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

WO 2 0 2 5 / 0 6 (12) International application published under the Patent Cooperation Treaty (19) International Bureau of WIPO (43) International Publication Date: 27 March 2025 (27.03.2025) WIPO PCT (51) International Patent Classification: A61K 31 / 545 (2006.01) A61K 31 / 454 (2006.01) A61K 45 / 06 (2006.01) A61P 31 / 04 (2006.01) (21) International Application Number: PCT / CN2024 / 109115 (22) International Application Date: 1 August 2024 (01.08.2024) (25) Application Language: Chinese (26) Publication Language: Chinese (30) Priority: 202311205221.8 September 18, 2023 (18.09.2023) CN (71) Applicant: SHENZHEN CHINA RESOURCES GOSUN PHARMACEUTICALS, CO., LTD. [CN / CN]; No. 2, Kaifeng Road, Shangmeilin, Futian District, Shenzhen, Guangdong 518049, China (CN). HUASHAN HOSPITAL, FUDAN UNIVERSITY [CN / CN]; No. 12, Urumqi Middle Road, Jing'an District, Shanghai 200040, China (CN). (72) Inventor: HU, Fupin; No. 12, Urumqi Middle Road, Jing'an District, Shanghai 200040, China (CN). HUANG, Quanhua; No. 2, Kaifeng Road, Shangmeilin, Futian District, Shenzhen, Guangdong 518049, China (CN). GUO, Yan; No. 12, Urumqi Middle Road, Jing'an District, Shanghai 200040, China (CN). ZHANG, Yong; No. 2, Kaifeng Road, Shangmeilin, Futian District, Shenzhen, Guangdong 518049, China (CN). WU, Shi; No. 12, Urumqi Middle Road, Jing'an District, Shanghai 200040, China (CN). ZHANG, Weiwei; No. 2, Kaifeng Road, Shangmeilin, Futian District, Shenzhen, Guangdong 518049, China (CN). HAN, Renru; No. 12, Urumqi Middle Road, Jing'an District, Shanghai 200040, China (10)International Publication No. WO 2025 / 060701 A1 (CN). LI, Xin; No. 12, Urumqi Middle Road, Jing'an District, Shanghai 200040, China (CN). LA, Baolin; No. 2, Kaifeng Road, Shangmeilin, Futian District, Shenzhen 518049, China (CN). ZHONG, Yihua; No. 2, Kaifeng Road, Shangmeilin, Futian District, Shenzhen 518049, China (CN). (74) Agent: MERITS IP LTD.; Room 506, 5th Floor, South Office Building, No. 29-2, Dongzhong Street, Dongcheng District, Beijing 100027, China (CN). (81) Designated countries (unless otherwise specified, each requiring national protection): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, РA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW (84) Designated countries (unless otherwise specified, each requiring available regional protection): ARIPO (BW, CV, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST, SZ, TZ, UG, ZM, ZW), L (AM, AZ, BY, KG, KZ, RU, TJ, TM), (AL, AT,ВЕ, BG, CH, CY, CZ, DE, DK, EE, E, FI, FR, GB, GR, HR, HU. IE, IS, IT, LT, LU, LV., MC, ME, MK, MT, NL, NО. PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Specifications: - Additional Antibacterial Compound (Activity 21(3)). (54) Title: ANTIBACTERIAL COMPOSITION AND ANTIBACTERIAL DRUG (54) Antibacterial composition and antibacterial drug (57) Abstract: An antibacterial composition and an antibacterial drug. The antibacterial composition comprises a cephalosporin and a zidebactam, wherein the cephalosporin comprises at least one of ceftobiprole and a ceftobiprole derivative; and the mass ratio of the cephalosporin to zidebactam is calculated on the basis of C20H22NgO6S2. 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 cephalosporinor zidebactam. (57) Abstract: An antibacterial composition and an antibacterial drug, the antibacterial composition comprising cephalosporin and zidabactam, wherein the cephalosporin comprises at least one of cefbirol and cefbirol derivatives; the mass ratio of cephalosporin to zidabactam, calculated as C 20H 22N 8O 6S 2, is 0.1:1 to 10:1. By combining cephalosporin and zidabactam, a synergistic effect is achieved between cephalosporin and zidabactam, thereby giving the antibacterial composition excellent antibacterial activity and good antibacterial activity against bacteria resistant to cephalosporin or zidabactam alone. WO 2025 / 060701 Specification PCT / CN2024 / 109115 Antibacterial Composition and Antibacterial Drug This application claims priority to Chinese Patent Application No. 202311205221.8, filed on September 18, 2023, the entire contents of which are incorporated herein by reference. Technical Field This application belongs to the technical field of antibacterial drugs, specifically relating to an antibacterial composition and an antibacterial drug. Background Art Cefbirol is a broad-spectrum cephalosporin that exerts its bactericidal activity in susceptible bacteria by binding to penicillin-binding proteins (BPs). PBPs bound by cefbirol include PBPs with decreased sensitivity to various β-lactams, such as PBP2a in methicillin-resistant Staphylococcus aureus (MRSA), and PBP2b and PBP2x in Streptococcus pneumoniae (penicillin-intermediate and resistant). This gives cefbirol activity against methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria (including some Pseudomonas aeruginosa). With the widespread clinical application of cefbirol, bacteria resistant to it have gradually emerged, such as KPC-producing carbapenemase-producing Klebsiella pneumoniae, leading to reduced or no antibacterial activity of cefbirol against some bacteria. The present application aims to provide an antibacterial composition or antibacterial kit and antibacterial drug to further enhance the antibacterial effect against cefbirol-resistant bacteria and solve the current technical problem of reduced or no antibacterial activity of cefbirol against some bacteria. In a first aspect, embodiments of the present application provide an antibacterial composition or antibacterial kit. The antibacterial composition comprises cephalosporins and zidabactam: wherein the cephalosporin includes one or more of cefbirol and cefbirol derivatives; the mass ratio of cephalosporin to zidabactam, calculated as C2H22N&OS2, is 0.1:1 to 10:1. The antibacterial composition or antibacterial kit of this application, through the combination of cephalosporins and zidabactam, simultaneously controls cephalosporins.The mass ratio of cephalosporin to zidabactam allows cephalosporins and zidabactam to synergistically enhance each other's antibacterial activity, thereby increasing the antibacterial activity of the antibacterial composition and giving it excellent antibacterial effects, especially against cefbirol-resistant bacteria. Secondly, embodiments of this application provide an antibacterial drug. This antibacterial drug includes the aforementioned antibacterial composition. Because the antibacterial composition of this application has excellent antibacterial activity, this antibacterial drug also possesses excellent antibacterial activity. Detailed Embodiment 1 WO 2025 / 060701 PCT / CN2024 / 109115 To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative of this application and are not intended to limit this application. 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 refer to any combination of these items, including any combination of single or multiple items. For example, "at least one of a, b, or", or "at least one of a, b, and", can both represent: a, b, ca-b (i.e., a and b), ac, bc, or abc, where a, b, and can be single or multiple. It should be understood that in the various embodiments of this application, the order of the above processes does not imply the order of execution. Some or all 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 this application. The terminology used in the embodiments of this application is for the purpose of describing specific embodiments only and is not intended to limit this application. The singular forms "a," "the," and "the" used in the embodiments of this application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise. The weights of the relevant components mentioned in the embodiments of this application can refer not only to the specific content of each component, but also to the proportional relationship between the weights of the components. Therefore, any scaling up or down of the content of the relevant components according to the embodiments of this application is within the scope disclosed in the embodiments of this application. Specifically, the mass mentioned in the embodiments of this application can be a well-known unit of mass in the chemical industry, such as pg, mg, g, or kg. Cefbirol is a new generation of broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus and Gram-negative bacteria (including some Pseudomonas aeruginosa). Its mechanism of action is similar to other cephalosporins; it is a bactericidal agent during the reproductive phase, interfering with bacterial cell wall synthesis by binding to PBPs, inhibiting bacterial growth, and ultimately leading to bacterial death. However, with the development of cephalosporins...In clinical applications, bacterial resistance to cefbirol has gradually increased. To address the technical problem of reduced or non-existent antibacterial activity of cefbirol against resistant bacteria in existing technologies, this application proposes the following technical solution. Firstly, this application provides an antibacterial composition or antibacterial kit. The antibacterial composition or kit includes cephalosporin and zidabactam. The cephalosporin includes at least one of cefbirol and a cefbirol derivative, and may include only one active ingredient (cefbirol or a cefbirol derivative), or two active ingredients (cefbirol and a cefbirol derivative). The mass ratio of cephalosporin to zidabactam, calculated as C20 H22N&OS2, is 0.1:1 to 10:1. When cephalosporins contain cefbirol, the molecular formula of cefbirol is C20H22NOS2, and its 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-bipyrrolidine]-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): 2 WO 2025 / 060701 N HO-N NS 이N Ο OOH Formula (1) PCT / CN2024 / 109115 When cephalosporins contain cefbirol derivatives, the cefbirol derivative refers to a derivative based on the above-mentioned cefbirol. The chemical name of zidabactam contained in the antibacterial composition or antibacterial kit of this application is (2S,5R)-7-oxo-2-(2-((R)-piperidin-3-carboxyl)-1-yl)-1,6-dichlorobicyclo[3.2.1]octane-6-yl sulfate monoester. The structural formula of zidabactam is shown in formula (2): HN H Ο NN Ο HH,. 0 OH Formula (2). Of course, zidabactam can also be a derivative of the structure shown in formula (2) above, having similar activity to that of formula (2). The antibacterial composition or kit of this application combines cephalosporins and zidabactam, while controlling the mass ratio of cephalosporins and zidabactam within a specific range, so that cephalosporins and zidabactam have a synergistic effect, thereby improving the antibacterial effect of the antibacterial composition or kit. This allows the antibacterial composition or kit to have excellent antibacterial activity against bacteria resistant to cephalosporins alone or zidabactam alone. In some embodiments, the mass ratio of cephalosporin to zidabactam in the antibacterial composition or kit, calculated as cefoperazone (molecular formula C20H22NOS2), can be further 0.1:1 to 8:1, or even more...In the initial demonstration, the ratio can be 0.1:1 to 4:1, and in further demonstrations, it can be 0.1:1 to 2.5:1. Specifically, the mass ratio of cephalosporin to zidabactam in the demonstrations 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, etc., which are typical but not limiting mass ratios. Wherein, when the cephalosporin contains only cefbirol, the mass ratio refers to the mass ratio of cefbirol (calculated as C20H22NOS2) to zidabactam; when the cephalosporin contains only a cefbirol derivative, the mass ratio refers to the mass ratio of the cefbirol derivative (calculated as C20H22NOS2) to zidabactam. When the cephalosporin includes both cefbirol and its derivatives, the mass ratio refers to the mass ratio of the sum of cefbirol and its derivatives (calculated as C20H22NO6S2) to zidabactam. Controlling the mass ratio of cephalosporin to zidabactam within this range further promotes the synergistic effect between cephalosporin and zidabactam, thereby further enhancing the antibacterial activity of the antimicrobial composition or antimicrobial cartridge. In some embodiments, the cephalosporin and zidabactam contained in the antimicrobial composition or antimicrobial cartridge may be mixed. The mixing of cephalosporins and zidabactam improves the uniformity of the antimicrobial composition or kit, and facilitates its use, eliminating the need for further mixing before application. In some embodiments, the cephalosporins and zidabactam exhibit synergistic effects against bacteria. 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. In some embodiments, when the cephalosporin and zidabactam are used in combination, cefbirol has a MIC50 of less than or equal to 4 mg / L against the bacteria, preferably 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. In some embodiments, the bacteria are KPC-2 type carbapenem-producing bacteria.In some embodiments, when the cephalosporin and zidabactam are used in combination, cefbirol has a MIC00 of less than or equal to 8 mg / L against the bacteria, preferably 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. In some embodiments, the bacteria are OXA-48 carbapenem-producing bacteria. In some embodiments, the bacteria are Gram-negative bacteria. In some embodiments, the bacteria are Escherichia coli and / or Klebsiella pneumoniae; 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. In some embodiments, the cephalosporin and zidabactam in the antibacterial composition or antibacterial kit may also be disposed separately and mixed before use. For example, when the antimicrobial composition is prepared as an injection, cephalosporins and zidabactam can be packaged separately and then mixed before injection, or the cephalosporins and zidabactam can be injected separately. This separation of cephalosporins and zidabactam further improves the quality stability of each component in the antimicrobial composition. In some embodiments, when the cephalosporin includes a cefibiro derivative, the cefibiro derivative can be a compound capable of being converted to form cefibiro. In specific examples, the cefibiro derivative can include at least one of cefibiro salt, cefibiro ester, and cefibiro ester derivative. The cefibiro salt is a salt formed based on cefibiro, such as an alkali metal salt, hydrochloride, bromate, acetate, sulfate, etc., of cefibiro. In further examples, the alkali metal salt of cefibiro can be a sodium or potassium salt. Cefibiro ester is a compound containing an ester group formed based on cefibiro. In some embodiments, the cefbiroform ester can be a compound with the structure shown in formula (3), the molecular formula of which 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-dioxacyclopenten-4-yl)methoxy)yl)-2-oxo-[1,3'-bipyrrolidine]-3-ylidene)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid. 4 WO 2025 / 060701 HO NN H2N SN ὅ -N OH Formula (3) HC. The cefbiro ester shown in formula (3) of PCT / CN2024 / 109115 is a prodrug of cefbiro. After entering the human body, it is hydrolyzed to form cefbiro. The cefbiro ester shown in formula (3) is beneficial to improving the stability of the compound.In some embodiments, the cefbiro ester derivative may further include a cefbiro ester salt formed from cefbiro ester. Further, the cefbiro ester salt may include at least one of the following: acetate, sulfate, hydrochloride, bromate, or alkali metal salt of cefbiro ester. Further, the alkali metal salt of cefbiro ester may be a sodium or potassium salt. The formation of a salt between cefbiro ester and cefbiro ester can improve the water solubility of both cefbiro ester and cefbiro ester, thereby resulting in a shorter reconstitution time when the antibacterial composition is formulated as an injection. Simultaneously, the formation of a sodium salt helps reduce irritation during injection administration. In some embodiments, the sodium salt formed from cefbiro ester as shown in formula (3) may be cefbiro ester sodium. The molecular formula of cefbilodil sodium is C26H25N8NaO11S2, and its chemical name is (6R,7R)-7-((Z)-2-(5-amino-1,2,4-diazol-3-yl)-2-(hydroxyimino)acetamido]-3-((E)-((R)-1'-(((5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methoxy)yl)-2-oxo-[1,3'-bipyrrolidine]-3-ylidene)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid monosodium salt. The structural formula of cefbilodil sodium is shown in formula (4): -OH NHN H₂N HC SN Ο N Ο O 0 ONa (4) After cefbiromate of formula (3) is converted into cefbiromate sodium of formula (4), its water solubility is improved, thereby further improving the water solubility of the antibacterial composition and reducing the irritation of the antibacterial composition when used in injections such as intravenous injections. Secondly, embodiments of this application provide an antibacterial drug. The antibacterial drug includes the antibacterial composition described above in this application. Because the antibacterial composition of this application has excellent antibacterial activity, the antibacterial drug also has excellent antibacterial activity. In some embodiments, the antibacterial drug further includes pharmaceutically acceptable excipients, such as solvents, excipients, pH adjusters, etc. In some embodiments, the antibacterial drug can be an injection. In some embodiments, the antibacterial drug includes a drug for treating at least one of NDM-type carbapenemase-producing bacteria, KPC-type carbapenemase-producing bacteria, and OXA-type carbapenemase-resistant bacteria. In some embodiments, NDM-type carbapenemase-producing bacteria include Escherichia coli. In a further embodiment, when the antibacterial drug is applied to NDM-type carbapenemase-producing bacteria... When using KPC-producing 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. In some embodiments, KPC-producing carbapenemase bacteria include Klebsiella pneumoniae. In further embodiments, when the antimicrobial agent is applied to KPC-producing...When using 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. In some embodiments, OXA-type carbapenemase-producing bacteria include Klebsiella pneumoniae. In further embodiments, when the antibacterial drug is applied to 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. The antibacterial compositions of the present application embodiments have excellent antibacterial activity against NDM-type carbapenemase-producing Escherichia coli, KPC-type carbapenemase-producing Klebsiella pneumoniae, and OXA-type carbapenemase-producing Klebsiella pneumoniae, making the antibacterial drugs of the present application embodiments effective against infections caused by these bacteria. In some embodiments, the dosage of the antibacterial drug is zidabactam at a concentration of 4 mg / L to 8 mg / L in the application environment. Specifically, the concentration of zidabactam can be 4 mg / L, 5 mg / L, 6 mg / L, 7 mg / L, or 8 mg / L. Controlling the concentration of zidabactam within this range further enhances the synergistic effect between cephalosporins and zidabactam. The term "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 site within the human body, such as blood, tissues, or organs, or it can be an in vitro environment, such as a drug formulation, drug delivery 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 both free and bound forms). It is usually expressed as the mass of the drug and its metabolites per liter of liquid (e.g., mg / L or μg / L). In some embodiments, the antibacterial drug includes at least one of the following: drugs for treating pulmonary infections, drugs for treating bloodstream infections, and drugs for treating urinary tract infections. In further embodiments, the treatment of pulmonary infections, bloodstream infections, and urinary tract infections may be caused by multidrug-resistant, extensively drug-resistant, or pan-drug-resistant bacteria. In some embodiments, the above-described antibacterial composition or antibacterial kit or the above-described antibacterial drug is used to treat pulmonary infections, bloodstream infections, and / or urinary tract infections. In a second aspect, embodiments of this application provide the use of the above-described antibacterial drug in the preparation of a medicament for treating pulmonary infections, bloodstream infections, and / or urinary tract infections. In a third aspect, embodiments of this application provide a method for treating pulmonary infections, bloodstream infections, and / or urinary tract infections, comprising administering the above-described antibacterial composition or kit or the above-described antibacterial drug to a subject in need. In a third aspect, embodiments of this application provide the use of a therapeutically effective amount of cephalosporin and a therapeutically effective amount of zidabactam in the preparation of a medicament, medicament combination, or kit for treating pulmonary infections, bloodstream infections, and / or urinary tract infections; wherein the therapeutically effective amounts of cephalosporin and zidabactam may be administered simultaneously, separately, or sequentially.The cephalosporin includes one or more of cefbirol and cefbirol derivatives; the mass ratio of the cephalosporin to zidabactam, calculated as C20HzzNOS2, is 0.1:1 to 10:1, preferably 0.1:1 to 8:1. The following examples illustrate the antibacterial compositions and their applications, as well as antibacterial drugs, of this application. Example 1 6 WO 2025 / 060701 PCT / CN2024 / 109115 According to the CLSI (Clinical and Laboratory Standards Institute) M07-A11 (2018 edition) recommendation, the minimum inhibitory concentration (MIC) of cefbirol and zidabactam against clinical isolates was determined using the broth-microdilution method. It should be noted that in this application, MIC50 refers to the minimum drug concentration that inhibits the growth of 50% of the test bacteria, and MICoo refers to the minimum drug concentration that inhibits the growth of 90% of the test bacteria. Antibacterial drug: Cefbirol, manufactured by Shenyang Sanjiu Pharmaceutical Co., Ltd., content: 92.1%, batch number: YF / BALP141 / 000. Zidabactam, manufactured by Target M01 Company, batch number: 149661. As mentioned above, the English name of zidabactam is Zidabactam, and its chemical name is (2S,5R)-7-oxo-2-(2-((R)-piperidin-3-yl)-1-carboxyl)-1,6-diazabicyclo[3.2.1]octane-6-yl sulfate monoester. Test bacteria: 24 strains of KPC or OXA type β-lactamase genotype. Specifically, 24 strains of Klebsiella pneumoniae were included, of which 12 produced KPC-2 carbapenemase and 12 produced OXA-232 carbapenemase. 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). Culture medium: Cationic-adjusted Mueller-Hinton broth (CAMHB), a product of BBL Corporation, USA. Inoculum size: Pure colonies were prepared with physiological saline to a 0.5 McFarland turbidity, appropriately diluted, and added to 96-well U-bottom microplates (containing 50 μL of antibacterial drug solution). The inoculum size was 5 × 10⁵ CFU / mL. Culture conditions: Ambient air, 35℃-12℃, 16-20 hours. Preparation of antibacterial solutions: Take cefoperazone and zidabactam separately, and prepare them according to the CLSI (Conditional Classification of Antibacterial Drugs) and the drug instructions.Six groups of antibacterial solutions, A1 to A6, were prepared by dissolving and diluting the solutions. Group A1 was a control group containing only cefbirol, and Group A2 was a control group containing only zidabactam. Groups A1, A3 to A6 each included different antibacterial solutions with cefbirol concentrations ranging from 128 mg / L to 0.06 mg / L, and Group A2 included different antibacterial solutions with zidabactam concentrations ranging from 128 mg / L to 0.06 mg / L. The specific concentrations within the 128 mg / L to 0.06 mg / L range for groups A1 to A6 are: 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. The components contained in the antibacterial solutions of groups A1 to A6 are shown in Table 1. Table 1. Concentrations of Cefbirol / Zidabactam in Antibacterial Solutions of Groups A1 to A6 Group | Cefbirol Concentration | Zidabactam Concentration Range | Concentration Ratio (Cefbirol:Zidabactam) A | 128 mg / L - 0.06 mg / L | A | 128 mg / L - 0.06 mg / L | A3 | 128 mg / L - 0.06 mg / L | Based on Cefbirol concentration 1: A4 | 128 mg / L - 0.06 mg / L | Based on Cefbirol concentration 2: A5 | 128 mg / L - 0.06 mg / L | Fixed at 4 mg | A6 | 128 mg / L - 0.06 mg / L | Fixed at 8 mg | 128:4, 64:4, 32:4, 16:4, 8:4, 4:4, 2:4. 1:4.0.5:4.0.25:4.0.125:4. 0.06:4 128:8、 64:8, 32:8. 16:8. 8:8, 4:8, 2:4, 1:8, 0.5:8, 0.25:8、 0.125:8, 0.06:8 Note: The concentrations in Table 1 are mass concentrations, therefore the concentration ratios in Table 1 are equal to the mass ratios. Test results: Currently, there are no CLSI or EUCAST breakpoints for cefbirol / enzyme inhibitors, therefore the antibacterial activity of cefbirol / enzyme inhibitors is judged according to the standard of cefbirol. The results of the drug susceptibility test were statistically analyzed using WHONET 5.6 software. 7 WO 2025 / 060701 PCT / CN2024 / 109115 The partial inhibitory concentration index (FIC) of cefoperazone and zidabactam in combination was calculated according to the following formula (1), and the results are shown in Tables 2 to 5. (FIC) Index MIC of the combined drug MIC of drug B MIC of drug A MIC of drug B(1) Rule: The drug A in formula (1) is cefbiprole, and drug B is zidobactam. The judgment of the synergistic effect of the combination medication follows the following principles: (1) FIC ≤ 0.5: synergistic effect, indicating that the antibacterial activity of the two drugs after combination is significantly greater than that of each single drug; (2) FIC > 0.5-1: additive effect, indicating that when the two drugs are combined, their antibacterial activity is slightly increased compared with any single drug; (3) FIC > 1-2: irrelevant effect, indicating that the activity of neither antibacterial drug is affected by the other drug; (4) FIC > 2: antagonistic effect, indicating that the activity of one antibacterial drug is weakened by the other antibacterial drug. Table 2. In vitro antibacterial activity of cefbiprole / zidobactam of Example 1 against tested bacteria Bacteria (strains) | Antibacterial drug | MIC (mg / L) | FIC | Interpretation | --- | --- | --- | --- | --- MIC range | MIC₅₀ | MIC₉₀ | Mode Klebsiella pneumoniae (12 strains) A1 | | 128 | 128 | 128 | 128 | | A2 | | 128 | 128 | 128 | 128 | Calculated as 128 | A3 | KPC-2 | 2-8 | 2 | 2 | 2 | | A4 | | 128-2 | 128-0.03 | 128-1 | 128-0.02 | | A5 | | | 0.06 | 0.06 | 0.5 | 0.5 | | A6 | | | 0.125 | 0.06 | 0.5 | | A1 | | 128-4 | 128-0.03 | 0.125 | | A2 | | 128-8 | 128-0.07 | | | Klebsiella pneumoniae (12 strains) producing OXA-48 A1L | A | 128 | 128 | 128 | 128 | | A3 | | 128 | 128 | 64 | 128 | | A4L | | 128-2 | 64-0.05 | 1 | | A4 | | 128-2 | 64-0.06 | Synergy | A5 | | 0.06 | 0.06 | 0.5 | 0.5 | | A5 | | 128-4 | 64-0.06 | Same | A6 | | 0.06 | 0.06 | | | A6 | | 0.06-0.25 | 0.06 | 0.25 | 0.06 | 0.06 | | | 128 | 64-0.13 | | Note: In Table 2, MIC in group A2 refers to the concentration of zidobactam, and MIC in groups A1, A3 to A6 refers to the concentration of cefbiprole. As shown in Table 2, in group A5, when the concentration of zidobactam is 4 mg / L, the MIC₅₀ of cefbiprole against KPC-2-type carbapenemase-producing Klebsiella pneumoniae is 0.5 mg / L, and the concentration ratio of cefbiprole to zidobactam at this time is 0.5:4 = 0.125:1; the MIC₉₀ of cefbiprole against OXA-232-type carbapenemase-producing Klebsiella pneumoniae is ≤ 0.06 mg / L, and the concentration ratio of cefbiprole to zidobactam at this time is 0.06:4 = 0.015:1. In group A6, when the concentration of zidobactam is 8 mg / L, cefbiprole against KPC-2-producingThe MIC3 of cefbirol against type OXA-232 carbapenemase-induced Klebsiella pneumoniae was 0.125 mg / L, at which point the concentration ratio of cefbirol to zidabactam was 0.125:4 = 0.032:1. The MIC50 of cefbirol against type OXA-232 carbapenemase-induced Klebsiella pneumoniae was less than or equal to 0.06 mg / L, at which point the concentration ratio of cefbirol to zidabactam was 0.06:4 = 0.015:1. Furthermore, as shown in Table 2, the FIC values ​​of groups A3 and A4 were lower than those of group A6, indicating that at a cefbirol:zidabactam weight ratio of 1:1 to 2:1, the ratio showed better synergistic effect compared to the 0.015:1 ratio in group A6. The antibacterial results of cefbirol / zidabactam in groups A1 to A6 are shown in Tables 3 to 5. 8 WO 2025 / 060701 Table 3. Antibacterial Results of Cefbirol / Zidabactam PCT / CN2024 / 109115 Drug Concentration Serial Number Bacterial Species Bacterial Annotation A1 Group A2 Group A3 Group A4 Group A5 Group A6 Group 1 18%09-043 kp: KPC-2 128 >128 2 4 0.5 2 18%09-045 kp: KPC-2 128 128 2 2 0.5 0.125 3 18%09-0:9 kp: KPC-2 128 128 2 2 0.5 0.06 4 18 W09 047 k KPC-2 128 128 2 4 <0.06 <0.06 5 18 W09 0:9 kpn KPC-2 128 >128 2 2 0.5 <0.06 6 18 W09 050 kp KPC-2 128 128 2 2 0.25 0.125 7 18 :%09-0:5 kpn KРC-2 128 128 4 8 4 2 18 13-013 kpn KPC-2 >128 >128 2 4 <0.06 <0.06 9 18 W13 0:⑆ kpa KPC-2 128 128 4 4 0.25 10 18-813-05 kp KP-2 128 128 2 2 0.5 0.125 11 18-13-026 Кр KPC-2 128 128 4 8 0.5 12 18--813-0:7 kpi KIC-2 128 1 2 <0.06 <0.06 13 20-W-1-001 kp OXA-232 128 128 2 8 0.5 0.06 14 20-81-02 kpu (OXA-232 128 128 2 4 ≤0.06 15 20-81-003 kpa OXA-232 128 42 0.06 <0.06 16 20-W1-00-1 kpn ОXA-232 128 128 2 4 <0.06 0.125 17 20 F1 005 kpn OXA-232 128 128 2 2 <0.06 0.06 1 20 F 007 kp: OXA-232 128 2 2 4 0.06 <0.06 19 20-81-008 kpn (OXA-232 >128 64 2 4 <0.06 0.125 20 20-W1-009 kp OXA-232 128 128 4 4 0.06 0.25 21 200-7-01) kp: OXA-232 128 1 1 2 <0.06 0,125 22 20-01-01 ky OXA-232 128 8 ? 4 0.06 <0.06 23 20 1 012 k OXA-232 128 128 2C 0.5 0.25 24 20 1 013 kpn OXA-232 128 4 2 4 <0.06 <0.06 Note: In Table 3, the drug concentration in group A2 refers to the concentration of zidabhatin, and the drug concentrations in groups A1, A3 to A6 refer to the concentration of cefoperazone. Table 4. MIC Distribution and Cumulative Inhibition Rate of Cefbirol / Zidabactam against KPC-Producing Carbapenemase-Induced Klebsiella pneumoniae in Example 1 WO 2025 / 060701 PCT / CN2024 / 109115 MIC (mg / L.) Antimicrobial Agent 0.06 0.125 0.25 0.5 1 2 4 128 >128 Number of Strains A Cumulative Number of Strains 12 12 Cumulative Inhibition Rate (%) 100 Number of Strains 1 4 7 A2 Group Cumulative Number of Strains 5 12 Cumulative Inhibition Rate (%) 8.3 41.7 100 Number of Strains 8 3 A3 1 Cumulative Number of Strains 9 12 Cumulative Inhibition Rate (%) 8.3 75 100 Number of Strains 6 4 2 A4 Group Cumulative Number of Strains 6 10 12 Cumulative Inhibition Rate (%) 50) 83.3 100 Number of strains 3 A5 group cumulative strains 3 4 11 12 Cumulative and bacterial count (1) 25 33.3 75 91.7 100 Hai5 3 1 A6 group cumulative strains cumulative and bacterial count (1) 5 8 १ 10 Π 12 41.7 66.7 75 833 91.7 100 Note: In Table 4, the MIC of group A2 refers to the concentration of zidabhatin, and the MIC of groups A1, A3 to A6 refers to the concentration of cefbirol. Table 5. Example 1 Cefbirol / zidabhatin on the production of OXA-232MIC Distribution and Cumulative Inhibitory Rate of Carbapenemase-Induced Klebsiella pneumoniae Antimicrobial Drug MIC (mg / Al.) 0.06 0.125 0.25 0.5 1 2 4 8 64 128 >128 Number 12 AI Cumulative Bacterial Count 12 Cumulative Inhibitory Rate (1) 100 Strain 1 2 42V Cumulative Bacterial Count 2 4 5 6 12 Cumulative Inhibitory Rate (%) 8.3 16.7 33.3 41.7 50 66.7 100 Number of Bacteria 9 A3 Number 2 11 12 Cumulative Inhibitory Rate (%) 16.7 91.7 100 Strain Count 4 7 A4 Cumulative Bacterial Count 4 11 12 Cumulative Inhibitory Rate (%) 33.3 91.7 100 Bacteria 1 AS Cumulative bacterial count 9 12 Liu Cumulative bacterial count (%) 75 91.7 100 Count 7 3 2 A6 Cumulative fast 7 10 12 Red Cumulative bacterial count (%) 58.3 83.3 100 10 (19) *EP004781993A1* (11) EP 4 781 993 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: 29.07.2026 Bulletin 2026 / 31 (21) Application number: 24867118.2 (22) Date of filing: 01.08.2024 (51) International Patent Classification (IPC): A61K 31 / 545 (2006.01) A61K 31 / 454 (2006.01) A61K 45 / 06 (2006.01) A61P 31 / 04 (2006.01) (52) Cooperative Patent Classification (CPC): Y02A 50 / 30 (86) International application number: PCT / CN2024 / 109115 (87) International publication number: WO 2025 / 060701 (27.03.2025 Gazette 2025 / 13) (84) Designated Contracting States: AL AT BE BG CH CYCZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR Designated Extension States: BA Designated Validation States: GE KH MA MD TN (30) Priority: 18.09.2023 CN 202311205221 (71) Applicant: Shenzhen China Resources Gosun Pharmaceuticals Co., Ltd. Shenzhen, Guangdong 518049 (CN) (72) Inventors: • HU, Fupin Shanghai 200040 (CN) • HUANG, Quanhua Shenzhen, Guangdong 518049 (CN) • GUO, Yan Shanghai 200040 (CN) • ZHANG, Yong Shenzhen, Guangdong 518049 (CN) • WU, Shi Shanghai 200040 (CN) • ZHANG, Weiwei Shenzhen, Guangdong 518049 (CN) • HAN, Renru Shanghai 200040 (CN) • LI, Xin Shanghai 200040 (CN) • LAI, Baolin Shenzhen, Guangdong 518049 (CN) • ZHONG, Yihua Shenzhen, Guangdong 518049 (CN) (74) Representative: Dai, Simin Reyda IP A073 157, Quai du Président Roosevelt 92130 Issy-les-Moulineaux (FR) (54) ANTIBACTERIAL COMPOSITION AND ANTIBACTERIAL DRUG (57) An antibacterial composition and an antibacter- ial drug. The antibacterial compositioncomprises cepha- losporin and zidebactam, wherein cephalosporin com- prises at least one of ceftobiprole and a ceftobiprole derivative; and cephalosporin is calculated on the basis of C20H22N8O6S2, and the mass ratio of the cephalos- porin 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. EP 4 78 1 99 3 A 1 Processed by Luminess, 75001 PARIS (FR) Description

[0001] The present application claims priority to the Chinese patent application 202311205221.8 filed on September 18, 2023, and the contents of the Chinese patent application are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present disclosure belongs to the technical field of antibacterial drugs, andspecifically relates to an antibacterial composition and an antibacterial drug. BACKGROUND

[0003] Ceftobiprole is a broad-spectrum cephalosporin that exerts bactericidal activity in susceptible strains by binding to penicillin binding proteins (PBPs). The PBPs bound by ceftobiprole include PBPs with decreased susceptibility to multiple β-lactams, such as PBP2a in methicillin-resistant Staphylococcus aureus (MRSA), and PBP2b and PBP2x in Streptococcus pneumoniae (penicillin-intermediate and -resistant), thereby endowing ceftobiprole with activity against methicillin-resistant Staphylococcus aureus (MRSA) and against Gram-negative bacteria, including some Pseudomonas aeruginosa.

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

[0005] The purpose of the present disclosure is to provide an antibacterial composition or an antibacterial kit, as well as an antibacterial drug, so as to further enhance the antibacterial effect against ceftobiprole-resistant bacteria, and to address the technical problem currently observed in which ceftobiprole exhibits reduced antibacterial activity or no antibacterial activity against some bacteria.

[0006] In the first aspect, an embodiment of the present disclosure provides an antibacterial composition or an antibacterial kit, wherein the antibacterial composition comprises a cephalosporin and zidebactam;

[0007] wherein the cephalosporin comprises one or more of ceftobiprole or a ceftobiprole derivative;

[0008] the cephalosporin is calculated as C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 10:1.

[0009] The antibacterial composition or the antibacterial kit of the embodiment of the present disclosure, through the compounding of thecephalosporin and zidebactam and simultaneous control of the mass ratio of the cephalosporin to zidebactam, enables the cephalosporin and zidebactam to exert a synergistic antibacterial effect on each other, thereby increasing the antibacterial activity of the antibacterial composition, making the antibacterial composition exhibit excellent antibacterial effects, especially the antibacterial effect against ceftobiprole-resistant bacteria.

[0010] In the second aspect, an embodiment of the present disclosure provides an antibacterial drug, wherein the antibacterial drug comprises the aforementioned antibacterial composition of the present disclosure.

[0011] Owing to the excellent antibacterial activity exhibited by the antibacterial composition of the present disclosure, the antibacterial drug of the present disclosure correspondingly possesses such excellent antibacterial activity as well. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0012] In order to make the technical problems tobe solved, technical solutions, and beneficial effects of the present disclosure more clear and comprehensible. Hereinafter, the present disclosure will be further elaborated on in conjunction with the embodiments. It should be understood that the specific embodiments described herein are solely for illustrating the present disclosure and are not intended to limit the scope of the present disclosure.

[0013] In the present disclosure, "at least one" means one or more, and "more than one" means two or more. "At least one of the following (item(s))" or similar expressions refers to any combination of these items, including any combination of single item(s) or multiple item(s). For example, "at least one (item) of a, b, or c", or "at least one (item) of a, b, and c", may each indicate: a, b, c, a-b (i.e., a and b), a-c, b-c, or a-b-c, wherein a, b, and c may each be single or may be multiple.

[0014] It should be understood that in various embodiments of the present disclosure, themagnitude of the serial numbers of the aforementioned processes does not indicate the order of execution; some or all of the steps may be executed in parallel or in sequence; the execution order of each process should be determined by its function and intrinsic logic, and should not constitute any limitation on the implementation process of the embodiments of the present disclosure.

[0015] The terms used in the embodiments of the present disclosure are solely for the purpose of describing specific 2 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 embodiments and are not intended to limit the present disclosure. The singular forms "a", "the", and "said" used in the embodiments of the present disclosure and the appended claims are also intended to include the plural form, unless the context clearly indicates otherwise.

[0016] The weights of relevant components mentioned in the embodiments of the specification of the present disclosure may refer not merely to the specific content of eachcomponent, but may also indicate the proportional relationship of weights among each component; therefore, any proportional scaling up or scaling down of the component contents specified in the embodiments of the specification of the present disclosure is deemed to be within the scope disclosed in the embodiments of the specification of the present disclosure. Specifically, the mass described in the embodiments of the specification of the present disclosure may be represented by mass units commonly known in the chemical engineering field, such as µg, mg, g, or kg.

[0017] Ceftobiprole is a new-generation broad-spectrum cephalosporin that exhibitsantibacterial activity against methicillin-resistant Staphylococcus aureus and against Gram-negative bacteria (including some Pseudomonas aeru- ginosa). Its mechanism of action is similar to other cephalosporins, as a bactericide during the reproductive phase, it binds to PBPs, interferes with bacterial cell wall synthesis, inhibits bacterialgrowth, and ultimately causes bacterial death. However, with the clinical application of ceftobiprole, bacterial resistance to ceftobiprole has been increasingly enhanced. To resolve the technical problem in the prior art that ceftobiprole shows reduced antibacterial activity or no antibacterial activity against drug-resistant bacteria, the embodiments of the present disclosure propose the following technical solutions.

[0018] In the first aspect, an embodiment of the present disclosure provides an antibacterial composition or an antibacterial kit. The antibacterial composition or the antibacterial kit comprises a cephalosporin and zidebactam.

[0019] Among them, the cephalosporin comprises at least one of ceftobiprole or a ceftobiprole derivative, and may comprise either a single active ingredient, ceftobiprole or a ceftobiprole derivative, or may comprise both active ingredients simultaneously, namely ceftobiprole and a ceftobiprole derivative.

[0020] The cephalosporin is calculatedas C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 10:1.

[0021] When the cephalosporin comprises ceftobiprole, the molecular formula of ceftobiprole is C20H22N8O6S2, and the 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’-bipyrrolidin]‑3-ylidene)methyl)‑5-thia‑1-azabicyclo[4.2.0]oct‑2-ene‑2-carboxylic acid, and the structural formu- la is shown in formula (1):

[0022] When the cephalosporin comprises a ceftobiprole derivative, the ceftobiprole derivative refers to a derivative based on the aforementioned ceftobiprole.

[0023] The chemical name of zidebactam, as comprised in the antibacterial composition or the antibacterial kit of the present disclosure, is (2S,5R)‑7-oxo‑2‑(2‑((R)‑piperidine‑3-carbonyl)hydrazine‑1-carbonyl)‑1,6-diazabicyclo[3.2.1]oc- tan‑6-yl hydrogen sulfate. The structural formula of zidebactam is shown in formula (2): 3 EP 4 781 993 A1 5 10 15 20 25 30 35 40 4550 55

[0024] Furthermore, zidebactam may also be a derivative of the structure shown in the aforementioned formula (2), exhibiting activity similar to that of the aforementioned formula (2).

[0025] The antibacterial composition or the antibacterial kit of the embodiments of the present disclosure, through the compounding of the cephalosporin and zidebactam and simultaneous control of the mass ratio of the cephalosporin to zidebactam within a specific range, enables the cephalosporin and zidebactam to exert a synergistic effect on each other, thereby enhancing the antibacterial effect of the antibacterial composition or the antibacterial kit, making the antibacterial composition or the antibacterial kit exhibit excellent antibacterial activity against bacteria resistant to cephalosporin monotherapy or to zidebactam monotherapy.

[0026] In some embodiments, in the antibacterial composition or the antibacterial kit, the cephalosporin derivative is calculated as ceftobiprole (molecularformula C20H22N8O6S2), and the mass ratio of the cephalosporin to zidebactam may further be 0.1:1 to 8:1; in further exemplary embodiments, it may be 0.1:1 to 4:1; in still further exemplary embodiments, it may be 0.1:1 to 2.5:1. In specific exemplary embodiments, the mass ratio of the cephalosporin to zidebactam may 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. Among them, when the cephalosporin comprises solely ceftobiprole, the mass ratio refers to the mass ratio of ceftobiprole calculated as C20H22N8O6S2 to zidebactam; when the cephalosporin comprises solely a ceftobiprole derivative, the mass ratio refers to the mass ratio of the ceftobiprole derivative calculated as C20H22N8O6S2 to zidebactam. When the cephalosporin comprises ceftobiprole and the ceftobiprole derivative, the mass ratio refers tothe mass ratio of the total amount of ceftobiprole and the ceftobiprole derivative, calculated as C20H22N8O6S2, to zidebactam.

[0027] Controlling the mass ratio of the cephalosporin to zidebactam within this range further promotes the synergistic effect on each other between the cephalosporin and zidebactam, thereby further enhancing the antibacterial activity of the antibacterial composition or the antibacterial kit.

[0028] In some embodiments, the cephalosporin and zidebactam comprised in the antibacterial composition or the antibacterial kit may be provided in a mixed form. By providing the cephalosporin and zidebactam in a mixed form, it is conducive to enhancing the product uniformity of the antibacterial composition or the antibacterial kit, while facilitating the use of the antibacterial composition or the antibacterial kit, such that the antibacterial composition or the antibacterial kit does not need to be mixed again prior to use.

[0029] In some embodiments, the cephalosporinand zidebactam exert a synergistic effect against bacteria.

[0030] In some embodiments, the cephalosporin and zidebactam exert a fractional 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, an FIC of 0.13, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01.

[0031] In some embodiments, when the cephalosporin and zidebactam are used in combination, ceftobiprole has an MIC50 of less than or equal to 4 mg / L against the bacteria, preferably an MIC50 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.

[0032] In some embodiments, the bacteria are KPC‑2 producing bacteria.

[0033] In some embodiments, when the cephalosporin and zidebactam are used in combination, ceftobiprole has an MIC90 of less than or equal to 8 mg / L against the bacteria,preferably an MIC90 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.

[0034] In some embodiments, the bacteria are OXA‑48 producing bacteria.

[0035] In some embodiments, the bacteria are Gram-negative bacteria.

[0036] In some embodiments, the bacteria are Escherichia coli and / or Klebsiella pneumoniae; in some embodiments, the bacteria are one or more of NDM producing bacteria, KPC producing bacteria, or OXA producing bacteria. 4 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55

[0037] In some embodiments, the cephalosporin and zidebactam in the antibacterial composition or the antibacterial kit may also be provided separately from each other and then mixed prior to use. For example, when the antibacterial composition is prepared as an injection, the cephalosporin and zidebactam can be packaged separately and then mixed together prior to injection, or the cephalosporin andzidebactam can be injected separately. By means of providing the cephalosporin and zidebactam separately, the qualitystability of each component in the antibacterial composition is further enhanced.

[0038] In some embodiments, when the cephalosporin comprises a ceftobiprole derivative, the ceftobiprole derivative may be a compound capable of being converted into ceftobiprole. In specific exemplary embodiments, the ceftobiprole derivative may comprise at least one of a ceftobiprole salt, a ceftobiprole ester, or a ceftobiprole ester derivative.

[0039] Among them, the ceftobiprole salt is a salt formed based on ceftobiprole, such as an alkali metal salt, hydrochloride, bromate, acetate, sulfate, and the like of ceftobiprole. In further exemplary embodiments, the alkali metal salt of ceftobiprole may be a sodium salt or a potassium salt. The ceftobiprole ester is a compound containing an ester group formed based on ceftobiprole.

[0040] In some embodiments, the ceftobiprole ester may be acompound having the structure as shown in formula (3), the molecular formula of which is C26H26N8O11S2, and the chemical name is (6R,7R)‑7‑((Z)‑2‑(5-amino‑1,2,4-thiadia- zol‑3-yl)‑2‑(hydroxyimino)acetamido]‑3‑((E)‑((R)‑1’‑(((5-methyl‑2-oxo‑1,3-dioxol‑4-yl)methoxy)carbonyl)‑2-oxo‑[1,3’-bi- pyrrolidin]‑3-ylidene)methyl)‑8-oxo‑5-thia‑1-azabicyclo[4.2.0]oct‑2-ene‑2-carboxylic acid.

[0041] The ceftobiprole ester shown in formula (3), as a prodrug of ceftobiprole, hydrolyzes into ceftobiprole after entering the human body; the ceftobiprole ester shown in formula (3) is conducive to enhancing the stability of the compound.

[0042] In some embodiments, the ceftobiprole ester derivative may also comprise a ceftobiprole ester salt formed from a ceftobiprole ester; in further aspects, the ceftobiprole ester salt may comprise at least one of an acetate, sulfate, hydrochloride, bromate, or alkali metal salt of a ceftobiprole ester. In a still further aspect, the alkali metal salt of the ceftobiproleester may be a sodium salt or a potassium salt. The salt formed from ceftobiprole and a ceftobiprole ester can enhance the water solubility of ceftobiprole and the ceftobiprole ester, thereby, when the antibacterial composition is made into an injection, the injection has a short reconstitution time; meanwhile, the formation of sodium salt is conducive to reducing the irritation associated with injection administration.

[0043] In some embodiments, the sodium salt formed from the ceftobiprole ester shown in formula (3) may be ceftobiprole ester sodium. The molecular formula of ceftobiprole ester sodium is C26H25N8NaO11S2, and the chemical name is monosodium (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’-bipyrrolidin]‑3-ylidene)methyl)‑8-oxo‑5-thia‑1-azabicyclo [4.2.0]oct‑2-ene‑2-carboxylate. The structural formula of ceftobiprole ester sodium is as shown in formula (4):

[0044] After the ceftobiprole ester shown in formula (3) forms the ceftobiprole ester sodium shown in formula (4), the water solubility is enhanced, thereby further enhancing the water solubility of the antibacterial composition and simulta- 5 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 neously reducing the irritation when the antibacterial composition is used as an injection, such as for intravenous injection.

[0045] In the second aspect, an embodiment of the present disclosure provides an antibacterial drug. The antibacterial drug comprises the aforementioned antibacterial composition of the present disclosure. Since the antibacterial composi- tion of the present disclosure exhibits excellent antibacterial activity, the antibacterial drug thus exhibits excellent antibacterial activity.

[0046] In some embodiments, the antibacterial drug further comprises a pharmaceutically acceptable excipient, such as a solvent, a bulking agent, or a pH regulator.

[0047] In some embodiments, theantibacterial drug may be an injection.

[0048] In some embodiments, the antibacterial drug comprises a drug used against at least one of NDM producing bacteria, KPC producing bacteria, or OXA producing bacteria.

[0049] In some embodiments, the NDM producing bacteria compriseEscherichiacoli. In further embodiments, when the antibacterial drug is applied to NDM producing Escherichia coli, the mass ratio of the cephalosporin to zidebactam may be 0.1:1 to 10:1, preferably 0.1:1 to 8:1.

[0050] In some embodiments, the KPC producing bacteria comprise Klebsiella pneumoniae. In further embodiments, when the antibacterial drug is applied to KPC producing Klebsiella pneumoniae, the mass ratio of the cephalosporin to zidebactam may be 0.1:1 to 10:1, preferably 0.1:1 to 8:1.

[0051] In some embodiments, the OXA producing bacteria comprise Klebsiella pneumoniae. In further embodiments, when the antibacterial drug is applied to OXA producing Klebsiella pneumoniae, the mass ratio of the cephalosporinto zidebactam may be 0.1:1 to 10:1, preferably 0.1:1 to 8:1.

[0052] The antibacterial composition of the embodiments of the present disclosure exhibits excellent antibacterial activity against NDM producing Escherichia coli, KPC producing Klebsiella pneumoniae, OXA producing Klebsiella pneumoniae, enabling the antibacterial drug of the embodiments of the present disclosure to exert a favorable therapeutic effects on infections caused by such bacteria.

[0053] In some embodiments, the dosage of the antibacterial drug is: the concentration of zidebactam in the application environment is from 4mg / L to 8 mg / L; in specificexemplary embodiments, the concentration of zidebactam may be4 mg / L, 5 mg / L, 6 mg / L, 7 mg / L, or 8 mg / L. Controlling the concentration of zidebactam within this range further enhances the synergistic effect on each other between the cephalosporin and zidebactam. The term "concentration in the application environment" as referred to herein means the concentration level of thedrug and its metabolite in a specific application environment, which can be a specific site in the human body, such as blood, tissue, or organ and the like, or it can be an in vitro environment, such as a drug formulation, a drug release system, or a drug delivery device. This concentration can be the concentration of the free (not bound to protein or other molecule) drug, or it can be the total drug concentration (including free and bound drugs). It is usually expressed as the mass of the drug and its metabolite in each liter of fluid (such as mg / L or µg / L).

[0054] In some embodiments, the antibacterial drug comprises a drug for treating at least one of pulmonary infection, bloodstream infection, or urinary tract infection. In further embodiments, treating pulmonary infection, bloodstream infection, and urinary tract infection can be caused by multidrug-resistant, extensively drug-resistant, or pan-drug- resistant bacteria.

[0055] In some embodiments, the aforementioned antibacterialcomposition or the antibacterial kit or the aforemen- tioned antibacterial drug is used for treating pulmonary infection, bloodstream infection and / or urinary tract infection.

[0056] In a second aspect, an embodiment of the present disclosure provides a use of the aforementioned antibacterial drug in the manufacture of a medicament for treating pulmonary infection, bloodstream infection and / or urinary tract infection.

[0057] In a third aspect, an embodiment of the present disclosure provides a method of treating pulmonary infection, bloodstream infection and / or urinary tract infection, comprising administering the aforementioned antibacterial composi- tion or kit or the aforementioned antibacterial drug to a subject in need thereof.

[0058] In a third aspect, an embodiment of the present disclosure provides a use of a therapeutically effective amount of a cephalosporin and a therapeutically effective amount of zidebactam in the manufacture of a medicament, drug combination, or kit fortreating pulmonary infection, bloodstream infection and / or urinary tract infection; wherein the therapeutically effective amount of the cephalosporin and zidebactam may be administered simultaneously, separately, or sequentially; wherein the cephalosporin comprises one or more of ceftobiprole or a ceftobiprole derivative; the cephalosporin is calculated as C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 10:1, preferably 0.1:1 to 8:1.

[0059] The antibacterial compositions and uses thereof and antibacterial drugs and the like in the embodiments of the present disclosure are illustrated below through multiple specific examples. 6 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 Example 1

[0060] As recommended by CLSI (Clinical and Laboratory Standards Institute) M07-A11 (2018 edition), the Broth- microdilution method is adopted to determine the minimum inhibitory concentration (MIC) of ceftobiprole and zidebactam against clinical isolates. It should be notedthat, in the present disclosure, MIC50 refers to the minimum drug concentration that inhibits the growth of 50% of the tested bacteria, and MIC90 refers to the minimum drug concentration that inhibits the growth of 90% of the tested bacteria.

[0061] Antibacterial drug: ceftobiprole, manufacturer: Shenyang Sanjiu Pharmaceutical, content: 92.1%, batch num- ber: YF / BALP141 / 000. Zidebactam, manufacturer: Target M01 company, batch number: 149661. Zidebactam, as described above, the English name is Zidebactam, and the chemical name is: (2S,5R)‑7-oxo‑2‑(2‑((R)‑piperidine‑3- carbonyl)hydrazine‑1-carbonyl)‑1,6-diazabicyclo[3.2.1]octan‑6-yl hydrogen sulfate.

[0062] Tested strains: a total of 24 genotypic strains producing KPC or OXA β-lactamase. Specifically, the tested strains include 24 strains of Klebsiella pneumoniae, including 12 KPC‑2 producing strains and 12 OXA‑232 producing strains.

[0063] Quality control strains: Escherichia coli ATCC 25922, (KPC‑2 producing) Klebsiella pneumoniae ATCCBAA‑1705, and (NDM‑1 producing) Klebsiella pneumoniae ATCC BAA‑2146.

[0064] Medium: cation-adjusted Mueller-Hinton broth (CAMHB), a product of BBL Company, USA.

[0065] Inoculum size: Pure isolated colonies were adjusted with normal saline to 0.5 McFarland turbidity. After appropriate dilution, the suspension was added to the wells of a 96-well U-bottom microplate (containing 50 µL antibacterial drug solution). The inoculum size was 5 × 105 CFU / mL.

[0066] Culture conditions: air environment, 35°C ± 2°C, 16 to 20 hours.

[0067] Preparation of Antibacterial Drug Solution : Ceftobiprole and zidebactam were taken separately, dissolution and dilution were performed according to the antibacterial drug reference to the CLSI standards and the drug package insert, A1 to A6, a total of 6 groups of antibacterial drug solutions, were prepared, among which, group A1 was the control group containing solely the single agent ceftobiprole, and group A2 was the control group containing solely the singleagent zidebactam. Different antibacterial drug solutions with ceftobiprole concentrations ranging from 128 mg / L to 0.06 mg / L were respectively included in groups A1 and A3 to A6, and different antibacterial drug solutions with zidebactam concentrations ranging from 128 mg / L to 0.06 mg / L were included in group A2. The specific concentrations within the range of 128 mg / L to 0.06 mg / L in groups A1 to A6 were respectively 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, or 0.06 mg / L, respectively. The components contained in the antibacterial drug solutions of groups A1 to A6 are shown in Table 1. Table 1. Concentrations of ceftobiprole / zidebactam contained in the antibacterial drug solutions of groups A1 to A6 Group Concentration of ceftobiprole Concentration of zidebactam Concentration ratio (ceftobiprole: zidebactam) Group A1 128 mg / L to 0.06 mg / L / / Group A2 / 128 mg / L to 0.06 mg / L / Group A3 128 mg / L to 0.06 mg / L Adjusted based onconcentra- tion of ceftobiprole 1:1 Group A4 128 mg / L to 0.06 mg / L Adjusted based on ceftobi- prole concentration 2:1 Group A5 128 mg / L to 0.06 mg / L Fixed at 4 mg / L 128:4, 64:4, 32:4, 16:4, 8:4, 4:4, 2:4, 1:4, 0.5:4, 0.25:4, 0.125:4, 0.06:4 Group A6 128 mg / L to 0.06 mg / L Fixed at 8 mg / L 128:8, 64:8, 32:8, 16:8, 8:8, 4:8, 2:4, 1:8, 0.5:8, 0.25:8, 0.125:8, 0.06:8 Note: The concentrations in Table 1 are mass concentrations; therefore, the concentration ratio in Table 1 is equal to the mass ratio.

[0068] Experimental results: Currently, there are no established CLSI or EUCAST breakpoints for ceftobiprole / β- lactamase inhibitor. Therefore, the antibacterial activity of ceftobiprole / β-lactamase inhibitor is evaluated in accordance with the standards for ceftobiprole. WHONET 5.6 software is used to perform statistical analysis on the results of antibacterial susceptibility test. The fractional inhibitory concentration index (FIC) for the combination of ceftobiprole and zidebactam iscalculated according to Equation (1). The results are shown in Tables 2 to 5. 7 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55

[0069] In Equation (1), drug A is ceftobiprole, and drug B is zidebactam. The synergistic effects of the combination are interpreted based on the following criteria: (1) FIC ≤ 0.5: synergy, indicating that the antibacterial activity after the combination of the two drugs is significantly higher than that of each single agent; (2) 0.5 < FIC ≤ 1: additive effect, indicating that the combination of the two drugs has slightly increased antibacterial activity compared to either single agent; (3) 1 < FIC ≤ 2: indifferent effect, indicating that the activities of both antibacterial drugs are not affected by the other drug; (4) FIC > 2: antagonism, indicating that the activity of one antibacterial drug is attenuated by the other antibacterial drug. Table 2. In vitro antibacterial activity of ceftobiprole / zidebactam against the tested bacteria in Example 1 Bacteria(strains) Antibacterial drug MIC (mg / L) FIC Explanation MIC range MIC 50 MIC 90 Mode KPC‑2 pro- ducing Kleb- siella pneu- moniae (12 strains) Group Al >128 >128 >128 >128 Calculated as 128 / Group A2 1 to >128 >128 >128 >128 Calculated as 128 / Group A3 1 to 4 2 4 2 2 / 128+2 / 128=0. 03 Synergy Group A4 2 to 8 2 8 2 2 / 128+1 / 128=0. 02 Synergy Group A5 ≤0.06 to 4 0.5 1 0.5 0.5 / 128+4 / 128= 0.03 Synergy Group A6 ≤0.06 to 2 0.12 5 1 ≤0.06 0.125 / 128+8 / 12 8=0.07 Synergy OXA‑48 pro- ducing Kleb- siella pneu- moniae (12 strains) Group A1 >128 >128 >128 >128 Calculated as 128 / Group A2 1 to >128 64 >128 >128 / / Group A3 1 to 4 2 2 2 2 / 128+2 / 64=0.0 5 Synergy Group A4 2 to 8 4 4 4 4 / 128+2 / 64=0.0 6 Synergy Group A5 ≤0.06 to 1 ≤0.0 6 0.5 ≤0.06 0.06 / 128+4 / 64= 0.06 Synergy Group A6 ≤0.06 to 0.25 ≤0.0 6 0.25 ≤0.06 0.06 / 128+8 / 64= 0.13 Synergy Note: In Table 2, the MIC for group A2 refers to the concentration of zidebactam, and the MIC for groups A1 and A3 to A6 refers to the concentration of ceftobiprole.

[0070] As shown in Table 2, in group A5, when the concentration of zidebactam is 4 mg / L, the MIC50 of ceftobiprole against KPC‑2 producing Klebsiella pneumoniae is 0.5 mg / L; at which point the concentration ratio of ceftobiprole to zidebactam is 0.5:4 (i.e., 0.125:1); the MIC50 of ceftobiprole against OXA‑232 producing Klebsiella pneumoniae is less than or equal to 0.06 mg / L;and the concentration ratio of ceftobiprole to zidebactam is calculated as 0.06:4 (i.e., 0.015:1).

[0071] In group A6, when the concentration of zidebactam is 8 mg / L, the MIC50 of ceftobiprole against KPC‑2 producing Klebsiella pneumoniae is 0.125 mg / L; at which point the concentration ratio of ceftobiprole to zidebactam is 0.125:4 (i.e., 0.032:1); the MIC50 of ceftobiprole against OXA‑232 producing Klebsiella pneumoniae is less than or equal to 0.06 mg / L; the concentration ratio of ceftobiprole to zidebactam is calculated as 0.06:4 (i.e., 0.015:1).

[0072] In addition, as shown in Table 2, the FICs values of groupsA3 and A4 are all lower than that of group A6, indicating that under the condition that the mass ratio of ceftobiprole to zidebactam ranging from 1:1 to 2:1, the synergistic effect is superior to that of the 0.015:1 ratio in group A6. The antibacterial results of ceftobiprole / zidebactam for groups A1 to A6 are shown in Tables 3 to 5. 8 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 Table 3. Antibacterial results of ceftobiprole / zidebactam No. Strain No. Bacteria Notes Drug concentration Group A1 Group A2 Group A3 Group A4 Group A5 Group A6 1 18-W09‑043 kpn KPC‑2 >128 >128 2 4 0.5 1 2 18-W09‑045 kpn KPC‑2 >128 >128 2 2 0.5 0.125 3 18-W09‑046 kpn KPC‑2 >128 128 2 2 0.5 ≤0.06 4 18-W09‑047 kpn KPC‑2 >128 128 2 4 ≤0.06 ≤0.06 5 18-W09‑049 kpn KPC‑2 >128 >128 2 2 0.5 ≤0.06 6 18-W09‑050 kpn KPC‑2 >128 128 2 2 0.25 0.125 7 18-W09‑051 kpn KPC‑2 >128 >128 4 8 4 2 8 18-W13‑043 kpn KPC‑2 >128 >128 2 4 ≤0.06 ≤0.06 9 18-W13‑044 kpn KPC‑2 >128 >128 4 4 1 0.25 10 18-W13‑045 kpn KPC‑2 >128 128 2 2 0.50.125 11 18-W13‑046 kpn KPC‑2 >128 >128 4 8 1 0.5 12 18-W13‑047 kpn KPC‑2 >128 1 1 2 ≤0.06 ≤0.06 13 20-W4‑001 kpn OXA‑232 >128 >128 2 8 0.5 ≤0.06 14 20-W4‑002 kpn OXA‑232 >128 >128 2 4 1 ≤0.06 15 20-W4‑003 kpn OXA‑232 >128 4 1 2 ≤0.06 ≤0.06 16 20-W4‑004 kpn OXA‑232 >128 >128 2 4 ≤0.06 0.125 17 20-W4‑005 kpn OXA‑232 >128 128 2 2 ≤0.06 ≤0.06 18 20-W4‑007 kpn OXA‑232 >128 2 2 4 ≤0.06 ≤0.06 19 20-W4‑008 kpn OXA‑232 >128 64 2 4 ≤0.06 0.125 20 20-W4‑009 kpn OXA‑232 >128 128 4 4 ≤0.06 0.25 21 20-W4‑010 kpn OXA‑232 >128 1 1 2 ≤0.06 0.125 22 20-W4‑011 kpn OXA‑232 >128 8 2 4 ≤0.06 ≤0.06 23 20-W4‑012 kpn OXA‑232 >128 >128 2 2 0.5 0.25 24 20-W4‑013 kpn OXA‑232 >128 4 2 4 ≤0.06 ≤0.06 Note: In Table 3, the drug concentration in group A2 refers to the concentration of zidebactam, and the drug con- centrations in groups A1 and A3 to A6 are the concentrations of ceftobiprole. Table 4. MIC distribution and cumulative inhibition rate of ceftobiprole / zidebactam against KPC producing Klebsiella pneumoniaein Example 1 Antibacterial drug MIC (mg / L) 0.06 0.125 0.25 0.5 1 2 4 8 128 >128 Group A1 Number of strains 12 Cumulative number of strains 12 Cumulative inhibition rate (%) 100 Group A2 Number of strains 1 4 7 Cumulative number of strains 1 5 12 Cumulative inhibition rate (%) 8.3 41.7 100 Group A3 Number of strains 1 8 3 Cumulative number of strains 1 9 12 Cumulative inhibition rate (%) 8.3 75 100 9 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Antibacterial drug MIC (mg / L) 0.06 0.125 0.25 0.5 1 2 4 8 128 >128 Group A4 Number of strains 6 4 2 Cumulative number of strains 6 10 12 Cumulative inhibition rate (%) 50 83.3 100 Group A5 Number of strains 3 1 5 2 1 Cumulative number of strains 3 4 9 11 12 Cumulative inhibition rate (%) 25 33.3 75 91.7 100 Group A6 Number of strains 5 3 1 1 1 1 Cumulative number of strains 5 8 9 10 11 12 Cumulative inhibition rate (%) 41.7 66.7 75 83.3 91.7 100 Note: In Table 4, the MIC for group A2 refers to the concentration of zidebactam, andthe MIC for groups A1 and A3 to A6 refers to the concentration of ceftobiprole. Table 5. MIC distribution and cumulative inhibition rate of ceftobiprole / zidebactam against OXA‑232 producing Klebsiella pneumoniae in Example 1 Antibacterial drug MIC (mg / L) 0.06 0.125 0.25 0.5 1 2 4 8 64 128 >128 Group A1 Number of strains 12 Cumulative number of strains 12 Cumulative inhibition rate (%) 100 Group A2 Number of strains 1 1 2 1 1 2 4 Cumulative number of strains 1 2 4 5 6 8 12 Cumulative inhibition rate (%) 8.3 16.7 33.3 41.7 50 66.7 100 Group A3 Number of strains 2 9 1 Cumulative number of strains 2 11 12 Cumulative inhibition rate (%) 16.7 91.7 100 Group A4 Number of strains 4 7 1 Cumulative number of strains 4 11 12 Cumulative inhibition rate (%) 33.3 91.7 100 10 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Antibacterial drug MIC (mg / L) 0.06 0.125 0.25 0.5 1 2 4 8 64 128 >128 Group A5 Number of strains 9 2 1 Cumulative number of strains 9 11 12 Cumulative inhibition rate(%) 75 91.7 100 Group A6 Number of strains 7 3 2 Cumulative number of strains 7 10 12 Cumulative inhibition rate (%) 58.3 83.3 100 Note: In Table 5, the MIC for group A2 refers to the concentration of zidebactam, and the MIC for groups A1 and A3 to A6 refers to the concentration of ceftobiprole.

[0073] As shown in Tables 2 to 5, the MIC50 and MIC90 of ceftobiprole alone in group A1 against KPC producing Klebsiella pneumoniae and OXA‑232 producing Klebsiella pneumoniae are both greater than or equal to 128 mg / L. This indicates that ceftobiprole alone exhibits no antibacterial activity against either KPC producing Klebsiella pneumoniae or OXA‑232 producing Klebsiella pneumoniae.

[0074] In group A2, the MIC50 and MIC90 of zidebactam alone against KPC producing Klebsiella pneumoniae are both greater than 128 mg / L, and the MIC50 and MIC90 against OXA‑232 producing Klebsiella pneumoniae are 64 mg / L and greater than 128 mg / L, respectively. This indicates that zidebactam alone exhibits noantibacterial activity against KPC producing Klebsiella pneumoniae, and exhibits weak antibacterial activity against OXA‑232 producing Klebsiella pneumoniae.

[0075] For KPC producing Klebsiella pneumoniae, the MIC50 of groups A3 and A4 are both 2 mg / L, the MIC90 are 4 mg / L and 8 mg / L, respectively, and the MIC50 of groups A5 and A6 are 0.5 mg / L and 0.125 mg / L, respectively, and the MIC90 are both 1 mg / L. The combination of ceftobiprole and zidebactam exhibits excellent antibacterial activity against KPC producing Klebsiella pneumoniae. Compared with ceftobiprole alone, ceftobiprole and zidebactam combinations with different ratios formulations show a reduction in MIC90 ranging from greater than 16-fold to greater than 128-fold against KPC producing Klebsiella pneumoniae, and the combination of ceftobiprole and zidebactam exhibits extremely strong synergistic antibacterial activity.

[0076] For OXA‑232 producingKlebsiella pneumoniae, the MIC50 and MIC90 of group A3 are both 2 mg / L, theMIC50 and MIC90 of group A4 are both 4 mg / L, the MIC50 and MIC90 of group A5 are less than or equal to 0.06 mg / L and 0.5 mg / L, respectively, and the MIC50 and MIC90 of group A6 are less than or equal to 0.06 mg / L and 0.25 mg / L, respectively. The combination of ceftobiprole and zidebactam exhibits excellent antibacterial activity against OXA‑232 producing Klebsiella pneumoniae. Compared with ceftobiprole alone, ceftobiprole and zidebactam combinations with different ratios formula- tions show a reduction in MIC90 ranging from greater than 32-fold to greater than 512-fold against OXA‑232 producing Klebsiella pneumoniae, and the combination of ceftobiprole and zidebactam exhibits extremely strong synergistic antibacterial activity. Examples 2 to 7

[0077] Examples 2 to 7 adopt the same method as Example 1 to examine the antibacterial activity against 24 strains of Klebsiella pneumoniae (including 12 KPC‑2 producing strains and 12 OXA‑232 producing strains) when the mass ratios ofceftobiprole to zidebactam are 1.5:1, 2.5:1, 4:1, 8:1, 10:1, and 0.1:1, respectively. The concentration range of ceftobiprole in Examples 2 to 7 is shown in Table 6, and the results are shown in Table 7. In Examples 1 to 7, the concentration ratio of ceftobiprole to zidebactam is the same as the mass ratio. 11 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 Comparative Example A1

[0078] Comparative Example A1 adopts the same method as Example 1 to examine the antibacterial activity against 24 strains of Klebsiella pneumoniae (including 12 KPC‑2 producing strains and 12 OXA‑232 producing strains) when a different ceftobiprole and zidebactam mass ratio is 11:1, the concentration range of ceftobiprole in Comparative Example A1 is shown in Table 6, and the results are shown in Table 7. Table 6. Concentrations of ceftobiprole / zidebactam in Examples 2 to 7 and Comparative Example A1 Group Concentration of ceftobiprole Concentration of zidebactam Concentration ratio (ceftobiprole: zidebactam)Example 2 128 mg / L to 0.06 mg / L Adjusted based on concentra- tion of ceftobiprole 1.5:1 Example 3 128 mg / L to 0.06 mg / L Adjusted based on concentra- tion of ceftobiprole 2.5:1 Example 4 128 mg / L to 0.06 mg / L Adjusted based on concentra- tion of ceftobiprole 4:1 Example 5 128 mg / L to 0.06 mg / L Adjusted based on concentra- tion of ceftobiprole 8:1 Example 6 128 mg / L to 0.06 mg / L Adjusted based on concentra- tion of ceftobiprole 10:1 Example 7 128 mg / L to 0.06 mg / L Adjusted based on concentra- tion of ceftobiprole 0.1:1 Comparative Ex- ample A1 128 mg / L to 0.06 mg / L Adjusted based on concentra- tion of ceftobiprole 11:1 Table 7. In vitro antibacterial activity of ceftobiprole / zidebactam in Examples 2 to 7 and Comparative Example A1 against the tested bacteria Bacteria (strains) Bacteria (strains) Example / Comparative Example Mass ratio of ceftobiprole and zidebactam MIC50 (ceftobiprole) MIC50 corresponding concentration of zidebactam FIC KPC‑2 pro- ducing Kleb- siella pneu- moniae (12strains) Example 2 1.5:1 2 1.33 2 / 128+1.33 / 128 =0.03 Example 3 2.5:1 2 0.8 2 / 128+0.8 / 128 =0.02 Example 4 4:1 2 0.5 2 / 128+0.5 / 128 =0.02 Example 5 8:1 4 0.5 4 / 128+0.5 / 128 =0.04 Example 6 10:1 4 0.4 4 / 128+0.4 / 128 =0.03 Example 7 0.1:1 0.5 5 0.5 / 128+5 / 128 =0.04 Comparative Example A1 11:1 8 0.73 8 / 128+0.73 / 128 =0.07 12 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Bacteria (strains) Bacteria (strains) Example / Comparative Example Mass ratio of ceftobiprole and zidebactam MIC50 (ceftobiprole) MIC50 corresponding concentration of zidebactam FIC OXA‑48 pro- ducing Kleb- siella pneu- moniae (12 strains) Example 2 1.5:1 4 2.7 4 / 128+2.7 / 128 =0.05 Example 3 2.5:1 4 1.6 4 / 128+1.6 / 128 =0.04 Example 4 4:1 8 2 8 / 128+2 / 128=0 .08 Example 5 8:1 8 1 8 / 128+1 / 128=0 .07 Example 6 10:1 8 0.8 8 / 128+0.8 / 128 =0.07 Example 7 0.1:1 0.25 2.5 0.25 / 128+2.5 / 1 28=0.02 Comparative Example A1 11:1 16 1.5 16 / 128+1.5 / 128 =0.14 Note: In Table 7, the MIC in Examples 2 to 7 and in Comparative Example A1 refersto the concentration of ceftobi- prole.

[0079] As shown in Table 7, in the antibacterial activity of ceftobiprole against OXA‑232 producing Klebsiella pneu- moniae and KPC‑2 producing Klebsiella pneumoniae, the FIC index under the condition that the mass ratio of ceftobiprole to zidebactam is 0.1:1 to 10:1 is less than the FIC index at the mass ratio of ceftobiprole to zidebactam of 11:1. This indicates that within the range of 0.1:1 to 10:1 for the mass ratio of ceftobiprole to zidebactam, there is a better synergistic effect. Comparative Example B1

[0080] An investigation of the combined-use ratio of ceftobiprole and vaborbactam was conducted. The investigation method is the same as in the examples, with the solelydifference being that zidebactam in the antibacterial drug solutions of groups A2 to A6 in Example 1 is replaced with vaborbactam, and the numbering of groups A2 to A6 is correspondingly modified to groups B2 to B6.

[0081] The manufacturer of vaborbactam is GLP Bio company,batch number: GC193691. The chemical name of vaborbactam is (3R,6S)‑2-hydroxy‑3‑[[2‑(2-thienyl)acetyl]amino]‑1,2-oxaborinane‑6-acetic acid; the structural formula is shown in formula (5):

[0082] The results of this comparative example are shown in Tables 8 to 9. 13 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 Table 8. In vitro antibacterial activity of ceftobiprole / vaborbactam against the tested bacteria Bacteria (strains) Antibacterial drug MIC (mg / L) MIC range MIC50 MIC90 Mode KPC‑2 producing Klebsiella pneumoniae (12 strains) Group B2 >128 >128 >128 >128 Group B3 32 to 64 32 64 32 Group B4 32 to 64 64 64 64 Group B5 64 to >128 >128 >128 >128 Group B6 32 to >128 >128 >128 >128 OXA‑48 producing Klebsiella pneumo- niae (12 strains) Group B2 >128 >128 >128 >128 Group B3 128 to >128 128 >128 128, >128 Group B4 128 to >128 >128 >128 >128 Group B5 128 to >128 >128 >128 >128 Group B6 128 to >128 >128 >128 >128 Note: In Table 8, the MIC for group B2 refers to the concentration ofvaborbactam, and the MIC for groups B3 to B6 refers to the concentration of ceftobiprole. Table 9. MIC distribution and cumulative inhibition rate of ceftobiprole / vaborbactam against the tested bacteria Antibacterial drug KPC producing OXA producing MIC (mg / L) MIC (mg / L) 32 64 128 >128 128 >128 Number of strains 12 12 Group B2 Cumulative number of strains 12 12 Cumulative inhibition rate (%) 100 100 Number of strains 8 4 6 6 Group B3 Cumulative number of strains 8 12 6 12 Cumulative inhibition rate (%) 66.7 100 50 100 Number of strains 2 10 2 10 Group B4 Cumulative number of strains 2 12 2 12 Cumulative inhibition rate (%) 16.7 100 16.7 100 Number of strains 1 1 10 1 11 Group B5 Cumulative number of strains 1 2 12 1 12 Cumulative inhibition rate (%) 8.3 16.7 100 8.3 100 Number of strains 1 1 1 9 1 11 Group B6 Cumulative number of strains 1 2 3 12 1 12 Cumulative inhibition rate (%) 8.3 16.7 25 100 8.3 100 Note: In Table 9, the MIC for group B2 refers to the concentration ofvaborbactam, and the MIC for groups B3 to B6 refers to the concentration of ceftobiprole.

[0083] As shown in Tables 8 to 9, the MIC50 and MIC90 of vaborbactam alone in group B2 against KPC producing Klebsiella pneumoniae and OXA‑232 producing Klebsiella pneumoniaeare both greater than 128 mg / L, and vaborbactam alone exhibits no antibacterial activity against KPC producing Klebsiella pneumoniae and OXA‑232 producing Klebsiella pneumoniae.

[0084] For KPC producing Klebsiella pneumoniae, the MIC50 and MIC90 of group B3 are 32 mg / L and 64 mg / L, respectively; the MIC50 and MIC90 of group B4 are both 64 mg / L; and the MIC50 and MIC90 of groups B5 and B6 are both greater than 128 mg / L. The combination of ceftobiprole and vaborbactam exhibits weak antibacterial activity against KPC producing Klebsiella pneumoniae.

[0085] For OXA‑232 producing Klebsiella pneumoniae, the MIC50 and MIC90 of group B3 are 128 mg / L and greater than 14 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 128 mg / L,respectively, and the MIC50 and MIC90 of groups B3, B5, and B6 are all greater than 128 mg / L. The combination of ceftobiprole and vaborbactam exhibits no antibacterial activity against KPC producing Klebsiella pneumoniae. Comparative Example B2

[0086] An investigation of the combined-use ratio of ceftobiprole and relebactam was conducted. The investigation method is the same as in the aforementioned examples, with the difference being that zidebactam in the antibacterial drug solutions of groups A2 to A6 in the aforementioned example is replaced with relebactam, and the numbering of groups A2 to A6 is correspondingly modified to groups C2 to C6.

[0087] The manufacturer of relebactam is Biochempartner, batch number: 20201209. The chemical name of relebac- tam is (1R,2S,5R)‑7-oxo‑2‑(piperidin‑4-ylcarbamoyl)‑1,6-diazabicyclo[3.2.1]octan‑6-yl hydrogen sulfate; the structural formula is shown in formula (6):

[0088] The results of this comparative example are shown in Tables 10 to 11. Table10. In vitro antibacterial activity of ceftobiprole / relebactam against the tested bacteria Bacteria (strains) Antibacterial drug MIC (mg / L) MIC range MIC50 MIC90 Mode KPC‑2 producing Klebsiella pneumoniae (12 strains) Group C2 128 to >128 >128 >128 >128 Group C3 8 to 32 16 32 16 Group C4 8 to 32 16 32 16 Group C5 8 to >128 32 128 32 Group C6 2 to 32 16 32 32 OXA‑48 producing Group C2 128 to >128 >128 >128 >128 Group C3 32 to 64 64 64 64 Klebsiella pneumoniae (12 strains) Group C4 32 to 64 64 64 64 Group C5 128 to >128 >128 >128 >128 Group C6 128 to >128 >128 >128 >128 Note: In Table 10, the MIC for group C2 refers to the concentration of relebactam, and the MIC for groups C3 to C6 refers to the concentration of ceftobiprole. Table 11. MIC distribution and cumulative inhibition rate of ceftobiprole / relebactam against the tested bacteria Antibacterial drug KPC producing OXA producing MIC (mg / L) MIC (mg / L) 2 4 8 16 32 64 128 >128 32 64 128 >128 Number of strains 3 9 5 7 15 EP 4 781 993 A15 10 15 20 25 30 35 40 45 50 55 (continued) Antibacterial drug KPC producing OXA producing MIC (mg / L) MIC (mg / L) 2 4 8 16 32 64 128 >128 32 64 128 >128 Group C2 Cumulative number of strains 3 12 5 12 Cumulative inhibition rate (%) 25 100 41.7 100 Number of strains 3 7 2 5 7 Group C3 Cumulative number of strains 3 10 12 5 12 Cumulative inhibition rate (%) 25 83.3 100 41.7 100 Number of strains 2 7 3 1 11 Group C4 Cumulative number of strains 2 9 12 1 12 Cumulative inhibition rate (%) 16.7 75 100 8.3 100 Number of strains 2 6 2 1 1 1 11 Group C5 Cumulative number of strains 2 8 10 11 12 1 12 Cumulative inhibition rate (%) 16.7 66.7 83.3 91.7 100 8.3 100 Number of strains 1 1 1 4 5 1 11 Group C6 Cumulative number of strains 1 2 3 7 12 1 12 Cumulative inhibition rate (%) 8.3 16.7 25 58.3 100 8.3 100 Note: In Table 11, the MIC for group C2 refers to the concentration of relebactam, and the MIC for groups C3 to C6 refers to the concentration of ceftobiprole.

[0089] As shown in Tables 10 to11, the MIC50 and MIC90 of relebactam alone in group C2 against KPC producing Klebsiella pneumoniae and OXA‑232 producing Klebsiella pneumoniae are both greater than 128 mg / L, and relebactam alone exhibits no antibacterial activity against KPC producing Klebsiella pneumoniae and OXA‑232 producing Klebsiella pneumoniae.

[0090] For KPC producing Klebsiella pneumoniae, the MIC50 of groups C3, C4, and C6 are all 16 mg / L, the MIC90 are all 16 mg / L, when ceftobiprole and relabactam are used in combination, the ratios of ceftobiprole to relabactam are 1:1 and 2:1, as well as when the concentration of relabactam is 8 mg / L, the antibacterial activity against KPC producing Klebsiella pneumoniae is general. The MIC50 and MIC90 of group C5 are 32 mg / L and 128 mg / L, respectively, when the concentration 16 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 of relebactam is 4 mg / L, the combination use of ceftobiprole and relebactam exhibits weak antibacterial activity against KPC producing Klebsiellapneumoniae.

[0091] For OXA‑232 producing Klebsiella pneumoniae, the MIC50 and MIC90 of groups C3 and C4 are both 64 mg / L; when ceftobiprole and relebactam are used in combination, at ceftobiprole-to-relebactam ratios of 1:1 and 2:1, the antibacterial activity is weak. In groups C5 and C6, MIC50 and MIC90 are both greater than 128 mg / L; when the concentration of relebactam is 4 mg / L and 8 mg / L, the combination of ceftobiprole and relebactam has no antibacterial activity. Comparative Example B3

[0092] An investigation of the combined-use ratio of ceftobiprole and taniborbactam was conducted. The investigation method is the same as in Example 1, with the difference being that zidebactam in the antibacterial drug solutions of groups A2 to A6 in Example 1 is replaced with taniborbactam, and the numbering of groups A2 to A6 is correspondingly modified to groups D2 to D6.

[0093] The manufacturer of taniborbactam is MCE company, batch number: 80267. The chemical name of tanibor- bactam is(R)‑3‑(2‑((1r,4R)‑4‑((2-aminoethyl)amino)cyclohexyl)acetamido)‑2-hydroxy‑3,4-dihydro‑2H-benzo[e][1,2]ox- aborinine‑8-carboxylic acid, and the structural formula is shown in formula (7):

[0094] The results of this comparative example are shown in Tables 12 to 13. Table 12. In vitro antibacterial activity of ceftobiprole / taniborbactam against the tested bacteria Bacteria (strains) Antibacterial drug MIC (mg / L) MIC range MIC50 MIC90 Mode KPC‑2 producing Klebsiella pneumoniae (12 strains) Group D2 >128 >128 >128 >128 Group D3 4 to 32 8 16 8 Group D4 8 to 32 16 16 16 Group D5 4 to 32 16 32 16 Group D6 1 to 32 8 16 8 OXA‑48 producing Klebsiella pneumoniae (12 strains) Group D2 >128 >128 >128 >128 Group D3 16 to 32 16 32 16 Group D4 16 to 32 32 32 32 Group D5 16 to 128 64 128 128 Group D6 8 to 64 32 64 64 Note: In Table 12, the MIC for group D2 refers to the concentration of relebactam, and the MIC for groups D3 to D6 refers to the concentration of ceftobiprole. 17 EP 4 781 993 A1 5 10 15 2025 30 35 40 45 50 55 Table 13. MIC distribution and cumulative inhibition rate of ceftobiprole / taniborbactam against KPC‑2 producing and OXA‑232 producing Klebsiella pneumoniae Antibacterial drug KPC producing OXA producing MIC (mg / L) MIC (mg / L) 1 4 8 16 32 >128 8 16 32 64 128 >128 Number of strains 12 12 Group D2 Cumulative number of strains 12 12 Cumulative inhibition rate (%) 100 100 Number of strains 2 8 1 1 8 4 Group D3 Cumulative number of strains 2 10 11 12 8 12 Cumulative inhibition rate (%) 16.7 83.3 91.7 100 66.7 100 Number of strains 4 7 1 1 11 Group D4 Cumulative number of strains 4 11 12 1 12 Cumulative inhibition rate (%) 33.3 91.7 100 8.3 100 Number of strains 1 2 7 2 1 5 6 Group D5 Cumulative number of strains 1 3 10 12 1 6 12 Cumulative inhibition rate (%) 8.3 25 83.3 100 8.3 50 100 Group D6 Number of strains 2 2 6 1 1 1 5 6 Cumulative number of strains 2 4 10 11 12 1 6 12 Cumulative inhibition rate (%) 16.7 33.3 83.3 91.7 100 8.3 50 100 Note: In Table 13, the MIC forgroup D2 refers to the concentration of relebactam, and the MIC for groups D3 to D6 refers to the concentration of ceftobiprole.

[0095] As shown in Tables 12 to 13, the MIC90 of taniborbactam alone in group D2 against KPC producing Klebsiella pneumoniaeand OXA‑232 producingKlebsiellapneumoniaeare both greater than 128 mg / L.Taniborbactam alone shows no antibacterial activity against both KPC producing Klebsiella pneumoniae and OXA‑232 producing Klebsiella pneu- moniae. 18 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55

[0096] For KPC producing Klebsiella pneumoniae, the MIC50 and MIC90 of groups D3 to D6 are in the range of 8 to 32 mg / L, and the combination of ceftobiprole and taniborbactam shows certain antibacterial activity against KPC producing Klebsiella pneumoniae.

[0097] For OXA‑232 producing Klebsiella pneumoniae, the MIC90 of groups D3, D4, and D6 is in the range of 32 to 64 mg / L, and the MIC30 and MIC90 of group D5 are 64 mg / L and 128 mg / L, respectively. The combination ofceftobiprole and taniborbactam shows weak antibacterial activity against OXA‑232 producing Klebsiella pneumoniae. Comparative Example B4

[0098] An investigation of the combined-use ratio of ceftobiprole and AAI 101 was conducted. The investigation method is the same as in Example 1, with the difference being that zidebactam in the antibacterial drug solutions of groups A2 to A6 in Example 1 is replaced with AAI 101, and the numbering of groups A2 to A6 is correspondingly modified to groups E2 to E6.

[0099] The manufacturer of AAI 101 is MCE company, 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; the structural formula is shown as follows:

[0100] The results of this comparative example are shown in Tables 14 to 15. Table 14. In vitro antibacterial activity of ceftobiprole / AAI 101 against the tested bacteria Bacteria (strains) Antibacterial drug MIC(mg / L) MIC range MIC50 MIC90 Mode KPC‑2 producing Klebsiella pneumoniae (12 strains) Group E2 >128 >128 >128 >128 Group E3 64 to >128 128 >128 128 Group E4 128 to >128 >128 >128 >128 Group E5 >128 >128 >128 >128 Group E6 >128 >128 >128 >128 OXA‑48 producing Klebsiella pneumoniae (12 strains) Group E2 >128 >128 >128 >128 Group E3 32 to >128 128 >128 128 Group E4 64 to >128 128 >128 128 Group E5 128 to >128 >128 >128 >128 Group E6 128 to >128 >128 >128 >128

[0141] Note: In Table 14, the MIC for group E2 refers to the concentration of relebactam, and the MIC for groups E3 to E6 refers to the concentration of ceftobiprole. 19 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 Table 15. MIC distribution and cumulative inhibition rate of ceftobiprole / AAI 101 against the tested bacteria Antibacterial drug KPC producing OXA producing MIC (mg / L) MIC (mg / L) 64 128 >128 32 64 128 >128 Group E2 Number of strains 12 12 Cumulative number of strains 12 12 Cumulative inhibition rate (%) 100 100 Group E3Number of strains 1 7 4 1 3 5 3 Cumulative number of strains 1 8 12 1 4 9 12 Cumulative inhibition rate (%) 8.3 66.7 100 8.3 33.3 75 100 Group E4 Number of strains 4 8 2 8 2 Cumulative number of strains 4 12 2 10 12 Cumulative inhibition rate (%) 33.3 100 16.7 83.3 100 Group E5 Number of strains 12 1 11 Cumulative number of strains 12 1 12 Cumulative inhibition rate (%) 100 8.3 100 Group E6 Number of strains 12 3 9 Cumulative number of strains 12 3 12 Cumulative inhibition rate (%) 100 25 100 Note: In Table 15, the MIC for group E2 refers to the concentration of relebactam, and the MIC for groups E3 to E6 refers to the concentration of ceftobiprole.

[0101] As shown in Tables 14 to 15, the MIC50 and MIC90 of AAI 101 alone in group E2 against KPC producing Klebsiella pneumoniae and OXA‑232 producing Klebsiella pneumoniae are both greater than or equal to 128 mg / L. AAI 101 alone shows no antibacterial activity against both KPC producing Klebsiella pneumoniae and OXA‑232 producingKlebsiella pneumoniae.

[0102] For OXA‑232 producing Klebsiella pneumoniae, the MIC50 and MIC90 of group E3, group E4, group E5, and group E6 are all greater than or equal to 128 mg / L, and the combination of ceftobiprole and AAI 101 shows no antibacterial activity against OXA‑232 producing Klebsiella pneumoniae.

[0103] Comprehensively comparing Examples 1 to 7, Comparative Example A1, and Comparative Examples B1 to B4, ceftobiprole alone shows no antibacterial activity against KPC producing Klebsiella pneumoniae and OXA‑232 producing Klebsiella pneumoniae. Ceftobiprole in combination with zidebactam shows excellent antibacterial activity against these bacteria, while ceftobiprole in combination with other β-lactamase inhibitors shows no antibacterial activity or weak antibacterial activity against these bacteria. This indicates that the antibacterial composition of the examples of the present disclosure, through the compounding of ceftobiprole and zidebactam, enables the cephalosporinand zidebactam to exert a synergistic effect on each other, thereby effectively enhancing the antibacterial activity of the antibacterial composition.

[0104] The examples set forth above merely exemplify several implementation modes of the present disclosure; although the descriptions are relatively specific and detailed, it shall not be construed as a limitation on the patent scope of the present disclosure. It should be noted that, for those of ordinary skill in the art, numerous modifications and improvements can still be made without departing from the conception of the present disclosure, and such modifications and improvements all fall within the protection scope of the present disclosure. Accordingly, the patent protection scope of the present disclosure shall be subject to the appended claims. Claims 1. An antibacterial composition or an antibacterial kit, wherein the antibacterial composition or the antibacterial kit comprises a cephalosporin and zidebactam; wherein thecephalosporin comprises at least one of ceftobiprole or a ceftobiprole derivative; the cephalosporin is calculated as C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 10:1. 20 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 2. The antibacterial composition or the antibacterial kit according to claim 1, wherein the cephalosporin is calculated as C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 8:1, preferably 0.1:1 to 4:1, more preferably 0.1:1 to 2.5:1. 3. The antibacterial composition or the antibacterial kit according to claim 1, wherein the ceftobiprole derivative comprises at least one of a ceftobiprole ester, a ceftobiprole ester derivative, or a ceftobiprole salt; preferably, the ceftobiprole salt comprises at least one of an alkali metal salt, hydrochloride, bromate, acetate, or sulfate of ceftobiprole; preferably, the alkali metal salt of ceftobiprole comprises at least one of a potassium salt or a sodium salt;preferably, the ceftobiprole ester derivative comprises at least one of an alkali metal salt, hydrochloride, bromate, acetate, or sulfate of a ceftobiprole ester; preferably, the alkali metal salt of the ceftobiprole ester comprises at least one of a potassium salt or a sodium salt. 4. The antibacterial composition or the antibacterial kit according to any one of claims 1 to 3, wherein the cephalosporin and zidebactam exert a synergistic effect against bacteria; preferably, the cephalosporin and zidebactam exert a fractional inhibitory concentration index of less than or equal to 0.5 against the bacteria, preferably exert a fractional inhibitory concentration index of less than or equal to 0.2, and more preferably exert a fractional inhibitory concentration index of less than or equal to 0.15. 5. The antibacterial composition or the antibacterial kit according to any one of claims 1 to 4, wherein, when the cephalosporin and zidebactam are used in combination, ceftobiprole has an MIC50of less than or equal to 4 mg / L against the bacteria, preferably an MIC50 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; preferably, when the cephalosporin and zidebactam are used in combination, ceftobiprole has an MIC90 of less than or equal to 8 mg / L against the bacteria, preferably an MIC90 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. 6. The antibacterial composition or the 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 producing bacteria, KPC producing bacteria, or OXA producing bacteria. 7. An antibacterial drug, comprising the antibacterial composition or the antibacterial kit as defined in any oneof claims 1 to 6. 8. The antibacterial drug according to claim 7, wherein the antibacterial drug comprises a drug used against one or more of NDM producing bacteria, KPC producing bacteria, or OXA producing bacteria; and / or, the dosage of the antibacterial drug is: the concentration of zidebactam in the application environment is 4 mg / L to 8 mg / L. 9. The antibacterial drug according to claim 8, wherein the NDM producing bacteria comprise Escherichia coli; and / or the KPC producing bacteria comprise Klebsiella pneumoniae; and / or the OXA producing bacteria comprise Klebsiella pneumoniae. 10. The antibacterial drug according to any one of claims 7 to 9, wherein the antibacterial drug comprises a drug for treating at least one of pulmonary infection, bloodstream infection, or urinary tract infection; and / or the antibacterial drug comprises an injection. 11. The antibacterial composition or the antibacterial kit as defined in any one of claims 1 to 6 or the antibacterial drug as defined inany one of claims 7 to 10, for use in treating pulmonary infection, bloodstream infection and / or urinary tract infection. 12. Use of the antibacterial composition or the antibacterial kit as defined in any one of claims 1 to 6 or the antibacterial drug as defined in any one of claims 7 to 10 in the manufacture of a medicament for treating pulmonary infection, 21 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 bloodstream infection and / or urinary tract infection. 13. A method of treating pulmonary infection, bloodstream infection and / or urinary tract infection, comprising adminis- tering to a subject in need thereof the antibacterial composition or the antibacterial kit as defined in any one of claims 1 to 6 or the antibacterial drug as defined in any one of claims 7 to 10. 14. Use of a therapeutically effective amount of a cephalosporin and a therapeutically effective amount of zidebactam in the manufacture of a medicament, drug combination, or kit for treating pulmonary infection,bloodstream infection and / or urinary tract infection; wherein the therapeutically effective amount of the cephalosporin and zidebactam may be administered simultaneously, separately, or sequentially; wherein the cephalosporin comprises one or more of ceftobiprole or a ceftobiprole derivative; the cephalosporin is calculated as C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 10:1, preferably 0.1:1 to 8:1, more preferably 0.1:1 to 4:1, more preferably 0.1:1 to 2.5:1. 22 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 23 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 24 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 25 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 26 EP 4 781 993 A1 5 10 15 20 25 30 35 40 45 50 55 27 EP 4 781 993 A1 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken incompiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • CN 202311205221

[0001]

Claims

1. An antibacterial composition or an antibacterial kit, wherein the antibacterial composition or the antibacterial kit comprises a cephalosporin and zidebactam; wherein the cephalosporin comprises at least one of ceftobiprole or a ceftobiprole derivative; the cephalosporin is calculated as C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 10:1.

2. The antibacterial composition or the antibacterial kit according to claim 1, wherein the cephalosporin is calculated as C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 8:1, preferably 0.1:1 to 4:1, more preferably 0.1:1 to 2.5:1.

3. The antibacterial composition or the antibacterial kit according to claim 1, wherein the ceftobiprole derivative comprises at least one of a ceftobiprole ester, a ceftobiprole ester derivative, or a ceftobiprole salt; preferably, the ceftobiprole salt comprises at least one of an alkali metal salt, hydrochloride, bromate, acetate, or sulfate of ceftobiprole; preferably, the alkali metal salt of ceftobiprole comprises at least one of a potassium salt or a sodium salt; preferably, the ceftobiprole ester derivative comprises at least one of an alkali metal salt, hydrochloride, bromate, acetate, or sulfate of a ceftobiprole ester; preferably, the alkali metal salt of the ceftobiprole ester comprises at least one of a potassium salt or a sodium salt.

4. The antibacterial composition or the antibacterial kit according to any one of claims 1 to 3, wherein the cephalosporin and zidebactam exert a synergistic effect against bacteria; preferably, the cephalosporin and zidebactam exert a fractional inhibitory concentration index of less than or equal to 0.5 against the bacteria, preferably exert a fractional inhibitory concentration index of less than or equal to 0.2, and more preferably exert a fractional inhibitory concentration index of less than or equal to 0.15.

5. The antibacterial composition or the antibacterial kit according to any one of claims 1 to 4, wherein, when the cephalosporin and zidebactam are used in combination, ceftobiprole has an MIC50 of less than or equal to 4 mg / L against the bacteria, preferably an MIC50 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; preferably, when the cephalosporin and zidebactam are used in combination, ceftobiprole has an MIC90 of less than or equal to 8 mg / L against the bacteria, preferably an MIC90 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.

6. The antibacterial composition or the 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 producing bacteria, KPC producing bacteria, or OXA producing bacteria.

7. An antibacterial drug, comprising the antibacterial composition or the antibacterial kit as defined in any one of claims 1 to 6.

8. The antibacterial drug according to claim 7, wherein the antibacterial drug comprises a drug used against one or more of NDM producing bacteria, KPC producing bacteria, or OXA producing bacteria; and / or, the dosage of the antibacterial drug is: the concentration of zidebactam in the application environment is 4 mg / L to 8 mg / L.

9. The antibacterial drug according to claim 8, wherein the NDM producing bacteria comprise Escherichia coli; and / or the KPC producing bacteria comprise Klebsiella pneumoniae; and / or the OXA producing bacteria comprise Klebsiella pneumoniae.

10. The antibacterial drug according to any one of claims 7 to 9, wherein the antibacterial drug comprises a drug for treating at least one of pulmonary infection, bloodstream infection, or urinary tract infection; and / or the antibacterial drug comprises an injection.

11. The antibacterial composition or the antibacterial kit as defined in any one of claims 1 to 6 or the antibacterial drug as defined in any one of claims 7 to 10, for use in treating pulmonary infection, bloodstream infection and / or urinary tract infection.

12. Use of the antibacterial composition or the antibacterial kit as defined in any one of claims 1 to 6 or the antibacterial drug as defined in any one of claims 7 to 10 in the manufacture of a medicament for treating pulmonary infection, bloodstream infection and / or urinary tract infection.

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

14. Use of a therapeutically effective amount of a cephalosporin and a therapeutically effective amount of zidebactam in the manufacture of a medicament, drug combination, or kit for treating pulmonary infection, bloodstream infection and / or urinary tract infection; wherein the therapeutically effective amount of the cephalosporin and zidebactam may be administered simultaneously, separately, or sequentially; wherein the cephalosporin comprises one or more of ceftobiprole or a ceftobiprole derivative; the cephalosporin is calculated as C20H22N8O6S2, and the mass ratio of the cephalosporin to zidebactam is 0.1:1 to 10:1, preferably 0.1:1 to 8:1, more preferably 0.1:1 to 4:1, more preferably 0.1:1 to 2.5:1.