Use of meropenem or aztreonam in combination with nalidixic acid in the preparation of antibacterial medicaments

Abstract

The present application relates to the technical field of medicine, in particular to the application of meropenem or aztreonam combined with nalidixic acid in the preparation of antibacterial drugs. The checkerboard dilution method minimum inhibitory concentration test, dynamic time-kill curve and galleria mellonella animal test prove that nalidixic acid can enhance the antibacterial activity of meropenem or aztreonam against carbapenem-resistant klebsiella pneumoniae, reduce the minimum inhibitory concentration of meropenem or aztreonam against carbapenem-resistant klebsiella pneumoniae, and when meropenem or aztreonam is combined with nalidixic acid, the combination shows significant synergistic antibacterial effect in vitro and in vivo against carbapenem-resistant klebsiella pneumoniae. Meropenem combined with nalidixic acid has synergistic antibacterial effect against OXA-48, NDM, KPC, IMP, VIM-producing carbapenem-resistant klebsiella pneumoniae; aztreonam combined with nalidixic acid has synergistic antibacterial effect against KPC-producing carbapenem-resistant klebsiella pneumoniae.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the application of meropenem or aztreonam in combination with nalidixic acid in the preparation of antibacterial drugs. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Klebsiella pneumoniae ( Klebsiella pneumoniae Klebsiella pneumoniae (KP) is a Gram-negative bacterium belonging to the Enterobacteriaceae family. It is a common opportunistic pathogen that can exist in the human respiratory and intestinal tracts, and is associated with various infections, including pneumonia, sepsis, urinary tract infections, bacteremia, meningitis, and purulent liver abscesses. Carbapenem antibiotics are used to control Klebsiella pneumoniae infection; however, with the widespread use of carbapenem antibiotics in recent years, carbapenem-resistant Klebsiella pneumoniae has emerged. Klebsiella pneumoniae Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections have gradually emerged and become widespread. Controlling carbapenem-resistant Klebsiella pneumoniae infections is difficult, and the mortality rate is high, making it an independent risk factor for death.

[0004] Currently, there are few effective treatments for carbapenem-resistant Klebsiella pneumoniae (CRP) infection, and clinical research data on these drugs is very limited. Antibiotics with good antibacterial activity against CRP have limitations when used as monotherapy. For example, polymyxins are prone to heterogeneous resistance and have significant nephrotoxicity and neurotoxicity, as well as low lung tissue penetration; tigecycline has low blood concentrations; and ceftazidime / avibactam is ineffective against CRP infections caused by metalloenzymes (type B β-lactamases). Furthermore, with the widespread clinical use of antibiotics, the resistance rate of CRP to drugs such as polymyxins and tigecycline is rapidly increasing.

[0005] Therefore, there is an urgent need to explore novel drug strategies that can overcome carbapenem-resistant Klebsiella pneumoniae infection. Summary of the Invention

[0006] To overcome the above problems, the present invention provides the application of meropenem or aztreonam in combination with nalidixic acid in the preparation of antibacterial drugs.

[0007] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0008] In a first aspect, the invention provides the use of nalidixic acid in the preparation of a medicament that enhances the antibacterial effect of meropenem or aztreonam, wherein the bacterium is carbapenem-resistant Klebsiella pneumoniae.

[0009] In one or more embodiments, the types of carbapenem-resistant Klebsiella pneumoniae producing carbapenemases include: oxacillinase-48 (OXA-48), New Delhi metallo-β-lactamase (NDM), Klebsiella pneumoniae carbapenemase (KPC), imipenem metallo-β-lactamase (IMP), and Verona integron-encoded metallo-β-lactamase (VIM).

[0010] OXA-48 belongs to class D β-lactamases, NDM belongs to class B β-lactamases, KPC belongs to class A β-lactamases, IMP belongs to class B β-lactamases, and VIM belongs to class B β-lactamases.

[0011] In one or more embodiments, the mass ratio of nalidixic acid to meropenem is (2~64):(1~64); preferably 2:8, 16:8, 64:64, 8:1 or 8:8.

[0012] The mass ratio of nalidixic acid to aztreonam is (16~64):32, preferably 32:32.

[0013] A second aspect of the present invention provides the use of meropenem or aztreonam in combination with nalidixic acid in the preparation of an antibacterial drug; wherein the bacterium is carbapenem-resistant Klebsiella pneumoniae.

[0014] In one or more embodiments, the types of carbapenem-resistant Klebsiella pneumoniae producing carbapenemases include: oxacillinase-48 (OXA-48), New Delhi metallo-β-lactamase (NDM), Klebsiella pneumoniae carbapenemase (KPC), imipenem metallo-β-lactamase (IMP), and Verona integron-encoded metallo-β-lactamase (VIM).

[0015] OXA-48 belongs to class D β-lactamases, NDM belongs to class B β-lactamases, KPC belongs to class A β-lactamases, IMP belongs to class B β-lactamases, and VIM belongs to class B β-lactamases.

[0016] In one or more embodiments, the mass ratio of nalidixic acid to meropenem is (2~64):(1~64); preferably 2:8, 16:8, 64:64, 8:1 or 8:8.

[0017] The mass ratio of nalidixic acid to aztreonam is (16~64):32, preferably 32:32.

[0018] A third aspect of the present invention provides an antibacterial drug comprising meropenem or aztreonam and nalidixic acid;

[0019] The bacteria in question is carbapenem-resistant Klebsiella pneumoniae.

[0020] In one or more embodiments, the types of carbapenem-resistant Klebsiella pneumoniae producing carbapenemases include: oxacillinase-48 (OXA-48), New Delhi metallo-β-lactamase (NDM), Klebsiella pneumoniae carbapenemase (KPC), imipenem metallo-β-lactamase (IMP), and Verona integron-encoded metallo-β-lactamase (VIM).

[0021] OXA-48 belongs to class D β-lactamases, NDM belongs to class B β-lactamases, KPC belongs to class A β-lactamases, IMP belongs to class B β-lactamases, and VIM belongs to class B β-lactamases.

[0022] In one or more embodiments, the mass ratio of nalidixic acid to meropenem is (2~64):(1~64); preferably 2:8, 16:8, 64:64, 8:1 or 8:8.

[0023] The mass ratio of nalidixic acid to aztreonam is (16~64):32, preferably 32:32.

[0024] In one or more embodiments, the drug further includes pharmaceutically acceptable carriers, excipients, and diluents.

[0025] The non-pharmaceutical active ingredients that may be included, such as carriers, excipients, and diluents, are well known in the art, and those skilled in the art can determine that they meet clinical standards.

[0026] Preferably, the carrier, excipients, and diluents include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil.

[0027] Preferably, the dosage form of the drug is a suspension, emulsion, granules, spray, injection, transdermal absorbent, a dosage form suitable for transfection, tablet, powder, granules or capsule.

[0028] A fourth aspect of the present invention provides a pharmaceutical composition comprising the antibacterial agent described in the third aspect.

[0029] The beneficial effects of this invention are as follows:

[0030] This invention demonstrates, through checkerboard dilution minimum inhibitory concentration (MIC) tests, dynamic time-bacterial-killing curves, and *Gnaphalium affine* animal experiments, that nalidixic acid can enhance the antibacterial activity of meropenem or aztreonam against carbapenem-resistant *Klebsiella pneumoniae*, and reduce the MIC of meropenem or aztreonam against carbapenem-resistant *Klebsiella pneumoniae*. Meropenem or aztreonam combined with nalidixic acid exhibits a significant synergistic antibacterial effect against carbapenem-resistant *Klebsiella pneumoniae* in vitro and in vivo. Meropenem combined with nalidixic acid shows a synergistic antibacterial effect against carbapenem-resistant *Klebsiella pneumoniae* producing OXA-48, NDM, KPC, IMP, and VIM; aztreonam combined with nalidixic acid shows a synergistic antibacterial effect against KPC-producing carbapenem-resistant *Klebsiella pneumoniae*. Attached Figure Description

[0031] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0032] Figure 1 Time-bactericidal curve of meropenem combined with nalidixic acid in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae NCTC13442;

[0033] Figure 2 Time-bactericidal curve of meropenem combined with nalidixic acid in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae KP26;

[0034] Figure 3 Time-bactericidal curve of meropenem combined with nalidixic acid in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae KP27;

[0035] Figure 4 Time-bactericidal curve of meropenem combined with nalidixic acid in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae KP29;

[0036] Figure 5 Time-bactericidal curve of meropenem combined with nalidixic acid in vitro against carbapenem-resistant Klebsiella pneumoniae KPn24;

[0037] Figure 6 Time-bactericidal curve of meropenem combined with nalidixic acid in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae NCTC13439;

[0038] Figure 7 The time-bactericidal curve of in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae KP27 by the combination of aztreonam and nalidixic acid.

[0039] Figure 8The time-bactericidal curve of the combination of aztreonam and nalidixic acid in vitro against carbapenem-resistant Klebsiella pneumoniae KP29.

[0040] Figure 9 The time-survival curves for meropenem or aztreonam in combination with nalidixic acid in the treatment of carbapenem-resistant Klebsiella pneumoniae infection with large wax moth are shown. Among them, a is the time-survival curve for meropenem in combination with nalidixic acid in the treatment of carbapenem-resistant Klebsiella pneumoniae KP26 infection with large wax moth, and b is the time-survival curve for aztreonam in combination with nalidixic acid in the treatment of carbapenem-resistant Klebsiella pneumoniae KP27 infection with large wax moth.

[0041] Figure 10 The image shows the periodic acid-Schiff (PAS) staining of meropenem combined with nalidixic acid in the treatment of carbapenem-resistant Klebsiella pneumoniae KP26 infection of the giant wax moth. Among them, a is the control group, b is the meropenem monotherapy group, c is the nalidixic acid monotherapy group, and d is the meropenem combined with nalidixic acid group.

[0042] Figure 11 PAS staining images of *Klebsiella pneumoniae* KP27 infection treated with aztreonam and nalidixic acid in combination. In the images, a is the control group, b is the aztreonam monotherapy group, c is the nalidixic acid monotherapy group, and d is the aztreonam and nalidixic acid combination group. Detailed Implementation

[0043] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0044] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0045] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0046] Quality control strain: Klebsiella pneumoniae ATCC BAA-1705.

[0047] Experimental strains: carbapenem-resistant Klebsiella pneumoniae NCTC13442, carbapenem-resistant Klebsiella pneumoniae KP26, carbapenem-resistant Klebsiella pneumoniae KP27, carbapenem-resistant Klebsiella pneumoniae KP29, carbapenem-resistant Klebsiella pneumoniae KPn24, and carbapenem-resistant Klebsiella pneumoniae NCTC13439.

[0048] Both the quality control strains and the experimental strains were obtained from the strain library previously established by our research group. The types of carbapenemases produced by the experimental strains were identified using bacterial immunochromatographic reagents, and the results are shown in Tables 1 and 2. Strain NCTC13442 produces OXA. 48 types of carbapenemases were identified. Strain NCTC13439 produced VIM-type carbapenemases, strain KP26 produced NDM-type carbapenemases, strains KP27 and KP29 both produced KPC-type carbapenemases, and strain KPn24 produced IMP-type carbapenemases.

[0049] Both the quality control strains and the experimental strains are stored in Before use, subculture the bacteria on Mueller-Hinton agar (MHA) at 80 °C, with at least two subcultures. Pick a single colony from the medium and resuspend it in cation-adjusted Mueller-Hinton broth (CAMHB). Incubate overnight at 35 °C using a shaker. Adjust the bacterial suspension to 1 × 10⁻⁶ using a McFarland turbidimetric tube. 9 Quantity / mL, for later use.

[0050] Aztreonam raw material was dissolved in sterile water, while nalidixic acid and meropenem were dissolved in dimethyl sulfoxide (DMSO) to prepare drug stock solutions with a final concentration of 10 mg / mL. These stock solutions were stored in sterile centrifuge tubes, labeled, and kept at -20 ℃ for later use.

[0051] Example 1

[0052] Checkerboard dilution method for determining the in vitro static antibacterial activity against carbapenem-resistant Klebsiella pneumoniae using meropenem or aztreonam in combination with nalidixic acid:

[0053] The checkerboard dilution method was used for drug combination experiments. In each 96-well plate, the first well of row 8 contained no drug, but only 100 μL of bacterial suspension and 100 μL of CAMHB medium as a growth control well. The second well of column 12 contained only 200 μL of CAMHB medium as a negative control well. In rows 1-7 (except column 12), 50 μL of high- to low-concentration nalidixic acid working solution was added sequentially to each row. In columns 2-11, 50 μL of low- to high-concentration meropenem or aztreonam working solution was added sequentially to each column. Except for column 12, 100 μL of diluted bacterial suspension was added to each well of the 96-well plate. If the total volume of all wells was less than 200 μL, CAMHB medium was used to make up the difference. The final inoculum concentration was 1 × 10⁻⁶. 6 CFU / mL. The 96-well plate was capped and incubated in a 35 ℃ incubator for 18-20 h; the minimum inhibitory concentration (MIC) was observed and recorded when the drug was used alone or in combination.

[0054] The growth of bacteria in each well was recorded in accordance with the CLSI M100 standard published by the Clinical and Laboratory Standards Institute (CLSI). The minimum inhibitory concentration (MIC) is defined as the concentration of a drug that can inhibit more than 90% of bacteria.

[0055] Synergistic effect evaluation:

[0056] The combined drug susceptibility test results are used to determine the interaction between the two drugs using the fractional inhibitory concentration index (FICI). The formula for calculating FICI is as follows:

[0057] FICI = FIC A +FIC B =C A / MIC A +C B / MIC B ;

[0058] FICI stands for Partial Antimicrobial Concentration Index. A and FIC B These represent the MIC values ​​of drugs A and B used in combination, divided by the MIC values ​​of drugs A and B used alone. A and MIC B These are the minimum inhibitory concentrations (MICs) of drugs A and B when used alone, and C. A With C BThey are the respective concentrations of the two drugs when the same therapeutic effect is achieved during their combined use. FICI ≤ 0.5 indicates a synergistic effect when the two drugs are used in combination; 0.5 < FICI ≤ 1 indicates an additive effect when the two drugs are used in combination; 1 < FICI ≤ 2 indicates no interaction when the two drugs are used in combination; FICI > 2 indicates an antagonistic effect when the two drugs are used in combination.

[0059] The results of the in vitro static anti - carbapenem - resistant Klebsiella pneumoniae effect of the combination of meropenem and nalidixic acid are shown in Table 1.

[0060] The results of the in vitro static anti - carbapenem - resistant Klebsiella pneumoniae effect of the combination of aztreonam and nalidixic acid are shown in Table 2.

[0061] Table 1 Results of the in vitro static anti - carbapenem - resistant Klebsiella pneumoniae effect of the combination of meropenem and nalidixic acid

[0062]

[0063] In Table 1, MIC A is the minimum inhibitory concentration of nalidixic acid when used alone, MIC B is the minimum inhibitory concentration of meropenem when used alone, C A is the minimum inhibitory concentration of nalidixic acid when nalidixic acid and meropenem are used in combination, C B is the minimum inhibitory concentration of meropenem when nalidixic acid and meropenem are used in combination, and FICI is the fractional inhibitory concentration index of the combination of nalidixic acid and meropenem.

[0064] Table 2 Results of the in vitro static anti - carbapenem - resistant Klebsiella pneumoniae effect of the combination of aztreonam and nalidixic acid

[0065]

[0066] In Table 2, MIC A is the minimum inhibitory concentration of nalidixic acid when used alone, MIC B is the minimum inhibitory concentration of aztreonam when used alone, C A is the minimum inhibitory concentration of nalidixic acid when nalidixic acid and aztreonam are used in combination, C B is the minimum inhibitory concentration of aztreonam when nalidixic acid and aztreonam are used in combination, and FICI is the fractional inhibitory concentration index of the combination of nalidixic acid and meropenem.

[0067] As shown in Tables 1 and 2, nalidixic acid, meropenem, and aztreonam, when used alone, exhibited weak antibacterial activity against carbapenem-resistant Klebsiella pneumoniae. The MIC ranges were 16–512 μg / mL for nalidixic acid, 8–512 μg / mL for meropenem, and 64–512 μg / mL for aztreonam. However, in vitro static antibacterial activity against carbapenem-resistant Klebsiella pneumoniae was observed when meropenem or aztreonam was combined with nalidixic acid. The FICI range for meropenem and nalidixic acid against OXA-48, NDM, KPC, IMP, and VIM-producing carbapenem-resistant Klebsiella pneumoniae ranged from 0.187 to 0.500, demonstrating a synergistic effect. The FICI for aztreonam and nalidixic acid against KPC-producing carbapenem-resistant Klebsiella pneumoniae was 0.125, also demonstrating a synergistic effect.

[0068] Example 2

[0069] Meropenem or aztreonam in combination with nalidixic acid in in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae:

[0070] Colonies incubated overnight at 35 °C on MHA plates were picked up with a sterile inoculation loop and suspended in phosphate buffered saline (PBS), adjusting the bacterial suspension concentration to 1 × 10⁻⁶. 9 CFU / mL. The bacterial culture was then further diluted to 1×10⁻⁶ using CAMHB medium. 6 The working bacterial suspension was prepared at CFU / mL. The working concentration was then divided into four groups: one group was added directly to a 96-well plate as a control group (100 μL per well); the other three groups were prepared by adding the raw material stock solution to each well to achieve the combined concentrations of meropenem or aztreonam, nalidixic acid, and meropenem or aztreonam and nalidixic acid, respectively, with three replicates per group. After sealing, the 96-well plate was placed in a microplate reader and incubated at 35 °C. Kinetic monitoring was performed using a microplate reader at 600 nm wavelength, with OD readings taken every hour. 600nm The OD values ​​were continuously measured for 24 hours. After the experiment, the values ​​were calculated based on the OD values ​​at each time point. 600nm The time-sterilization curve is plotted.

[0071] Results of in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae using meropenem in combination with nalidixic acid are as follows: Figures 1-6 As shown.

[0072] The results of in vitro dynamic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae using a combination of aztreonam and nalidixic acid are as follows: Figures 7-8 As shown.

[0073] The results showed that, taking the combination of meropenem and nalidixic acid against strain NCTC13442 as an example, compared with the control group (no drug), there was no significant difference in bacterial growth between the nalidixic acid single-drug group and the meropenem single-drug group, while the meropenem and nalidixic acid combined group showed significant dynamic antibacterial activity. Figure 1 For the other five strains, the combination of meropenem and nalidixic acid also demonstrated significant dynamic antibacterial effects. Figures 2-6 This indicates that the combination of meropenem and nalidixic acid exhibits good in vitro dynamic antibacterial effect against carbapenem-resistant Klebsiella pneumoniae within 24 hours. Similarly, as... Figures 7-8 The dynamic antibacterial effect of aztreonam combined with nalidixic acid against two KPC-producing carbapenem-resistant Klebsiella pneumoniae strains was also confirmed by time-bactericidal curves, indicating that the combination of aztreonam and nalidixic acid has a good in vitro dynamic antibacterial effect against KPC-producing carbapenem-resistant Klebsiella pneumoniae within 24 h.

[0074] Example 3

[0075] Meropenem or aztreonam in combination with nalidixic acid for in vivo treatment against carbapenem-resistant Klebsiella pneumoniae:

[0076] Larvae of the large wax moth, weighing 250±10 mg, were selected. The experimental strain KP26 was cultured overnight in CAMHB medium, and the bacterial suspension was adjusted to the following concentration: 1×10⁻⁶. 9 CFU / mL. Using a 50 μL microsyringe, 10 μL of bacterial suspension was injected into the peritoneal cavity of the larva through the first right hindleg. Two hours after infection, 10 μL of different drugs were injected (the final in vivo drug concentration was 2 μg / larva). The control group of *Eriocheir sinensis* larvae was injected with 10 μL of sterile PBS to reduce errors due to potential lethal effects. Each group contained 15 larvae. After injection, the larvae were placed in sterile glass petri dishes and incubated at 35 °C. The survival rate of each group of larvae was recorded daily until day 4, and time-survival curves were plotted.

[0077] Two days after infection and treatment of the large wax moth, one larva was randomly selected from each group, and 7 mm frozen tissue sections were prepared using a cryostat. The sections were then stained with PAS, and the histopathological differences of the large wax moth sections in each group were observed under a microscope.

[0078] In in vivo experiments against carbapenem-resistant Klebsiella pneumoniae, the strains corresponding to the optimal effects determined in the in vitro experiments against carbapenem-resistant Klebsiella pneumoniae in Examples 1 and 2 were used. Specifically, the in vivo effects of meropenem combined with nalidixic acid against carbapenem-resistant Klebsiella pneumoniae KP26 and the in vivo effects of aztreonam combined with nalidixic acid against carbapenem-resistant Klebsiella pneumoniae KP27 were investigated. Compared with the control group or the single-drug group, the combination of meropenem and nalidixic acid significantly improved the survival rate of *Klebsiella pneumoniae* moths infected with carbapenem-resistant Klebsiella pneumoniae KP26. Figure 9 (a) Microscopic examination of histopathological sections of the large wax moth revealed numerous black nodules composed of bacteria in the tissues of the control group and the single-drug treatment group. However, the number of black nodules in the meropenem and nalidixic acid combination group was significantly reduced compared to the other three groups. Figure 10 Similarly, the combination of aztreonam and nalidixic acid showed good in vivo antibacterial efficacy against carbapenem-resistant Klebsiella pneumoniae KP27-infected giant wax moths. Specifically, compared with the control group and the single-drug group, the combination treatment of aztreonam and nalidixic acid significantly improved the survival rate of carbapenem-resistant Klebsiella pneumoniae KP27-infected giant wax moths and reduced their tissue bacterial load. Figure 9 b and Figure 11 ).

[0079] This invention demonstrates, through checkerboard dilution minimum inhibitory concentration (MIC) tests, dynamic time-bacterial growth curves, and *Gnaphalium affine* animal experiments, that nalidixic acid can enhance the antibacterial activity of meropenem or aztreonam against carbapenem-resistant *Klebsiella pneumoniae*, and reduce the MIC of meropenem or aztreonam against carbapenem-resistant *Klebsiella pneumoniae*. Meropenem or aztreonam, when used in combination with nalidixic acid, exhibits a significant synergistic antibacterial effect against carbapenem-resistant *Klebsiella pneumoniae*.

[0080] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. The application of nalidixic acid in the preparation of drugs that enhance the antibacterial effect of meropenem, wherein the bacterium is carbapenem-resistant Klebsiella pneumoniae, and the carbapenem-resistant Klebsiella pneumoniae is carbapenem-resistant Klebsiella pneumoniae NCTC13442, carbapenem-resistant Klebsiella pneumoniae KP26, carbapenem-resistant Klebsiella pneumoniae KP27, carbapenem-resistant Klebsiella pneumoniae KP29, carbapenem-resistant Klebsiella pneumoniae KPn24, and carbapenem-resistant Klebsiella pneumoniae NCTC13439.

2. The application as described in claim 1, characterized in that, The mass ratio of nalidixic acid to meropenem is (2~64):(1~64).

3. The application of nalidixic acid in the preparation of drugs that enhance the antibacterial effect of aztreonam, wherein the bacterium is carbapenem-resistant Klebsiella pneumoniae, and the carbapenem-resistant Klebsiella pneumoniae is carbapenem-resistant Klebsiella pneumoniae KP27 or carbapenem-resistant Klebsiella pneumoniae KP29.

4. The application as described in claim 3, characterized in that, The mass ratio of nalidixic acid to aztreonam is (16~64):

32.

5. Application of meropenem combined with nalidixic acid in the preparation of antibacterial drugs; wherein the bacterium is carbapenem-resistant Klebsiella pneumoniae, and the carbapenem-resistant Klebsiella pneumoniae is carbapenem-resistant Klebsiella pneumoniae NCTC13442, carbapenem-resistant Klebsiella pneumoniae KP26, carbapenem-resistant Klebsiella pneumoniae KP27, carbapenem-resistant Klebsiella pneumoniae KP29, carbapenem-resistant Klebsiella pneumoniae KPn24, and carbapenem-resistant Klebsiella pneumoniae NCTC13439.

6. The application as described in claim 5, characterized in that, The mass ratio of nalidixic acid to meropenem is (2~64):(1~64).

7. Application of aztreonam in combination with nalidixic acid in the preparation of antibacterial drugs; wherein the bacterium is carbapenem-resistant Klebsiella pneumoniae, and the carbapenem-resistant Klebsiella pneumoniae is carbapenem-resistant Klebsiella pneumoniae KP27 or carbapenem-resistant Klebsiella pneumoniae KP29.

8. The application as described in claim 7, characterized in that, The mass ratio of nalidixic acid to aztreonam is (16~64):

32.

9. An antibacterial drug, characterized in that, Including meropenem and nalidixic acid; The bacteria is carbapenem-resistant Klebsiella pneumoniae; The carbapenem-resistant Klebsiella pneumoniae strains are carbapenem-resistant Klebsiella pneumoniae NCTC13442, KP26, KP27, KP29, KPn24, and NCTC13439.

10. The antibacterial drug as described in claim 9, characterized in that, The mass ratio of nalidixic acid to meropenem is (2~64):(1~64).

11. An antibacterial drug, characterized in that, Including aztreonam and nalidixic acid; The bacteria is carbapenem-resistant Klebsiella pneumoniae; The carbapenem-resistant Klebsiella pneumoniae are carbapenem-resistant Klebsiella pneumoniae KP27 and carbapenem-resistant Klebsiella pneumoniae KP29.

12. The antibacterial drug as described in claim 11, characterized in that, The mass ratio of nalidixic acid to aztreonam is (16~64):

32.

13. A pharmaceutical composition, characterized in that, Includes the antibacterial drug as described in any one of claims 9 to 12.

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