
In the claim 1 to 4 each described pharmaceutical composition the preparation anti-Acinetobacter bauamnnii medicine in purposes.
6. each described pharmaceutical composition prevents and/or treats the purposes in the medicine of the disease that Acinetobacter bauamnnii causes in preparation in the claim 1 to 4.
7. according to claim 5 or 6 described purposes; Wherein, Said Acinetobacter bauamnnii is responsive Acinetobacter bauamnnii of carbapenem antibiotic and/or the drug-fast Acinetobacter bauamnnii of carbapenem antibiotic, is preferably the drug-fast Acinetobacter bauamnnii of carbapenem antibiotic.
8. purposes according to claim 6, wherein, said disease is infection, is preferably in respirator dependency pneumonia, septicemia, urinary tract infection and the wound infection one or more.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2664434C2 (en) * | 2016-12-01 | 2018-08-17 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Санкт-Петербургский государственный университет" (СПбГУ) | Antimicrobial combination for carbapenem-resistant gram-negative bacteria of the type klebsiella pneumoniae producing metal-β-lactamase |
| CN110373447A (en) * | 2019-07-25 | 2019-10-25 | 长沙市第三医院 | A kind of multidrug resistance Gram-negative bacteria Combination susceptibility testing card and preparation method |
| CN111511368A (en) * | 2017-12-25 | 2020-08-07 | 湘北威尔曼制药股份有限公司 | Composition containing piperacillin, pharmaceutical preparation and application thereof |
| CN111939156A (en) * | 2020-08-24 | 2020-11-17 | 天津现代创新中药科技有限公司 | Combined antibacterial pharmaceutical composition and application thereof |
| CN113382734A (en) * | 2019-03-05 | 2021-09-10 | 广州新创忆药物临床研究有限公司 | Composition for treating carbapenem antibiotic-resistant acinetobacter baumannii infection |
-
2010
- 2010-11-26 CN CN2010105685562A patent/CN102475703A/en active Pending
Non-Patent Citations (4)
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| CARLOS R.V. KIFFER等: "In vitro synergy test of meropenem and sulbactam against clinical isolates of Acinetobacter baumannii", 《DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE》 * |
| WEN-CHIEN KO等: "In vitro and in vivo activity of meropenem and sulbactam against a multidrug-resistant Acinetobacter baumannii strain", 《JOURNAL OF ANTIMICROBIAL OF CHEMOTHERAPY》 * |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2664434C2 (en) * | 2016-12-01 | 2018-08-17 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Санкт-Петербургский государственный университет" (СПбГУ) | Antimicrobial combination for carbapenem-resistant gram-negative bacteria of the type klebsiella pneumoniae producing metal-β-lactamase |
| CN111511368A (en) * | 2017-12-25 | 2020-08-07 | 湘北威尔曼制药股份有限公司 | Composition containing piperacillin, pharmaceutical preparation and application thereof |
| CN111511368B (en) * | 2017-12-25 | 2023-05-09 | 湘北威尔曼制药股份有限公司 | Composition containing piperacillin sodium and sulbactam sodium for treating drug-resistant acinetobacter baumanii infection |
| CN113382734A (en) * | 2019-03-05 | 2021-09-10 | 广州新创忆药物临床研究有限公司 | Composition for treating carbapenem antibiotic-resistant acinetobacter baumannii infection |
| CN113382734B (en) * | 2019-03-05 | 2023-07-21 | 广州新创忆药物临床研究有限公司 | Composition for treating carbapenem-resistant antibiotic Acinetobacter baumannii infection |
| CN110373447A (en) * | 2019-07-25 | 2019-10-25 | 长沙市第三医院 | A kind of multidrug resistance Gram-negative bacteria Combination susceptibility testing card and preparation method |
| CN111939156A (en) * | 2020-08-24 | 2020-11-17 | 天津现代创新中药科技有限公司 | Combined antibacterial pharmaceutical composition and application thereof |
| CN111939156B (en) * | 2020-08-24 | 2022-04-12 | 天津现代创新中药科技有限公司 | Combined antibacterial pharmaceutical composition and application thereof |
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Application publication date: 20120530 |