Compositions containing pharmaceutical formulations and antibacterial agents

Abstract

The present invention relates to the combined use of meropenem with one or more antibiotic resistance breakers, a pharmaceutical composition containing the same, and a method for treating bacterial infections comprising administering the same. In particular, the present invention relates to a pharmaceutical composition comprising (a) meropenem, (b) avibactam, and (c) EDTA.

Description

Field of the Invention

[0001] The present invention relates to a formulation of meropenem and one or more antibiotic resistance breakers, a pharmaceutical composition containing them, and a method for treating bacterial infections including administering the same. Background of the Invention

[0002] Bacterial infections remain one of the major causes of human diseases. One of the major challenges in the treatment of bacterial infections is the ability of bacteria to acquire resistance to one or more antibacterial agents over time. Examples of multi-drug resistant (MDR) bacteria and carbapenem-resistant (CR) bacteria that have acquired resistance to typical antibacterial agents include Escherichia coli, Klebsiella, and Acinetobacter. To address the problem of the emergence of drug resistance in bacteria, a switch is made to new antibacterial agents. This is more expensive and sometimes more toxic. Also, since bacteria often acquire resistance to new antibacterial agents over time, this may not be a permanent solution. Generally, bacteria are particularly efficient at acquiring resistance because they grow very rapidly and have the ability to transfer resistance genes while replicating.

[0003] The treatment of infections caused by drug-resistant bacteria remains an important challenge for medical personnel.

[0004] Arora et al. reported the microbiological efficacy of a meropenem-EDTA formulation in a tertiary intensive care unit (Arora and Charu Dutt et al., "Comparison of the microbiological efficacy of a meropenem-ethylenediaminetetraacetic acid formulation compared to meropenem in a tertiary intensive care unit" (2019)).

[0005] Hafi et al. have reported on the efficacy evaluation of carbapenem / β-lactamase inhibitors against carbapenem-resistant Gram-negative bacteria in vitro and in vivo (El Hafi and Bassam et al., "Efficacy evaluation of carbapenem / β-lactamase inhibitors against carbapenem-resistant Gram-negative bacteria in vitro and in vivo", Frontiers in Microbiology 10 (2019): 933).

[0006] IN212237 is a heterocyclic compound that has been reported to be active as a β-lactamase inhibitor when used in combination with β-lactamine antibiotics.

[0007] For many years, there has been a need to develop new methods for treating infectious diseases that are resistant to existing treatments and methods. Remarkably, the inventors have developed pharmaceutical formulations and compositions thereof that exhibit antibacterial activity even against highly resistant bacterial strains. Objective of the Invention

[0008] The object of the present invention is to provide a combination of meropenem and one or more antibiotic resistance breakers. The combination can exist, for example, in bulk form. Alternatively, the combination can exist in a pharmaceutical composition. The pharmaceutical composition may further contain one or more pharmaceutically acceptable excipients.

[0009] Another object of the present invention is to provide a method for producing a pharmaceutical combination containing meropenem and one or more antibiotic resistance breakers.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising a combination of meropenem and one or more antibiotic resistance breakers together with one or more pharmaceutically acceptable excipients.

[0011] Another object of the present invention is to provide a method for treating a bacterial infection in a subject, the method comprising administering to the subject a combination of an effective amount of meropenem and one or more antibiotic resistance breakers. The combination may be present in a pharmaceutical composition.

[0012] A further object of the present invention is to provide a combination of meropenem and one or more antibiotic resistance breakers for use in the treatment of bacterial infections. The combination may be present in a pharmaceutical composition. The pharmaceutical composition may further contain one or more pharmaceutically acceptable excipients. [Overview of the project]

[0013] According to one aspect of the present invention, a combination of (a) meropenem and (b) one or more antibiotic resistance breakers is provided. The combination can exist, for example, in bulk form. Alternatively, the combination can exist in a pharmaceutical composition. The pharmaceutical composition may further contain one or more pharmaceutically acceptable excipients.

[0014] According to another aspect of the present invention, a combination of (a) meropenem and (b) one or more antibiotic resistance breakers is provided. The one or more antibiotic resistance breakers include, for example, avibactam and EDTA.

[0015] According to another aspect of the present invention, a pharmaceutical composition is provided comprising (a) meropenem, (b) avibactam and one or more antibiotic resistance breakers such as EDTA, and (c) one or more pharmaceutically acceptable excipients.

[0016] According to yet another aspect of the present invention, a method for treating a bacterial infection in a subject is provided. The method comprises administering to the subject an effective amount of a combination formulation comprising (a) meropenem, (b) avibactam, and EDTA. The combination formulation may be present in a pharmaceutical composition. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients. Detailed description of the invention

[0017] The following description is provided to aid in a comprehensive understanding of exemplary embodiments of the present invention. Various specific details are included to aid in that understanding, but these should be considered merely examples.

[0018] Accordingly, those skilled in the art will understand that various changes and modifications can be made to the embodiments described herein without departing from the scope of the invention. Furthermore, for clarity and brevity, descriptions of well-known functions and configurations have been omitted.

[0019] The terms and phrases used in the following description and claims are not limited to their bibliographic meanings, but are used solely to enable the inventors to understand the invention clearly and consistently. Accordingly, as will be apparent to those skilled in the art, the following description of exemplary embodiments of the invention is provided for illustrative purposes only and is not intended to limit the scope of the invention as defined by the appended claims and their equivalents.

[0020] It should be understood that the singular forms "one" and "the" also include the plural form unless the context clearly indicates otherwise.

[0021] Features described and / or illustrated in relation to one embodiment may be used in a similar or analogous manner, and / or in combination with or instead of features of other embodiments, in one or more other embodiments.

[0022] It should be emphasized that the terms “contains” and “contains” are used to identify the presence of a described feature, process, or component, but do not exclude the presence or addition of one or more other features, processes, components, or groups thereof.

[0023] The present invention relates to pharmaceutical formulations and compositions thereof, comprising meropenem and one or more antibiotic resistance breakers, and to methods for treating highly resistant bacterial infections.

[0024] As used herein, the term “antibiotic resistance breaker” includes non-antibiotic components that do not possess antimicrobial activity on their own but, when used in combination with antibiotics, enhance their antimicrobial activity and help overcome resistance barriers.

[0025] As used herein, the term “infectious disease” refers to the proliferation of parasites in the human body, the invasion and proliferation of pathogenic microorganisms into the body, causing disease through local cell damage, secretion of toxins, or antigen-antibody reactions in the host, and diseases caused by the invasion of pathogenic microorganisms into the body. This does not include the normal flora of the intestinal tract.

[0026] As used herein, the term “bacterial infection” refers to the growth of bacteria in the human body, i.e., an infection caused by the bacteria described herein.

[0027] As used herein, the terms “to treat,” “to treat,” or “treatment” refer to administering the combination formulations described herein for preventive and / or therapeutic purposes. “Prophylactic treatment” refers to treating subjects who are not yet infected but are susceptible to or at risk of infection (preventing bacterial infection). “Therapeutic treatment” refers to treating subjects who are already suffering from an infection. As used herein, the terms “to treat,” “to treat,” or “treatment” refer to administering the combination formulations described herein, with or without additional pharmaceutically active or inactive components, for the following purposes: (i) To alleviate or eliminate a bacterial infection, one or more symptoms of a bacterial infection, or a combination thereof, (ii) To slow the progression of a bacterial infection, one or more symptoms of a bacterial infection, or a combination thereof, (iii) To alleviate the severity of a bacterial infection, one or more symptoms of a bacterial infection, or a combination thereof, (iv) To suppress the clinical signs of bacterial infection, or (v) To suppress signs of harmful symptoms of bacterial infection

[0028] As used herein, the terms “pharmaceutically effective dose,” “therapeutic effective dose,” or “effective dose” refer to the amount of the combination formulation described herein that is effective in having or producing a therapeutic effect in a subject. For example, the “therapeutic effective dose,” “pharmaceutically effective dose,” or “effective dose” of the combination formulation described herein is the amount necessary to produce the desired therapeutic effect, which can be determined by clinical trial results, infection studies in model animals, and / or in vitro studies (e.g., on agar or broth media). Such an effective dose depends on several factors, including, but are not limited to, the microorganisms involved (e.g., bacteria), the characteristics of the subject (e.g., height, weight, sex, age, and medical history), the severity of the infection, and the type of antimicrobial agent used. In prophylactic treatment, a prophylactic effective dose refers to the amount that may be effective in preventing a bacterial infection.

[0029] The terms “administration” or “administering” refer to, and include, the delivery of the combination described herein to a subject. This includes, for example, any suitable method that helps deliver the combination to the site of infection. The combination may be present in a pharmaceutical composition, which may further include one or more pharmaceutically acceptable excipients. The method of administration may vary depending on various factors such as the type, nature, and amount of components of the combination, including meropenem, one or more antibiotic resistance breakers, and inactive components (excipients), the potential or actual site of infection, the microorganisms involved, the severity of the infection, the age and physical condition of the subject, etc. Suitable routes for administering a pharmaceutical composition containing the combination described herein include, for example, oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, rectal, and vaginal. Suitable dosage forms of a pharmaceutical composition containing the combination described herein include, for example, gene guns, skin patches, eye drops, and mouthwashes. When the combination formulations described herein are formulated as pharmaceutical compositions, one method of administering such pharmaceutical compositions is to mix the components (for example, in an appropriate unit dosage form such as tablets, capsules, solutions, or powders) and then administer the dosage form to a subject. Alternatively, the components may be administered separately (simultaneously or sequentially), provided that these components achieve a beneficial therapeutic level and produce a synergistic and / or desired effect as a whole pharmaceutical composition.

[0030] As used herein, the term “growth” refers to the growth of one or more microorganisms, including the reproduction or growth of a population of such microorganisms (e.g., Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloaca). The term “growth” also includes the maintenance of ongoing metabolic processes of a microorganism, including processes that sustain the survival of the microorganism.

[0031] As used herein, the term “effectiveness” refers to the ability of a treatment, pharmaceutical composition, or pharmaceutically active ingredient to produce a desired biological effect in a subject. For example, the term “antimicrobial effect” of a composition or antimicrobial agent refers to the ability of the composition or antimicrobial agent to prevent or treat a bacterial infection in a subject.

[0032] As used herein, the terms “synergistic” or “synergistic effect” refer to a situation where two or more drugs interact and their combined effect is greater than the effect of each individual drug.

[0033] As used herein, the term “antimicrobial agent” means any substance, compound, combination of substances, or combination of compounds that can (i) inhibit, reduce, or prevent bacterial growth; (ii) inhibit or reduce the ability of bacteria to cause infectious diseases in a subject; or (iii) inhibit or reduce the ability of bacteria to grow or maintain infectivity in the environment. The term “antimicrobial agent” also means any compound that can reduce the infectivity or toxicity of bacteria.

[0034] As used herein, the term "β-lactam antimicrobial agent" refers to a compound that has antimicrobial activity and contains a β-lactam nucleus in its molecular structure. Typical examples include, but are not limited to, penicillin, cephalosporin, monobactam, and carbapenem.

[0035] As used herein, the terms “β-lactamase” or “β-lactamase enzyme” refer to an enzyme, protein, or other substance that breaks down a β-lactam ring. The term “β-lactamase” includes enzymes produced by bacteria that have the ability to partially or completely hydrolyze the β-lactam ring in β-lactam compounds.

[0036] As used herein, the term “broad-spectrum β-lactamase” (ESBL) includes β-lactamase enzymes capable of conferring bacterial resistance to various β-lactam antimicrobial agents such as penicillin, cephalosporins, and aztreonam.

[0037] As used herein, the term "carbapenamase" refers to a β-lactamase capable of hydrolyzing carbapenems.

[0038] As used herein, the term "β-lactamase inhibitor" refers to a compound that can partially or completely inhibit the activity of one or more β-lactamase enzymes. Representative non-limiting examples include avibactam, sulbactam, and clavulanic acid.

[0039] As used herein, the terms “colony-forming unit” or “CFU” refer to an estimate of the number of viable bacterial cells per ml of sample. Typically, a “bacterial colony” refers to a cluster of individual bacteria that have grown together.

[0040] As used herein, the term "meropenem" refers to a carbapenem antibiotic used to treat a variety of bacterial infections. Its spectrum of action includes many Gram-positive and Gram-negative bacteria (including Pseudomonas) as well as anaerobic bacteria. The IUPAC name of meropenem is (4R,5S,6S)-3-(((3S,5S)-5-(dimethylcarbamoyl)pyrrolidine-3-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), its CAS number is 119478-56-7, and its chemical formula is C 17 H 25 It is N3O5S, and its molar mass is 383.46 g·mol. -1Meropenem can exist in a non-ionized form or as a pharmaceutically acceptable salt thereof. Therefore, the term "meropenem" encompasses the compound in its non-ionized form, as well as its pharmaceutically acceptable salts. Its structural formula is shown below. JPEG2026517813000001.jpg3675

[0041] As used herein, the term "avibactam" refers to a non-β-lactam β-lactamase inhibitor, whose IUPAC name is [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]bisulfate and whose CAS number is 1192500-31-4. The chemical formula of avibactam is C7H 11 It is N3O6S, and its molar mass is 265.24 g·mol. -1 Avibactam can exist in a non-ionized form or as a pharmaceutically acceptable salt thereof. Therefore, the term "avibactam" encompasses the compound in its non-ionized form, as well as its pharmaceutically acceptable salts. Its structural formula is shown below. JPEG2026517813000002.jpg4376

[0042] As used herein, the terms “EDTA,” “ethylenediaminetetraacetic acid,” or “EDTA acid” refer to the aminopolycarboxylic acid represented by the formula [CH2N(CH2CO2H)2]2. The IUPAC name of EDTA is N,N′-(ethane-1,2-diyl)bis[N-(carboxymethyl)glycine], and its CAS numbers are 60-00-4 (free acid) and 6381-92-6 (disodium dihydrate). The chemical formula of EDTA is C 10 H 16 It is N2O8, and its molar mass is 292.244 g·mol. -1EDTA is available in several forms, particularly as salts such as disodium EDTA, calcium sodium edetate, and tetrasodium EDTA. Therefore, the term "EDTA" encompasses the non-ionized form of the compound, as well as its pharmaceutically acceptable salts. Its structural formula is shown below. JPEG2026517813000003.jpg5164

[0043] As used herein, the terms “combination,” “combination of active ingredients,” or “pharmaceutical combination” refer to the combination of meropenem, one or more antibiotic resistance breakers, and optionally one or more additional antimicrobial agents. In specific embodiments, the active ingredient combination includes meropenem, avibactam, and EDTA. Thus, the active ingredient combination (e.g., meropenem, one or more antibiotic resistance breakers, and optionally one or more additional antimicrobial agents) may be administered together, for example, in a single pharmaceutical dosage form. Alternatively, the active ingredient combination (e.g., meropenem, one or more antibiotic resistance breakers, and optionally one or more additional antimicrobial agents) may be administered separately, for example, in separate pharmaceutical dosage forms. The active ingredient combination (e.g., meropenem, one or more antibiotic resistance breakers, and optionally one or more additional antimicrobial agents) may be incorporated into pharmaceutical compositions that are marketed independently of each other. In this case, instructions regarding the combined use of the active ingredients, whether simultaneous or sequential, to exert a synergistic effect, as defined below, are attached to the package, for example, a leaflet, or to other information provided to physicians and healthcare professionals (e.g., verbal or written communication). This can refer to either a fixed combination preparation in a single dosage unit form or a kit of components for combined administration. The combination preparations of active ingredients may be administered simultaneously and independently, or separately with time intervals between administrations, especially if these time intervals result in a synergistic effect between the combined active ingredients.

[0044] As used herein, terms such as “concurrent administration,” “combined administration,” or “combined” are intended to encompass the administration of a combination of selected active ingredients to a single subject (e.g., one patient) who requires it, and are intended to include treatment regimens in which the active ingredients are not necessarily administered via the same route and / or simultaneously.

[0045] The term "fixed combination drug" means that a combination of active ingredients is administered to a patient simultaneously in the form of a single physical substance or dosage. In other words, a combination of active ingredients can be present in a single dosage form, for example, in a single tablet or a single capsule.

[0046] The term "non-fixed combination formulation" means that the combination of active ingredients is administered to the patient simultaneously or sequentially as separate entities without specific time constraints, and such administration delivers the compounds into the patient's body at therapeutically effective levels. For example, the ratio of the total amount of active ingredient (i) to the total amount of active ingredient (ii) administered in the formulation of the combination formulation may vary to meet the needs of the patient population being treated, or to meet the needs of a single patient, which may differ depending on the patient's age, sex, weight, etc.

[0047] The terms “pharmaceutically inactive ingredient,” “inactive ingredient,” “carrier,” or “excipient” refer to, and include, compounds or substances used to facilitate the administration of a compound (e.g., an active ingredient), for example, by increasing the solubility of said compound. Non-limiting examples of typical solid carriers include starch, lactose, dicalcium phosphate, sucrose, and kaolin. Non-limiting examples of typical liquid carriers include sterile water, saline solution, buffer solutions, nonionic surfactants, and edible oils. Various adjuvants commonly used in the art may also be included. These and other such compounds are described in the literature, e.g., the Merck Index (Merck & Company, Rahway, NJ). The concept of incorporating various ingredients into pharmaceutical compositions is described, for example, in Gilman et al., Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th edition, Pergamon Press, 1990, which is incorporated herein by reference in its entirety.

[0048] As used herein, the term “subject” refers to vertebrates or invertebrates, including mammals. The term “subject” includes humans, animals, birds, fish, or amphibians. Typically, non-exclusive examples of “subject” include humans, cats, dogs, horses, sheep, cattle, pigs, lambs, rats, mice, and guinea pigs.

[0049] As used herein, the term "pharmaceutically acceptable salt" refers to one or more salts of a given compound that possess the desired pharmacological activity of the free compound and are not biologically or otherwise undesirable. Generally, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit-to-risk ratio.

[0050] In a broader sense, the present invention relates to a combination of meropenem and one or more antibiotic resistance breakers, a pharmaceutical composition containing the same, and a method for treating a bacterial infection comprising administering the same.

[0051] Specifically, the present invention relates to a combination of (a) meropenem, (b) avibactam, and (c) EDTA, a pharmaceutical composition containing the same, and a method for treating a bacterial infection comprising administering the same.

[0052] Surprisingly, the inventors discovered that a combination of (a) meropenem, (b) avibactam, and (c) EDTA exhibited unexpectedly improved antimicrobial effects even against highly resistant bacteria, including those producing broad-spectrum β-lactamase enzymes (ESBLs) and carbapenamases (metallo-β-lactamases).

[0053] Surprisingly, a pharmaceutical composition containing meropenem, avibactam, and EDTA was found to exhibit unexpectedly synergistic antimicrobial activity even against highly resistant strains. While we do not intend to be bound by any theory, it is thought that the combination of antibiotic resistance breakers such as avibactam and EDTA (both β-lactamase inhibitors) with meropenem (a β-lactam antibiotic) inhibits the β-lactamase enzyme involved in the degradation of meropenem, thereby enhancing antimicrobial activity and helping to overcome resistance barriers.

[0054] The present invention relates to a pharmaceutical combination comprising (a) an effective amount of meropenem, (b) an effective amount of avibactam, and (c) an effective amount of EDTA.

[0055] In one embodiment, a pharmaceutical combination is provided comprising (a) 1 to 10 g of meropenem, (b) 1 to 5 g of avibactam, and (c) 100 to 300 mg of EDTA or a pharmaceutically acceptable salt thereof.

[0056] The individual doses of meropenem or avibactam may be modified according to clinical requirements.

[0057] In one embodiment, the compounding agent comprises one of the following dosages: (i) about 3 g of meropenem and about 1.5 g of avibactam, 111 mg of EDTA or a pharmaceutically acceptable salt; or (ii) about 3 g of meropenem and about 1.5 g of avibactam, 222 mg of EDTA or a pharmaceutically acceptable salt; or (iii) Approximately 3 g of meropenem and approximately 3 g of avibactam, 111 mg of EDTA or a pharmaceutically acceptable salt; or (iv) Approximately 3 g of meropenem and approximately 3 g of avibactam, 222 mg of EDTA or a pharmaceutically acceptable salt; or (v) Approximately 6 g of meropenem and approximately 1.5 g of avibactam, 111 mg of EDTA or a pharmaceutically acceptable salt; or (vi) Approximately 6 g of meropenem, approximately 3 g of avibactam, and approximately 3 g of 222 mg of EDTA or pharmaceutically acceptable salt.

[0058] In one embodiment, the EDTA is present in a range of about 0.001 to about 15 mg / ml after reconstitution. Preferably, the EDTA is present in a range of about 0.1 to about 10 mg / ml after reconstitution. Most preferably, the EDTA is present in a range of about 1 to about 5 mg / ml after reconstitution.

[0059] In one embodiment, the present invention provides a pharmaceutical composition comprising (a) meropenem, (b) avibactam, and (c) EDTA, and one or more pharmaceutically acceptable carriers or excipients.

[0060] The pharmaceutical composition or active ingredient according to the present invention can be formulated into various dosage forms, such as solid, semi-solid, liquid, and aerosol formulations. Typical, non-limiting examples of some dosage forms include tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs, ointments, gels, creams, and liposome compositions.

[0061] In some embodiments, the pharmaceutical composition according to the present invention is in the form of a powder or solution. In some other embodiments, the pharmaceutical composition according to the present invention exists in the form of a powder or solution that can be reconstituted by adding a suitable reconstituted diluent before administration. In some other embodiments, the pharmaceutical composition according to the present invention is in the form of a frozen composition that can be diluted with a suitable reconstituted diluent before administration. Typical non-limiting examples of suitable reconstituted diluents include water for injection, 5% dextrose, 0.9% saline, and 5% dextrose + 0.9% saline.

[0062] In some other embodiments, the pharmaceutical composition according to the present invention exists in a form that can be used directly for parenteral administration.

[0063] The compositions according to the present invention can be formulated into various dosage forms in which the active ingredient and / or excipients may be present together or as separate ingredients. When the various ingredients in the composition are formulated as a mixture, such a composition can be delivered to a subject by administering such mixture using any suitable route of administration. Alternatively, the pharmaceutical compositions according to the present invention can be formulated into dosage forms in which one or more ingredients (e.g., an active ingredient or an inactive ingredient) are present as separate ingredients. Compositions or dosage forms in which the ingredients are present as individual ingredients rather than a mixture can be administered in several ways. In one method, the ingredients are mixed in a desired proportion, reconstituted with a suitable reconstitution diluent, and then administered as needed. Alternatively, the composition or ingredients (active ingredient or inactive ingredient) may be administered separately (simultaneously or sequentially) in appropriate proportions, thereby achieving the same or equivalent level of treatment or effect as when an equivalent mixture is administered.

[0064] In some embodiments, the pharmaceutical composition according to the present invention is formulated into dosage forms such that meropenem, avibactam, and EDTA are present in the composition together or as separate components. In other embodiments, the pharmaceutical composition according to the present invention is formulated into dosage forms such that meropenem, avibactam, and EDTA are present in the composition as separate components.

[0065] In another embodiment of the present invention, the required amount of the pharmaceutical composition is provided in a sealed, airtight container such as a vial, ampoule, syringe, packet, pouch, or auto-injector. These containers can contain the composition disclosed in the present invention in single doses or multiple doses up to 10 times. The internal space of the sealed, airtight container comprises a filling volume occupied by the formulation of the present invention and a headspace volume aseptically occupied by an inert gas-restricted minute atmosphere, the minute atmosphere essentially consisting of one or more inert gases selected from the group consisting of noble gases and nitrogen. Thus, the ratio of filling volume to headspace volume is 1:1 or greater.

[0066] A pharmaceutically effective dose of the composition may be provided in the form of a dose concentrate in a sealed, airtight container having sufficient headspace volume to introduce a suitable amount of aqueous solvent / compatible diluent selected from the group consisting of sterile water for injection, germicidal water for injection, and isotonic sterile sodium chloride solution, which is sufficient to form a suitable reconstituted solution of the composition.

[0067] In the case of a unit dose / multiple dose of the composition, a pharmaceutically effective dose can be provided in a sealed, airtight container having sufficient headspace volume to introduce an appropriate amount of aqueous solvent. The unit dose / multiple dose is in the form of an appropriate reconstituted solution of the composition.

[0068] When used as an injectable preparation, the composition may be provided in the form of a sterile, dry powder in a sealed, airtight container to form a pharmaceutically acceptable, fixed-dose formulation for reconstitution before intramuscular or intravenous administration for the treatment of the bacterial infection.

[0069] Alternatively, the composition may be provided in a sealed container, such as a clear glass vial, covered with a suitable halogenated stopper and seal, for reconstitution for intramuscular or intravenous administration for the treatment of the bacterial infection. When the composition is provided in a reconstituted form in a sealed, airtight container, the internal space of the container may include a filling volume occupied by the reconstituted form of the composition and a headspace volume aseptically occupied by an inert gas-restricted minute atmosphere, the inert gas-restricted minute atmosphere may essentially consist of one or more inert gases selected from the group consisting of noble gases and nitrogen, preferably nitrogen, the volume of nitrogen gas being 5% or less of the headspace volume, and the ratio of the filling volume to the headspace volume being 1:1 or greater.

[0070] In one embodiment, the pharmaceutical composition according to the present invention is used for the treatment of bacterial infections.

[0071] In another embodiment, a method for treating a bacterial infection in a subject is provided, the method comprising administering to the subject an effective amount of a pharmaceutical composition according to the present invention. In the dosage form in which meropenem, avibactam, and EDTA are present as separate components in the composition, meropenem may be administered before, after, or concurrently with the administration of EDTA and avibactam.

[0072] In yet another embodiment, a method is provided for treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of (a) meropenem, (b) avibactam, and (c) EDTA.

[0073] In another embodiment, a method for treating a bacterial infection in a subject is provided, the method comprising administering to the subject a daily dose, namely (a) 1 to 10 g of meropenem, (b) 1 to 5 g of avibactam, and (c) 100 to 300 mg of EDTA.

[0074] In another embodiment, a method for treating a bacterial infection in a subject is provided, the method comprising administering the subject the daily dose at 8-hour intervals.

[0075] In some embodiments, a method for treating a bacterial infection in a subject is provided, the method comprising administering to the subject a daily dose, i.e., (a) meropenem, (b) avibactam, and (c) EDTA in any of the following amounts: (i) about 3 g of meropenem and about 1.5 g of avibactam, 111 mg of EDTA or a pharmaceutically acceptable salt; or (ii) about 3 g of meropenem and about 1.5 g of avibactam, 222 mg of EDTA or a pharmaceutically acceptable salt; or (iii) Approximately 3 g of meropenem and approximately 3 g of avibactam, 111 mg of EDTA or a pharmaceutically acceptable salt; or (iv) Approximately 3 g of meropenem and approximately 3 g of avibactam, 222 mg of EDTA or a pharmaceutically acceptable salt; or (v) Approximately 6 g of meropenem and approximately 1.5 g of avibactam, 111 mg of EDTA or a pharmaceutically acceptable salt; or (vi) Approximately 6 g of meropenem, approximately 3 g of avibactam, and approximately 3 g of 222 mg of EDTA or pharmaceutically acceptable salt.

[0076] In some embodiments, a method for treating a bacterial infection in a pediatric patient is provided, which comprises administering to the subject a daily dose, namely (a) about 10 to about 40 mg / kg of meropenem, (b) about 10 to about 12.5 mg / kg of avibactam, and (c) about 1.85 to about 3.7 mg / kg of EDTA.

[0077] In yet another embodiment, in the method according to the present invention, meropenem is administered before, after, or concurrently with the administration of avibactam and EDTA.

[0078] In yet another embodiment, in the method according to the present invention, the daily doses of (a) meropenem, (b) avibactam, and (c) EDTA are administered at 8-hour intervals.

[0079] In yet another embodiment, in the method according to the present invention, (a) meropenem, (b) avibactam, and (c) EDTA are administered as an intravenous infusion over a period of about 30 to about 120 minutes.

[0080] In the methods according to the present invention, the pharmaceutical compositions and / or other pharmaceutically active ingredients disclosed herein may be administered by any suitable method that helps deliver the composition, its components, or the active ingredient to a desired site. The method of administration may vary depending on various factors, such as the properties of the components of the pharmaceutical composition and the active ingredient, the potential or actual site of infection, the microorganisms involved (e.g., bacteria), the severity of the infection, the age of the subject, and the physical condition. Non-limiting examples of administration of compositions according to the present invention to a subject include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, rectal, vaginal, gene gun, skin patch, eye drops, ear drops, or mouthwash. In some embodiments, the compositions according to the present invention or one or more active ingredients are administered parenterally.

[0081] In one embodiment, a method is provided for enhancing the antibacterial effect in a subject, the method comprising co-administering meropenem, avibactam, and EDTA. In another embodiment, a method is provided for enhancing the antibacterial effect in a subject, the method comprising co-administering meropenem, avibactam, and EDTA.

[0082] A wide variety of bacterial infections can be treated using the compositions and methods according to the present invention.

[0083] The pharmaceutical compositions and methods according to the present invention are useful for the treatment or prevention of several infections, including, for example, urinary tract infections, complicated urinary tract infections, respiratory infections, pneumonia, surgical infections, intra-abdominal infections, skin and soft tissue infections, and bloodstream infections.

[0084] In one embodiment, the pharmaceutical composition and method according to the present invention are used for the treatment or prevention of infections caused by resistant bacteria. In another embodiment, the composition and method according to the present invention are used for the treatment or prevention of infections caused by bacteria that produce one or more β-lactamase enzymes.

[0085] Generally, the pharmaceutical compositions and methods disclosed herein are also effective in treating infections caused by bacteria that are considered to be less susceptible or insensitive to one or more known antimicrobial agents or compositions thereof. Non-exclusive examples of such bacteria known to have acquired resistance to various antimicrobial agents include Acinetobacter, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, and Citrobacter. Examples of Embodiments

[0086] Examples of specific embodiments are shown below. <1> ~ <75> These are illustrative examples only and do not limit the scope of the disclosed subject matter as defined by the claims. Examples of these embodiments encompass all combinations, subcombinations, and multiple references (e.g., multiple dependencies) described herein.

[0087] Embodiment <1> A composition comprising meropenem and one or more antibiotic resistance breakers.

[0088] Embodiment <2> Bulk form, embodiment <1> The composition of.

[0089] Embodiment <3> Embodiments of a pharmaceutical composition <1> A composition comprising one or more pharmaceutically acceptable excipients.

[0090] Embodiment <4> Embodiments of a pharmaceutical composition in unit dose form <1> A composition comprising one or more pharmaceutically acceptable excipients.

[0091] Embodiment <5> The embodiment includes one or more antibiotic resistance breakers, including avibactam. <1> ~ <4> Any one of the following compositions.

[0092] Embodiment <6> The embodiment includes one or more antibiotic resistance breakers comprising 1 to 5 g of avibactam. <1> ~ <4> Any one of the following compositions.

[0093] Embodiment <7> The embodiment includes one or more antibiotic resistance breakers comprising 1.5 to 3 g of avibactam. <1> ~ <4> Any one of the following compositions.

[0094] Embodiment <8> The embodiment includes one or more antibiotic resistance breakers comprising 3 ± 1 g of avibactam. <1> ~ <4> Any one of the following compositions.

[0095] Embodiment <9> The embodiment includes one or more antibiotic resistance breakers comprising 3 ± 0.5 g of avibactam. <1> ~ <4> Any one of the following compositions.

[0096] Embodiment <10> The embodiment includes one or more antibiotic resistance breakers comprising 3 g of avibactam. <1> ~ <4> Any one of the following compositions.

[0097] Embodiment <11> The embodiment includes one or more antibiotic resistance breakers comprising 1.5 ± 0.5 g of avibactam. <1> ~ <4> Any one of the following compositions.

[0098] Embodiment <12> The embodiment includes one or more antibiotic resistance breakers comprising 1.5 ± 0.25 g of avibactam. <1> ~ <4> Any one of the following compositions.

[0099] Embodiment <13> The embodiment includes one or more antibiotic resistance breakers comprising 1.5 g of avibactam. <1> ~ <4> Any one of the following compositions.

[0100] Embodiment <14> The embodiment includes one or more antibiotic resistance breakers, including EDTA. <1> ~ <13> Any one of the following compositions.

[0101] Embodiment <15> The embodiment includes one or more antibiotic resistance breakers containing 100 to 300 mg of EDTA. <1> ~ <13> Any one of the following compositions.

[0102] Embodiment <16> The embodiment includes one or more antibiotic resistance breakers comprising 110 to 225 mg of EDTA. <1> ~ <13> Any one of the following compositions.

[0103] Embodiment <17> The embodiment includes one or more antibiotic resistance breakers containing 222 ± 20 mg of EDTA. <1> ~ <13> Any one of the following compositions.

[0104] Embodiment <18> The embodiment includes one or more antibiotic resistance breakers containing 222 ± 10 mg of EDTA. <1> ~ <13> Any one of the following compositions.

[0105] Embodiment <19> The embodiment in which the one or more antibiotic resistance breakers include 222 ± 5 mg of EDTA. <1> ~ <13> A composition according to any one of the items.

[0106] Embodiment <20> The embodiment in which the one or more antibiotic resistance breakers include 222 mg of EDTA <1> ~ <13> A composition according to any one of the items.

[0107] Embodiment <21> The embodiment includes one or more antibiotic resistance breakers comprising 111 ± 10 mg of EDTA. <1> ~ <13> A composition according to any one of the items.

[0108] Embodiment <22> The embodiment in which the one or more antibiotic resistance breakers include 111 ± 5 mg of EDTA. <1> ~ <13> A composition according to any one of the following items.

[0109] Embodiment <23> The embodiment includes one or more antibiotic resistance breakers containing 111 ± 2.5 mg of EDTA. <1> ~ <13> Any one of the following compositions.

[0110] Embodiment <24> The embodiment in which the one or more antibiotic resistance breakers include 111 mg of EDTA <1> ~ <13> Any one of the following compositions.

[0111] Embodiment <25> The embodiment includes one or more antibiotic resistance breakers, including avibactam and EDTA. <1> ~ <13> Any one of the following compositions.

[0112] Embodiment <26> The embodiment includes one or more antibiotic resistance breakers comprising 1 to 5 g of avibactam and 100 to 300 mg of EDTA. <1> ~ <13> A composition according to any one of the following items.

[0113] Embodiment <27> Embodiments in which the one or more antibiotic resistance breakers include 1.5 to 3 g of avibactam and 110 to 225 mg of EDTA <1> ~ <13> A composition according to any one of the items.

[0114] Embodiment <28> Embodiments in which the one or more antibiotic resistance breakers include 1.5 ± 0.5 g of avibactam and 111 ± 10 mg of EDTA <1> ~ <13> A composition according to any one of the items.

[0115] Embodiment <29> The embodiment includes one or more antibiotic resistance breakers comprising 1.5 ± 0.25 g of avibactam and 111 ± 5 mg of EDTA. <1> ~ <13> A composition according to any one of the items.

[0116] Embodiment <30> Embodiments in which the one or more antibiotic resistance breakers include 1.5 ± 0.15 g of avibactam and 111 ± 5 mg of EDTA <1> ~ <13> A composition according to any one of the items.

[0117] Embodiment <31> Embodiments in which 1 to 10 g of meropenem is present. <1> ~ <30> A composition according to any one of the items.

[0118] Embodiment <32> Embodiments in which 3 to 6 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0119] Embodiment <33> Embodiments in which 6 ± 1 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0120] Embodiment <34> Embodiments in which 6 ± 0.5 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0121] Embodiment <35> Embodiments in which 6 ± 0.25 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0122] Embodiment <36> Embodiment in which 6 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0123] Embodiment <37> Embodiments in which 3 ± 0.5 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0124] Embodiment <38> Embodiments in which 3 ± 0.25 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0125] Embodiment <39> Embodiments in which 3 ± 0.15 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0126] Embodiment <40> Embodiments in which 3 g of meropenem is present. <1> ~ <30> Any one of the following compositions.

[0127] Embodiment <41> Embodiments of unit dosage forms selected from the group consisting of oral tablets, oral capsules, powders, oral solutions, oral suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs, ointments, gels, creams, liquid injections, and liposome compositions. <1> ~ <40> A composition according to any one of the items.

[0128] Embodiment <42> Embodiments of unit dose forms formulated for delivery to human subjects via oral, intravenous, topical, respiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, lung, intraocular, intratracheal, rectal, or vaginal. <1> ~ <40> A composition according to any one of the items.

[0129] Embodiment <43> An embodiment in dry powder form, suitable for reconstitution in a liquid carrier for parenteral administration. <1> ~ <40> A composition according to any one of the items.

[0130] Embodiment <44> An embodiment in dry powder form, suitable for reconstitution in a liquid carrier for parenteral administration, further comprising one or more pharmaceutically acceptable excipients in dry form. <1> ~ <40> A composition according to any one of the items.

[0131] Embodiment <45> Suitable for reconstitution in a liquid carrier for parenteral administration, further comprising one or more pharmaceutically acceptable excipients in dry form, and in dry powder form. <1> ~ <40> A composition according to any one of the above, wherein the one or more pharmaceutically acceptable excipients comprises at least one of a buffer, a pH adjuster, an antioxidant, and a preservative.

[0132] Embodiment <46> This is a unit dose form of dry powder contained in a vial, suitable for reconstitution in a liquid carrier for parenteral administration, and is an embodiment of <1> ~ <40> A composition according to any one of the items.

[0133] Embodiment <47> This embodiment is a unit dose form of dry powder contained in a glass vial, suitable for reconstitution in a liquid carrier for parenteral administration. <1> ~ <40> A composition according to any one of the items.

[0134] Embodiment <48> This embodiment is in the form of a dry powder and is suitable for reconstitution in a liquid carrier for parenteral administration. <1> ~ <40> A composition according to any one of the above, wherein the liquid carrier comprises at least one of water for injection, physiological saline, and glucose.

[0135] Embodiment <49> Embodiments of a liquid injection preparation, suitable for parenteral administration, comprising a liquid carrier containing at least one of sterile water for injection, physiological saline, and glucose. <1> ~ <40> A composition according to any one of the items.

[0136] Embodiment <50> Embodiments of a liquid injection preparation suitable for parenteral administration, comprising a liquid carrier containing at least one of sterile water for injection, 0.9% physiological saline, and 5% glucose. <1> ~ <40> A composition according to any one of the items.

[0137] Embodiment <51> Embodiments administered parenterally <43> ~ <50> A composition according to any one of the items.

[0138] Embodiment <52> Embodiments administered parenterally at 8-hour intervals. <43> ~ <50> A composition according to any one of the items.

[0139] Embodiment <53> Embodiments administered by intravenous infusion <43> ~ <50> A composition according to any one of the items.

[0140] Embodiment <54> The embodiment is administered as an intravenous infusion over a period of approximately 30 to 120 minutes. <43> ~ <50> A composition according to any one of the items.

[0141] Embodiment <55> A method for treating an infectious disease, comprising an embodiment effective in treating the infectious disease in a human subject who is suffering from or at risk of suffering from the infectious disease. <1> ~ <54> A method comprising administering the pharmaceutical composition described in any one of the items.

[0142] Embodiment <56> Embodiments in which the aforementioned infectious disease is a bacterial infection <55> Methods used.

[0143] Embodiment <57> Embodiments in which the aforementioned infection is a bacterial infection caused by resistant bacteria <55> Methods used.

[0144] Embodiment <58> Embodiments in which the infectious disease is a bacterial infection caused by bacteria that produce one or more types of β-lactamase enzymes <55> Methods used.

[0145] Embodiment <59> Embodiments in which the infection is a bacterial infection caused by a resistant bacterium including at least one of Acinetobacter, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, and Citrobacter <55> Methods used.

[0146] Embodiment <60> Embodiments in which the infection is a urinary tract infection, complicated urinary tract infection, respiratory tract infection, pneumonia, surgical infection, intra-abdominal infection, skin and soft tissue infection, or bloodstream infection <55> ~ <59> The method described in any one of the items.

[0147] Embodiment <61> Embodiment in which the administration of the pharmaceutical composition is by intravenous infusion, thereby the daily dose to the human subject is (a) meropenem approximately 10 to approximately 40 mg / kg, (b) avibactam approximately 10 to approximately 12.5 mg / kg, and (c) EDTA approximately 1.85 to approximately 3.7 mg / kg. <55> ~ <60> The method described in any one of the items.

[0148] Embodiment <62> Embodiments in which administration of the pharmaceutical composition results in a daily dose to the human subject of (a) approximately 25 ± 10 mg / kg of meropenem, (b) approximately 11.25 ± 4 mg / kg of avibactam, and (c) 2.775 ± 0.6 mg / kg of EDTA. <55> ~ <60> The method described in any one of the items.

[0149] Embodiment <63> Embodiments in which the administration of the pharmaceutical composition results in a daily dose to the human subject of (a) approximately 25 ± 5 mg / kg of meropenem, (b) approximately 11.25 ± 2 mg / kg of avibactam, and (c) 2.775 ± 0.3 mg / kg of EDTA. <55> ~ <60> The method described in any one of the items.

[0150] Embodiment <64> Embodiments in which administration of the pharmaceutical composition results in a daily dose to the human subject of (a) approximately 25 ± 2.5 mg / kg of meropenem, (b) approximately 11.25 ± 1 mg / kg of avibactam, and (c) 2.775 ± 0.15 mg / kg of EDTA. <55> ~ <60> The method described in any one of the items.

[0151] Embodiment <65> Embodiments in which the administration of the pharmaceutical composition results in a daily dose to the human subject of (a) meropenem approximately 10 to approximately 40 mg / kg, (b) avibactam approximately 10 to approximately 12.5 mg / kg, and (c) EDTA approximately 1.85 to approximately 3.7 mg / kg. <55> ~ <60> The method described in any one of the items.

[0152] Embodiment <66> Embodiment in which the administration of the pharmaceutical composition is by intravenous infusion, thereby the daily dose to the human subject is (a) approximately 25 ± 5 mg / kg of meropenem, (b) approximately 11.25 ± 2.2 mg / kg of avibactam, and (c) approximately 2.275 ± 0.5 mg / kg of EDTA. <55> ~ <60> The method described in any one of the items.

[0153] Embodiment <67> Embodiment in which the administration of the pharmaceutical composition is by intravenous infusion, thereby the daily dose to the human subject is (a) meropenem approximately 25 ± 2.5 mg / kg, (b) avibactam approximately 11.25 ± 1.1 mg / kg, and (c) EDTA approximately 2.275 ± 0.25 mg / kg. <55> ~ <60> The method described in any one of the items.

[0154] Embodiment <68> Embodiment in which the administration of the pharmaceutical composition is by intravenous infusion, thereby the daily dose to the human subject is (a) meropenem approximately 25 ± 1.5 mg / kg, (b) avibactam approximately 11.25 ± 0.5 mg / kg, and (c) EDTA approximately 2.275 ± 0.15 mg / kg. <55> ~ <60> The method described in any one of the items.

[0155] Embodiment <69> In one embodiment, meropenem is administered simultaneously with avibactam and EDTA. <55> ~ <68> The method described in any one of the items.

[0156] Embodiment <70> In one embodiment, the meropenem is administered before the administration of avibactam and EDTA. <55> ~ <68> The method described in any one of the items.

[0157] Embodiment <71> In one embodiment, the meropenem is administered after the administration of avibactam and EDTA. <55> ~ <68> The method described in any one of the items.

[0158] Embodiment <72> Embodiments in which meropenem, avibactam, and EDTA are present in the same dosage form. <55> ~ <68> The method described in any one of the items.

[0159] Embodiment <73> Embodiments in which meropenem, avibactam, and EDTA are not present in the same dosage form. <55> ~ <68> Any one of the methods described in item 1.

[0160] Embodiment <74> Embodiment in which meropenem is present in the first dosage form, and avibactam and EDTA are present in the second dosage form. <55> ~ <68> Any one of the methods described in item 1.

[0161] Embodiment <75> The method according to any one of embodiments <55> to <68>, wherein the meropenem is present in the first dosage form, the avibactam is present in the second dosage form, and the EDTA is present in the third dosage form.

Example

[0162] The following examples illustrate the present invention. These examples are presented to illustrate the present invention and do not limit the scope of the present invention. The antibacterial activities of various formulations according to the present invention against resistant strains were examined.

[0163] In a typical test, the MIC test was performed by the microdilution method according to the CLSI susceptibility test criteria. A 0.5 M MacFarland suspension in CA-MHB containing TES was diluted 100-fold to prepare a bacterial inoculum of about 1×10 6 CFU / mL. A microtiter plate well containing 50 μL of an antibacterial solution at twice the final concentration was serially diluted with 50 μL of the inoculum to obtain a final inoculum with a concentration of about 5×10 5 CFU / mL (the target test concentration of the antibacterial agent). The test microtiter plate was cultured according to the CLSI guidelines and visually determined. The MIC value corresponded to the first well where no growth was visually observed.

[0164] Example 1 The antibacterial activities of amikacin (AMK) and ceftazidime-avibactam (CZA) were low against all isolates (606 strains) isolated in India, and their MIC 90 values were >64 μg / mL or >32 μg / mL, respectively. The MIC 50 value and MIC 90 value of meropenem (MEM) were >32 μg / mL, respectively. Compared with MEM alone, the antibacterial activity was significantly improved when used in combination of three agents. For MEM / AVI [4 mg / L] / EDTA [10 mM] and MEM / AVI [4 mg / L] / EDTA [20 mM], the MIC 90The decreases were 0.06 μg / mL and ≤0.002 μg / mL, respectively. MEM / AVI[8 mg / L] / EDTA[10 mM] and MEM / AVI[8 mg / L] / EDTA[20 mM] showed the following differences compared to MEM alone: 90 The level significantly improved to ≤0.002 μg / mL.

[0165] The results are shown in Table 1. JPEG2026517813000004.jpg65150

[0166] In the MEM-NS (meropenem-insensitive -85.9%) group, isolates (n=534) showed low antimicrobial activity with MEM alone, and the MIC was low. 50 and MIC 90 The MICs were >32 μg / mL for each, with an MIC range of 2 to >32 μg / mL. MICs for MEM / AVI[4 mg / L] / EDTA[10 mM] and MEM / AVI[4 mg / L] / EDTA[20 mM] 90 The values ​​were 0.06 and ≤0.002 μg / mL, respectively. MIC of MEM / AVI[8 mg / L] / EDTA[10 mM] and MEM / AVI[8 mg / L] / EDTA[20 mM] 90 The value was ≤0.002 μg / mL.

[0167] Example 2 Table 2 shows the results of the antimicrobial activity of amikacin, ceftazidime avibactam, a combination of ceftriaxone, sulbactam, and EDTA, and meropenem and a combination of meropenem, avibactam, and EDTA against highly resistant strains of Enterobacteriaceae. As can be seen from this table, the activity of the comparison compounds was low against all Enterobacteriaceae isolates (n=301) isolated in India, and the MICs of AMK and CZA were low. 90 The MICs for CRO / S4 / E10 were >64 μg / mL and >32 μg / mL, respectively. 90 The concentration was 16 μg / mL.

[0168] MEM's MIC 50 and MIC90 The MIC range was >32 μg / mL (MIC range: ≤0.015 to >32 μg / mL), and 250 out of 301 isolates (82.7%) (MEM NS) showed meropenem resistance. When used in combination with AVI [4 mg / L] and with 10 mM or 20 mM EDTA, the MIC was 90 However, these decreased to 0.125 and ≤0.002 μg / mL, respectively. Similarly, when used in combination with AVI [8 mg / L], the MIC for 10 mM or 20 mM EDTA decreased. 90 These values ​​improved to 0.015 and ≤0.002 μg / mL, respectively.

[0169] JPEG2026517813000005.jpg62150

[0170] Against Enterobacteriaceae isolates from the MEM-NS group (n=250, 82.7%), MEM alone showed low antibacterial activity, and the MIC (Minimum Indication) 50 and MIC 90 The MIC was >32 μg / mL, and the MIC range was 2 to >32 μg / mL. MEM / AVI[4 mg / L] / EDTA[10 mM] and MEM / AVI[4 mg / L] / EDTA[20 mM] were MIC 90 The values ​​were quite low, at 0.12 μg / mL and 0.004 μg / mL, respectively.

[0171] Example 3 Table 3 shows the results of the antimicrobial activity of amikacin, ceftazidime avibactam, a combination of ceftriaxone, sulbactam, and EDTA, and meropenem and a combination of meropenem, avibactam, and EDTA against highly resistant strains of Escherichia coli. 50 and MIC 90 The concentration was >32 μg / mL. In combination therapy with MEM / AVI[4 mg / L] / EDTA[10 mM], antibacterial activity was significantly improved compared to MEM alone, and the MIC was higher. 90 The concentration was 0.004 μg / mL.

[0172] JPEG2026517813000006.jpg59150

[0173] The MIC of MEM was measured against MEM-NS E. coli isolates (n=105, 88.2%). 50 and MIC 90 The MIC was >32 μg / mL. However, with MEM / AVI[4 mg / L] / EDTA[10 mM] and MEM / AVI[4 mg / L] / EDTA[20 mM], 90 These levels were quite low, at 0.004 μg / mL and ≤0.002 μg / mL, respectively.

[0174] Example 4 Table 4 shows the antimicrobial activity of amikacin, ceftazidime avibactam, a combination of ceftriaxone, sulbactam, and EDTA, and meropenem, as well as a combination of meropenem, avibactam, and EDTA, against highly resistant strains of Klebsiella (93.3% Mem NS). As can be seen from this table, MEM alone had an MIC of >32 μg / mL against Klebsiella pneumoniae. 90 The activity of AMK and CZA was shown to be MIC, respectively. 90 The levels were much lower, >64 μg / mL and >32 μg / mL. Regarding CRO / S4 / E10, the MIC was... 90 The concentration was 64 μg / mL.

[0175] The combination of MEM / AVI [4 mg / L] and EDTA (10 mM or 20 mM) showed higher activity, and the MIC 90 These were 0.25 μg / mL and 0.12 μg / mL, respectively. On the other hand, with the combined use of MEM / AVI [8 mg / L] and EDTA (10 mM or 20 mM), the MIC was 90 These values ​​were further improved to 0.06 μg / mL and ≤0.002 μg / mL, respectively.

[0176] JPEG2026517813000007.jpg52147

[0177] MEM alone showed low antibacterial activity against MEM-NS Klebsiella pneumoniae isolates (n=112, 93.3%), and MIC 50 and MIC 90 The MIC was >32 μg / mL, and the MIC range was 4 to >32 μg / mL. For MEM / AVI[4 mg / L] / EDTA[10 mM] and MEM / AVI[4 mg / L] / EDTA[20 mM], 90 The concentrations were 0.25 μg / mL and 0.12 μg / mL, respectively.

[0178] Example 5 Table 5 shows the antimicrobial activity of amikacin, ceftazidime avibactam, a combination of ceftriaxone, sulbactam, and EDTA, and meropenem and a combination of meropenem, avibactam, and EDTA against highly resistant non-Enterobacteriaceae strains. As can be seen from this table, the activity of the comparison compounds was low, and AMK and CZA were MIC 90 The values ​​were >64 μg / mL and >32 μg / mL respectively, but the MIC for CRO / S4 / E10 was 90 However, the level was low at ≤0.03 μg / mL.

[0179] MEM's MIC 50 and MIC 90 The MIC was >32 μg / mL, but when used in combination with AVI [4 mg / L / 8 μg / mL] and EDTA (10 mM or 20 mM), 90 The value improved significantly further to ≤0.002 μg / mL.

[0180] JPEG2026517813000008.jpg53148

[0181] For MEM-NS non-fermented strains (n=284, 88.9%), MEM alone showed the following MIC 90The MIC ranged from 4 to 32 μg / mL, indicating low antibacterial activity. MEM / AVI[4 and 8 mg / L] / EDTA[10 mM] and MEM / AVI[4 and 8 mg / L] / EDTA[20 mM] showed an MIC of ≤0.002 μg / mL. 90 The value was shown.

[0182] Example 6 Table 6 shows the antibacterial activity of amikacin, ceftazidime avibactam, a combination of ceftriaxone, sulbactam, and EDTA, and meropenem and a combination of meropenem, avibactam, and EDTA against highly resistant strains of Pseudomonas aeruginosa. As can be seen from this table, the activity of the control group was very low, but the maximum MIC of CRO / S4 / E10 was low. 90 The MIC was very low, ≤0.03 μg / mL. MEM alone had an MIC of >32 μg / mL. 90 This showed that, however, in combination preparations of MEM or MEM / AVI [4 and 8 mg / L] and EDTA (10 mM or 20 mM), the MIC 90 This was significantly improved to ≤0.002 μg / mL.

[0183] JPEG2026517813000009.jpg54148

[0184] MEM alone showed low antibacterial activity against MEM-NS Pseudomonas aeruginosa (n=120, 92.7%), and MIC 90 The MIC was >32 μg / mL, and the MIC ranged from 4 to >32 μg / mL. The MIC significantly decreased in all tested combinations, and the MIC for MEM / AVI[4 and 8 mg / L] / EDTA[10 mM] and MEM / AVI[4 and 8 mg / L] / EDTA[20 mM] was lower. 90 The level decreased significantly to ≤0.002 μg / mL or less.

[0185] Example 7 Table 7 shows the antimicrobial activity of amikacin, ceftazidime avibactam, a combination of ceftriaxone, sulbactam, and EDTA, and meropenem and a combination of meropenem, avibactam, and EDTA against highly resistant strains of Acinetobacter baumannii. As can be seen from this table, the activity of the comparator drugs AMK and CZA is shown below. 90 Although the values ​​were high at >64 μg / mL and >32 μg / mL respectively, the MIC of CRO / S4 / E10 90 However, it was low at ≤0.002 μg / mL. MEM alone showed that MIC 90 It showed >32 μg / mL. However, when MEM or MEM / AVI [4 and 8 mg / L] was used in combination with EDTA (10 mM or 20 mM), the MIC 90 The level decreased significantly to ≤0.002 μg / mL.

[0186] JPEG2026517813000010.jpg56139

[0187] MEM alone showed low antibacterial activity against MEM-NS Acinetobacter baumannii isolates (n=163, 98.2%), and MIC 90 For >32 μg / mL, the MIC range was 32 to >32 μg / mL. On the other hand, with MEM / AVI[4 and 8 mg / L] / EDTA[10 and 20 mM], the MIC was 90 The value was significantly lower, at ≤0.002 μg / mL.

[0188] Example 8 Table 8 shows the results of the antibacterial activity of amikacin, ceftazidime avibactam, a combination of ceftriaxone, sulbactam, and EDTA, and meropenem and a combination of meropenem, avibactam, and EDTA against highly resistant strains of Stenotrophomonas maltophilia. As can be seen from this table, MEM alone had an MIC of >32 μg / mL. 50 and MIC 90 This showed that with the combined use of MEM / AVI[4 / 8 mg / L] / EDTA[10 / 20 mM], the MIC 90The value was ≤0.002 μg / mL, which was significantly lower.

[0189] JPEG2026517813000011.jpg56145

[0190] Example 9 The effect of body fluids on the minimum inhibitory concentration (MIC) of a combination drug of meropenem, avibactam, and EDTA.

[0191] the purpose: The combination of meropenem (MEM) with avibactam (AVI) and EDTA at different concentrations was tested. The in vitro activity of the three compound combinations against sets of Gram-negative bacterial clinical isolates (from India) was examined in cation-modified Müller-Hinton broth (CA-MHB) and CA-MHB supplemented with different body fluids (human serum (25% and 50%), pooled urine (25% and 50%), bovine surfactant (1% and 5%), and human ascites (25% and 50%).

[0192] method: To confirm resistance to bodily fluids, a resistance screening was performed on a total of 60 isolates. Prior to susceptibility testing, a total of 19 isolates were selected, including ATCC strains and non-repeated clinically relevant Escherichia coli (n=6), Klebsiella pneumoniae (n=3), Pseudomonas aeruginosa (n=6), Acinetobacter baumannii (n=3), and Enterobacter cloacae (n=1). The compounds under test include a combination of meropenem with AVI (4 mM) and EDTA (10 mM) (MEM / A4 / E10), a combination of meropenem with AVI (4 mM) and EDTA (20 mM) (MEM / A4 / E20), a combination of meropenem with AVI (8 mM) and EDTA (10 mM) (MEM / A8 / E10), a combination of meropenem with AVI (8 mM) and EDTA (20 mM) (MEM / A8 / E20), meropenem (MEM), a combination of ceftriaxone with sulbactam (4 mM) and EDTA (10 mM) (CRO / S10 / E10), ceftazidime avibactam (CZA), amikacin (AMK), tigecycline, and minocycline. The clinical isolates were collected from hospitalized patients at a tertiary care center in India. Following the recommendations of the Clinical Laboratory Standards Institute (CLSI), the sensitivity of isolates to various test formulations was tested using the microdilution method in CA-MHB medium and CA-MHB medium supplemented with various body fluids.

[0193] result: For all isolates tested, the MIC of MEM was >32 μg / mL, whereas the MEM / AVI[4 / 8 mg / L] / EDTA[10 mM or 20 mM] combination showed potent activity in CA-MHB, with MICs ranging from ≤0.002 to 0.25 μg / mL in CA-MHB medium against E. coli and Klebsiella pneumoniae producing CTX-M and NDM β-lactamase, respectively (Tables 1, 2, 3, and 4). Similarly, MEM / AVI [4 / 8 mg / L] and EDTA [10 / 20 mM] showed potent activity with an MIC of ≤0.002 μg / mL against MEM-NS Acinetobacter baumannii producing OXA / NDM, MEM-NS Acinetobacter baumannii co-producing NDM and OXA, and Pseudomonas aeruginosa producing NDM / VIM in CA-MHB medium (Tables 1, 2, 3, and 4). However, with respect to the test formulations, adding body fluids of different concentrations to CA-MHB medium did not adversely affect the antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacter cloaca, which were included in this study.

[0194] Table 1: In vitro activity of meropenem / EDTA 10 mM / avibactam [4 mg / L] in body fluids JPEG2026517813000012.jpg91153JPEG2026517813000013.jpg68153No proliferation under one or more conditions.

[0195] Table 2: In vitro activity of meropenem / EDTA 20 mM / avibactam [4 mg / L] in body fluids JPEG2026517813000014.jpg96155JPEG2026517813000015.jpg69153No proliferation under one or more conditions.

[0196] Table 3: In vitro activity of meropenem / EDTA 10 mM / avibactam [8 mg / L] in body fluids JPEG2026517813000016.jpg96155JPEG2026517813000017.jpg39154No proliferation under one or more conditions.

[0197] Table 4: In vitro activity of meropenem / EDTA 20 mM / avibactam [8 mg / L] in body fluids JPEG2026517813000018.jpg97155JPEG2026517813000019.jpg68156No growth under one or more conditions.

[0198] Conclusion: The combination of three agents, MEM / AVI [4 / 8 mg / L] / EDTA [10 or 20 mM], showed activity in various body fluids, and no effect on the MIC against isolates of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacter cloacae was observed.

[0199] Example 10 Minimum inhibitory concentration (MIC) profile of EDTA

[0200] Objective: The in vitro activity of ethylenediaminetetraacetic acid (EDTA) against a panel of Gram-negative clinical isolates (from India) was tested in cation-adjusted Mueller-Hinton broth (CA-MHB) and MHB.

[0201] Methods: Prior to susceptibility testing, a total of 80 isolates were selected, including ATCC strains and non-duplicate clinically relevant Escherichia coli (n = 20), Klebsiella pneumoniae (n = 20), Pseudomonas aeruginosa (n = 21), and Acinetobacter baumannii (n = 19). These clinical isolates were collected from inpatients at a tertiary medical center in India. The susceptibility of these isolates to EDTA at various test concentrations (1.25, 2.5, 5, 10, 20, 40, and 80 mM) was tested by the microbroth dilution method in CA-MHB medium and MHB.

[0202] Results: The MIC of EDTA against all isolates tested in CA-MHB medium 50 and MIC 90 were 10 mM and >80 mM, respectively. On the other hand, in MHB medium, its MIC 50 and MIC 90The concentrations were 2.5 mM and 80 mM, respectively (Table 1). In CA-MHB medium, the MIC of EDTA against Enterobacteriaceae was 50 and MIC 90 These values ​​were 40 mM and >80 mM, respectively. Furthermore, their MICs against non-fermenting bacteria were also determined. 50 and MIC 90 All values ​​were ≤0.125 mM. In MHB medium, the MIC of EDTA against Enterobacteriaceae bacteria was determined. 50 and MIC 90 The MICs were 10 mM and 80 mM, respectively. Furthermore, their MICs against non-fermenting bacteria were also measured. 50 and MIC 90 All values ​​were ≤0.125 mM. In CA-MHB medium, the MIC of EDTA against E. coli 50 and MIC 90 The MICs were 10 mM and 80 mM, respectively. Furthermore, its MIC for Klebsiella pneumoniae was also measured. 50 and MIC 90 These values ​​were 80 mM and >80 mM, respectively. In MHB medium, the MIC of EDTA against E. coli 50 and MIC 90 The MICs were 2.5 mM and 20 mM, respectively (four times lower than in the case of CA-MHB). Furthermore, its MIC against Klebsiella pneumoniae was also determined. 50 and MIC 90 All of these values ​​were 80 mM (approximately the same as in the case of CA-MHB). In CA-MHB medium, the MIC of EDTA against Pseudomonas aeruginosa 50 and MIC 90 The MIC values ​​were 10 mM and 20 mM, respectively. In addition, lower MIC values ​​of ≤1.25 mM or less were observed for Acinetobacter baumannii. Equivalent EDTA activity was observed against Pseudomonas aeruginosa and Acinetobacter baumannii in MHB medium and CA-MHB medium.

[0203] JPEG2026517813000020.jpg85129

[0204] Table 1: MIC of EDTA for all tested isolates in CA-MHB medium and MHB medium 50 MIC 90 , and the range of MIC

[0205] Conclusion: The MIC of EDTA for all isolates tested in CA-MHB medium and MHB medium 90 The concentrations were >80 mM and 80 mM, respectively. EDTA may or may not be active against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, regardless of the presence of cations in MHB and the type of resistance mechanism.

[0206] Example 11 Tests on the frequency of resistance (FOR)

[0207] the purpose: In vitro studies were performed to measure the frequency of resistance in the eight characterized isolates.

[0208] method: • Isolates: 8 isolates - Escherichia coli (3), Klebsiera Newmonier (2), Acinetobacter baumannii (1), and Pseudomonas aeruginosa (2) • Test compound: Meropenem, Meropenem / avibactam (4), Meropenem / EDTA (10 mM), and Meropenem / avibactam (4) / EDTA (10 mM) • Concentration of antibiotic used: JPEG2026517813000021.jpg89152JPEG2026517813000022.jpg28151

[0209] result: JPEG2026517813000023.jpg82152JPEG2026517813000024.jpg28150TMTC - countless.

[0210] Conclusion: The test compound meropenem / avibactam (4) / EDTA (10) has a low tendency to induce resistance against the tested isolates.

[0211] Example 12 Time - Kill Assay (TKA)

[0212] Objective: An in vitro Time - Kill Assay (TKA) was performed to measure the log reduction values in five characterized MDR isolates.

[0213] Methods: · Isolates: Five isolates - Escherichia coli (3) and Klebsiella pneumoniae (2) · Test compounds: Meropenem, meropenem / avibactam (4), meropenem / EDTA (10 mM), and meropenem / avibactam (4) / EDTA (10 mM) · 1 log - 90% killing, 2 log - 99% killing, and 3 log - 99.9% killing. Bactericidal: 3 - log reduction (99.9% killing) · MIC: JPEG2026517813000025.jpg40151

[0214] Results: For Escherichia coli isolates: JPEG2026517813000026.jpg63152 For Klebsiella pneumoniae isolates: JPEG2026517813000027.jpg82152

[0215] Conclusion: The test compound (a combination of three agents: MEM / AVI [4 / 8 mg / L] / EDTA [10 or 20 mM]) showed a significant time- and concentration-dependent logarithmic reduction / bactericidal effect against all tested isolates of Escherichia coli and Klebsiella pneumoniae.

[0216] As will be apparent to those skilled in the art, various substitutions and modifications can be made to the invention disclosed herein without departing from the spirit of the invention. Therefore, it should be understood that while the invention is specifically disclosed by preferred embodiments and optional features, modifications and changes to the concepts disclosed herein can be made by those skilled in the art. Such modifications and changes are considered to fall within the scope of the invention.

[0217] It is important to understand that the words and terms used herein are for illustrative purposes only and should not be interpreted restrictively. The use of “contains,” “constitutes,” or “has,” and variations thereof, is intended to encompass the items listed below and their equivalents, as well as other items.

[0218] It should be noted that, as used in this specification and the appended claims, the singular forms “one” and “the” also include the plural form unless the context clearly indicates otherwise. Therefore, for example, when referring to “a type of excipient,” it includes not only one type of excipient but also two or more different excipients.

Claims

1. A pharmaceutical composition comprising (a) an effective amount of meropenem, (b) an effective amount of avibactam, and (c) an effective amount of EDTA.

2. The pharmaceutical composition according to claim 1, wherein meropenem is present in an amount of 1 to 10 g, avibactam is present in an amount of 1 to 5 g, and EDTA is present in an amount of 100 to 300 mg.

3. The pharmaceutical composition according to claim 2, comprising meropenem, avibactam, and EDTA in any of the following amounts. (i) approximately 3 g of meropenem, approximately 1.5 g of avibactam, and approximately 111 mg of EDTA; or (ii) Approximately 3 g of meropenem, approximately 1.5 g of avibactam, and approximately 222 mg of EDTA; or (iii) about 3 g of meropenem, about 3 g of avibactam, and about 111 mg of EDTA; or (iv) Approximately 3 g of meropenem, approximately 3 g of avibactam, and approximately 222 mg of EDTA; or (v) Approximately 6 g of meropenem, approximately 1.5 g of avibactam, and approximately 111 mg of EDTA; or (vi) Approximately 6 g of meropenem, approximately 3 g of avibactam, and approximately 222 mg of EDT

4. A pharmaceutical composition comprising (a) meropenem, (b) avibactam, and (c) EDTA, and one or more pharmaceutically acceptable carriers or excipients.

5. A method for treating a bacterial infection in a subject, comprising administering to the subject an effective amount of (a) meropenem, (b) avibactam, and (c) EDTA.

6. The method according to claim 5, comprising administering to the subject a daily dose of (a) 1 to 10 g of meropenem, (b) 1 to 5 g of avibactam, and (c) 100 to 300 mg of EDTA.

7. The method according to claim 6, comprising administering to the subject (a) meropenem, (b) avibactam, and (c) EDTA in any one of the following amounts as a daily dose. (i) approximately 3 g of meropenem, approximately 1.5 g of avibactam, and approximately 111 mg of EDTA; or (ii) Approximately 3 g of meropenem, approximately 1.5 g of avibactam, and approximately 222 mg of EDTA; or (iii) about 3 g of meropenem, about 3 g of avibactam, and about 111 mg of EDTA; or (iv) Approximately 3 g of meropenem, approximately 3 g of avibactam, and approximately 222 mg of EDTA; or (v) Approximately 6 g of meropenem, approximately 1.5 g of avibactam, and approximately 111 mg of EDTA; or (vi) Approximately 6 g of meropenem, approximately 3 g of avibactam, and approximately 222 mg of EDT

8. A method for treating a bacterial infection in a pediatric patient, comprising administering to the patient a daily dose of (a) about 10 to about 40 mg / kg of meropenem, (b) about 10 to about 12.5 mg / kg of avibactam, and (c) about 1.85 to about 3.7 mg / kg of EDTA.

9. The method according to any one of claims 5 to 8, wherein meropenem is administered before, after, or concurrently with the administration of avibactam and EDTA.

10. The method according to any one of claims 5 to 9, wherein the daily dose of (a) meropenem, (b) avibactam, and (c) EDTA is administered at 8-hour intervals.

11. The method according to any one of claims 5 to 10, wherein the doses of (a) meropenem, (b) avibactam, and (c) EDTA are administered as an intravenous infusion over a period of approximately 30 to 120 minutes.

12. A pharmaceutical composition comprising (a) meropenem, (b) one or more antibiotic resistance breakers including at least one of avibactam and EDTA, and (c) one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition according to claim 12, comprising meropenem, avibactam, EDTA, and one or more pharmaceutically acceptable excipients.

14. The pharmaceutical composition according to claim 12, comprising 1 to 10 g of meropenem, 1 to 5 g of avibactam, 100 to 300 mg of EDTA, and one or more pharmaceutically acceptable excipients.

15. The pharmaceutical composition according to claim 12, comprising 3-6 g of meropenem, 1.5-3 g of avibactam, 110-225 mg of EDTA, and one or more pharmaceutically acceptable excipients.

16. The pharmaceutical composition according to any one of claims 12 to 15, in the form of a dry powder suitable for reconstitution with a liquid, or in the form of an injectable solution.

17. A pharmaceutical composition according to any one of claims 12 to 15, which is in a unit dose form and is formulated for delivery to a human subject intravenously or parenterally.

18. A method for treating an infectious disease, comprising administering to a human subject who is suffering from or at risk of contracting an infectious disease a pharmaceutical composition according to any one of claims 12 to 17 in an amount effective for treating the infectious disease and for an effective period of time.

19. The method according to claim 18, wherein the infectious disease is a bacterial infection.

20. The method according to claim 18, wherein the infectious disease is a bacterial infection caused by a resistant bacterium.

21. The method according to claim 18, wherein the infection is a bacterial infection caused by bacteria that produce one or more β-lactamase enzymes.

22. The method according to claim 18, wherein the infection is a bacterial infection caused by a resistant bacterium comprising at least one of Acinetobacter, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, and Citrobacter.

23. The method according to claim 18, wherein the infection is a urinary tract infection, a complicated urinary tract infection, a respiratory infection, pneumonia, a surgical infection, an intra-abdominal infection, an infection of the skin and soft tissues, or an infection of the bloodstream.

24. The method according to claim 18, wherein the daily dose to the human subject by administration of the pharmaceutical composition is (a) about 10 to about 40 mg / kg of meropenem, (b) about 10 to about 12.5 mg / kg of avibactam, and (c) about 1.85 to about 3.7 mg / kg of EDTA.

25. The method according to claim 18, wherein the administration of the pharmaceutical composition is by intravenous infusion, thereby the daily dose to the human subject is (a) about 10 to about 40 mg / kg of meropenem, (b) about 10 to about 12.5 mg / kg of avibactam, and (c) about 1.85 to about 3.7 mg / kg of EDTA.

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