阅读说明：本技术 治疗细菌感染的方法 (Methods of treating bacterial infections ) 是由 大卫·C·格里菲斯 迈克尔·N·达德利 杰弗里·S·洛蒂特 奥尔加·洛莫夫思卡亚 于 2016-04-20 设计创作，主要内容包括：本文公开了治疗或改善细菌感染的方法,包括联合施用包含环硼酸酯化合物I的组合物与美罗培南。在一些实施方案中,所述细菌感染是下呼吸道感染。(Disclosed herein are methods of treating or ameliorating a bacterial infection comprising administering a composition comprising a cyclic boronic acid ester compound I in combination with meropenem. In some embodiments, the bacterial infection is a lower respiratory tract infection.)

1. Use of compound I or a pharmaceutically acceptable salt thereof and meropenem in the manufacture of a medicament for treating or ameliorating a bacterial infection in a subject having reduced renal function in need of treatment of the bacterial infection,

wherein the amount of compound I or a pharmaceutically acceptable salt thereof is about 1.0g and the amount of meropenem is about 1.0g,

wherein a plasma clearance of compound I of about 3.4L/h to about 6.1L/h and a plasma clearance of meropenem of about 4.5L/h to about 7.0L/h is achieved,

wherein the subject has a creatinine clearance level of equal to or greater than 30ml/min and less than 50ml/min, and wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are administered every 8 hours (q8 h).

2. Use of compound I or a pharmaceutically acceptable salt thereof and meropenem in the manufacture of a medicament for treating or ameliorating a bacterial infection in a subject having reduced renal function in need of treatment of the bacterial infection,

wherein the amount of compound I or a pharmaceutically acceptable salt thereof is about 1.0g and the amount of meropenem is about 1.0g,

wherein a plasma clearance of compound I of about 2.0L/h to about 3.4L/h and a plasma clearance of meropenem of about 3.2L/h to about 4.5L/h is achieved,

wherein the subject has a creatinine clearance level of equal to or greater than 20ml/min and less than 30ml/min, and wherein Compound I or a pharmaceutically acceptable salt thereof and meropenem are administered every 12 hours (q12 h).

3. The use of any one of claims 1 to 2, wherein the bacterial infection is a lower respiratory tract infection.

4. The use of any one of claims 1 to 2, wherein the medicament is used by intravenous infusion.

5. The use of claim 4, wherein the intravenous infusion is completed in about 1 hour to about 5 hours.

6. The use of claim 5, wherein the intravenous infusion is completed within about 3 hours.

7. The use according to any one of claims 1 to 2, wherein compound I or a pharmaceutically acceptable salt thereof is administered before or after meropenem.

8. The use according to any one of claims 1 to 2, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are in a single dosage form.

9. The use of claim 8, wherein the single dosage form further comprises a pharmaceutically acceptable excipient, diluent or carrier.

10. The use of any one of claims 1-2, wherein the subject has an infection caused by enterobacter.

Technical Field

Embodiments of the present application relate to antimicrobial compounds, compositions, their use as therapeutic agents, and their manufacture.

Antibiotics have been an effective tool in the past century for the treatment of infectious diseases. Bacterial infections are almost completely controlled in developed countries from the development of antibiotic treatments to the end of the eighties of the nineteenth century. However, in response to the pressure to use antibiotics, multiple resistance mechanisms have become widespread and threaten the clinical utility of antibacterial therapy. The increase in antibiotic-resistant strains has been particularly prevalent in major hospitals and care centers. The consequences of increased drug resistant strains include higher morbidity and mortality, longer patient hospitalization and increased treatment costs.

Various bacteria have evolved β -lactam deactivating enzymes, i.e., β -lactamases that have efficacy against a variety of β -lactams. Beta-lactamases can be classified into 4 classes based on their amino acid sequence, i.e., the Ambler class A, B, C and D. Enzymes in class A, C and class D include the active site serine beta-lactamases, and the less frequently encountered class B enzymes are Zn-dependent. These enzymes catalyze the chemical degradation of β -lactam antibiotics, rendering them inactive. Some beta-lactamases are transferable within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multi-resistant strains severely limited the available therapeutic options for β -lactams.

The increase of bacterial strains expressing class D beta-lactamases, such as Acinetobacter baumannii, is a threat of emerging multidrug resistance. Acinetobacter baumannii strains express A, C and class D beta-lactamase. Class D beta-lactamases such as the OXA family of beta-lactam antibiotics (e.g., imipenem, Merck's) for destroying carbapenem typesActive carbapenem component of (e)) are particularly effective (Montefour, k.; crit. care Nurse 2008, 28, 15; perez, f. et al, Expert rev, anti infection, ther, 2008, 6, 269; bou, G.; Martinez-Beltran, j.antimicrob. ages chemither.2000, 40, 428.2006, 50, 2280; bou, g, et al, j.animicrob.ingredients chemither.2000, 44, 1556). This poses an urgent threat to the effective use of the drugs in this classification for the treatment and prevention of bacterial infections. In fact, the number of catalogued serine-based beta-lactamases has proliferated from less than 10 to over 300 variants in the seventies of the nineteenth century. These problems have prompted the development of five "generations" of cephalosporins. When initially administered to clinical practice, broad spectrum cephalosporins resist hydrolysis by the prevalent class A beta-lactamases, TEM-1 and SHV-1. However, the development of drug resistant strains due to the evolution of single amino acid substitutions in TEM-1 and SHV-1 resulted in the emergence of a broad spectrum of beta-lactamase (ESBL) phenotypes.

Recently, new beta-lactamases have been developed which hydrolyze carbapenem-based antimicrobials including imipenem, biapenem, doripenem, meropenem and ertapenem, as well as other beta-lactam antibiotics. These carbapenemases belong to the molecules A, B and class D. Class A KPC carbapenemases are mainly in Klebsiella pneumoniae (Klebsiella pneumoniae), but are now reported in other Enterobacter (Enterobacteriaceae), Pseudomonas aeruginosa (Pseudomonas aeruginosa) and Acinetobacter baumannii. KPC carbapenemases were first described in north carolina in 1996, but since then widely spread in the united states. Especially in the new york city area, where the spread within several major hospitals and the reports of patient morbidity have been reported, has become problematic. These enzymes have also been recently reported in france, greece, sweden, uk, and have recently been reported to spread suddenly in germany. Treatment of resistant strains with carbapenems may be associated with adverse outcomes.

Another mechanism of beta-lactamase-mediated resistance to carbapenems involves a combination of osmotic or efflux mechanisms coupled with the overproduction of beta-lactamases. One example is that loss of porin associated with overproduction of ampC beta-lactamases leads to resistance to imipenem in pseudomonas aeruginosa. Overexpression of efflux pumps in combination with overproduction of ampC beta-lactamases may also lead to resistance to carbapenems such as meropenem.

Since there are mainly three molecular classes of serine-based beta-lactamases and each class contains a large number of beta-lactamase variants, inhibition of one or a few beta-lactamases is unlikely to be of therapeutic value. Genetic beta-lactamase inhibitors are almost ineffective against at least class a carbapenemases, against chromosome-and plasmid-mediated class C cephalosporinase, and against many class D oxacillin enzymes. Thus, there is a need for improved beta-lactamase inhibitor combination therapies.

Background

Summary of The Invention

Some embodiments described herein relate to a method of treating a bacterial infection comprising administering to a subject in need thereof an effective amount of compound I or a pharmaceutically acceptable salt thereof:

wherein the amount of compound I or a pharmaceutically acceptable salt thereof is from about 1.0g to about 3.0g and the amount of meropenem is from about 1.0g to about 3.0 g.

Some embodiments described herein relate to a method of treating a bacterial infection comprising selecting for treatment a subject having reduced renal function who is in need of treatment for the bacterial infection; administering to the subject an effective amount of compound I or a pharmaceutically acceptable salt thereof and meropenem.

Some embodiments described herein relate to a method of treating or ameliorating a lower respiratory tract infection, comprising administering to a subject in need thereof an effective amount of compound I or a pharmaceutically acceptable salt thereof and meropenem.

In some embodiments, the method further comprises administering an additional agent selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

In some embodiments, the subject treated by the above method is a mammal. In some further embodiments, the subject is a human.

Brief Description of Drawings

Figure 1 is a graph depicting plasma concentration curves (mg/L) of compound I at various doses as a function of time following a single intravenous infusion in healthy subjects in the study disclosed in example 1.

Figure 2 is a graph depicting compound I dose versus AUC (hr mg/L) after single or multiple doses in healthy subjects in the study disclosed in example 1.

Fig. 3 is a graph depicting plasma concentration curves (mg/L) of compound I alone and in combination with meropenem after 3 hours infusion in healthy adult subjects in the study disclosed in example 2.

Fig. 4 is a graph depicting plasma concentration curves (mg/L) of meropenem alone and in combination with compound I after 3 hours of infusion in healthy adult subjects in the study disclosed in example 2.

Fig. 5 is a graph depicting plasma concentration curves (mg/L) of compound I alone and in combination with meropenem following single and 7-day TID (i.e. three times daily) dosing by 3 hour infusion in healthy adult subjects in the study disclosed in example 3.

Fig. 6 is a graph depicting plasma concentration curves (mg/L) of meropenem alone and in combination with compound I after single and 7-day TID (i.e. three times daily) dosing by 3 hour infusion in healthy adult subjects in the study disclosed in example 3.

Fig. 7 is a graph depicting plasma concentration curves (mg/L) of 2g of compound I alone and in combination with 2g meropenem after single and multiple doses by 3 hour infusion in healthy subjects in the study disclosed in example 4.

Fig. 8 is a graph depicting plasma concentration curves (mg/L) of 2g of compound I alone and in combination with 2g meropenem after single and multiple doses by 1 hour infusion in healthy subjects in the study disclosed in example 4.

Fig. 9 is a graph depicting the mean plasma concentration curve (mg/L) of compound I after 1 hour or 3 hours infusion of 2g of compound I in combination with 2g of meropenem in healthy subjects in the study disclosed in example 4.

Fig. 10 is a graph depicting plasma concentration curves (mg/L) of 2g meropenem alone and in combination with 2g compound I after single and multiple doses by 3 hour infusion in healthy subjects in the study disclosed in example 4.

Fig. 11 is a graph depicting plasma concentration curves (mg/L) of 2g meropenem alone and in combination with 2g compound I after single and multiple doses by 1 hour infusion in healthy subjects in the study disclosed in example 4.

Fig. 12 is a graph depicting the mean plasma concentration curve (mg/L) of meropenem after 1 hour or 3 hour infusion of 2g compound I in combination with 2g meropenem in healthy subjects in the study disclosed in example 4.

Fig. 13 is a graph depicting plasma concentration curves (mg/L) of meropenem open-loop lactam after 1 hour infusion of 2g meropenem alone and in combination with 2g compound in healthy subjects in the study disclosed in example 4.

Fig. 14 is a graph depicting the mean plasma concentration curve (mg/L) of meropenem open-loop lactam after 1 hour or 3 hours infusion of 2g meropenem in combination with 2g compound I in healthy subjects in the study disclosed in example 4.

Figure 15 is a graph depicting creatinine clearance, combined clearance of 1g compound I and 1g meropenem in subjects with varying degrees of renal injury in a study disclosed in example 5.

Fig. 16 is a graph depicting the mean plasma concentration curve (μ g/mL) of meropenem before and after the start of a third 2g infusion of meropenem over 3 hours in the study disclosed in example 6.

Fig. 17 is a graph depicting the mean plasma concentration curve (μ g/mL) of compound I before and after the start of a third infusion of compound I2g over a 3 hour period in the study disclosed in example 6.

Fig. 18 is a graph depicting mean plasma and epithelial cell lining fluid (ELF) concentration curves (μ g/mL) of meropenem at bronchoscopy and bronchoalveolar lavage (BAL) (meropenem 2g dose, infusion over 3 hours) in the study disclosed in example 6.

Figure 19 is a graph depicting mean plasma and epithelial cell lining (ELF) concentration curves (μ g/mL) for compound I at bronchoscopy and bronchoalveolar lavage (BAL) (compound I2g dose, infusion over 3 hours) in the study disclosed in example 6.

Fig. 20 is a graph depicting the mean plasma concentration curves (μ g/mL) of compound I and meropenem before and after the start of a third infusion of meropenem 2 g/compound I2g over 3 hours in the study disclosed in example 6.

Fig. 21 is a graph depicting the mean epithelial cell lining fluid (ELF) concentration curves (μ g/mL) for compound I and meropenem at bronchoscopy and bronchoalveolar lavage (BAL) (meropenem 2g dose, infusion over 3 hours) in the study disclosed in example 6.

Fig. 22 is a graph depicting the activity of 1g meropenem/1 g compound I administered by 3 hour infusion every 8 hours on certain strains of carbapenem-resistant klebsiella pneumoniae in an in vitro hollow fiber model.

Fig. 23 is a graph depicting the activity of 1g meropenem/1 g compound I administered by 3 hour infusion every 8 hours on certain strains of carbapenem-resistant klebsiella pneumoniae in an in vitro hollow fiber model.

Fig. 24 is a graph depicting the activity of 2g meropenem/2 g compound I administered by 3 hour infusion every 8 hours on certain strains of carbapenem-resistant klebsiella pneumoniae in an in vitro hollow fiber model.

Fig. 25 is a graph depicting the activity of 1g meropenem/1 g compound I administered by 3 hour infusion every 8 hours on certain pseudomonas aeruginosa strains in an in vitro hollow fiber model.

Fig. 26 is a graph depicting representative pharmacokinetic profiles of 2g meropenem and 2g compound I administered by 3 hour infusion every 8 hours in an in vitro hollow fiber model.

Fig. 27 is a graph depicting the activity of 2g meropenem administered by 3 hour infusion every 8 hours on certain pseudomonas aeruginosa strains in an in vitro hollow fiber model.

Fig. 28 is a graph depicting the activity of 2g meropenem/2 g compound I administered by 3 hour infusion every 8 hours on certain pseudomonas aeruginosa strains in an in vitro hollow fiber model.

Detailed description of the embodiments

Definition of

The term "reagent" or "test reagent" includes any substance, molecule, element, compound, entity, or combination thereof. It includes, but is not limited to, for example, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, and the like. It may be a natural product, a synthetic compound or a chemical compound or a combination of two or more substances. Unless otherwise specified, the terms "agent," "substance," and "compound" are used interchangeably herein.

The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes humans, cows, horses, dogs, cats, rats and mice, but also includes many other species.

The term "microbial infection" refers to the invasion of a host organism by a pathogenic microorganism, whether the organism is a vertebrate, invertebrate, fish, plant, bird or mammal. This includes the overgrowth of microorganisms (which are typically present in or on the body of mammals or other organisms). More generally, a microbial infection can be any situation where the presence of a microbial population destroys a host mammal. Thus, a mammal is "suffering" from a microbial infection when an excess of microbial population is present in or on the body of the mammal, or when the effect of the presence of a microbial population is to destroy cells or other tissue of the mammal. In particular, the description applies to bacterial infections. It is noted that the compounds of the preferred embodiments may also be used to treat microbial growth or contamination of cell cultures or other culture media or inanimate surfaces or objects, and nothing herein should limit the preferred embodiments to only treating higher organisms, except as expressly specified in the claims.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the composition. In addition, various adjuvants such as those commonly used in the art may be included. These and other such compounds are described in the literature, for example, in Merck Index, Merck & Company, Rahway, NJ. Reasons for including various ingredients in pharmaceutical compositions are described, for example, in Gilman et al (eds.) (1990); goodman and Gilman: the Pharmacological Basis of Therapeutics, 8 th edition, Pergamon Press.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the preferred embodiments and which is not biologically or otherwise undesirable. In many cases, the compounds of the preferred embodiments are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and like salts; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297 to Johnston et al, published on 9/11 1987 (incorporated herein by reference in its entirety).

"solvate" refers to a compound formed by the interaction of a solvent with EPI, a metabolite, or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

As used herein, "subject" means a human or non-human mammal, e.g., a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, e.g., a chicken, as well as any other vertebrate or invertebrate animal.

The therapeutic effect alleviates one or more symptoms of the infection to some extent, and includes curing the infection. By "curing" is meant eliminating the symptoms of active infection, including eliminating an excessive number of viable microorganisms of those involved in the infection. However, even after a cure is obtained, there may still be some long-term or permanent effects of the infection (e.g., extensive tissue damage).

As used herein, "treatment (Treat), (treatment) or (treating)" refers to the administration of a pharmaceutical composition for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to the treatment of a patient who has not yet suffered an infection, but who is predisposed to, or otherwise at risk of, a particular infection, whereby the treatment reduces the likelihood of the patient developing the infection. The term "therapeutic treatment" refers to administering a treatment to a patient already suffering from an infection.

Method of treatment

Some embodiments described herein relate to a method of treating a bacterial infection comprising administering to a subject in need thereof an effective amount of compound I or a pharmaceutically acceptable salt thereof:

wherein the amount of compound I or a pharmaceutically acceptable salt thereof is from about 1.0g to about 3.0g and the amount of meropenem is from about 1.0g to about 3.0 g.

In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof is about 2.0 g. In some embodiments, the amount of meropenem is about 2.0 g. In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof and meropenem are each about 2.0 g.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are administered at least once daily. In some embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are administered 3 times daily. In other embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is about 6.0g and wherein the daily dose of meropenem is about 6.0 g.

In some embodiments, the administering is by intravenous infusion. In some embodiments, the intravenous infusion is completed in about 1 hour to about 5 hours. In other embodiments, the intravenous infusion is completed within about 3 hours.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered before or after meropenem. In some other embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are in a single dosage form. In some embodiments, the single dosage form further comprises a pharmaceutically acceptable excipient, diluent or carrier.

Subject with reduced renal function

Some embodiments described herein relate to a method of treating a bacterial infection comprising selecting for treatment a subject having reduced renal function who is in need of treatment for the bacterial infection; administering to the subject an effective amount of compound I or a pharmaceutically acceptable salt thereof and meropenem. In some embodiments, the subject has a creatinine clearance ≧ 30ml/min and < 50 ml/min. In some embodiments, the subject has a creatinine clearance ≧ 20ml/min and < 30 ml/min. In some embodiments, the subject has a creatinine clearance ≧ 10ml/min and < 20 ml/min. In some embodiments, the subject has a creatinine clearance < 10 ml/min. In some embodiments, the bacterial infection is a lower respiratory tract infection.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 250mg to about 2.0 g. In other embodiments, compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 500mg to about 1.0 g. In some such embodiments, compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.0 g. In some other embodiments, compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 500 mg. In some embodiments, meropenem is administered in a dose of about 250mg to about 2.0 g. In other embodiments, meropenem is administered in a dose of about 500mg to about 1.0 g. In some such embodiments, meropenem is administered at a dose of about 1.0 g. In some other embodiments, meropenem is administered at a dose of about 500 mg. In other embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are both administered at a dose of about 1.0 g. In some other embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are both administered at a dose of about 500 mg.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are administered at least once daily (every 24 hours). In some embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are administered 2 times daily (every 12 hours). In some embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are administered 3 times daily (every 8 hours). In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is about 3.0g and wherein the daily dose of meropenem is about 3.0 g. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is about 2.0g and wherein the daily dose of meropenem is about 2.0 g. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is about 1.0g and wherein the daily dose of meropenem is about 1.0 g. In still other embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is about 500mg and wherein the daily dose of meropenem is about 500 mg.

In some embodiments, the administering is by intravenous infusion. In some such embodiments, the intravenous infusion is completed in about 1 hour to about 5 hours. In other embodiments, the intravenous infusion is completed within about 3 hours.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered before or after meropenem. In some other embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are in a single dosage form. In some embodiments, the single dosage form further comprises a pharmaceutically acceptable excipient, diluent or carrier.

Subjects with lower respiratory tract infections

Some embodiments described herein relate to a method of treating or ameliorating a lower respiratory infection comprising administering to a subject in need thereof an effective amount of compound I or a pharmaceutically acceptable salt thereof and meropenem.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 250mg to about 5.0 g. In other embodiments, compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.0g to about 3.0 g. In other embodiments, the amount of compound I is about 2.0 g. In some embodiments, meropenem is administered in a dose of about 250mg to about 5.0 g. In other embodiments, meropenem is administered in a dose of about 1.0g to about 3.0 g. In other embodiments, the amount of meropenem is about 2.0 g. In some embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are both administered at a dose of about 2.0 g.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are administered at least once daily. In some embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are administered 3 times daily. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is from about 3.0g to about 6.0g and wherein the daily dose of meropenem is from about 3.0g to about 6.0 g. In other embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is about 6.0g and wherein the daily dose of meropenem is about 6.0 g.

In some embodiments, the administering is by intravenous infusion. In some such embodiments, the intravenous infusion is completed in about 1 hour to about 5 hours. In other embodiments, the intravenous infusion is completed within about 3 hours.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered before or after meropenem. In some other embodiments, compound I or a pharmaceutically acceptable salt thereof and meropenem are in a single dosage form. In some embodiments, the single dosage form further comprises a pharmaceutically acceptable excipient, diluent or carrier.

In any of the embodiments of the methods described herein, the method may further comprise administering an additional agent selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

In some embodiments, the subject treated by the above method is a mammal. In some further embodiments, the subject is a human.

In any of the embodiments of the methods described herein, the treatment is for an infection caused by a carbapenem-resistant enterobacterium.

Indications of

The compositions described herein comprising compound I and the carbapenem compound meropenem may be used to treat bacterial infections. Bacterial infections that can be treated with the combination of compound I and meropenem can include a broad spectrum of bacteria. Exemplary organisms include gram-positive, gram-negative, aerobic and anaerobic bacteria, such as staphylococci (Staphylococcus), lactobacilli (Lactobacillus), streptococci (Streptococcus), Sarcina (Sarcina), Escherichia (Escherichia), Enterobacter (Enterobacter), Klebsiella (Klebsiella), Pseudomonas (Pseudomonas), Acinetobacter (Acinetobacter), Mycobacterium (Mycobacterium), Proteus (Proteus), Campylobacter (Campylobacter), Citrobacter (Citrobacter), neisseria (Nisseria), bacillus (bacillus), Bacteroides (Bacteroides), Peptococcus (Peptococcus), Clostridium (Clostridium), Salmonella (Salmonella), Shigella (gella), Serratia (sartoria), Serratia (Serratia), Haemophilus (Haemophilus), and other organisms.

Further examples of bacterial infections include Pseudomonas aeruginosa (Pseudomonas aeruginosa), Pseudomonas fluorescens (Pseudomonas fluorescens), Pseudomonas acidovorans (Pseudomonas acidiformis), Pseudomonas alcaligenes (Pseudomonas alcaligenes), Pseudomonas putida (Pseudomonas putida), Stenotrophomonas maltophilia (Stenotrophia), Burkholderia cepacia (Burkholderia cepacia), Aeromonas hydrophila (Aeromonas hydrophila), Escherichia coli (Escherichia coli), Citrobacter freundii (Citrobacter freundii), Salmonella typhimurium (Salmonella typhimurium), Salmonella typhi (Salmonella typhimurium), Salmonella paratyphi (Salmonella parayphi), Salmonella typhimurium (Shigella), Shigella dysenteriae (Shigella dysenteriae), Salmonella enteriae (Salmonella enterica), Salmonella enterica (Salmonella enterica), Salmonella enterica, Salmonella enterella enterica, Salmonella typhimurium, Salmonella typhi, and, Serratia marcescens (Serratia marcescens), Francisella tularensis (Francisella tularensis), Morganella morganii (Morganella morganii), Proteus mirabilis (Proteus mirabilis), Proteus vulgaris (Proteus vulgaris), Providencia alcaligenes (Providence caligenes), Providencia rettgeri (Providence rettgeri), Providencia sturtii (Providence sturtii), Acinetobacter baumannii (Acinetobacter baumannii), Acinetobacter calcoaceticus (Acinetobacter calcoaceticus), Acinetobacter haemolyticus (Acinetobacter haemolyticus), Yersinia enterocolitica (Yersinia Yersinia), Yersinia pestis (Yersinia), Yersinia pestis (Bonderella parahaemolytica), Yersis (Bonderella parahaemolytica), Yersinia parahaemolytica (Bonderella), Yersinia parahaemophilus (Bonderella parahaemophilus), Yersinia pertussis parahaemophilus (Bondersonii), Yersinia pestis (Yersinia), Yersinia parahaemophila), Yersinia pestis (Bonderella parahaemophila), Yersinia pestis (Yersinia) and Yersinia pestis (Bonderella parahaemolytica), Yersinia) can be, Yersinia parahaemophila, Yersinia, Yersi, Haemophilus haemolyticus (Haemophilus haemolyticus), Haemophilus parahaemolyticus (Haemophilus parahaemolyticus), Haemophilus ducreyi (Haemophilus ducreyi), Pasteurella multocida (Pasteurella multocida), Pasteurella haemolyticus (Pasteurella haemolytica), Branhamella catarrhalis (Branhamella catarrhalis), Helicobacter pylori (Helicobacter pylori), Campylobacter foetidulus (Campylobacter fetalis), Campylobacter jejuni (Campylobacter jejuni), Campylobacter coli (Campylobacter coli), Bordetella Borrelia (Borrelia burgdorferi), Vibrio cholerae (Vibrio cholerae), Vibrio parahaemolyticus (Vibrio parahaemolyticus), Salmonella parahaemolyticus (Salmonella), Salmonella choleraesuis (Legiononii), Salmonella cholerae (Legionlla), Salmonella vaginalis (Salmonella), Salmonella cholerae (Salmonella), Salmonella cholera meningitidis), Salmonella cholera (Salmonella), Salmonella, Salmon, Bacteroides 3452A homologous group (Bacteroides 3452A homology group), Bacteroides vulgatus (Bacteroides vulgatus), Bacteroides ovatus (Bacteroides ovatus), Bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), Bacteroides monoides (Bacteroides uniflora), Bacteroides exxoides (Bacteroides eggertii), Bacteroides viscera Bacteroides (Bacteroides sphaericus), Clostridium difficile (Clostridium difficile), Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium avium (Mycobacterium avium), Mycobacterium intracellulare (Mycobacterium intracellulare), Mycobacterium leprae (Mycobacterium tuberculosis), Corynebacterium diphtheriae (Corynebacterium diaphysis), Streptococcus ulceroides (Streptococcus faecalis), Streptococcus faecalis (Staphylococcus aureus), Streptococcus faecalis (Streptococcus faecalis), Streptococcus faecalis (Streptococcus faecalis), Streptococcus (Streptococcus faecalis), Streptococcus faecalis (Streptococcus), Streptococcus faecalis (Streptococcus faecalis), Streptococcus faecalis (Streptococcus), Streptococcus faecalis (Streptococcus faecalis (Streptococcus), Streptococcus faecalis (Streptococcus), Streptococcus faecalis (, Staphylococcus intermedius (Staphylococcus intermedius), Staphylococcus suis subsp.hyicus (Staphylococcus hyicus), Staphylococcus haemolyticus (Staphylococcus haemolyticus), Staphylococcus hominis (Staphylococcus hominis), or Staphylococcus saccharolyticus (Staphylococcus saccharolyticus).

In some embodiments, the infection is caused by a bacterium selected from the group consisting of: pseudomonas aeruginosa, Pseudomonas fluorescens, stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter hemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenza, Haemophilus haemolyticus, Haemophilus parahaemolyticus, helicobacter pylori, Campylobacter foetidus, Campylobacter jejuni, Campylobacter coli, Vibrio parahaemolyticus, Legionella pneumophilus, Listeria monocytogenes, gonorrhoea, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovate, Bacteroides thetaiotaomicron, Bacteroides monoides, Bacteroides evanescens or Bacteroides visceral.

In some embodiments, the bacterial infection is a gram-negative infection. In some embodiments, the bacterial infection is a lower respiratory tract infection. In some embodiments, the bacterial infection is caused by pseudomonas aeruginosa. In some embodiments, the bacterial infection is caused by klebsiella pneumoniae.

Antibacterial compounds

Compound I has the structure shown below:

in some embodiments, compound I may be converted to or present in equilibrium with the alternative form due to the ease of exchange of the boron ester. Thus, in some embodiments, compound I may be present in combination with one or more of these forms. For example, compound I can exist in combination with one or more open chain forms (formula Ia), dimer forms (formula Ib), cyclic dimer forms (formula Ic), trimer forms (formula Id), cyclic trimer forms (formula Ie), and the like. Compound I and enantiomers, diastereomers or tautomers thereof, or pharmaceutically acceptable salts thereof, are described in U.S. patent No. 8,680,136, which is incorporated by reference in its entirety.

Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a variety of infections. It is a beta-lactam and belongs to the subclass of carbapenems. It has the following structure:

some embodiments include methods of treating or preventing a bacterial infection comprising administering to a subject in need thereof an effective amount of compound I and meropenem, wherein compound I can be in any of the forms described above or a combination thereof.

Some embodiments further comprise administering an additional agent, either as a separate composition or in the same composition. In some embodiments, the additional agent comprises an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent. In some embodiments, the additional agent comprises an antibacterial agent, such as an additional beta-lactam.

In some embodiments, the additional beta-lactam comprises amoxicillin, ampicillin (pivampicillin, patatin, methicillin, phthalazinone), epicillin, carbenicillin (carbenicillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin (pimecrocillin), sulbenicillin, benzylpenicillin (G), cloxacillin, benzathine, procarbacillin, adecillin, penacilin, phenoxymethylpenicillin (V), propicillin, benoxine phenoxymethylpenicillin, phenanthrillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, mexil, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, panipenem, cephalopenem, apremin, tebucenemelapenem, tebucipenem, and tebucipenem, Thiepenem, ceftizoline, cephaloacetonitrile, cefadroxil, cephalexin, cefalexin, cefaloin, ceftazidime, cephalothin, cefapirin, ceftriazine, cefazedone, cefazeflon, cephradine, cefixadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, cefotiam, cefpropyne, cefbuperazone, cefuroxime, ceftizoxime, cefoxitin, cefotetan, cefmetazole, chlorocefixime, cefixime, ceftazidime, ceftriaxone, cefcapene, cefixime, cefditoren, cefetamet, cefepime, cefpodoxime, cefodizime, cefoperazone, cefteram, ceftibuten, cefotaxime, flomoxef, cefixime, cefaloxime, cefprozil, cefditoren, cefprozil, Cefepime, ceftizoxime, cefpirome, cefquinome, cefprozil, ceftaroline, ceftolozane, CXA-101, RWJ-54428, MC-04, 546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefvigilaxin, aztreonam, tigimonam, carumonam, RWJ-442831, RWJ-333441, RWJ-333442, S649266, GSK3342830 and AIC 499.

In some embodiments, the additional beta-lactam comprises ceftazidime, doripenem, ertapenem, imipenem, or panipenem.

Some embodiments include pharmaceutical compositions comprising a therapeutically effective amount of any one of the foregoing compounds and a pharmaceutically acceptable excipient.

Administration of andpharmaceutical composition

Some embodiments include a pharmaceutical composition comprising: (a) a safe and therapeutically effective amount of compound I, or its corresponding enantiomer, diastereomer or tautomer, or a pharmaceutically acceptable salt thereof; (b) meropenem, and (c) a pharmaceutically acceptable carrier.

Compound I and meropenem are administered at therapeutically effective doses (e.g., doses sufficient to provide treatment of the previously described disease states). In some embodiments, a single dose of compound I and meropenem may be from about 250mg to about 5000mg or from about 1000mg to about 3000 mg. In some embodiments, compound I and meropenem may be administered at least once a day, for example 1 to 5 times a day.

A combination comprising compound I or its corresponding enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, and meropenem may be administered by any accepted mode of administration of agents for similar uses, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. Intravenous, oral and parenteral administration are common in therapeutic indications, which are the subject of the preferred embodiments.

Compound I and meropenem may be formulated as pharmaceutical compositions for the treatment of these conditions. Standard pharmaceutical formulation techniques, such as those disclosed in The Science and Practice of Pharmacy, 21 st edition, Lippincott Williams and Wilkins (2005) of Remington, are used and are incorporated herein by reference in their entirety.

In addition to compound I and meropenem, some embodiments include compositions comprising a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein means one or more compatible solid or liquid filler diluents or encapsulating substances suitable for administration to a mammal. The term "compatible" as used herein means that the components of the composition are capable of being mixed with the subject compound and with each other in the absence of an interaction that would significantly reduce the efficacy of the composition under ordinary use conditions. Of course, the pharmaceutically acceptable carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration, preferably to the animal (preferably a mammal) being treated.

Some examples of substances that may be used as pharmaceutically acceptable carriers or components thereof are: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as tween; wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tabletting reagent and stabilizer; an antioxidant; a preservative; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically acceptable carrier to be used in conjunction with the combination is determined essentially by the manner in which the combination is to be administered.

The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound suitable for administration to an animal, preferably a mammalian subject, in a single dose according to good medical practice. However, a single or unit dosage form of a formulation is not intended to be administered once a day or once per course of treatment. It is contemplated that such dosage forms are administered once, twice, three times or more daily, and may be administered as an infusion over a period of time (e.g., about 30 minutes to about 2-6 hours), or as a continuous infusion, and may be given more than once during a course of treatment, although single administrations are not specifically excluded. The skilled artisan will recognize that the formulation does not specifically consider the entire course of therapy and will leave such decisions to those skilled in the therapeutic arts rather than the formulation arts.

The above useful compositions may be in any of a variety of suitable forms for a variety of routes of administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parental (parental) routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation and are obtained using available methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be employed. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, solubilizing agents, surfactants, and encapsulating substances. Optional pharmaceutically active materials may be included which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for obtaining dosage forms for use in the methods described herein are described in the following references, all incorporated herein by reference: modern pharmaceuticals, 4 th edition, chapters 9 and 10 (Banker and Rhodes eds., 2002); lieberman et al, Pharmaceutical Dosage Forms: tablets (1989); and Ansel, Introduction to pharmaceutical delivery Forms 8 th edition (2004). In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered orally. In some other embodiments, the pharmaceutical composition is administered intraperitoneally.

A variety of oral dosage forms may be used, including such solid forms as tablets, capsules, granules, and bulk powders. These oral forms contain a safe and effective amount of the compound, usually at least about 5% and up to about 90%. The tablets may be compressed, die-printed, enteric-coated, sugar-coated, film-coated or multi-compressed tablets, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted with non-effervescent granules, and effervescent formulations reconstituted with effervescent granules, which include suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants and flavoring agents.

Pharmaceutically acceptable carriers suitable for use in preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants such as: inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrating agents such as starch, alginic acid and crosslinked carboxymethyl cellulose; lubricants, for example, magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Colorants, such as FD & C dyes, may be added for appearance. Sweetening agents and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The choice of carrier component depends on secondary considerations such as taste, cost and storage stability, which are not critical and readily available to the skilled person.

Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for use in preparing such compositions are well known in the art. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, gum tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also comprise one or more components such as sweeteners, flavoring agents and colors as disclosed above.

Such compositions may also be coated by conventional means, typically with a pH-dependent or time-dependent coating, such that the subject compound is released in the vicinity of the desired topical application in the gastrointestinal tract, or at different times to amplify the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, acrylic resin coatings, waxes, and shellac.

The compositions described herein may optionally comprise other pharmaceutical actives.

Other compositions useful for achieving systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise: one or more soluble filler materials, such as sucrose, sorbitol and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, pigments, antioxidants and flavoring agents disclosed above may also be included.

The liquid composition (which is formulated for topical ophthalmic application) is formulated such that it can be topically applied to the eye. While optimal comfort may sometimes not be achieved due to formulation considerations (e.g., drug stability), comfort should be maximized as much as possible. In cases where comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic application. Additionally, ophthalmically acceptable liquids should be packaged for single use, or contain preservatives to prevent contamination over multiple uses.

For ophthalmic applications, solutions or drugs are usually prepared using physiological saline solution as the primary medium. The ophthalmic solution should preferably be kept at a comfortable pH with a suitable buffer system. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Likewise, a variety of useful vehicles may be used in the ophthalmic formulations disclosed herein. These media include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.

Tonicity adjusting agents may be added as needed or convenient. They include, but are not limited to, salts (specifically sodium chloride, potassium chloride), mannitol and glycerol, or any other suitable ophthalmically acceptable tonicity modifier.

A variety of buffers and methods for adjusting pH may be used, so long as the resulting formulation is ophthalmically acceptable. For many compositions, the pH is from 4 to 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. The pH of these formulations can be adjusted with acids or bases as needed.

Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

Other excipient components that may be included in ophthalmic formulations are chelating agents. A useful chelating agent is edetate disodium, but other chelating agents may be substituted for it or combined with it.

For topical application, creams, ointments, gels, solutions or suspensions, etc., containing the compounds disclosed herein are used. Topical formulations may typically include a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and an emollient.

For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent (e.g., saline or dextrose solution). Suitable excipients may be included to achieve the desired pH including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition is from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea and EDTA. Other non-limiting examples of suitable excipients present in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Other acceptable excipients are described in the following: powell et al, Complex of Excipients for specialized Formulations, PDA J Pharm Sci and Tech1998, 52238-: current uses and Future Directions, PDA J Pharm Sci and Tech 2011, 65287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteria-inhibiting or fungi-inhibiting solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

The resulting composition may be infused into a patient over a period of time. In various embodiments, the infusion time is from 5 minutes to a continuous infusion, from 10 minutes to 8 hours, from 30 minutes to 4 hours, and from 1 hour to 3 hours. In one embodiment, the drug is infused over a 3 hour period. The infusion may be repeated at desired dosing intervals, which may include, for example, 6 hours, 8 hours, 12 hours, or 24 hours.

The compositions for intravenous administration may be provided to the caregiver in one or more solid forms which are reconstituted with a suitable diluent, such as sterile water, saline, or aqueous dextrose, shortly prior to administration. The reconstituted concentrated solution may be further diluted into an injection having a volume of about 25ml to about 1000ml, about 30ml to about 500ml, or about 50ml to about 250 ml. In other embodiments, the composition is provided in a ready-to-use solution for parenteral administration. In still other embodiments, the composition is provided in the form of a solution that is further diluted prior to administration. In embodiments that include the administration of a combination of a compound described herein with other agents, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately.

The actual dosage of the active compounds described herein depends on the particular compound and the condition to be treated; the selection of appropriate dosages is well known to the skilled artisan.

Kit for intravenous administration

Some embodiments include kits comprising compound I and the carbapenem antibacterial agent meropenem. In some embodiments, the kit is for intravenous administration.

In one embodiment, both components are provided in a single sterile container. In the case of solids for reconstitution, the reagents may be pre-blended and added to the container simultaneously, or may be a dry powder that is filled into the container in two separate steps. In some embodiments, the solid is a sterile crystalline product. In other embodiments, the solid is a lyophilizate. In one embodiment, the two components are lyophilized together. Non-limiting examples of agents that aid in lyophilization include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. One embodiment includes an unsterilized solid that is irradiated prior to or after introduction into the container.

In the case of liquids, the agent may be dissolved or dispersed in a diluent to be administered. In further embodiments, the solution or dispersion may be further diluted prior to application. Some embodiments include providing the fluid in an intravenous bag (IV bag). The liquid may be frozen to improve stability.

In one embodiment, the container includes other ingredients, such as a pH adjuster, a solubilizer, or a dispersant. Non-limiting examples of pH adjusters include NaOH, sodium carbonate, sodium acetate, HCl, and citric acid.

In an alternative embodiment, the two components may be provided in separate containers. Each container may comprise a solid, a solution or a dispersion. In such embodiments, the two containers may be provided in a single package, or may be provided separately. In one embodiment, the compounds described herein are provided as a solution, while the additional agent (e.g., antibacterial agent) is provided as a solid ready for reconstitution. In one such embodiment, a solution of a compound described herein is used as a diluent to reconstitute the other agent.

In some embodiments, the kit may comprise one or more additional medicaments selected from antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, or anti-allergic agents. The additional drug may be prepared in the same manner as described above.

Examples

The following examples, including experiments and results obtained, are provided for illustrative purposes only and should not be construed as limiting the present application.

Example 1

Example 1 provides a clinical study summary of the safety, tolerability and pharmacokinetics of beta-lactamase inhibitor compound I in healthy adult subjects.

The method comprises the following steps: in a single ascending dose (250mg, 500mg, 750mg, 1000mg, 1250mg, 1500mg and 2000mg) period, 56 healthy subjects were enrolled into 7 cohorts, 8 subjects per cohort. Thirty-two additional subjects were then enrolled into 4 cohorts over a multiple dose period (250mg, 1000mg, 1500mg, and 2000mg given every 8 hours for 7 days). In each cohort, subjects were randomly assigned to compound I (n-6) or saline placebo (n-2). All infusions were administered over 3 hours. Plasma and urine samples were obtained after single or multiple doses and assayed for compound I content using a calibrated HPLC/MS method.

As a result: table 1 summarizes the pharmacokinetic averages of compound I at different doses. Compound I concentration curves as a function of time and compound I AUC curves as a function of dose after a single intravenous infusion (single IV fusion) are illustrated in fig. 1 and 2, respectively.

Table 1.

Dose of Compound I, mg

The maximum concentration of compound I was reached at the end of the 3 hour infusion. After single and multiple doses, compound I exposure (Cmax and AUC) increased in a dose-proportional manner (see fig. 1 and 2). There is no evidence of accumulation of multiple doses, consistent with the observed terminal half-life (< 2 hours). The volume of distribution and plasma clearance are independent of dose. The high concentrations of fig. 1 and 2 were measured in urine. All dose groups showed a urine recovery of 80% or more over 48 hours.

No subjects discontinued the study due to Adverse Events (AE) and no Severe Adverse Events (SAE) were observed. AEs were similar between compound I-and placebo-treated subjects, with no evidence of increased incidence or severity of AEs with increasing dose, and all AEs were mild or moderate.

Conclusion: compound I was safe and well tolerated at all doses tested. AUC and Cmax increase proportionally independent of dose.

Example 2

Example 2 provides a summary of clinical studies of the safety, tolerability and pharmacokinetics of beta-lactamase inhibitors (compound I alone, meropenem alone and a combination of both) in healthy adult subjects.

Method: eighty healthy subjects were enrolled as one member of 5 cohorts during a single escalating dose period (250mg, 1000mg, 1500mg and 2000mg of compound I combined with 1g or 2g meropenem). In each group, a single dose of compound I or meropenem was administered to subjects on day 1 and compound I or meropenem was administered on day 3. The combination of both drugs was administered on day 7. All drugs were infused over 3 hours. Plasma and urine samples were obtained and assayed using a calibration HPLC/MS method. Figures 3 and 4 illustrate the pharmacokinetics of compound I alone and in combination with meropenem after 3 hours of infusion in healthy adult subjects and the pharmacokinetics of meropenem alone and in combination with compound I after 3 hours of infusion in healthy adult subjects, respectively.

Results: the pharmacokinetic parameters for each drug alone and in the combination of compound I and meropenem using the non-compartmental model method are shown in tables 2 and 3 below. Table 2 summarizes the compound I pharmacokinetic parameters (data as mean ± standard deviation) after a single dose of compound I administered alone or in combination with meropenem as a 3 hour infusion to healthy volunteers. Table 3 summarizes the single doses administered alone or in combination with compound I as a 3 hour infusion into healthy volunteersMeropenem pharmacokinetic parameters after meropenem of (data as mean ± standard deviation).

Table 2.

C_maxMaximum drug concentration observed; AUC (0-tcal) is the area of the drug concentration-time curve from time zero to final time; Vss-Steady State apparent volume distribution

Table 3.

Cmax-the maximum drug concentration observed; AUC (0-Tlast) is the area under the drug concentration-time curve from time zero to final time; Vss-Steady State apparent volume distribution

The maximum concentration of compound I and meropenem was reached at the end of the 3 hour infusion. Compound I and meropenem exposure (Cmax and AUC) increased proportionally with dose. The PK parameters for compound I and meropenem showed no significant change in PK properties for both drugs after single dose alone or in combination (table 2 and table 3). The meropenem PK observed in this study, alone and in combination with compound I, was consistent with the open literature. See, for example, lodiet.p. et al, "networking of molecular in-situ linking fluid of substrates with a vehicle-associated cyclone, and" inorganic Agents Chemotherm.2011; 55(4): 1606-10 and Kuti J.L. et al, "Use of Monte Carlo simulation to design an optimized pharmacodynamics dynamics for polymerization," J Clin Pharmacol.2003; 43(10): 1116-23.

Table 4 summarizes the Adverse Events (AE) that occurred during treatment observed in > 3 subjects receiving the combination of Compound I and meropenem. No subjects were discontinued by AE and no SAE was observed. There was no evidence that the number or severity of AEs increased with increasing doses of drugs, either alone or in combination, and all AEs were mild or moderate in severity.

Table 4.

Adverse events occurring during treatment observed in > 3 subjects receiving Compound I/Meropenem

Conclusion: compound I alone and in combination with 1g or 2g meropenem was safe and well tolerated in all doses tested. AUC and Cmax increased proportionally with dose, and pharmacokinetic parameters of compound I and meropenem were similar. Meropenem or compound I had no effect on PK of other agents.

Example 3

Example 3 provides a summary of clinical studies of the safety, tolerability and pharmacokinetics of beta-lactamase inhibitors (compound I alone, meropenem alone and a combination of both) after 7 days TID (three times a day) in healthy adult subjects.

Method: eighty healthy subjects were enrolled into 5 cohorts during a single escalating dose period (250mg, 1000mg, 1500mg and 2000mg compound I in combination with 1g or 2g meropenem). In each cohort, subjects were administered compound I or meropenem on day 1, followed by a crossover administration of compound I or meropenem on day 3, followed by a combined administration of compound I and meropenem on day 7, followed by TID dosing for 7 days. All infusions were administered over 3 hours. Enhanced plasma and urine PK samples were obtained after dosing and determined using a calibrated HPLC/MS method. Figures 5 and 6 illustrate the plasma pharmacokinetics of compound I alone and in combination with meropenem after single and 7 day TID dosing by 3 hour infusion in healthy subjects, and meropenem alone and in combination with compound I after single and 7 day TID dosing by 3 hour infusion in healthy subjects, respectively.

Results: the pharmacokinetic parameters for each drug alone and in combination in the compound I/meropenem group at 1g/1g and 2g/2g using the non-compartmental model method are shown in tables 5 and 6 below. Table 5 summarizes the pharmacokinetic parameters of compound I (mean ± standard deviation) after a single dose (single) as a 3 hour infusion into healthy volunteers, and after a single (initial) followed by 7 days of TID dosing (final) of compound I administered in combination with meropenem. Table 6 summarizes meropenem pharmacokinetic parameters (mean ± standard deviation) after a single dose (single) as a 3 hour infusion to healthy volunteers, and after a single (initial) followed by a 7 day TID dose (final) of meropenem administered in combination with compound I.

Table 5.

Table 6.

Cmax-the maximum drug concentration observed; AUC (0-Tlast) is the area under the drug concentration-time curve from time zero to final time; vss is the steady state apparent distribution volume; initial dose given TID for the first-7 days; final dose after final-7 days TID dosing

The maximum concentration of compound I and meropenem was reached at the end of the 3 hour infusion. Compound I and meropenem Exposure (C)_maxAnd AUC) increases proportionally with dose. The PK parameters of compound I and meropenem, alone or in combination, showed no significant change in PK properties for both drugs (see table 5 and table 6). No accumulation of compound I or meropenem was observed after TID administration for 7 days. The meropenem PK observed in this study, alone and in combination with compound I, was consistent with the open literature.

Table 7 summarizes the number of subjects with AEs occurring during at least one treatment (%) and the number of adverse events in the multiple dose phases. One subject receiving meropenem 1 g/compound I2g was discontinued early due to AE in thrombophlebitis. All AEs were mild or moderate in severity, except 2. Only mild nausea was observed in subjects receiving 2g meropenem, alone or in combination. There is no evidence that the addition of compound I altered the AE profile of meropenem.

Table 7.

Number of subjects with at least one AE occurring during treatment (%) and number of adverse events in a multiple dose phase

Conclusion: compound I alone and in combination with 1g or 2g meropenem was safe and well tolerated at all doses tested, with no evidence of altering the safety of meropenem by the addition of compound I. No accumulation of compound I or meropenem was observed after TID administration for 7 days. Meropenem had no effect on the pharmacokinetics of compound I and vice versa.

Example 4

Example 4 provides a preliminary study summary of the pharmacokinetics of the combination of compound I (2g) and meropenem (2g) by 1 hour or 3 hour infusion in healthy adult subjects.

Results: fig. 7 and 8 illustrate the pharmacokinetics of compound I after 3 hour or 1 hour infusion (2g of compound I alone and in combination with 2g of meropenem) in healthy subjects, respectively. Figure 9 summarizes the mean pharmacokinetics of compound I after 1 or 3 hour infusion of 2g of compound I in combination with 2g meropenem in healthy subjects. For compound I, no effect of meropenem on the pharmacokinetics of compound I was observed at both infusion rates. Furthermore, the infusion rate had no significant effect on compound I exposure (p ═ 0.18).

Fig. 10 and 11 illustrate the pharmacokinetics of meropenem after 3 hour or 1 hour infusion (2g meropenem alone and in combination with 2g compound I) in healthy subjects, respectively. Figure 12 summarizes the mean pharmacokinetics of meropenem after 1 hour or 3 hour infusion of 2g meropenem in combination with 2g compound I in healthy subjects. Fig. 13 and 14 illustrate the pharmacokinetics of meropenem open-loop lactam after 1 hour of infusion of 2g alone and in combination with 2g of compound I and the average pharmacokinetics of meropenem open-loop lactam after 1 hour or 3 hours of infusion of 2g of meropenem in combination with 2g of compound I.

For meropenem, no effect of compound I on the pharmacokinetics of meropenem was observed at both infusion rates. Meropenem exposure (AUC) after a 3 hour infusion of 2g meropenem was consistent with the published literature. There was an increase in meropenem exposure (AUC) with 1 hour infusion compared to 3 hour infusion. Meropenem exposure (AUC) after 1 hour infusion of 2g meropenem was about 48% higher than that observed after 3 hours infusion of 2g meropenem (211mg h/L vs 142mg h/L). Meropenem weight-adjusted clearance (Cl) after 1 hour infusion of 2g meropenem was about 25% slower than that observed after 3 hours infusion (0.141/h/kg versus 0.191/h/kg; p ═ 0.015). For the differences observed in meropenem weight-adjusted clearance, the likely reason is due to high C_maxResulting in saturated renal clearance at 2g dose, or longer infusion times with reduced "dose" due to degradation (ring opening of β -lactam leading to formation of meropenem ring-opened-lactam).

Example 5

Example 5 provides an open label study summary of the safety and pharmacokinetics of the combination of compound I and meropenem in subjects with reduced renal function, including patients using standard hemodialysis.

The safety and pharmacokinetics of a single intravenous administration of 1g meropenem plus 1g compound I infused over 3 hours were evaluated. Forty-one subjects were enrolled into 5 groups based on their degree of renal insufficiency. The five groups include: patients with normal renal function (CrCl ≥ 90ml/min), mild renal injury (CrCl 60ml/min-89ml/min), moderate renal injury (CrCl 30 ml/min-60 ml/min), severe renal injury (CrCl < 30ml/min), and patients with end stage renal disease requiring hemodialysis. Patients who rely on renal replacement therapy rather than standard hemodialysis (including continuous veno-venous hemofiltration, continuous veno-venous hemodialysis, and continuous renal replacement therapy) were not studied.

Fig. 15 shows the relationship between estimated GFR and meropenem or compound I plasma clearance. The plasma clearance of both drugs remained similar over the range of renal function as evidenced by the clustering of values and the linear decline in clearance as renal function decreased.

The removal of meropenem and compound I during hemodialysis was studied in 9 patients with severe renal insufficiency dependent long-term hemodialysis. The patient received a single dose of meropenem 1 g/compound I1g, followed by a hemodialysis procedure. Both meropenem and compound I were removed from plasma by hemodialysis. These indicate that maintenance doses of various drugs should be administered after the dialysis procedure (adjusted for the extent of potential endogenous kidney function).

Determining the combination of Compound I/meropenem doses in patients with renal impairment

Dose adjustments were determined based on the degree of renal injury by analyzing pharmacokinetic estimates for each subject and determining exposure based on possible dosing regimens for meropenem or compound I. The objective is to maintain exposure (e.g., AUC) over the entire range of renal function to be as consistent as possible over the entire range of renal function. Given the PK-PD analysis in a non-clinical model (which shows that AUC is related to the efficacy of compound I), AUC is a suitable controller of the efficacy of this agent. Since T > MIC is an important PK-PD index for meropenem, for efficacy, different dosing intervals were evaluated to ensure T > MIC_{Break point}Above threshold (T > MIC > 40%). For the purpose of this analysis, the predicted sensitivity breakpoint for meropenem was 8 μ g/ml based on 2 gram dose and 3 hour infusion. For both meropenem and compound I, the free form drug (blood) is consideredThe plasma protein binding rates were 6% and 33%, respectively).

Meropenem

Table a shows the PK-PD index for the three potential dose regimes in terms of meropenem PK measured in each subject, meropenem AUC measured in each patient and each patient. In all subjects (see shaded cell), meropenem dose regimens were identified for each of the renal functional layers that met or reached the target exposure (T > MIC of at least 40%).

Table a summarizes the analysis of different meropenem dosing regimens for individual subjects. The PK-PD target for meropenem is at least 40% of the dosing interval T > MIC, where the MIC is 8 μ g/mL. Shading in the different creatinine clearance groups indicates the recommended meropenem dosing regimen.

Table a.

Compound I

Table B shows the compound I AUC measured in each patient and the 24h AUC for the three potential dosing regimens, based on the compound I clearance measured in each subject. Since AUC is the target PK measure and compound I clearance remains close to meropenem clearance, the unit dose and 24 hour dose remain at a 1: 1 ratio over the entire renal function range.

Consideration of subjects with creatinine clearance < 10ml/min

As shown in fig. 15, meropenem non-renal clearance accounts for a greater proportion of total clearance when creatinine clearance is below 10 ml/min. In contrast, compound I has no measurable non-renal clearance. Thus, in order to maintain a 1: 1 dose ratio to provide therapeutic exposure of each component and avoid accumulation of compound I, patients with creatinine clearance < 10ml/min should receive hemodialysis every 3 days (i.e., twice weekly).

Table B provides a summary of the analysis of the different compound I dosing regimens by the individual subjects enrolled in the study. Shading in the different creatinine clearance groups indicates the recommended meropenem dosing regimen.

TABLE B expected 24h AUC (MG < u > HR/L) for the free form of Compound I

Based on the above analysis, the compound I/meropenem combination dosing regimen in table C may be used in subjects with impaired renal function.

Table C: compound I/meropenem combination dosage based on renal function

¹The dosing regimen assumes that the patient receives at least two hemodialysis sessions per week. In these patients, the maintenance dose of the combination should be administered as soon as possible after the dialysis procedure. For example, if the subject is scheduled to receive the combination at 18:00, but hemodialysis at 13:00, the planned 18:00 combination dose should be administered after the dialysis procedure is completed (rather than waiting to 18: 00).

In conclusion, dose adjustment of renal function can be based on meropenem or compound I, since both drugs are affected similarly as renal function declines. For subjects with creatinine clearance equal to or greater than 50ml/min, no dose adjustments are required. A standard dose of 2g compound I/2g meropenem TID (every 8 hours) can be used. For subjects with creatinine clearance equal to or greater than 30ml/min and less than 50ml/min, a reduced dose of 1g compound I/1g meropenem TID (every 8 hours) can be used and still achieve the desired effect. For subjects with creatinine clearance equal to or greater than 20ml/min and less than 30ml/min, a reduced dose of 1g compound I/1g meropenem administered every 12 hours may be used. For subjects with creatinine clearance equal to or greater than 10ml/min and less than 20ml/min, a reduced dose of 500mg compound I/500mg meropenem administered every 12 hours may be used. For subjects with creatinine clearance less than 10ml/min, a reduced dose of 500mg compound I/500mg meropenem administered every 24 hours may be used.

Example 6

Example 6 provides a summary of a randomized, open label clinical study evaluating plasma, epithelial cell lining fluid (ELF) and Alveolar Macrophage (AM) concentrations of a combination of 2g compound I/2g meropenem ("the combination") in healthy adult subjects.

For lower respiratory tract infections, epithelial cell lining fluid (ELF) and Alveolar Macrophages (AM) have been advocated as important sites of infection for common extracellular and intracellular pathogens, respectively. Studies using bronchoscopy and bronchoalveolar lavage (BAL) are needed that can reliably assess intrapulmonary penetration of antibiotics into ELF and AM. The main objective of this pharmacokinetic study was to determine and compare the plasma, ELF and AM concentrations of compound I and meropenem administered after multiple intravenous administrations (2g meropenem per 2g compound I, q8h, 3 administrations) in healthy male and female adult subjects. A secondary objective of this study was to assess the safety and tolerability of intravenously administered combinations in healthy adult subjects.

Pharmacokinetic analysis method

Study design and object. A total of twenty-five (n-25) male and female subjects were included in the pharmacokinetic analysis, meeting the study inclusion criteria and completing all phases of the pharmacokinetic study. Each subject received the combination administered every 8 hours (2g of meropenem/2 g of compound I) for a total of three doses under direct observation at the study site. Blood samples were collected to measure drug concentrations in plasma before (time 0) and at 1.5, 2.95, 3.083, 3.25, 3.5, 4, 6, and 8 hours after the start of 3 hours intravenous infusion of the third combination dose. Each subject had a single standardized bronchoscopy, with BAL scheduled at intervals after the final dose of the combination, as shown in the following table:

urea is commonly used as an endogenous marker to estimate the apparent volume of ELF. Blood samples were obtained to determine plasma urea concentrations just prior to scheduled bronchoscopy. Equal parts of BAL were obtained to determine urea concentration in BAL and cell counts with differences. Standardized bronchoscopy with BAL procedures for collecting samples in the lungs has been previously described in the following references.

Drug and urea assaysSample preparation procedures and determinations of meropenem, compound I and meropenem ring-opened lactam concentrations in plasma, ELF and AM were performed using high performance liquid chromatography with mass spectrometric detection in Micro Constants, inc., san diego, canada (reported for MC 14B-0013, MC 14B-0015, MC 14I-011 and MC 14I-0012). The urea concentration in plasma and BAL was performed in a microplate-based method using an o-phthalaldehyde developing solution in Micro Constants, inc.

Pharmacokinetic calculation of plasma concentrations.A non-compartmental model approach was used to generate pharmacokinetic parameters of meropenem, compound I and meropenem open-loop lactam in plasma. After the start of the third combined dose of intravenous infusion, peak plasma concentrations (C) were read from the observed plasma concentration-time curve_max) And reach C_max(T_max) Time of (d). Using the linear logarithmic trapezoidal rule (Version 6.3, Pharsight Corporation, Cary, North Carolina), the area under the plasma concentration-time curve over 8 hours after the third dose (AUC) was calculated_0-8). The elimination rate constant (β) is determined by nonlinear least squares regression. Elimination of half-life (t) by calculation of the natural logarithm of beta divided by 2_1/2). For meropenem and Compound I, with intercalationStandard non-compartmental equation calculated appearance of the programClearance (CL) and distribution volume term (V)_ss)。

Calculation of ELF volume and antibiotic concentration in ELF and AM.Calculation of ELF volume and drug concentration in ELF and AM was performed using BAL supernatant and lung (alveolar) cells ("cell pellet") from aspirates recovered from 2 nd, 3 rd and 4 th instillations (BAL 2). The drug concentration (ABX) in epithelial cell lining fluid (ELF) was determined as follows_ELF)：

ABX_ELF＝ABX_BALx(V_BAL/V_ELF)

Wherein ABX_BALIs the measured concentration of meropenem, Compound I or meropenem Ring-opened lactam in BAL solution, V_BALIs the volume of BAL liquid aspirated, and V_ELFIs the ELF volume sampled by BAL. V_ELFThis is derived from:

V_ELF＝V_BALxUrea_BAL/Urea_P

wherein Urea_BALIs the concentration of Urea in the BAL liquor and Urea_PIs the concentration of urea in plasma.

The drug concentration (ABX) in Alveolar Cells (AC) was determined as follows_AM)：

ABX_AM＝ABX_M/V_AC

Wherein ABX_MIs the measured concentration of meropenem, Compound I or meropenem Ring-opened lactam in 1ml of cell suspension, and V_ACIs the volume of alveolar cells in 1ml of cell suspension. Differential cell counts were performed to determine the number of macrophages present. The average macrophage cell volume of 2.42. mu.l/106 cells was used to calculate the volume of alveolar cells in the pellet suspension.

Concentration ratios of ELF and AM to simultaneous plasma concentrations were calculated for each subject and summarized for each group at each sampling time. Mean and median concentrations of meropenem and compound I from bronchopulmonary sampling times (e.g., 1.5, 3.25, 4, 6, and 8 hours) were used to estimate AUC for plasma, ELF, and AM_0-8. The 8 hour sampling time was also used as a time zero value for determining the area terms of plasma, ELF and AM. By means of linear laddersDetermining AUC of each matrix by shape method_0-8. Calculating AUC of ELF and plasma and AM and plasma_0-8And (4) proportion.

Results

Twenty-six (26) healthy adult subjects participated in the study. One subject discontinued the study due to adverse events and did not undergo the pharmacokinetic phase (e.g., blood sample collection to measure drug concentration in plasma and BAL and bronchoscopy at scheduled sampling time [4 hours ]). The characteristics of 25 subjects who received three dose combinations and completed all phases of the pharmacokinetic study are recorded in table 8.

Fig. 16 shows the mean (± SD) plasma concentrations of meropenem before and after the start of intravenous infusion of the third combination dose. Mean (± SD) C of plasma meropenem concentrations_maxAnd AUC_0-858.2. + -. 10.8. mu.g/mL and 185.5. + -. 33.6. mu.g.h/mL, respectively. Table 9 summarizes the mean (± SD) pharmacokinetic parameters of meropenem in plasma. Figure 17 shows the mean (± SD) plasma concentrations of compound I before and after the start of intravenous infusion of the third combination dose. Mean (± SD) C of plasma Compound I concentration_maxAnd AUC_0-859.0. + -. 8.4. mu.g/mL and 204.2. + -. 34.6. mu.g.h/mL, respectively. Table 10 summarizes the mean (± SD) pharmacokinetic parameters of compound I in plasma.

Fig. 18 illustrates the mean (± SD) concentration of meropenem in plasma and ELF at bronchopulmonary sampling time. The mean concentrations of meropenem in plasma and ELF were 1.36 to 41.2. mu.g/mL and 2.51 to 28.3. mu.g/mL, respectively. Table 11 records the mean (± SD) concentration of meropenem in plasma, ELF and AM after the final dose at five bronchopulmonary sampling times. The concentration of meropenem in alveolar cells was below the quantifiable limit of all samples.

Figure 19 illustrates mean (± SD) concentrations of compound I in plasma, ELF and AM at bronchopulmonary sampling times. The mean concentrations of compound I in plasma and ELF were 2.74. mu.g/mL to 51.1. mu.g/mL and 2.61. mu.g/mL to 26.1. mu.g/mL, respectively. Fig. 20 and 21 illustrate similar magnitude and time course of meropenem and compound I concentrations in plasma and ELF. Table 12 records the mean (± SD) concentration of compound I in plasma, ELF and AM after the final dose at five bronchopulmonary sampling times. The alveolar macrophage concentration of compound I was measurable and ranged from 1.26 μ g/mL to 93.9 μ g/mL for all samples.

Table 13 reports the mean (± SD) ratio of ELF of meropenem to concurrent plasma concentrations. The average ratio of ELF to simultaneous plasma concentrations of meropenem was 0.525 to 2.13 over a 8 hour period after drug administration. AUC based on mean and median ELF concentrations_0-8The values were 111.7. mu.g.h/mL and 102.4. mu.g.h/mL, respectively. Based on mean AUC_0-8Value and median AUC_0-8The ratio of ELF to total plasma meropenem concentration of values was 0.63 and 0.58, respectively. Based on mean AUC_0-8Value and median AUC_0-8The ratio of ELF to unbound plasma meropenem concentration (protein binding rate 2%) was 0.65 and 0.59, respectively.

Table 14 reports the mean (± SD) ratio of ELF and AM of compound I to concurrent plasma concentrations. The average ratio of ELF and AM of compound I to simultaneous plasma concentrations was 0.45 to 1.01 and 0.062 to 2.58, respectively, over a period of 8 hours after drug administration. AUC based on mean and median ELF concentrations_0-8The values were 105.1. mu.g-hr/mL and 96.7. mu.g-hr/mL, respectively. Based on mean AUC_0-8Value and median AUC_0-8The ratio of ELF to total plasma compound I concentration of values was 0.53 and 0.48, respectively. Based on mean AUC_0-8Value and median AUC_0-8The ratio of ELF to unbound plasma compound I concentration (protein binding rate 33%) was 0.79 and 0.72, respectively.

Summary of the invention

Similar time course and magnitude of meropenem and compound I concentrations were obtained in plasma and ELF as 3-hour intravenous infusions of the combination (2g meropenem/2 g compound I) administered every 8 hours. AUC based on ELF and total plasma concentration_0-8The intrapulmonary permeabilities of meropenem and compound I of values were approximately 63% and 53%, respectively. When considering unbound plasma concentrations, the permeabilities of meropenem and compound I were 65% and 79%, respectively. The results of this study are the discoveryThe 2g of ropinonam/2 g of compound I combination provides support as a potential antimicrobial agent for the treatment of bacterial infections of the lower respiratory tract caused by susceptible pathogens.

The concentration of meropenem in alveolar cells was below the quantifiable limit for all samples. In contrast, the concentration of compound I was measurable for all alveolar cell samples, and the AM concentration was 1.26 μ g/mL to 93.9 μ g/mL. Notably, the two subjects at the 6 hour sampling time had the highest recorded concentrations of compound I in AM (35.4 μ g/mL and 93.9 μ g/mL), thus broadening the average ratio of AM to plasma concentration (2.58 ± 3.57, table 14). These two subjects had very high concentrations of red blood cells in their BAL fluid (176,000 cells/mm)³And 226,250 cells/mm³) This may contribute to this high level of AM concentration.

Based on maximum plasma concentration and AUC_0-8Comparison of values, the proportion of systemic exposure of meropenem ring-opened lactam to meropenem was approximately 11% and 15%, respectively. During the first 6 hours after meropenem administration, the mean ELF concentration of meropenem open-loop lactam was only 1.81 to 2.69 μ g/mL, and all ELF concentrations of meropenem open-loop lactam were below the quantifiable limit at the 8 hour sampling time. Only three AM concentrations of meropenem ring-opened lactam were measurable and ranged from 1.91 to 8.46 μ g/mL.

Conte et al administered meropenem at a dose of 500mg, 1g or 2g every 8 hours, by intravenous infusion for 30 minutes, for a total of four administrations. The mean meropenem ELF concentrations at 1, 2, 3, 5 and 8 hours were 5.3. mu.g/mL, 2.7. mu.g/mL, 1.9. mu.g/mL, 0.7. mu.g/mL and 0.2. mu.g/mL for the 500mg dose, and 7.7. mu.g/mL, 4.0. mu.g/mL, 1.7. mu.g/mL, 0.8. mu.g/mL and 0.03. mu.g/mL for the 1 gram dose. The ratio of ELF concentration to total plasma concentration at the sampling time was 0.49 to 2.3 for the 500mg dose, and 0.32 to 0.53 for the 1 gram dose. AUC based on ELF and total plasma concentration for 500mg and 1 gram doses_0-8The intrapulmonary permeabilities of meropenem of values were approximately 43% and 28%, respectively. Average meropenem ELF concentration and penetration ratio at 1 and 3 hour sampling times for 2 gram dosesExamples are 2.9. mu.g/mL and 2.8. mu.g/mL and 0.05 and 0.22, respectively. For a 2 gram dose, the observed number is limited (n-8) and for ELFAUC_0-8Calculation of the value is not possible.

Due to differences in the study design, the results of the meropenem study in this study were not directly comparable to the results of Conte et al. The study evaluated a 2 gram dose of meropenem infused over an extended period of 3 hours and administered in combination with compound I. Furthermore, the present study collected ELF concentrations more extensively (n-30) during the 8 hour dosing interval, which allowed an accurate estimate of AUC_0-8The value is obtained. Higher mean concentrations of meropenem in plasma and ELF were observed after 2 grams administration using prolonged infusion (range: 1.36 μ g/mL to 41.2 μ g/mL and 2.51 μ g/mL to 28.3 μ g/mL, respectively). Longer infusion of carbapenem may also provide higher permeability to ELF as previously reported for biapenem (Kikuchi et al). The average ratio of ELF to simultaneous plasma concentrations of meropenem was 0.525 to 2.13 over an 8 hour period. AUC based on mean and median ELF concentrations_0-8The values were 111.7. mu.g.h/mL and 102.4. mu.g.h/mL, respectively. Based on mean AUC_0-8Value and median AUC_0-8The ratio of ELF to total plasma meropenem concentration of values was 0.63 and 0.58, respectively. These data support further studies of compound I/meropenem combination for the treatment of pulmonary infections.

TABLE 8 Properties of study subjects receiving the combination 3 administrations at 8 hour intervals

Data are expressed as mean ± SD, except for gender,

m ═ male; f ═ female

BMI-body mass index-weight [ kg]Div (height [ m)])²

TABLE 9 non-compartmental model pharmacokinetic parameters of meropenem 2G in plasma at 8-hour intervals, 3 doses

Data are presented as mean ± SD.

a. Each parameter estimation 25 objects

b. Each time the parameters estimate 5 objects

TABLE 10 non-compartmental model pharmacokinetic parameters of Compound I2G in plasma at 8-hour intervals, 3 administrations

Data are presented as mean ± SD.

a. Each parameter estimation 25 objects

b. Each time the parameters estimate 5 objects

TABLE 11 Meropenem concentrations in plasma, ELF and AM at bronchoscopy and BAL

Data are presented as mean. + -. SD

5 objects per sampling period

BQL-below quantifiable limit

TABLE 12 Compound I concentrations in plasma, ELF and AM at bronchoscopy and BAL

Data are presented as mean. + -. SD

5 objects per sampling period

TABLE 13 ratio of ELF to total plasma concentration of meropenem

Data are presented as mean. + -. SD

5 objects per sampling period

TABLE 14 ELF and AM ratio of Compound I to Total plasma concentration

Data are presented as mean. + -. SD

5 objects per sampling period

Example 7

Example 7 provides a summary of a hollow fiber model study of the pharmacokinetic profiles of a combination of compound I and meropenem administered by 3 hour infusion every 8 hours in two different dosing regimens (2g meropenem/2 g compound I and 1g meropenem/1 g compound I). The combination has high activity against gram-negative pathogens including KPC-producing, carbapenem-resistant klebsiella pneumoniae (k.pneumonia) and pseudomonas aeruginosa (p.aeruginosa). The aim of this study was to demonstrate the efficacy of meropenem in combination with compound I on clinical isolates of pseudomonas aeruginosa by using simulated human exposure in an in vitro hollow fiber model. The pharmacokinetic simulation was based on data from the clinical study disclosed in example 2.

The method comprises the following steps: three pseudomonas aeruginosa strains were tested. The Minimum Inhibitory Concentrations (MIC) were determined by the liquid medium microdilution method used for the CLSI reference method and are shown in table D.

In vitro PK-PD model: six medium sized hollow fiber filter elements (Fibercell systems) were used for each experiment. Three strains studied in duplicate were used for each experiment. Logarithmic phase cells were seeded and incubated for 2 hours to reach about 10 before treatment began⁸CFU/mL. The target PK parameters are listed in table E and table F. The exposure is based on published literature disclosed in example 2. For collecting samples from a central chamberThe drug concentration over 32 hours was determined and analyzed using LC-MS/MS method.

Enterobacter strains producing Klebsiella Pneumoniae Carbapenemase (KPC) with meropenem alone (MIC 8 μ g/ml to 512 μ g/ml) and with meropenem/Compound I (where Compound I is administered at a fixed concentration of 8 μ g/ml with meropenem, MIC 0.06 μ g/ml to 8 μ g/ml), and Pseudomonas aeruginosa strains with meropenem and meropenem/Compound I MIC2 μ g/ml to 8 μ g/ml, are used.

As a result:

exposure from the combined dosing regimen of 1g meropenem and 1g compound I with meropenem alone (MIC of 8 to 64. mu.g/ml) and with a combination of meropenem and compound I (wherein compound I is administered with meropenem at a fixed concentration of 4. mu.g/ml and the MIC of meropenem is from ≦ 0.06. mu.g/ml to 2. mu.g/ml) correlates with effective killing and no regrowth of KPC-producing Klebsiella pneumoniae strains at 32 hours (see FIGS. 22 and 23). Several clones of strains KP1061, KP1087, KP1004 and KP1074 that survived at 32 hours were tested for sensitivity to meropenem and the meropenem/compound I combination and found to be indistinguishable from pre-exposed strains.

On the other hand, less killing was observed for strain KP1099 with meropenem alone (MIC of 128 μ g/ml) and with a combination of meropenem and compound I (when compound I was applied at a fixed concentration of 4 μ g/ml, the MIC of meropenem dropped to 4 μ g/ml). See fig. 23. Regrowth was observed after 16 hours from the start of treatment. When clones of KP1099 that survived exposure to three doses of 1g meropenem/1 g compound I were studied, their sensitivity to meropenem/compound I decreased 16-32 fold, indicating resistance selection under inadequate exposure conditions.

Importantly, exposure from a 2g meropenem/2 g compound I dosing regimen was associated with effective killing and no regrowth/resistance development using the strains with meropenem alone and meropenem/compound I. For strain KP1094, the MIC of meropenem alone was as high as 512 μ g/ml. However, when compound I was administered with meropenem at a fixed concentration of 8 μ g/ml, the observed MIC of meropenem decreased to 8 μ g/ml (see fig. 24).

Due to the development of resistance to pseudomonas aeruginosa PAM3210 strain with meropenem and meropenem/compound I (when compound I is administered at a fixed concentration of 4 μ g/ml or 8 μ g/ml, the MIC of meropenem remains 2 μ g/ml), exposure from a 1g meropenem/1 g compound I dosing regimen still resulted in effective killing at 32 hours and no regrowth. However, regrowth and resistance development occurred in strains PAM3353 and PAM3377 with Meropenem with a MIC of 8. mu.g/ml (see FIG. 25).

For the efficacy of meropenem against simulated human exposure to pseudomonas aeruginosa in an in vitro hollow fiber model compared to the combination of compound I2 g/meropenem 2g, it was observed that the model effectively simulates human exposure of both meropenem and compound I. (see FIG. 26). Fig. 27 shows the antibacterial activity of meropenem in the model. By 3 hour infusion, q8h, 2g meropenem produced over 4 log kill of strains with MIC of 2mg/L and almost 4 log kill of strains with MIC of 4mg/L to 8 mg/L. Resistance developed in the strain with MIC of 8 mg/L. Figure 28 shows the antibacterial activity of 2g meropenem/2 g compound I combination in a model. This combination produced over 4 log bactericidal effects on all tested strains with no regrowth or resistance development over a 32 hour test period. The 2g meropenem/2 g compound I dosing regimen was effective against all three strains. No resistant mutants were identified in the surviving bacteria (see figure 28). Table G below summarizes the results.

In summary, PK/PD studies in an in vitro infection model showed that human exposure from a 2g/2g combination of meropenem/compound I was associated with broad killing of the target pathogen and prevention of resistance of the strain with immobilized compound I at 8 μ g/ml and meropenem with a MIC less than or equal to 8 μ g/ml. Furthermore, the 2g/2g dose combination reduced exposure associated with resistance development.

Furthermore, in this in vitro model, a combination of compound I2 g/meropenem 2g administered by three hour infusion every 8 hours was highly effective against pseudomonas aeruginosa strains with MIC as high as 8mg/L and no regrowth and no resistance development over the course of the 32 hour study. By infusion for 3 hours, q8h, meropenem 2g was effective against 2 of the 3 strains, but resistance developed in the third strain with a MIC of 8 mg/L.

The present invention relates to subject matter defined in the following sequentially numbered paragraphs:

1. a method of treating or ameliorating a bacterial infection, comprising administering to a subject in need thereof an effective amount of compound I or a pharmaceutically acceptable salt thereof:

wherein the amount of compound I or a pharmaceutically acceptable salt thereof is from about 1.0g to about 3.0g, and the amount of meropenem is from about 1.0g to about 3.0 g.

2. The method of paragraph 1, wherein the amount of compound I or pharmaceutically acceptable salt thereof is about 2.0 g.

3. The method of paragraph 1, wherein the amount of meropenem is about 2.0 g.

4. The method of any one of paragraphs 1 to 3, wherein the amount of compound I or pharmaceutically acceptable salt thereof and meropenem is about 2.0g each.

5. The method of any one of paragraphs 1 to 4, wherein compound I or the pharmaceutically acceptable salt thereof and meropenem are administered at least once daily.

6. The method of paragraph 5, wherein compound I or the pharmaceutically acceptable salt thereof and meropenem are administered 3 times daily.

7. The method of any one of paragraphs 1 to 6, wherein the daily dose of compound I or a pharmaceutically acceptable salt thereof is about 6.0g, and wherein the daily dose of meropenem is about 6.0 g.

8. The method of any of paragraphs 1 to 7, wherein the administering is by intravenous infusion.

9. The method of paragraph 8, wherein the intravenous infusion is completed in about 1 hour to about 5 hours.

10. The method of paragraph 9 wherein said intravenous infusion is completed within about 3 hours.

11. The method of any one of paragraphs 1 to 10, wherein compound I or a pharmaceutically acceptable salt thereof is administered before or after meropenem.

12. The method of any one of paragraphs 1 to 10, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are in a single dosage form.

13. The method of paragraph 12, wherein the single dosage form further comprises a pharmaceutically acceptable excipient, diluent or carrier.

14. The method of any of the preceding paragraphs, further comprising administering an additional agent selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

15. A method of treating or ameliorating a bacterial infection, comprising:

selecting for treatment a subject having reduced renal function who is in need of treatment for a bacterial infection;

administering to the subject an effective amount of compound I or a pharmaceutically acceptable salt thereof and meropenem.

16. The method of paragraph 15, wherein the subject has creatinine clearance ≧ 30ml/min and < 50 ml/min.

17. The method of paragraph 15, wherein the subject has creatinine clearance ≧ 20ml/min and < 30 ml/min.

18. The method of paragraph 15, wherein the subject has creatinine clearance ≧ 10ml/min and < 20 ml/min.

19. The method of paragraph 15, wherein the subject has creatinine clearance < 10 ml/min.

20. The method of any one of paragraphs 15 to 19, wherein the bacterial infection is a lower respiratory tract infection.

21. The method of any one of paragraphs 15 to 20, wherein compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 250mg to about 2.0 g.

22. The method of paragraph 21, wherein compound I or the pharmaceutically acceptable salt thereof is administered at a dose of about 500mg to about 1.0 g.

23. The method of paragraph 22, wherein compound I or the pharmaceutically acceptable salt thereof is administered at a dose of about 1.0 g.

24. The method of paragraph 22, wherein compound I or the pharmaceutically acceptable salt thereof is administered at a dose of about 500 mg.

25. The method of any one of paragraphs 15 to 24, wherein meropenem is administered in a dose of about 250mg to about 2.0 g.

26. The method of paragraph 25, wherein meropenem is administered in a dose of about 500mg to about 1.0 g.

27. The method of paragraph 26, wherein meropenem is administered at a dose of about 1.0 g.

28. The method of paragraph 26, wherein meropenem is administered at a dose of about 500 mg.

29. The method of any one of paragraphs 15 to 28, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are administered at a dose of about 1.0 g.

30. The method of any one of paragraphs 15 to 28, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are administered at a dose of about 500 mg.

31. The method of any one of paragraphs 15 to 30, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are administered at least once daily.

32. The method of paragraph 30, wherein compound I or the pharmaceutically acceptable salt thereof and meropenem are administered 2 times daily.

33. The method of paragraph 30, wherein compound I or the pharmaceutically acceptable salt thereof and meropenem are administered 3 times daily.

34. The method of paragraph 31, wherein the daily dose of compound I or pharmaceutically acceptable salt thereof is about 3.0g, and wherein the daily dose of meropenem is about 3.0 g.

35. The method of paragraph 31, wherein the daily dose of compound I or the pharmaceutically acceptable salt thereof is about 2.0g, and wherein the daily dose of meropenem is about 2.0 g.

36. The method of paragraph 31, wherein the daily dose of compound I or the pharmaceutically acceptable salt thereof is about 1.0g, and wherein the daily dose of meropenem is about 1.0 g.

37. The method of paragraph 31, wherein the daily dose of compound I or the pharmaceutically acceptable salt thereof is about 500mg, and wherein the daily dose of meropenem is about 500 mg.

38. The method of any one of paragraphs 15 to 37, wherein the administering is by intravenous infusion.

39. The method of paragraph 38, wherein the intravenous infusion is completed in about 1 hour to about 5 hours.

40. The method of paragraph 39 wherein said intravenous infusion is completed within about 3 hours.

41. The method of any one of paragraphs 15 to 40, wherein compound I or a pharmaceutically acceptable salt thereof is administered before or after meropenem.

42. The method of any one of paragraphs 15 to 40, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are in a single dosage form.

43. The method of paragraph 42, wherein said single dosage form further comprises a pharmaceutically acceptable excipient, diluent or carrier.

44. A method of treating or ameliorating a lower respiratory infection comprising administering to a subject in need thereof an effective amount of compound I or a pharmaceutically acceptable salt thereof:

45. the method of paragraph 44, wherein Compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 250mg to about 5.0 g.

46. The method of paragraph 45, wherein Compound I or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.0g to about 3.0 g.

47. The method of any one of paragraphs 44 to 46, wherein meropenem is administered in a dose of about 250mg to about 5.0 g.

48. The method of paragraph 47, wherein meropenem is administered in a dose of about 1.0g to about 3.0 g.

49. The method of any one of paragraphs 44 to 48, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are administered at a dose of about 2.0 g.

50. The method of any one of paragraphs 44 to 49, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are administered at least once daily.

51. The method of paragraph 50, wherein Compound I or a pharmaceutically acceptable salt thereof and meropenem are administered 3 times daily.

52. The method of any one of paragraphs 44 to 51, wherein the daily dose of compound I or a pharmaceutically acceptable salt thereof is from about 3.0g to about 6.0g, and wherein the daily dose of meropenem is from about 3.0g to about 6.0 g.

53. The method of any one of paragraphs 44 to 52, wherein the administration is by intravenous infusion.

54. The method of paragraph 53 wherein said intravenous infusion is completed in about 1 hour to about 5 hours.

55. The method of paragraph 54 wherein said intravenous infusion is completed within about 3 hours.

56. The method of any one of paragraphs 44 to 55, wherein compound I or a pharmaceutically acceptable salt thereof is administered before or after meropenem.

57. The method of any one of paragraphs 44 to 55, wherein compound I or a pharmaceutically acceptable salt thereof and meropenem are in a single dosage form.

58. The method of paragraph 57, wherein said single dosage form further comprises a pharmaceutically acceptable excipient, diluent or carrier.

59. The method of any one of paragraphs 1 to 58, wherein the subject has an infection caused by Enterobacter.