Antibacterial composition and antibacterial drug

Abstract

An antibacterial composition and an antibacterial drug. The antibacterial composition comprises cephalosporin and zidebactam, wherein cephalosporin comprises at least one of ceftobiprole and a ceftobiprole derivative; and cephalosporin is calculated on the basis of C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 10:1. The compounding of cephalosporin and zidebactam enables cephalosporin and zidebactam to exhibit a synergistic effect, thereby providing the antibacterial composition with an excellent antibacterial activity, and a good antibacterial activity on bacteria resistant to the single drug of cephalosporin or zidebactam.

Description

Antibacterial composition and antibacterial drug

[0001] This application claims priority to Chinese patent application No. 202311205221.8, filed on September 18, 2023, and cites the full text of the aforementioned Chinese patent application. Technical Field

[0002] The present application belongs to the technical field of antibacterial drugs, and specifically relates to an antibacterial composition and an antibacterial drug. Background Art

[0003] Cefpirole is a broad-spectrum cephalosporin that exerts its bactericidal activity against susceptible bacterial species by binding to penicillin-binding proteins (PBPs). Cefpirole binds to PBPs that have reduced susceptibility to various β-lactams, such as PBP2a in methicillin-resistant Staphylococcus aureus (MRSA) and PBP2b and PBP2x in penicillin-intermediate and -resistant Streptococcus pneumoniae. This provides cefpirole with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria, including some Pseudomonas aeruginosa.

[0004] With the promotion and application of cefpirole in clinical practice, bacteria resistant to cefpirole have gradually emerged, such as KPC-type carbapenemase-producing Klebsiella pneumoniae, resulting in reduced or no antibacterial activity of cefpirole against some bacteria.

[0005] Summary of the Invention

[0006] The purpose of the present application is to provide an antibacterial composition or antibacterial drug kit and antibacterial drug to further enhance the antibacterial effect against cefoperazone-resistant bacteria and solve the current technical problem that cefoperazone has reduced or no antibacterial activity against some bacteria.

[0007] In a first aspect, embodiments of the present application provide an antibacterial composition or antibacterial kit. The antibacterial composition comprises a cephalosporin and zidabactam;

[0008] Wherein, cephalosporins include one or more of cefpirole and cefpirole derivatives;

[0009] Cephalosporin C 20 H 22 The mass ratio of cephalosporin to zidabactam is 0.1:1 to 10:1 based on N8O6S2.

[0010] The antibacterial composition or antibacterial drug kit of the embodiment of the present application is compounded with cephalosporin and zidabactam, and the mass ratio of cephalosporin and zidabactam is controlled at the same time, so that the cephalosporin and zidabactam have an antibacterial synergistic effect on each other, thereby increasing the antibacterial activity of the antibacterial composition, so that the antibacterial composition has excellent antibacterial effect, especially antibacterial effect against cefoperazone-resistant bacteria.

[0011] In a second aspect, embodiments of the present application provide an antibacterial drug, which includes the antibacterial composition described above.

[0012] Since the antibacterial composition of the present application has excellent antibacterial activity, the antibacterial drug also has excellent antibacterial activity. DETAILED DESCRIPTION

[0013] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit this application.

[0014] In this application, "at least one" means one or more, and "more than one" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b, or c", or "at least one of a, b, and c" can all mean: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, and c can be single or multiple.

[0015] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0016] The terms used in the embodiments of the present application are for the purpose of describing specific embodiments only and are not intended to limit the present application. The singular forms "a", "an", "the" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms unless the context clearly indicates otherwise.

[0017] The weights of the relevant components mentioned in the examples of this application may not only refer to the specific content of each component, but also represent the weight ratio between the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the examples of this application, it is within the scope disclosed in the examples of this application. Specifically, the mass described in the examples of this application may be a mass unit known in the chemical industry, such as μg, mg, g, kg, etc.

[0018] Cefpirole is a new generation of broad-spectrum cephalosporin, with the activity of anti-methicillin-resistant Staphylococcus aureus and anti-gram-negative bacteria (including part of Pseudomonas aeruginosa), its mechanism of action is similar to other cephalosporins, is a bactericidal agent in the reproductive period, by being combined with PBPs, interferes with bacterial cell wall synthesis, inhibits bacterial growth, and ultimately causes the death of bacteria. But along with the application of cefpirole in clinical practice, the drug resistance of bacterium to cefpirole is gradually enhanced. In order to solve the technical problem that cefpirole reduces the antibacterial activity of drug-resistant bacteria or has no antibacterial activity in the prior art, the present application embodiment proposes following technical scheme.

[0019] In a first aspect, embodiments of the present application provide an antibacterial composition or antibacterial kit comprising cephalosporin and zidabactam.

[0020] The cephalosporin includes at least one of cefpirole and cefpirole derivatives, and may include only one active ingredient of cefpirole or a cefpirole derivative, or may include both active ingredients of cefpirole and a cefpirole derivative.

[0021] Cephalosporin C 20 H 22 The mass ratio of cephalosporin to zidabactam is 0.1:1 to 10:1 based on N8O6S2.

[0022] When cephalosporin contains cefoperazone, the molecular formula of cefoperazone is C 20 H 22 N8O6S2, chemical name is (6R,7R)-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido)-8-oxo-3-((E)-((R)-2-oxo-[1,3'-bipyrrolidino]-3-ylidene)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and its structural formula is shown in formula (1):

[0023] When the cephalosporin contains a cefpirole derivative, the cefpirole derivative refers to a derivative based on the above-mentioned cefpirole.

[0024] The chemical name of Zidabactam contained in the antibacterial composition or antibacterial kit of the present application is (2S,5R)-7-oxo-2-(2-((R)-piperidine-3-carbonyl)hydrazine-1-carbonyl)-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate monoester. The structural formula of Zidabactam is shown in Formula (2):

[0025] Of course, Zidabactam can also be a derivative of the structure shown in the above formula (2), having similar activity to the above formula (2).

[0026] The antibacterial composition or antibacterial kit of the embodiment of the present application is compounded with cephalosporin and zidabactam, and the mass ratio of cephalosporin to zidabactam is controlled within a specific range, so that the cephalosporin and zidabactam have a synergistic effect on each other, thereby improving the antibacterial effect of the antibacterial composition or antibacterial kit, so that the antibacterial composition or antibacterial kit can have excellent antibacterial activity against bacteria that are resistant to cephalosporin alone or to zidabactam alone.

[0027] In some embodiments, the cephalosporin biopharmaceutical in the antibacterial composition or antibacterial kit is cefoperazone (molecular formula C 20 H 22 N8O6S2), the mass ratio of cephalosporin to zidabactam can be further 0.1:1 to 8:1, in further examples, it can be 0.1:1 to 4:1, and in further examples, it can be 0.1:1 to 2.5:1. In specific examples, the mass ratio of cephalosporin to zidabactam can be 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 and other typical but non-limiting mass ratios. Wherein, when the cephalosporin contains only cefuroxime, the mass ratio refers to cefuroxime in C 20 H 22 The mass ratio of N8O6S2 to zidabactam; when the cephalosporin contains only cefpirole derivatives, the mass ratio refers to the mass ratio of cefpirole derivatives according to C 20 H 22 When cephalosporins include cefuroxime and its derivatives, the mass ratio refers to the sum of cefuroxime and its derivatives in terms of C 20 H 22 The mass ratio of N8O6S2 to zidaptom.

[0028] Controlling the mass ratio of cephalosporin to zidabactam within this range further promotes the synergistic effect between cephalosporin and zidabactam, thereby further improving the antibacterial activity of the antibacterial composition or antibacterial kit.

[0029] In some embodiments, the cephalosporin and zidabactam contained in the antibacterial composition or antibacterial kit may be mixed. Mixing the cephalosporin and zidabactam helps improve the product uniformity of the antibacterial composition or antibacterial kit and facilitates the use of the antibacterial composition or antibacterial kit, eliminating the need for mixing the antibacterial composition or antibacterial kit before use.

[0030] In some embodiments, the cephalosporin and zidabactam have a synergistic effect against bacteria.

[0031] In some embodiments, the cephalosporin and zidabactam have a partial inhibitory concentration index (FIC) of less than or equal to 0.5 against the bacteria, preferably less than or equal to 0.2, more preferably less than or equal to 0.15, or less than or equal to 0.13, for example, 0.13, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01.

[0032] In some embodiments, when the cephalosporin and zidabactam are used in combination, the MIC of cefoperazone against the bacteria is less than or equal to 4 mg / L. 50 , preferably having an MIC of less than or equal to 2 mg / L, less than or equal to 0.5 mg / L, less than or equal to 0.125 mg / L, or less than or equal to 0.06 mg / L 50 .

[0033] In some embodiments, the bacteria are KPC-2 type carbapenem-producing bacteria.

[0034] In some embodiments, when the cephalosporin and zidabactam are used in combination, the MIC of cefoperazone against the bacteria is less than or equal to 8 mg / L. 90 , preferably having an MIC of less than or equal to 4 mg / L, less than or equal to 2 mg / L, less than or equal to 1 mg / L, less than or equal to 0.5 mg / L, or less than or equal to 0.25 mg / L 90 .

[0035] In some embodiments, the bacteria are OXA-48-producing carbapenems.

[0036] In some embodiments, the bacteria are Gram-negative bacteria.

[0037] In some embodiments, the bacteria are Escherichia coli and / or Klebsiella pneumoniae;

[0038] In some embodiments, the bacteria are one or more of NDM-type carbapenemase-producing bacteria, KPC-type carbapenemase-producing bacteria, and OXA-type carbapenemase-resistant bacteria.

[0039] In some embodiments, the cephalosporin and zidabactam in an antibacterial composition or antibacterial kit can be separated and then mixed before use. For example, when the antibacterial composition is prepared as an injection, the cephalosporin and zidabactam can be packaged separately and then mixed before injection, or the cephalosporin and zidabactam can be injected separately. Separating the cephalosporin and zidabactam further improves the quality stability of the components in the antibacterial composition.

[0040] In some embodiments, when the cephalosporin includes a cefpirole derivative, the cefpirole derivative may be a compound that can be converted into cefpirole. In a specific example, the cefpirole derivative may include at least one of a cefpirole salt, cefpirole axetil, and a cefpirole axetil derivative.

[0041] Among them, cefbiro salt is a salt formed based on cefbiro, such as alkali metal salt, hydrochloride, bromate, acetate, sulfate, etc. of cefbiro. In further exemplary embodiments, the alkali metal salt of cefbiro can be sodium salt or potassium salt. Cefbiro axetil is a compound containing an ester group formed based on cefbiro.

[0042] In some embodiments, the cefoperazone can be a compound with a structure as shown in formula (3), the molecular formula of the compound is C26H26N8O11S2, and the chemical name is (6R,7R)-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-((E)-((R)-1'-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2-oxo-[1,3'-bipyrrolidine]-3-ylidene)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

[0043] Cefpirole axetil shown in formula (3) is a prodrug of cefpirole, which is hydrolyzed into cefpirole after entering the human body. Cefpirole axetil shown in formula (3) is beneficial to improving the stability of the compound.

[0044] In certain embodiments, the cefbirome derivatives may also include a cefbirome salt formed by cefbirome, and further, the cefbirome salt may include at least one of acetate, sulfate, hydrochloride, bromate, and alkali metal salts of cefbirome. Further, the alkali metal salt of cefbirome may be a sodium salt or a potassium salt. Cefbirome and cefbirome form a salt that can improve the water solubility of cefbirome and cefbirome, thereby making the injection have a short redissolution time when the antibacterial composition is prepared. Meanwhile, the formation of the sodium salt is beneficial to reducing the irritation during administration by injection.

[0045] In some embodiments, the sodium salt formed by cefpiroxetil shown in formula (3) can be cefpiroxetil sodium. The molecular formula of cefpiroxetil sodium is C26H25N8NaO11S2, and its chemical name is (6R, 7R)-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-((E)-((R)-1'-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2-oxo-[1,3'-bipyrrolidino]-3-ylidene)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt. The structural formula of cefpiroxetil sodium is shown in formula (4):

[0046] After the cefbiroximate represented by formula (3) is converted into the cefbiroximate sodium represented by formula (4), the water solubility is improved, thereby further improving the water solubility of the antibacterial composition and reducing the irritation of the antibacterial composition when used for injections such as intravenous injection.

[0047] In a second aspect, embodiments of the present application provide an antibacterial drug. The antibacterial drug comprises the antibacterial composition described above. Because the antibacterial composition described above has excellent antibacterial activity, the antibacterial drug also has excellent antibacterial activity.

[0048] In some embodiments, the antibacterial drug further includes pharmaceutically acceptable excipients, such as solvents, excipients, pH regulators, and the like.

[0049] In some embodiments, the antibacterial drug can be given as an injection.

[0050] In some embodiments, the antibacterial drug includes a drug for at least one of NDM-type carbapenemase-producing bacteria, KPC-type carbapenemase-producing bacteria, and OXA-type carbapenemase-resistant bacteria.

[0051] In some embodiments, the NDM-type carbapenemase-producing bacteria include Escherichia coli. In further embodiments, when the antibacterial drug is used for NDM-type carbapenemase-producing Escherichia coli, the mass ratio of cephalosporin to zidabactam can be 0.1:1 to 10:1, preferably 0.1:1 to 8:1.

[0052] In some embodiments, the KPC-type carbapenemase-producing bacteria include Klebsiella pneumoniae. In further embodiments, when the antibacterial drug is used to treat KPC-type carbapenemase-producing Klebsiella pneumoniae, the mass ratio of cephalosporin to zidabactam can be 0.1:1 to 10:1, preferably 0.1:1 to 8:1.

[0053] In some embodiments, the OXA-type carbapenemase-producing bacteria include Klebsiella pneumoniae. In further embodiments, when the antibacterial drug is used to treat OXA-type carbapenemase-producing Klebsiella pneumoniae, the mass ratio of cephalosporin to zidabactam can be 0.1:1 to 10:1, preferably 0.1:1 to 8:1.

[0054] The antibacterial composition of the embodiment of the present application has excellent antibacterial activity against NDM-type carbapenemase-producing Escherichia coli, KPC-type carbapenemase-producing Klebsiella pneumoniae, and OXA-type carbapenemase-producing Klebsiella pneumoniae, so that the antibacterial drug of the embodiment of the present application has a good effect on infections by these bacteria.

[0055] In some embodiments, the dosage of the antibacterial drug is such that the concentration of zidabactam in the application environment is 4 mg / L to 8 mg / L. In specific examples, the concentration of zidabactam can be 4 mg / L, 5 mg / L, 6 mg / L, 7 mg / L, and 8 mg / L. Controlling the concentration of zidabactam within this range further enhances the synergistic effect between cephalosporins and zidabactam. The "concentration in the application environment" refers to the concentration level of the drug and its metabolites in a specific application environment. This environment can be a specific part of the human body, such as blood, tissues, organs, etc., or it can be an in vitro environment, such as a pharmaceutical preparation, drug release system, or drug delivery device. This concentration can be the concentration of the free drug (not bound to proteins or other molecules) or the total drug concentration (including free and bound forms). It is usually expressed as the mass of the drug and its metabolites per liter of liquid (such as mg / L or μg / L).

[0056] In some embodiments, the antibacterial drug comprises at least one of a drug for treating lung infection, a drug for treating bloodstream infection, and a drug for treating urinary tract infection. In further embodiments, the lung infection, bloodstream infection, and urinary tract infection may be caused by multidrug-resistant, extensively drug-resistant, or pandrug-resistant bacteria.

[0057] In some embodiments, the antibacterial composition or antibacterial kit or the antibacterial drug is used to treat lung infection, bloodstream infection and / or urinary tract infection.

[0058] In a second aspect, an embodiment of the present application provides a use of the above-mentioned antibacterial drug in the preparation of a drug for treating lung infection, bloodstream infection and / or urinary tract infection.

[0059] In a third aspect, embodiments of the present application provide a method for treating lung infection, bloodstream infection and / or urinary tract infection, which comprises administering the above-mentioned antibacterial composition or kit or the above-mentioned antibacterial drug to a subject in need.

[0060] In a third aspect, the present invention provides an embodiment of a method for preparing a medicament, a drug combination, or a drug kit for treating lung infection, bloodstream infection, and / or urinary tract infection using a therapeutically effective amount of a cephalosporin and a therapeutically effective amount of zidabactam. The therapeutically effective amount of the cephalosporin and zidabactam can be administered simultaneously, separately, or sequentially.

[0061] Wherein, the cephalosporin includes one or more of cefpirole and cefpirole derivatives;

[0062] The cephalosporin is C 20 H 22 The mass ratio of the cephalosporin to the zidabactam is 0.1:1 to 10:1, preferably 0.1:1 to 8:1, based on N8O6S2.

[0063] The following uses a number of specific examples to illustrate the antibacterial composition of the present application, its application, and antibacterial drugs, etc.

[0064] Example 1

[0065] According to the recommendation of CLSI (Clinical and Laboratory Standards Institute) M07-A11 (2018 edition), the minimum inhibitory concentration (MIC) of cefoperazone and zidabactam against clinical isolates was determined by broth microdilution method. 50 MIC refers to the lowest drug concentration that inhibits the growth of 50% of the tested bacteria. 90 It refers to the lowest drug concentration that inhibits the growth of 90% of the tested bacteria.

[0066] Antibacterial drug: Cefuroxime, manufactured by Shenyang Sanjiu Pharmaceutical, content: 92.1%, batch number: YF / BALP141 / 000. Zidabactam, manufactured by Target M01, batch number: 149661. Zidabactam, as described above, is known as Zidebactam in English and chemically as (2S,5R)-7-oxo-2-(2-((R)-piperidine-3-carbonyl)hydrazine-1-carbonyl)-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate monoester.

[0067] Tested bacteria: A total of 24 strains of KPC or OXA β-lactamase-producing strains, including 24 strains of Klebsiella pneumoniae, of which 12 strains produced KPC-2 carbapenemase and 12 strains produced OXA-232 carbapenemase.

[0068] Quality control strains: Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC BAA-1705 (producing KPC-2 carbapenemase) and Klebsiella pneumoniae ATCC BAA-2146 (producing NDM-1 carbapenemase).

[0069] Culture medium: Cation-adjusted Mueller-Hinton broth (CAMHB), a product of BBL, USA.

[0070] Inoculation volume: Pure bacterial colonies were diluted with physiological saline to a turbidity of 0.5, appropriately diluted, and added to the wells of a 96-well U-bottom microtiter plate (containing 50 μL of antimicrobial solution). The inoculation volume was 5×105 CFU / mL.

[0071] Culture conditions: air environment, 35℃±2℃, 16-20 hours.

[0072] Preparation of Antimicrobial Solutions: Cefbirome and zildabactam were dissolved and diluted according to the CLSI and drug instructions for antimicrobial drugs to prepare six groups of antimicrobial solutions, A1 to A6. Group A1 served as a control group containing only cefbirome, and Group A2 served as a control group containing only zildabactam. Groups A1, A3, A3, and A6 included different antimicrobial solutions with cefbirome concentrations ranging from 128 mg / L to 0.06 mg / L, respectively. Group A2 included different antimicrobial solutions with zildabactam concentrations ranging from 128 mg / L to 0.06 mg / L. The specific concentrations within the range of 128 mg / L to 0.06 mg / L in Groups A1 to A6 were 128 mg / L, 64 mg / L, 32 mg / L, 16 mg / L, 8 mg / L, 4 mg / L, 2 mg / L, 1 mg / L, 0.5 mg / L, 0.25 mg / L, 0.125 mg / L, and 0.06 mg / L, respectively. The ingredients contained in the antibacterial solutions in Groups A1 to A6 are shown in Table 1.

[0073] Table 1. Concentrations of cefoperazone / zidabactam in antimicrobial solutions of groups A1 to A6

[0074] Note: The concentrations in Table 1 are mass concentrations, so the concentration ratios in Table 1 are equal to the mass ratios.

[0075] Test results: Currently, there are no CLSI or EUCAST breakpoints for cefpirole / zyme inhibitors. Therefore, the antimicrobial activity of cefpirole / zyme inhibitors was determined using the cefpirole standard. The susceptibility test results were statistically analyzed using WHONET 5.6 software. The fractional inhibitory concentration index (FIC) for the combined use of cefpirole and zidabactam was calculated according to the following formula (1). The results are shown in Tables 2 to 5.

[0076] In formula (1), drug A is cefoperazone and drug B is zidabactam. The synergistic effect of the combined drug use is determined according to the following principles:

[0077] (1) FIC less than or equal to 0.5: synergistic effect, indicating that the antibacterial activity of the two drugs combined is significantly greater than that of each drug alone;

[0078] (2) FIC greater than 0.5-1: additive effect. This indicates that the antibacterial activity of the two drugs combined is slightly increased compared to either drug alone;

[0079] (3) FIC greater than 1-2: no effect. This indicates that the activity of the two antimicrobial drugs is not affected by the other drug;

[0080] (4) FIC greater than 2: Antagonism, indicating that the activity of one antimicrobial drug is weakened by another.

[0081] Table 2. In vitro antibacterial activity of cefoperazone / zidabactam against the test bacteria in Example 1

[0082] Note: In Table 2, the MIC of group A2 refers to the concentration of zidabactam, and the MIC of groups A1 and A3 to A6 refers to the concentration of cefoperazone.

[0083] As shown in Table 2, in group A5, when the concentration of zidabactam was 4 mg / L, the MIC of cefoperazone against KPC-2 carbapenemase Klebsiella pneumoniae 50 The concentration ratio of cefoperazone to zidabactam is 0.5:4=0.125:1. The MIC of cefoperazone against OXA-232 carbapenemase Klebsiella pneumoniae is 0.5 mg / L. 50is less than or equal to 0.06 mg / L, at this time the concentration ratio of cefoperazone and zidabactam is 0.06:4=0.015:1.

[0084] In group A6, when the concentration of zidabactam was 8 mg / L, the MIC of cefuroxime against KPC-2 carbapenemase-producing Klebsiella pneumoniae was 50 The concentration ratio of cefoperazone to zidabactam is 0.125 mg / L, at which time the concentration ratio of cefoperazone to zidabactam is 0.125:4=0.032:1; the MIC of cefoperazone to OXA-232 carbapenemase Klebsiella pneumoniae is 50 is less than or equal to 0.06 mg / L, at this time the concentration ratio of cefoperazone and zidabactam is 0.06:4=0.015:1.

[0085] In addition, as shown in Table 2 , the FICs of groups A3 and A4 were both lower than those of group A6, indicating that the weight ratio of cefoperazone:zidabactam was 1:1 to 2:1, which had a better synergistic effect than that of group A6 at 0.015:1.

[0086] The antibacterial results of cefoperazone / zidabactam in groups A1 to A6 are shown in Tables 3 to 5.

[0087] Table 3. Antibacterial results of cefuroxime / zidabactam

[0088] Note: In Table 3, the drug concentration in group A2 refers to the concentration of zidabactam, and the drug concentration in groups A1 and A3 to A6 refers to the concentration of cefoperazone.

[0089] Table 4. MIC distribution and cumulative inhibition rate of cefoperazone / zidabactam against KPC-type carbapenemase-producing Klebsiella pneumoniae in Example 1

[0090] Note: In Table 4, the MIC of group A2 refers to the concentration of zidabactam, and the MIC of groups A1 and A3 to A6 refers to the concentration of cefoperazone.

[0091] Table 5. MIC distribution and cumulative inhibition rate of cefoperazone / zidabactam against OXA-232 carbapenemase-producing Klebsiella pneumoniae in Example 1

[0092] Note: In Table 5, the MIC of group A2 refers to the concentration of zidabactam, and the MIC of groups A1 and A3 to A6 refers to the concentration of cefoperazone.

[0093] As shown in Tables 2 to 5, the MICs of cefoperazone alone in group A1 against KPC-producing carbapenemase-producing Klebsiella pneumoniae and OXA-232-producing Klebsiella pneumoniae 50 and MIC 90The concentrations of cefoperazone alone were all greater than or equal to 128 mg / L. This indicates that cefoperazone alone has no antibacterial activity against Klebsiella pneumoniae producing KPC-type carbapenemase and Klebsiella pneumoniae producing OXA-232-type carbapenemase.

[0094] MIC of Zidabactam monotherapy in group A2 against KPC-type carbapenemase-producing Klebsiella pneumoniae 50 and MIC 90 All were greater than 128 mg / L, and the MICs for OXA-232 carbapenemase Klebsiella pneumoniae were 50 and MIC 90 The concentrations of zidabactam were 64 mg / L and greater than 128 mg / L, respectively. This indicates that zidabactam alone has no antibacterial activity against Klebsiella pneumoniae producing KPC-type carbapenemase and has weak antibacterial activity against Klebsiella pneumoniae producing OXA-232-type carbapenemase.

[0095] For KPC-type carbapenemase-producing Klebsiella pneumoniae, MICs of groups A3 and A4 50 The MICs were 2 mg / L. 90 The MICs of groups A5 and A6 were 4 mg / L and 8 mg / L, respectively. 50 0.5mg / L, 0.125mg / L, MIC 90 The MIC values ​​of the combination of cefbirome and zidabactam against KPC-type carbapenemase-producing Klebsiella pneumoniae were 1 mg / L. 90 The range of decrease was greater than 16 times to greater than 128 times, and the combination of ceftriaxone and zidabactam showed extremely strong synergistic antibacterial activity.

[0096] For OXA-232 carbapenemase-producing Klebsiella pneumoniae, the MICs of group A3 50 and MIC 90 The MIC of group A4 was 2 mg / L. 50 and MIC 90 The MIC of group A5 was 4 mg / L. 50 and MIC 90 The MICs of group A6 were less than or equal to 0.06 mg / L and 0.5 mg / L, respectively. 50 and MIC 90 The MICs of cefbirome and zidabactam in combination against OXA-232 carbapenemase-producing Klebsiella pneumoniae are less than or equal to 0.06 mg / L and 0.25 mg / L, respectively. The combination of cefbirome and zidabactam has excellent antibacterial activity against OXA-232 carbapenemase-producing Klebsiella pneumoniae. Compared with cefbirome alone, the MICs of different combinations of cefbirome and zidabactam against OXA-232 carbapenemase-producing Klebsiella pneumoniae are less than or equal to 0.06 mg / L and 0.25 mg / L, respectively. 90The range of decrease was greater than 32 times to greater than 512 times, and the combination of ceftriaxone and zidabactam showed extremely strong synergistic antibacterial activity.

[0097] Example 2 to Example 7

[0098] Examples 2 to 7 were prepared using the same method as in Example 1 to investigate the antibacterial activity of 24 strains of Klebsiella pneumoniae (12 of which produced KPC-2 carbapenemases and 12 produced OXA-232 carbapenemases) at a mass ratio of cefoperazone to zildabatam of 1.5:1, 2.5:1, 4:1, 8:1, 10:1, and 0.1:1, respectively. The concentration ranges of cefoperazone for Examples 2 to 7 are shown in Table 6, and the results are shown in Table 7. In Examples 1 to 7, the concentration ratio of cefoperazone to zildabatam was the same as the mass ratio.

[0099] Comparative Example A1

[0100] Comparative Example A1 used the same method as Example 1 to investigate the antibacterial activity of 24 strains of Klebsiella pneumoniae (12 of which produced KPC-2 carbapenemase and 12 produced OXA-232 carbapenemase) at different mass ratios of cefoperazone and zidabactam of 11:1. The concentration range of cefoperazone in Comparative Example A1 is shown in Table 6, and the results are shown in Table 7.

[0101] Table 6. Concentrations of cefoperazone / zidabactam in Examples 2-7 and Comparative Example A1

[0102] Table 7. In vitro antibacterial activity of cefoperazone / zidabactam against the test bacteria in Examples 2-7 and Comparative Example A1

[0103] Note: The MIC in Examples 2 to 7 and Comparative Example A1 in Table 7 refers to the concentration of cefoperazone.

[0104] As shown in Table 7, the FIC values ​​of cefpirole against OXA-232 carbapenemase-producing Klebsiella pneumoniae and KPC-2 carbapenemase-producing Klebsiella pneumoniae were lower when the mass ratio of cefpirole to zildabactam was 0.1:1 to 10:1 than when the mass ratio was 11:1. This indicates that the mass ratio of cefpirole to zildabactam in the range of 0.1:1 to 10:1 exhibits a more synergistic effect.

[0105] Comparative Example B1

[0106] The combined use ratio of cefoperazone and vibobactam was investigated in the same manner as in Example 1, except that vibobactam was used to replace zidabactam in the antibacterial drug solutions of groups A2 to A6 in Example 1, and the numbers of groups A2 to A6 were modified to groups B2 to B6 accordingly.

[0107] Vaborbactam is manufactured by GLP Bio, with batch number GC193691. Its chemical name is (3R,6S)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-1,2-oxaborane-6-acetic acid, and its structural formula is shown in Formula (5):

[0108] The results of this comparative example are shown in Tables 8 and 9.

[0109] Table 8. In vitro antibacterial activity of cefoperazone / virbobactam against the tested bacteria

[0110] Note: In Table 8, the MIC of group B2 refers to the concentration of virbobactam, and the MIC of groups B3 to B6 refers to the concentration of cefoperazone.

[0111] Table 9. MIC distribution and cumulative inhibition rate of cefoperazone / virbobactam against the tested bacteria

[0112] Note: In Table 9, the MIC of group B2 refers to the concentration of vibobactam, and the MIC of groups B3 to B6 refers to the concentration of cefoperazone.

[0113] As shown in Tables 8 and 9, the MICs of vilbobactam monotherapy in group B2 against KPC-type carbapenemase-producing Klebsiella pneumoniae and OXA-232-type carbapenemase-producing Klebsiella pneumoniae 50 and MIC 90 Both were greater than 128 mg / L. Virbobactam alone had no antibacterial activity against Klebsiella pneumoniae producing KPC-type carbapenemase and Klebsiella pneumoniae producing OXA-232-type carbapenemase.

[0114] For KPC-type carbapenemase-producing Klebsiella pneumoniae, the MIC of group B3 50 and MIC 90 The MICs of group B4 were 32 mg / L and 64 mg / L, respectively. 50 and MIC 90 The MICs of groups B5 and B6 were all 64 mg / L. 50 and MIC 90 The combined activity of cefoperazone and virbobactam against KPC-type carbapenemase-producing Klebsiella pneumoniae was weak.

[0115] For OXA-232 carbapenemase-producing K. pneumoniae, the MIC of group B3 50 and MIC 90 The MICs of groups B3, B5, and B6 were 128 mg / L and greater than 128 mg / L, respectively. 50 and MIC 90 The serum levels of cefoperazone and virbobactam were all above 128 mg / L. The combination of cefoperazone and virbobactam had no antibacterial activity against KPC-type carbapenemase-producing Klebsiella pneumoniae.

[0116] Comparative Example B2

[0117] The combined use ratio of cefoperazone and relebactam was investigated using the same method as in the above embodiment, except that relebactam was used to replace cefoperazone in the antibacterial drug solutions of groups A2 to A6 in the above embodiment, and the numbers of groups A2 to A6 were modified to groups C2 to C6 accordingly.

[0118] Relebactam is manufactured by Hanxiang Biotechnology, with batch number 20201209. The chemical name of Relebactam is (1R, 2S, 5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate monoester, and its structural formula is shown in Formula (6):

[0119] The results of this comparative example are shown in Tables 10 and 11.

[0120] Table 10. In vitro antibacterial activity of cefoperazone / relebactam against the tested bacteria

[0121] Note: In Table 10, the MIC of group C2 refers to the concentration of relebactam, and the MIC of groups C3 to C6 refers to the concentration of cefoperazone.

[0122] Table 11. MIC distribution and cumulative inhibition rate of cefoperazone / relebactam against the tested bacteria

[0123] Note: In Table 11, the MIC of group C2 refers to the concentration of relebactam, and the MIC of groups C3 to C6 refers to the concentration of cefoperazone.

[0124] As shown in Tables 10-11, the MICs of relebactam monotherapy in group C2 against KPC-type carbapenemase-producing Klebsiella pneumoniae and OXA-232-type carbapenemase-producing Klebsiella pneumoniae 50 and MIC 90 Both were greater than 128 mg / L. Relebactam alone had no antibacterial activity against Klebsiella pneumoniae producing KPC-type carbapenemase and Klebsiella pneumoniae producing OXA-232-type carbapenemase.

[0125] For KPC-type carbapenemase-producing Klebsiella pneumoniae, the MICs of groups C3, C4, and C6 50 Both were 16 mg / L, MIC 90 The antibacterial activity against KPC-type carbapenemase-producing Klebsiella pneumoniae was moderate when cefoperazone and relebactam were used in combination at a ratio of 1:1 and 2:1, and when the relebactam concentration was 8 mg / L. The MIC of group C5 was 50 and MIC 90 The concentrations of ceftriaxone and relebactam were 32 mg / L and 128 mg / L, respectively. When the concentration of relebactam was 4 mg / L, the combined use of ceftriaxone and relebactam had weak antibacterial activity against KPC-type carbapenemase-producing Klebsiella pneumoniae.

[0126] For OXA-232 carbapenemase-producing Klebsiella pneumoniae, MICs of groups C3 and C4 50 and MIC 90 The MIC values ​​of group C5 and group C6 were both 64 mg / L. When cefuroxime and relebactam were used together, the antibacterial activity was weak when the ratio of cefuroxime to relebactam was 1:1 and 2:1. 50 and MIC 90 Both were greater than 128 mg / L. When the concentration of relebactam was 4 mg / L and 8 mg / L, the combined use of cefoperazone and relebactam had no antibacterial activity.

[0127] Comparative Example B3

[0128] The combined use ratio of cefoperazone and tanibactam was investigated in the same manner as in Example 1, except that tanibactam was used to replace zidabactam in the antibacterial drug solutions of groups A2 to A6 in Example 1, and the numbers of groups A2 to A6 were modified to groups D2 to D6.

[0129] Taniborbactam is manufactured by MCE Corporation, with batch number 80267. The chemical name of Taniborbactam is (R)-3-(2-((1r,4R)-4-((2-aminoethyl)amino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborolan-8-carboxylic acid, and its structural formula is shown in Formula (7):

[0130] The results of this comparative example are shown in Tables 12 and 13.

[0131] Table 12. In vitro antibacterial activity of cefoperazone / talniborbactam against the tested bacteria

[0132] Note: In Table 12, the MIC of group D2 refers to the concentration of relebactam, and the MIC of groups D3 to D6 refers to the concentration of cefoperazone.

[0133] Table 13. MIC distribution and cumulative inhibition rate of cefoperazone / talniborbactam against KPC-2 and OXA-232 carbapenemase-producing Klebsiella pneumoniae

[0134] Note: In Table 13, the MIC of group D2 refers to the concentration of relebactam, and the MIC of groups D3 to D6 refers to the concentration of cefoperazone.

[0135] As shown in Tables 12 and 13, the MICs of talibobactam monotherapy in group D2 against KPC-type carbapenemase-producing Klebsiella pneumoniae and OXA-232-type carbapenemase-producing Klebsiella pneumoniae 90 The concentrations of talibobactam alone were greater than 128 mg / L. Tanibobactam alone had no antibacterial activity against Klebsiella pneumoniae producing KPC-type carbapenemase and OXA-232-type carbapenemase.

[0136] For KPC-type carbapenemase-producing K. pneumoniae, MICs for groups D3 to D6 50 and MIC 90 In the range of 8-32 mg / L, the combination of ceftriaxone and talniborbactam had certain antibacterial activity against KPC-type carbapenemase-producing Klebsiella pneumoniae.

[0137] For OXA-232 carbapenemase-producing Klebsiella pneumoniae, the MICs of groups D3, D4, and D6 90 The MIC of group D5 was in the range of 32-64 mg / L. 50 and MIC 90 The concentrations of cefoperazone and talniborbactam were 64 mg / L and 128 mg / L, respectively. The combination of cefoperazone and talniborbactam had weak antibacterial activity against OXA-232 carbapenemase-producing Klebsiella pneumoniae.

[0138] Comparative Example B4

[0139] The combined use ratio of cefoperazone and AAI 101 was investigated using the same method as in Example 1, except that zildabactam in the antibacterial drug solutions of groups A2 to A6 in Example 1 was replaced with AAI 101, and the numbers of groups A2 to A6 were modified to groups E2 to E6 accordingly.

[0140] AAI 101 is manufactured by MCE, with batch number 40984. The chemical name of AAI 101 is (2S,3S,5R)-3-methyl-3-[(3-methyltriazol-3-ium-1-yl)methyl]-4,4,7-trioxo-4-amino-6-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, and its structural formula is shown below:

[0141] The results of this comparative example are shown in Tables 14 and 15.

[0142] Table 14. In vitro antibacterial activity of cefoperazone / AAI 101 against the tested bacteria

[0143] Note: In Table 14, the MIC of group E2 refers to the concentration of relebactam, and the MIC of groups E3 to E6 refers to the concentration of cefoperazone.

[0144] Table 15. MIC distribution and cumulative inhibition rate of cefoperazone / AAI 101 against the tested bacteria

[0145] Note: In Table 15, the MIC of group E2 refers to the concentration of relebactam, and the MIC of groups E3 to E6 refers to the concentration of cefoperazone.

[0146] As shown in Tables 14 and 15, the MICs of AAI 101 alone in group E2 against KPC-producing carbapenemase-producing Klebsiella pneumoniae and OXA-232-producing Klebsiella pneumoniae 50 and MIC 90 AAI 101 alone has no antibacterial activity against Klebsiella pneumoniae that produces KPC-type carbapenemase and OXA-232-type carbapenemase.

[0147] For OXA-232 carbapenemase-producing Klebsiella pneumoniae, the MICs of groups E3, E4, E5, and E6 50 and MIC 90 Both were greater than or equal to 128 mg / L. The combination of ceftriaxone and AAI 101 had no antibacterial activity against OXA-232 carbapenemase-producing Klebsiella pneumoniae.

[0148] Comprehensive comparison of Examples 1 to 7, Comparative Example A1, and Comparative Examples B1 to B4 shows that cefbirome alone has no antibacterial activity against KPC-type carbapenemase-producing Klebsiella pneumoniae and OXA-232-type carbapenemase-producing Klebsiella pneumoniae. Cefbirome and zidabactam combined with these bacteria have excellent antibacterial activity, while cefbirome combined with other β-lactamase inhibitors has no antibacterial activity or weak antibacterial activity against these bacteria. This shows that the antibacterial composition of the present application embodiment, through the compounding of cefbirome and zidabactam, makes cefbirome and zidabactam play a synergistic role, thereby effectively improving the antibacterial activity of the antibacterial composition.

[0149] The above embodiments merely illustrate several implementation methods of the present application. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art could make various modifications and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. An antibacterial composition or antibacterial kit, characterized in that: The antibacterial composition or antibacterial kit comprises cephalosporin and zidabactam; Wherein, the cephalosporin includes at least one of cefuroxime and cefuroxime derivatives; The cephalosporin is C 20 H 22 Based on N8O6S2, the mass ratio of the cephalosporin to the zidabactam is 0.1:1 to 10:

1.

2. The antibacterial composition or antibacterial kit according to claim 1, wherein: The cephalosporin is C 20 H 22 In terms of N8O6S2, the mass ratio of the cephalosporin to the zidabactam is 0.1:1 to 8:1, preferably 0.1:1 to 4:1, and more preferably 0.1:1 to 2.5:

1.

3. The antibacterial composition or antibacterial kit according to claim 1, wherein: The cefbirome derivative comprises at least one of cefbirome axetil, a cefbirome axetil derivative, and a cefbirome salt; Preferably, the cefuroxime salt comprises at least one of an alkali metal salt, a hydrochloride, a bromate, an acetate, and a sulfate of cefuroxime; Preferably, the alkali metal salt of cefoperazone includes at least one of a potassium salt and a sodium salt; Preferably, the cefbiroxil derivative comprises at least one of an alkali metal salt, a hydrochloride, a bromate, an acetate, and a sulfate of cefbiroxil; Preferably, the alkali metal salt of cefoperoxetine includes at least one of a potassium salt and a sodium salt.

4. The antibacterial composition or antibacterial kit according to any one of claims 1 to 3, wherein: The cephalosporin and zidabactam have a synergistic effect on bacteria; Preferably, the cephalosporin and zidabactam have a partial inhibitory concentration index less than or equal to 0.5 against the bacteria, preferably a partial inhibitory concentration index less than or equal to 0.2, and more preferably a partial inhibitory concentration index less than or equal to 0.

15.

5. The antibacterial composition or antibacterial kit according to any one of claims 1 to 4, wherein: When the cephalosporin and zidabactam are used in combination, the MIC of cefoperazone against the bacteria is less than or equal to 4 mg / L 50 , preferably having a MIC of less than or equal to 2 mg / L, less than or equal to 0.5 mg / L, less than or equal to 0.125 mg / L, or less than or equal to 0.06 mg / L 50 ; Preferably, when the cephalosporin and zidabactam are used in combination, the MIC of cefoperazone against the bacteria is less than or equal to 8 mg / L. 90 , preferably having a MIC of less than or equal to 4 mg / L, less than or equal to 2 mg / L, less than or equal to 1 mg / L, less than or equal to 0.5 mg / L, or less than or equal to 0.25 mg / L 90 .

6. The antibacterial composition or antibacterial kit according to any one of claims 1 to 5, wherein: The bacteria are Gram-negative bacteria; Preferably, the bacteria are Escherichia coli and / or Klebsiella pneumoniae; Preferably, the bacteria are one or more of NDM-type carbapenemase-producing bacteria, KPC-type carbapenemase-producing bacteria, and OXA-type carbapenemase-resistant bacteria.

7. An antibacterial drug, characterized in that: The invention comprises the antibacterial composition or antibacterial drug kit as claimed in any one of claims 1 to 6.

8. The antibacterial drug according to claim 7, wherein The antibacterial drugs include one or more drugs for resisting NDM-type carbapenemase-producing bacteria, KPC-type carbapenemase-producing bacteria, and OXA-type carbapenemase-resistant bacteria; and / or, The dosage of the antibacterial drug is as follows: the concentration of the zidabatum in the application environment is 4 mg / L to 8 mg / L.

9. The antibacterial drug according to claim 8, wherein The NDM-type carbapenemase-producing bacteria include Escherichia coli; and / or The KPC-type carbapenemase-producing bacteria include Klebsiella pneumoniae; and / or The OXA-type carbapenemase-resistant bacteria include Klebsiella pneumoniae.

10. The antibacterial drug according to any one of claims 7 to 9, wherein The antibacterial drug includes at least one of a drug for treating lung infection, a drug for treating bloodstream infection, and a drug for treating urinary tract infection; and / or The antibacterial drugs include injections.

11. The antibacterial composition or antibacterial kit according to any one of claims 1 to 6 or the antibacterial drug according to any one of claims 7 to 10, which is used for treating lung infection, bloodstream infection and / or urinary tract infection.

12. Use of the antibacterial composition or antibacterial kit according to any one of claims 1 to 6 or the antibacterial drug according to any one of claims 7 to 10 in the preparation of a drug for treating lung infection, bloodstream infection and / or urinary tract infection.

13. A method for treating lung infection, bloodstream infection and / or urinary tract infection, comprising administering the antibacterial composition or antibacterial kit according to any one of claims 1 to 6 or the antibacterial drug according to any one of claims 7 to 10 to a subject in need thereof.

14. Use of a therapeutically effective amount of cephalosporin and a therapeutically effective amount of zidabactam in the preparation of a medicament, a medicament combination or a medicine kit for treating lung infection, bloodstream infection and / or urinary tract infection; wherein: The therapeutically effective amounts of cephalosporin and zidabactam may be administered simultaneously, separately or sequentially; Wherein, the cephalosporin includes one or more of cefpirole and cefpirole derivatives; The cephalosporin is C 20 H 22 In terms of N8O6S2, the mass ratio of the cephalosporin to the zidabactam is 0.1:1 to 10:1, preferably 0.1:1 to 8:1, more preferably 0.1:1 to 4:1, and more preferably 0.1:1 to 2.5:1.

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