阅读说明：本技术 一种治疗耐碳青霉烯类抗生素鲍曼不动杆菌感染的组合物 (Composition for treating carbapenem antibiotic-resistant acinetobacter baumannii infection ) 是由 不公告发明人 于 2019-03-05 设计创作，主要内容包括：本发明公开了一种治疗耐碳青霉烯类抗生素鲍曼不动杆菌感染的组合物。发明人研究发现,使用特定比例的舒巴坦头孢他啶的组合,对CR-Ab感染具有优异的治疗效果,其治疗效果甚至强于碳青霉烯和舒巴坦的组合物。(The invention discloses a composition for treating carbapenem-resistant antibiotic acinetobacter baumannii infection. The inventors have found that the use of a combination of sulbactam ceftazidime in a specific ratio has an excellent therapeutic effect on CR-Ab infection, even stronger than the combination of carbapenem and sulbactam.)

1. The application of the sulbactam and ceftazidime composition in preparing the medicine for treating carbapenem-resistant antibiotic acinetobacter baumannii infection is characterized in that: the dosage of the ceftazidime in the sulbactam and ceftazidime composition is 10-90% of the dosage of the sulbactam by mass.

2. Use according to claim 1, characterized in that: the dosage of the ceftazidime is 20 to 80 percent of the dosage of the sulbactam.

3. Use according to claim 1, characterized in that: the dosage of the ceftazidime is 20 to 40 percent of the dosage of the sulbactam.

4. Use according to claim 1 or 2, characterized in that: the carbapenem antibiotic is at least one of meropenem, imipenem, panipenem, biapenem or doripenem.

5. Use according to claim 4, characterized in that: the carbapenem-resistant antibiotic acinetobacter baumannii also has drug resistance to ceftazidime.

6. Use according to claim 1, characterized in that: the sulbactam and ceftazidime composition is a non-oral preparation.

7. Use according to claim 6, characterized in that: the sulbactam and ceftazidime composition is an injection or an inhalant.

8. Use according to claim 1, characterized in that: in the sulbactam and ceftazidime composition, the sulbactam and the ceftazidime are independently packaged or mixed and packaged.

9. Use according to claim 1, characterized in that: in the sulbactam and ceftazidime composition, the daily dose of sulbactam is 2-20 g.

10. Use according to claim 1 or 9, characterized in that: in the sulbactam and ceftazidime composition, the daily dose of the ceftazidime is 0.2-18 g.

Technical Field

The invention relates to the field of medicines, and particularly relates to a method for treating acinetobacter baumannii infection, particularly diseases caused by acinetobacter baumannii infection resistant to carbapenem antibiotics, and a composition thereof.

Background

Acinetobacter baumannii (Acinetobacter baumannii) belongs to non-fermented gram-negative bacteria and is an important pathogenic bacterium. Acinetobacter baumannii is increasingly recognized as an important cause of serious infections. Clinically, serious infection of systems such as respiration, blood, abdominal cavity, central nerve, urinary system, skin soft tissue and the like is closely related to acinetobacter baumannii.

Li Xiangxin et al (China J.antibiotics, 2007,32(12):762 and 764) retrospectively investigated the clinical distribution of Acinetobacter baumannii clinically isolated in 1 month to 2006 and 12 months 2002, and found that the 865 Acinetobacter baumannii isolated in 5 years mainly originated from respiratory tract specimens and accounted for 75.7%. Sungchengzao and the like (China critical illness emergency medicine, 2013,25(6): 369-; the detection rate is highest in intensive care units (ICU, accounting for 26.4%), respiratory department (accounting for 26.1%) and geriatric department (accounting for 23.1%). Liu Yi (International inspection medicine journal, 2015(13):1899-1901) retrospectively and statistically analyzes the sample source, the distribution of the disease area and the drug resistance change of 1678 Acinetobacter baumannii separated from the affiliated Pudong hospital of the Compound denier university from 2010 to 2014 10, and as a result, the clinically separated Acinetobacter baumannii mainly comes from respiratory tract samples (79.1%), and the distribution of the disease area mainly comes from intensive care units (21.1%), neurosurgery (17.7%) and cardiology (17.6%).

Various antibacterial drugs have different degrees of antibacterial activity on acinetobacter baumannii and have advantages and disadvantages respectively. Such as cephalosporins, quinolones, sulbactam-containing compound preparations, carbapenems, colistins, glycylcyclines, aminoglycoside antibiotics and the like. Among them, colistin has the best bacteriostatic effect on acinetobacter baumannii, but has poor tolerance. Glycylcyclines, aminoglycosides and the like have high hepatorenal toxicity. Quinolones carry the risk of disability. Higher adverse reactions often limit the clinical application of the drug. The cephalosporin has better safety, such as the third-generation cephalosporin ceftazidime has better antibacterial action on gram-negative bacteria, particularly has the best effect on pseudomonas aeruginosa, but has the medium antibacterial action on acinetobacter baumannii. Sulbactam also has better safety, but sulbactam is always used as a beta-lactamase inhibitor to be combined with other beta-lactam antibiotics to improve the antibacterial activity of the antibiotics, a compound preparation containing sulbactam is representative of ampicillin sulbactam, cefoperazone sulbactam and the like, and sulbactam has only moderate activity on acinetobacter baumannii. Carbapenem antibiotics such as imipenem, meropenem, panipenem, biapenem, doripenem and the like are very stable to beta-lactamase and have strong bacteriostatic action, typically imipenem and meropenem, but the carbapenem antibiotics are not as safe as cephalosporins and are strictly regulated and controlled in clinical use.

In recent years, the drug resistance of acinetobacter baumannii to antibacterial drugs is becoming more and more serious.

For example, the above Lichengxin et al found that the resistance of Acinetobacter baumannii clinically isolated in the months of 2002-2006 12 to commonly used antibacterial agents increased year by year; the Sunweian and the like find that the drug resistance rate of acinetobacter baumannii clinically separated from hospitalized patients in Beijing Pongan Hospital from 1 month to 12 months in 2012 to cefotaxime, piperacillin, meropenem, imipenem, ciprofloxacin, tetracycline and the like can reach 100%; the Liu Yi (a dynamic force) and the like find that 1678 Acinetobacter baumannii separated from Pudong hospital affiliated to the university of Compound Dane in 2010 from 1 month to 2014 from 10 months have high drug resistance to first-generation cephalosporins, second-generation cephalosporins, cephamycins, ampicillin and nitrofurantoin, the drug resistance rate reaches over 90 percent, and the drug resistance rate to carbapenems antibacterial drugs, aztreonam, cefoperazone sulbactam and ampicillin sulbactam also shows a remarkable rising trend. Chinese drug-resistant bacteria monitoring in 2017 (http:// www.sific.com.cn/InsidePuge/1000/67/7970. html) shows that clinically isolated acinetobacter baumannii has the drug resistance rate of 72% to ceftazidime, 62.1% to ampicillin and sulbactam, 66.7% to imipenem, 69.3% to meropenem and 43.5% to cefoperazone and sulbactam. Twelve drug resistant bacteria published by the world health organization in 2017 showed that acinetobacter baumannii ranks first in the severe drug resistance level.

Because of its good safety, sulbactam-related preparations have received attention in the treatment of drug-resistant acinetobacter baumannii infections. And sulbactam has a high MIC value for acinetobacter baumannii and a limited bacteriostatic effect. The combined synergistic effect of the compound preparation containing sulbactam on drug-resistant acinetobacter baumannii is researched.

The research on the effect of sulbactam on cephalosporin-resistant acinetobacter baumannii combined use is carried out by negotiating Hua et al (China J.antibiotics, 2006,31(8):488-491), and 56 clinically isolated drug-resistant or intermediate acinetobacter baumannii strains on Cefoperazone (CPZ), Ceftazidime (CAZ) or Cefotaxime (CTX) are divided into 3 groups, wherein the group A is resistant to more than 2 drugs, and the group B is only resistant to CPZ; group C is an intermediary to CPZ or CTX. And (3) detecting the Minimum Inhibitory Concentrations (MICs) of the sulbactam single agent and the sulbactam respectively combined with the 3 third-generation cephalosporins by adopting a trace broth dilution method. It was found that the sensitivity and resistance breakpoint concentrations of sulbactam in combination with any of CPZ, CAZ or CTX drugs did not result in a lower MICs of sulbactam than the MICs of sulbactam alone after combination. The conclusion is that the single agent of sulbactam has antibacterial activity on multi-drug resistant acinetobacter baumannii, but the sensitivity of the strains to the combined preparation is probably mainly that sulbactam plays a bactericidal effect.

Huangyi mountain and the like (Chinese practical medicine, 2009,4(31):34-35) find that the combined application of sulbactam and third-generation cephalosporin can effectively reduce the MIC value of the third-generation cephalosporin to multi-drug resistant Acinetobacter baumannii, and for the third-generation cephalosporin resistant strains, the combined preparation can reduce the MIC of the third-generation cephalosporin resistant strains to a sensitive range under the condition of reaching a certain drug concentration. However, from the data in this article, for Imipenem-resistant Acinetobacter baumannii in group C, the MIC value of ceftazidime is reduced after the combination of sulbactam and ceftazidime, but not reduced to the sensitive range (according to CLSI standard, the MIC value of ceftazidime sensitive to Acinetobacter baumannii is less than or equal to 8 mug/ml), which reflects that the clinical effect of the combination of the sulbactam and the ceftazidime is not good.

Zhou Meng lan, et al (J. Clin. inspection, 2018,36(1):22-24) selected clinical meropenem drug-resistant Acinetobacter baumannii 23 strain and meropenem sensitive Acinetobacter baumannii 21 strain, and a chessboard dilution method is adopted to carry out a combined drug sensitivity test, and a partial antibacterial concentration index (FIC) is calculated to judge the combined effect (synergy, partial synergy, irrelevance or antagonism). The result shows that the combined application of cefoperazone, tigecycline and sulbactam mainly has synergistic effect on the antibacterial effect of acinetobacter baumannii; the antibacterial effect of the combined application of imipenem, colistin and sulbactam on acinetobacter baumannii is mainly shown as synergistic and partial synergistic effect; the combined use of ceftazidime and sulbactam mainly shows unrelated effects. From the data in this article, for meropenem resistant A.baumannii MRAB, cephalosporin and sulbactam showed no synergistic effect, cefoperazone and sulbactam were mainly additive (43.5%), while ceftazidime and sulbactam were mainly irrelevant (52.2%).

The resistance mechanisms of bacteria are rather complex and differ from bacterium to bacterium. The main drug resistance mechanisms of acinetobacter baumannii are as follows: (1) production of antibacterial drug inactivating enzyme: β lactamase: group A TEM type, SHV type enzyme, group B metallo beta-lactamase, group C AmpC enzyme, group D OXA enzyme, etc., and (C) aminoglycoside modifying enzyme; (2) alteration of drug target of action: topoisomerase, 16SrRNA methylase gene mutation, etc.; (3) reduction of the amount of drug reaching the target site of action: including a decrease in outer membrane porin permeability and overexpression of efflux pumps. The genome of the acinetobacter baumannii shows that the acinetobacter baumannii is rich in efflux pump genes, and the high expression of efflux pumps plays an important role in multiple drug resistance of the acinetobacter baumannii. (Liu Qiu Dun, et al, J.China antibiotic, 2018,43(10):1179-

The resistance of acinetobacter baumannii to cephalosporins is mainly to produce a large amount of AmpC cephalosporinase. Because carbapenem antibiotics have high stability to AmpC enzyme, carbapenem antibiotics are generally used for treatment clinically for cephalosporin-resistant acinetobacter baumannii infection. However, the drug resistance mechanism of carbapenem drug-resistant acinetobacter baumannii is different, and the acinetobacter baumannii mainly produces OXA carbapenem enzyme, and plays important roles in the down-regulation of membrane channel protein expression, the over-expression of drug efflux pumps and the like. Therefore, targeted treatment is required for acinetobacter baumannii infection under different drug-resistant conditions. However, effective antibiotic compositions against carbapenem-resistant acinetobacter baumannii infection are lacking at present.

Disclosure of Invention

The invention aims to provide application of a sulbactam and ceftazidime composition in preparing a medicine for treating carbapenem-resistant antibiotic acinetobacter baumannii infection.

It is another object of the present invention to provide a method for treating carbapenem-resistant acinetobacter baumannii infection.

It is a further object of the present invention to provide a combination of sulbactam and ceftazidime for the treatment of carbapenem-resistant acinetobacter baumannii infections.

The technical scheme adopted by the invention is as follows:

the application of the sulbactam and ceftazidime composition in preparing the medicine for treating carbapenem-resistant antibiotic acinetobacter baumannii infection is that the dosage of the ceftazidime in the sulbactam and ceftazidime composition is 10-90% of that of the sulbactam by mass.

In some embodiments, the amount of ceftazidime in the combination of sulbactam and ceftazidime is 20% to 80% of the amount of sulbactam.

In some embodiments, the amount of ceftazidime in the combination of sulbactam and ceftazidime is 20% to 40% of the amount of sulbactam.

In some embodiments, the amount of ceftazidime in the combination of sulbactam and ceftazidime is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the amount of sulbactam.

In some embodiments, the carbapenem antibiotic is at least one of meropenem, imipenem, panipenem, biapenem, or doripenem.

In some embodiments, the carbapenem-resistant antibiotic acinetobacter baumannii is also resistant to ceftazidime.

In some embodiments, the sulbactam and ceftazidime composition is a non-oral formulation.

In some embodiments, the sulbactam and ceftazidime composition is an injection or an inhalation.

In some embodiments, the sulbactam and ceftazidime composition can be packaged in separate packages (i.e., the sulbactam and the ceftazidime are separately packaged and then combined), or in a mixed package (i.e., the sulbactam and the ceftazidime are mixed and then packaged). The two can be mixed and then used in the form of compound preparation, or can be used in combination in the form of single preparation.

In some embodiments, the daily dose of sulbactam in the sulbactam and ceftazidime composition is 2-20 g. The medicine can be administrated 2-4 times a day after divided dose.

In some embodiments, the daily dose of ceftazidime in the combination of sulbactam and ceftazidime is 0.2-18 g. The medicine can be administrated 2-4 times a day after divided dose.

A method of treating carbapenem-resistant antibiotic Acinetobacter baumannii infection comprising administering to a patient a therapeutically effective amount of sulbactam and ceftazidime, wherein the amount of ceftazidime is 10-90%, 20-80% or 20-40% by mass of the amount of sulbactam.

In some embodiments, the amount of ceftazidime is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the amount of sulbactam.

In some embodiments, the carbapenem-resistant antibiotic acinetobacter baumannii has the following properties: is resistant to at least one carbapenem antibiotic selected from meropenem, imipenem, panipenem, biapenem and doripenem.

In some embodiments, acinetobacter baumannii is also resistant to ceftazidime.

In some embodiments, sulbactam and ceftazidime are used in the form of a combination formulation.

In some embodiments, sulbactam and ceftazidime are used in combination in a single formulation.

In some embodiments, the method of administration is non-oral administration, preferably injection or inhalation administration.

The dose administered may be adjusted according to the severity of the disease in the clinic. In some embodiments, the daily dose of sulbactam may be 2-20 g and the daily dose of ceftazidime may be 0.2-18 g. The medicine can be administrated 2-4 times a day after divided dose.

The composition of sulbactam and ceftazidime for treating carbapenem-resistant antibiotic acinetobacter baumannii infection comprises, by mass, 10% -90%, 20% -80% or 20% -40% of ceftazidime.

In some embodiments, the carbapenem-resistant antibiotic acinetobacter baumannii has the following properties: is resistant to at least one carbapenem antibiotic selected from meropenem, imipenem, panipenem, biapenem and doripenem.

In some embodiments, acinetobacter baumannii is also resistant to ceftazidime.

In some embodiments, sulbactam and ceftazidime are packaged separately, or in a mixed package.

In some embodiments, the sulbactam and ceftazidime composition is a non-oral formulation. Further, it is an injection or an inhalant.

The invention has the beneficial effects that:

in some embodiments, the combination of sulbactam and ceftazidime is surprisingly effective in treating carbapenem-resistant acinetobacter baumannii infections even better than the combination of carbapenem-type antibiotics and sulbactam.

Drawings

Figure 1 is the in vitro cumulative inhibition of carbapenem-resistant acinetobacter baumannii by sulbactam in combination with low proportions of ceftazidime.

Figure 2 is a graph showing the in vitro long term bactericidal effect of sulbactam in combination with low proportions of ceftazidime on carbapenem-resistant antibiotic acinetobacter baumannii.

Detailed Description

The present invention will be described in detail with reference to the following embodiments. It should be understood that the summary of the detailed description section is illustrative and not restrictive, i.e., does not set forth any limitations on the summary of the invention.

Defining:

"ceftazidime" means: (6R,7R) -7- [ [ (2Z) -2- (2-aminothiazolo-4-yl) -2- [ (1-methoxy-1-methylthoxy) imino ] amino ] -8-oxol-3- [ (1-pyrido) methyl ] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxlate, or a hydrate, solvate, polymorph and/or pharmaceutically acceptable salt thereof. Such as ceftazidime pentahydrate, ceftazidime sodium, and the like. The amount used in the present invention is calculated in terms of (6R,7R) -7- [ [ (2Z) -2- (2-aminothiazole-4-yl) -2- [ (1-carbonyl-1-methyothoxy) imino ] amino ] -8-oxol-3- [ (1-pyridine) methyl ] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate.

"sulbactam" means: (2S,5R) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate-4,4-dioxide, or a hydrate, solvate, polymorph and/or pharmaceutically acceptable salt thereof. Such as sulbactam sodium and the like. The amount used in the present invention is calculated as (2S,5R) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate-4, 4-dioxide.

The sulbactam and ceftazidime composition can contain pharmaceutically applicable auxiliary materials according to the requirement of a dosage form.

"CLSI" means: clinical & Laboratory Standards Institute, the American Institute for Clinical and Laboratory Standards. Various publications published by CLSI are well known in the art, for example CLSI-M100 is the standard for performing antimicrobial drug susceptibility tests. CLSI-M02 is a paper method sensitivity test method for antibacterial drugs. CLSI-M07 is a test method for sensitivity of aerobic antibacterial drug dilution method. The CLSI also periodically modifies the documents it publishes. Those skilled in the art know that the latest CLSI files are the most valuable to refer to.

"MIC", i.e., minimum inhibitory concentration, refers to the lowest concentration of drug that inhibits visible bacterial growth (bacteria incubated at 37 ℃ for 24 h).

"drug resistance" in "drug-resistant acinetobacter baumannii" means: acinetobacter baumannii was tested with drugs according to the CLSI method (paper sheet method or dilution method), and the results were judged as drug resistance (resistance) according to the CLSI-M100 standard.