Gepotidacin for use in treatment of bacterial urinary tract infections

Abstract

To provide new and effective oral antibiotic treatment options for urinary tract infections (UTI) against multidrug-resistant pathogens and extended-spectrum beta-lactamase-producing Enterobacteriaceae pathogens, which impact the efficacy of currently available oral antibacterial treatment options.SOLUTION: Disclosed are methods for use in treating urinary tract infection, and compounds for use in the treatment, the method comprising the step of administering gepotidacin or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a human in need thereof, where the urinary tract infection is caused by one or more specific bacteria.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of US 62 / 828801, US 62 / 834112, US 62 / 841363, US 62 / 895594, US 62 / 841375, US 62 / 895590, US 62 / 841384, and US 62 / 895601, the entire disclosures of which are incorporated herein by reference.

[0002] Description of Federally Sponsored Research This invention was made with government support under Award No. HHSO100201300011C, awarded by the Biomedical Advanced Research and Development Authority (BARDA), within the Office of the Assistant Secretary for Preparedness and Response, in the United States Department of Health and Human Services. The government has certain rights in this invention.

[0003] The present invention relates to a method and / or use for treating bacterial infections caused by Gram - positive and Gram - negative bacteria, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof, as described herein, and / or a corresponding pharmaceutical composition.

Background Art

[0004] Over the past several decades, the frequency of antimicrobial resistance and its association with severe infectious diseases have been increasing at a fearsome rate.

[0005] For example, in the United States, the Centers for Disease Control and Prevention has estimated that all types of microorganisms, including bacteria, cause or contribute to approximately 1.7 million hospital-associated infections each year, resulting in 99,000 deaths.

[0006] Infections caused by multi-drug resistant Gram-positive and Gram-negative bacteria represent a significant burden to public health, not only from the perspective of morbidity and mortality, but also from the perspective of increased costs for patient management and implementation of infection prevention measures. For example, in Europe where hospital surveys have been conducted, Gram-negative infections are estimated to account for two-thirds of 25,000 deaths each year. Healthcare-associated infections can cause severe pneumonia, as well as infections of the urinary tract, bloodstream and other parts of the body. Many types are difficult to attack with antibiotics, and antibiotic resistance has spread to Gram-negative bacteria that can infect people outside of hospitals (see Pollack, Andrew. "Rising Threat of Infections Unfazed by Antibiotics" The New York Times, February 27, 2010). Such high rates of resistance increase morbidity, mortality and the costs associated with healthcare-associated infections.

[0007] Urinary tract infections (UTIs) are very common, with approximately 11% of women over the age of 18 experiencing at least one episode of acute cystitis each year. Half of these experience recurrent episodes more than once in their lifetime. The peak incidence occurs in young, sexually active women aged 18-29 years. UTIs can be caused by a variety of uropathogens, and the major uropathogens isolated from community-acquired UTIs are Escherichia coli (75%-90%) and Staphylococcus saprophyticus (5%-15%), although other bacteria have also been reported.

[0008] Due to the increasing multi-drug resistant pathogens and extended-spectrum beta-lactamase producing Enterobacteriaceae pathogens that affect the effectiveness of currently available oral antibacterial treatment options, therapies have been restricted, and thus new effective oral antibiotic treatment options for UTIs are needed. A patient's allergy or tolerance to a particular antibiotic must also be considered in determining the treatment course.

[0009] To date, various antibacterial agents have been developed and have become clinically important antimicrobial drugs. Researchers at GlaxoSmithKline reported a new class of antibacterial agents targeting type IIA topoisomerase that are active against broad-spectrum Gram-positive and Gram-negative bacteria [see Nature, Volume 466, pages 935 - 940 (August 19, 2010) and Gibson et al. Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase, ACS Infectious Disease, 2019, 5, 570 - 581]. International Patent Publication WO 2008 / 128942 and U.S. Patent No. 8,389,524, which are hereby incorporated by reference in their entirety, disclose tricyclic nitrogen-containing compounds as antibacterial compounds, pharmaceutical compositions, and their corresponding uses. SUMMARY OF THE INVENTION

[0010] Accordingly, there is a need for the development of new antibiotic compounds with more potent antimicrobial activity having a novel mechanism of action, and corresponding methods and / or uses for treating certain bacterial infections caused by certain Gram-positive and Gram-negative aerobic and anaerobic bacteria, in particular.

[0011] In a first aspect, the present invention is a method of treating urinary tract infection (UTI), comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the UTI is Staphylococcus saprophyticus; Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Haemophilus parainfluenzae, Haemophilus paraphrophilus, Klebsiella oxytoca, Klebsiella variicola, Leclercia adecarboxylata, Proteus hauseri, Proteus peneri, Serratia marcescens, Shigella boydii, Shigella flexneri, Shigella sonnei, Morganella morganii, Providencia rettgeri, drug-resistant Klebsiella pneumoniae, drug-resistant Escherichia coli, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, Pseudomonas putida; Staphylococcus lugdenensis, Streptococcus agalactiae, Streptococcus group F, Streptococcus group G, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis (Streptococcusoralis), Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis; Bilophila wadsworthia, Sutterella wadsworthensis, Clostridium bifermentans, Clostridium difficile, Eggethella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somerae, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella melaninogenica, Prevotellamelaninogenica), Veillonella alcalescens dispar, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium dentium, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus iners, Lactobacillus jensenii, Lactobacillus plantarum, and Lactobacillus rhamnosus A method caused by one or more bacteria selected from the group consisting of:

[0012] In another aspect, the present invention is a method for treating human urinary tract infection (UTI), comprising: a) A sample derived from a human suspected of having UTI is Staphylococcus saprophyticus; Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Parainfluenza bacterium, Haemophilus parafluenzae, Klebsiella oxytoca, Klebsiella variicola, Raoultella adecarboxylata, Proteus hauseri, Proteus penneri, Serratia marcescens, Shigella boydii, Shigella flexneri, Shigella sonnei, Morganella morganii, Providencia rettgeri, drug-resistant Klebsiella pneumoniae, drug-resistant Escherichia coli, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, Pseudomonas aeruginosa; Staphylococcus lugdunensis, Streptococcus agalactiae, Group F Streptococcus, Group G Streptococcus, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis; Bifidobacterium wadsworthia, Streptococcus wadsworthensis, Clostridium bifermentans, Clostridium difficile, Eggerthella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somerae, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella melaninogenica, Veillonella alcalescens dispar, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium dentium, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Acidophilus bacterium, Crispatus bacterium, Fermentans bacterium, Gasseri bacterium, Lactobacillus iners, Lactobacillus gensenii, Lactobacillus plantarum or Lactobacillus rhamnosus Determining whether it contains one or more bacteria selected from b) If one or more bacteria are identified in the sample of step (a) and determined to be the cause of the UTI, administering gepotidacin or a pharmaceutically acceptable salt thereof to the subject in a therapeutically effective amount A method comprising is provided.

[0013] In another aspect, the present invention is gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of UTI, wherein the UTI is Staphylococcus corrosus; Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Parainfluenza bacterium, Haemophilus parafluenzae, Klebsiella oxytoca, Klebsiella variicola, Raoultella adecarboxylata, Proteus hauseri, Proteus penneri, Serratia marcescens, Shigella boydii, Shigella flexneri, Sonne bacterium, Morganella bacterium, Providencia rettgeri, drug-resistant Klebsiella pneumoniae, drug-resistant Escherichia coli, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, Pseudoalteromonas bacterium; Staphylococcus lugdunensis, Streptococcus agalactiae, Group F streptococcus, Group G streptococcus, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis; Bifidobacterium wadsworthia, Streptococcus wadsworthensis, Clostridium beijerinckii, Clostridium difficile, Eggerthella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somerae, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella melaninogenica, Veillonella alcalescens dispar, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium dentium, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Acidophilus bacterium, Crispatus bacterium, Fermentum bacterium, Gasseri bacterium, Lactobacillus iners, Lactobacillus jensenii, Lactobacillus plantarum, and Lactobacillus rhamnosus Provided is gepotidacin or a pharmaceutically acceptable salt thereof, which is caused by one or more bacteria selected from the group consisting of

[0014] In another aspect, the present invention is the use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of UTI, wherein the UTI is Staphylococcus corrosus; Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Parainfluenza bacteria, Haemophilus parafluenzae, Klebsiella oxytoca, Klebsiella variicola, Raoultella adecarboxylata, Proteus hauseri, Proteus penneri, Serratia marcescens, Shigella boydii, Shigella flexneri, Shigella sonnei, Morganella morganii, Providencia rettgeri, drug-resistant Klebsiella pneumoniae, drug-resistant Escherichia coli, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, Pseudomonas bacteria; Staphylococcus lugdunensis, Streptococcus agalactiae, group F Streptococcus, group G Streptococcus, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis; The use of gepotidacin or a pharmaceutically acceptable salt thereof, caused by one or more bacteria selected from Bifidobacterium wadsworthia, Streptella wadsworthensis, Clostridium bifermentans, Clostridium difficile, Eggerthella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somerae, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella melaninogenica, Veillonella alcalescens dispar, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium dentium, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Acidophilus bacterium, Crispatus bacterium, Fermentum bacterium, Gasseri bacterium, Lactobacillus iners, Lactobacillus gensenii, Lactobacillus plantarum and Lactobacillus rhamnosus Provided is the use of gepotidacin or a pharmaceutically acceptable salt thereof, caused by one or more bacteria selected from the group consisting of.

Brief Description of the Drawings

[0015]

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BRIEF DESCRIPTION OF THE INVENTION

[0016] As used herein, the term "antibiotic" is synonymous with "antibacterial agent" and "antimicrobial agent".

[0017] Gepotidacin is a first-in-class triazaanthracene antibiotic that selectively inhibits bacterial DNA replication by means not utilized by any currently approved human therapeutic agent, thereby providing an opportunity to address an unmet medical need. Gepotidacin and its racemic form are disclosed in WO 2008 / 1289422. Gepotidacin is (2R)-2-({4-[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaanthracene-3,8-dione.

[0018]

CHEMICAL FORMULA

[0019] As used herein, the term "gepotidacin" may mean the gepotidacin free base or a salt of gepotidacin. When a composition contains a salt of gepotidacin, the stated amount of gepotidacin in the composition refers to the amount of the corresponding gepotidacin free base.

[0020] Gepotidacin has now been found to have surprising activity against certain bacteria that have not previously been shown to be active. This unique mode of activity means that it may provide an alternative treatment to conventional antibiotics for certain bacterial infections. Furthermore, gepotidacin has been found here to be particularly suitable for treating urinary tract infections (UTIs) due to its specific efficacy against certain bacteria that cause UTIs, its in vivo safety profile, and the fact that its activity is minimally affected by urine. Additionally, gepotidacin has been shown to maintain high and sustained concentrations in urine in vivo (see the examples herein). These unexpected properties of gepotidacin make it extremely suitable for use in the treatment of UTIs.

[0021] In a first aspect, the present invention provides a method of treating a UTI, the method comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the UTI is caused by one or more of the bacteria described herein.

[0022] As used herein, the phrase "caused by bacteria" can mean (1) a person skilled in the art can surmise the identity of the bacteria causing a UTI episode, for example, from a patient's medical history or local epidemiology, or (2) a person skilled in the art can prove or determine the identity of the causative bacteria using culture (or other diagnostic test) information obtained from an infected patient. Thus, in one embodiment, the present invention provides a method of treating a UTI, the method comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein it has been proven that the UTI is caused by one or more of the bacteria described herein. In another embodiment, the present invention provides a method of treating a UTI, the method comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the UTI is suspected or strongly suspected to be caused by one or more of the bacteria defined herein.

[0023] In one embodiment, the present invention provides a method for treating a UTI, comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the UTI is caused by a strain of bacteria described herein that is susceptible to gepotidacin or a pharmaceutically acceptable salt thereof.

[0024] As will be understood by those skilled in the art, "susceptible" means that when the recommended dosage is used at the site of infection, the isolate of the microorganism is inhibited by antimicrobial agent concentrations that are normally achievable. Susceptibility to gepotidacin can be determined by one skilled in the art from an isolate recovered from a sample of an infected subject using, for example, the standards published by the US Food and Drug Administration (Antibacterial Susceptibility Test Interpretive Criteria), the Clinical and Laboratory Standards Institute (e.g., Performance Standards for Antimicrobial Susceptibility Testing. 29th Edition CLSI Supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2019) or the European Union Committee on Antimicrobial Susceptibility Testing.

[0025] In one embodiment, as used herein, "sensitive to gepotidacin" or "gepotidacin sensitivity" means that the minimum inhibitory concentration (MIC) of gepotidacin (which can be measured in vitro or in vivo) against a bacterial isolate is 32 mg / L or less when measured by the broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines. In one embodiment, this means 16 mg / L or less. In one embodiment, this means 8 mg / mL or less. In one embodiment, this means 4 mg / L or less. In another embodiment, this means 2 mg / L or less. In another embodiment, this means 1 mg / L or less.

[0026] In one embodiment, prior to administration of gepotidacin or a pharmaceutically acceptable salt thereof, it is determined that the UTI is caused by one or more of the bacteria defined above. The determination can be made by any conventional means. For example, a sample, such as a urine or plasma sample, can be obtained from a human suspected of having a UTI and then tested for the presence of one or more of the bacteria defined in the present invention using any conventional means. If this culture information reveals the presence of one or more of the bacteria defined in the present invention and it is determined to be the cause of the UTI according to known diagnostic criteria, gepotidacin or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount. Those skilled in the art can use established diagnostic criteria, such as 3 10 4 CFU / mL, 10 5 CFU / mL or more than 10

[0027] In one embodiment, the present invention provides a method for treating cystitis caused by Staphylococcus saprophyticus, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof. In one embodiment, the cystitis is acute cystitis.

[0028] In a second aspect, the present invention provides a method for treating a urinary tract infection (UTI), the method comprising: (a) determining whether a human-derived sample suspected of having a UTI contains one or more bacteria as defined herein; and (b) if one or more bacteria are identified in the sample of step (a) and determined to be the cause of the UTI, administering gepotidacin or a pharmaceutically acceptable salt thereof to a subject in a therapeutically effective amount. Determining the presence of the bacteria of the present invention in a sample can be performed using any conventional means described above.

[0029] In one embodiment, the sample used in step (a) is a urine sample. In another embodiment, the sample is a blood, plasma or tissue sample.

[0030] In a third aspect, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of a UTI, wherein the UTI is caused by one or more bacteria as defined above.

[0031] In another aspect, the present invention provides the use of gepotidacin or a pharmaceutically acceptable salt thereof for the treatment of a urinary tract infection caused by a Gram-positive aerobic organism or a Gram-negative aerobic organism, wherein the Gram-positive aerobic organism is Staphylococcus saprophyticus, and the Gram-negative aerobic organism is selected from Acinetobacter baumannii anitratus, Acinetobacter pittii, Parainfluenza bacterium, Haemophilus parafluphilus, Klebsiella oxytoca, Klebsiella variicola, Proteus hauseri or Proteus penneri.

[0032] In one embodiment, in any of the aspects of the present invention, the bacterium is selected from Staphylococcus corrosus; Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Parainfluenza bacterium, Haemophilus parafluenzae, Klebsiella oxytoca, Klebsiella variicola, Raoultella adecarboxylata, Proteus hauseri, Proteus penneri, Serratia marcescens, Shigella boydii, Shigella flexneri, Sonne bacterium, Morganella morganii, Providencia rettgeri, drug-resistant Klebsiella pneumoniae, drug-resistant Escherichia coli, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, and Peptida bacterium.

[0033] In one embodiment, in any of the aspects of the present invention, the bacterium is selected from Staphylococcus corrosus, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Parainfluenza bacterium, Haemophilus parafluenzae, Klebsiella oxytoca, Klebsiella variicola, Raoultella adecarboxylata, Proteus hauseri, Proteus penneri, Morganella morganii, Providencia rettgeri, and Serratia marcescens.

[0034] In one embodiment, in any of the aspects of the present invention, the bacterium is selected from Staphylococcus corrosus, drug-resistant Staphylococcus corrosus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, drug-resistant Citrobacter koseri, Klebsiella oxytoca, Klebsiella variicola, Proteus hauseri, Proteus penneri, Serratia marcescens, drug-resistant Klebsiella pneumoniae, and drug-resistant Escherichia coli.

[0035] In one embodiment, in any of the aspects of the present invention, the bacterium is It is selected from Staphylococcus corrodens, drug-resistant Staphylococcus corrodens, Proteus hauseri, Proteus penneri, drug-resistant Klebsiella pneumoniae, and drug-resistant Escherichia coli.

[0036] In one embodiment, in any of the aspects of the present invention, the bacterium is selected from Staphylococcus corrodens and drug-resistant Staphylococcus corrodens.

[0037] In one embodiment, in any of the aspects of the present invention, the bacterium is Staphylococcus corrodens.

[0038] In one embodiment, in any of the aspects of the present invention, the bacterium is Morganella or Providencia rettgeri.

[0039] In one embodiment, the bacterium is non-drug-resistant or drug-resistant Morganella.

[0040] In one embodiment, the bacterium is non-drug-resistant or drug-resistant Providencia rettgeri.

[0041] In one embodiment, the bacterium is Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, or Peptida bacterium.

[0042] The present invention relates to a method for treating a bacterial infection, a compound for use in such treatment, and / or its use for treatment, wherein each bacterium can be selected from gram-negative aerobic organisms selected from the following list: Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Parainfluenza bacterium, Haemophilus paraffilum, Klebsiella oxytoca, Klebsiella variicola, Raoultella adecarboxylata, Proteus hauseri, Proteus penneri, or Serratia marcescens.

[0043] In another aspect, the present invention also provides that each of the Gram-negative aerobic organisms and / or Gram-positive aerobic organisms as defined hereinabove and throughout the present application can be either non-drug-resistant and / or drug-resistant organisms. Reference can be made to organisms that are either drug-resistant or non-drug-resistant (i.e., by way of example only, for example, drug-resistant Staphylococcus corrosus or non-drug-resistant Staphylococcus corrosus, or drug-resistant Escherichia coli (E. coli) and drug-resistant Klebsiella pneumoniae (K. pneumoniae) are listed, but not limited thereto).

[0044] As used herein, the term "drug-resistant" bacteria is synonymous with "non-susceptible" bacteria and refers to the form of bacteria that resist the effects of antibiotics or have reduced or no susceptibility to antibiotics. "Drug-resistant bacteria" include, for example, bacteria that produce extended-spectrum beta-lactamases (ESBLs), bacteria that produce carbapenemases (e.g., KPC, GES, OXA-48-like, NDM, VIM, and IMP), bacteria that are resistant to carbapenems due to deletion or efflux of OprD, bacteria that produce AmpC, and bacteria that have mutations in the quinolone resistance determining regions (QRDRs) of the gyrA and parC genes.

[0045] In the present invention, in one embodiment, the drug resistance of bacteria can be inferred (e.g., by knowing the patient's medical history, such as recurrent UTI). In another embodiment, drug resistance can be demonstrated by established techniques including phenotypic or genotypic determination.

[0046] In one embodiment, in the present invention, "drug resistance" means resistance or non-susceptibility as defined in M100 CLSI.

[0047] In one embodiment, the bacteria that cause UTI are resistant to or suspected of being resistant to antibiotics selected from the group consisting of fluoroquinolone antibiotics including ciprofloxacin and levofloxacin; ampicillin; amoxicillin / clavulanic acid; trimethoprim-sulfamethoxazole; cefazolin; azithromycin; methicillin; tetracycline; nitrofurantoin; mecillinam; ceftriaxone, cefixime; nitrofurantoin; and fosfomycin. In one embodiment, the bacteria that cause UTI are multi-drug resistant. In one embodiment, "multi-drug resistance" of the present invention means resistance to two clinically relevant antibiotic classes. In one embodiment, "multi-drug resistance" means resistance to three or more clinically relevant antibiotic classes.

[0048] In another aspect, the present invention provides for or relates to Gram-negative and / or Gram-positive aerobic or anaerobic organisms being drug resistant to antibiotics selected from the group consisting of, but not limited to, ciprofloxacin, azithromycin, and tetracycline.

[0049] In one embodiment, in any of the aspects of the present invention, the bacteria are selected from drug-resistant Klebsiella pneumoniae and drug-resistant Escherichia coli. In one embodiment, drug-resistant Staphylococcus corrodens, drug-resistant Klebsiella pneumoniae, or drug-resistant Escherichia coli are each resistant to one or more antibiotics selected from the group consisting of fluoroquinolone antibiotics including ciprofloxacin and levofloxacin; ampicillin; amoxicillin / clavulanic acid; trimethoprim-sulfamethoxazole; cefazolin; azithromycin; methicillin; tetracycline; nitrofurantoin; mecillinam; ceftriaxone, cefixime; nitrofurantoin; and fosfomycin. In one embodiment, drug-resistant Staphylococcus corrodens, drug-resistant Citrobacter koseri, and drug-resistant Klebsiella pneumoniae are each resistant to ampicillin.

[0050] In another aspect, the present invention relates to a method for treating a bacterial infection or other disease as defined in the present invention caused by Gram-negative and / or Gram-positive aerobic organisms, a compound for use in such treatment, and / or use for such treatment, wherein Gram-negative aerobic organisms such as Escherichia coli or Klebsiella pneumoniae are drug-resistant to antibiotics selected from, but not limited to, ampicillin, trimethoprim-sulfamethoxazole and ciprofloxacin / levofloxacin and cefazolin.

[0051] In one embodiment, the Gram-negative and / or Gram-positive aerobic organisms are drug-resistant to antibiotics selected from the group consisting of, but not limited to, ciprofloxacin, azithromycin or tetracycline.

[0052] In one embodiment, the drug-resistant bacteria are Escherichia coli that are resistant to two or more classes of antibiotics.

[0053] In one embodiment, the drug-resistant bacteria are Escherichia coli that are resistant to three or more classes of antibiotics.

[0054] In one embodiment, the drug-resistant organisms are a) Staphylococcus putrefaciens or Citrobacter koseri, b) Staphylococcus putrefaciens resistant to ampicillin, c) Staphylococcus putrefaciens resistant to methicillin, d) Citrobacter koseri resistant to ampicillin, e) Klebsiella pneumoniae resistant to ampicillin, or f) Escherichia coli resistant to ampicillin, g) Escherichia coli resistant to trimethoprim-sulfamethoxazole, h) Escherichia coli resistant to ciprofloxacin, i) Escherichia coli resistant to cefazolin, j) Escherichia coli resistant to ampicillin, ciprofloxacin and trimethoprim-sulfamethoxazole, k) Escherichia coli resistant to ampicillin, cefazolin, and trimethoprim-sulfamethoxazole, l) Staphylococcus epidermidis resistant to methicillin.

[0055] In one aspect, the present invention provides a method for treating uncomplicated UTI, comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the uncomplicated UTI is caused by one or more bacteria selected from Staphylococcus saprophyticus, drug-resistant Staphylococcus saprophyticus, Proteus hauseri, Proteus penneri, Morganella, Providencia rettgeri, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, Ptuida bacteria, drug-resistant Klebsiella pneumoniae, and drug-resistant Escherichia coli.

[0056] In one aspect, the present invention provides a method for treating uncomplicated UTI, comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the uncomplicated UTI is caused by one or more bacteria selected from Staphylococcus saprophyticus and drug-resistant Staphylococcus saprophyticus.

[0057] In one aspect, the present invention provides a method for treating uncomplicated UTI, comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the uncomplicated UTI is caused by drug-resistant Escherichia coli.

[0058] In one aspect, the present invention provides a method for treating uncomplicated UTI, comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the uncomplicated UTI is caused by multidrug-resistant Escherichia coli.

[0059] In one embodiment, in any of the aspects of the present invention, the bacterium is selected from Staphylococcus lugdunensis, Streptococcus agalactiae, group F streptococci, group G streptococci, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis and Streptococcus vestibularis.

[0060] In one embodiment, the present invention provides a method for treating urinary tract infections caused by Gram-positive aerobic organisms selected from Staphylococcus lugdunensis, Streptococcus agalactiae, group F streptococci, group G streptococci, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, and Streptococcus vestibularis, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0061] In one embodiment, the present invention provides a method for treating a bacterial infection selected from bloodstream infection, upper respiratory tract infection, lower respiratory tract infection, skin infection, soft tissue infection, intra-abdominal infection, gastrointestinal infection, genital tract infection, and urinary tract infection caused by a gram-positive aerobic organism selected from Staphylococcus lugdunensis, Streptococcus agalactiae, group F streptococcus, group G streptococcus, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, and Streptococcus vestibularis, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0062] In one embodiment, the Gram-positive aerobic organism is selected from coagulase-negative staphylococci selected from Staphylococcus capitis (S. capitis), Staphylococcus caprae (S. caprae), Staphylococcus cohnii (S. cohnii), Staphylococcus epidermidis (S. epidermidis), Staphylococcus haemolyticus (S. haemolyticus), Staphylococcus hominis (S. hominis), Staphylococcus intermedius (S. intermedius), Staphylococcus simulans (S. simulans) and Staphylococcus warneri (S. warneri), or the viridans streptococci are selected from Streptococcus anginosus (S. anginosus), Streptococcus australis (S. australis), Streptococcus constellatus (S. constellatus), Streptococcus cristatus (S. cristatus), Streptococcus gordonii (S. gordonii), Streptococcus infantarius (S. infantarius), Streptococcus infantis (S. infantis), Streptococcus intermedius (S. intermedius), Streptococcus massiliensis (S. massiliensis), Streptococcus mutans (S. mutans), Streptococcus oralis (S. oralis), Streptococcus parasanguinis (S. parasanguinis), Streptococcus salivarius (S. salivarius), Streptococcus sanguinis (S. sanguinis) and Streptococcus vestibularis (S. vestibularis).

[0063] In one embodiment, in any of the aspects of the present invention, the bacterium is selected from Staphylococcus lugdunensis, Streptococcus agalactiae, group F streptococci, group G streptococci, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis and Streptococcus vestibularis.

[0064] In one embodiment, the bacterium is Streptococcus agalactiae, group F streptococci, group G streptococci, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus oralis, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis or Streptococcus vestibularis.

[0065] In one embodiment, the bacterium is Streptococcus agalactiae.

[0066] In another embodiment, the bacterium is Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans or Staphylococcus warneri.

[0067] In another aspect, the present invention relates to a method of treating a urinary tract infection caused by a gram-positive aerobic organism selected from coagulase-negative staphylococci selected from Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans and Staphylococcus warneri, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0068] In another aspect, the present invention relates to a method of treating a urinary tract infection caused by a gram-positive aerobic organism selected from coagulase-negative staphylococci selected from Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans and Staphylococcus warneri, the method comprising administering a pharmaceutical composition comprising [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] at least one pharmaceutically acceptable excipient to a patient in need thereof.

[0069] In another aspect, the present invention relates to a method of treating a urinary tract infection caused by a gram-positive aerobic organism described herein, wherein the urinary tract infection is selected from uncomplicated urinary tract infection (uUTI), cystitis and acute cystitis.

[0070] In another aspect, the present invention relates to a method for treating cystitis or acute cystitis caused by a Gram-positive aerobic organism selected from coagulase-negative staphylococci selected from Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans and Staphylococcus warneri, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0071] In another aspect, the present invention relates to a method for treating cystitis or acute cystitis caused by a Gram-positive aerobic organism selected from coagulase-negative staphylococci selected from Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans and Staphylococcus warneri, the method comprising administering a pharmaceutical composition comprising [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] at least one pharmaceutically acceptable excipient, to a patient in need thereof.

[0072] In another aspect, the present invention relates to a method for treating uncomplicated urinary tract infection (uUTI) caused by a Gram-positive aerobic organism selected from coagulase-negative staphylococci selected from Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans and Staphylococcus warneri, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0073] In another aspect, the present invention is a method for treating uncomplicated urinary tract infections (uUTIs) caused by Gram-positive aerobic organisms that are coagulase-negative staphylococci selected from Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, and Staphylococcus warneri, [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] at least one or more pharmaceutically acceptable excipients comprising administering to a patient in need thereof a pharmaceutical composition comprising the method.

[0074] In another aspect, the present invention relates to a method for treating urinary tract infections caused by Gram-positive aerobic organisms described throughout the present application, wherein the Gram-positive aerobic organisms are non-drug resistant or drug resistant.

[0075] In another aspect, the present invention provides a method for treating a bacterial infection selected from bloodstream infection, upper respiratory tract infection, lower respiratory tract infection, skin infection, soft tissue infection, intra-abdominal infection, gastrointestinal infection, genital tract infection, and urinary tract infection, caused by a gram-negative anaerobic organism and / or a gram-positive anaerobic organism selected from Bifidobacterium wadsworthia, Streptococcus wadsworthensis, Clostridium bifermentans, Clostridium difficile, Eggerthella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somerae, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella melaninogenica, Veillonella alcalescens dispar, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium dentium, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Acidophilus bacterium, Crispatus bacterium, Fermentans bacterium, Gasseri bacterium, Lactobacillus iners, Lactobacillus gensenii, Lactobacillus plantarum, and Lactobacillus rhamnosus, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0076] In another aspect, the present invention relates to a method for treating a bacterial infection caused by a Gram-negative anaerobic organism and / or a Gram-positive anaerobic organism described herein, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0077] In another aspect, the present invention relates to a method for treating a bacterial infection caused by a Gram-negative anaerobic organism and / or a Gram-positive anaerobic organism described herein, the method comprising administering gepotidacin to a patient in need thereof.

[0078] In another aspect, the present invention relates to a method for treating a bacterial infection caused by a Gram-negative anaerobic organism and / or a Gram-positive anaerobic organism described herein, [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] a pharmaceutically acceptable excipient(s) The method comprises administering to a patient in need thereof a pharmaceutical composition comprising the same.

[0079] In another aspect, the present invention Bifidobacterium wadsworthia, Streptella wadsworthensis, Clostridium bifermentans, Clostridium difficile, Eggerthella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somerae, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella melaninogenica, Veillonella alcalescens dispar, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium dentium, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Acidophilus bacterium, Crispatus bacterium, Fermentans bacterium, Gasseri bacterium, Lactobacillus iners, Lactobacillus gensenii, Lactobacillus plantarum and Lactobacillus rhamnosus A method for treating a bacterial infection caused by, a compound for use in such treatment, and / or use for such treatment, relating to a method, compound, and / or use comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0080] In one embodiment, the bacterial infection is caused by Bacteroides species resistant to ceftriaxone, clindamycin, imipenem, moxifloxacin or piperacillin-tazobactam, and the Bacteroides species is selected from Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis and Bacteroides vulgatus.

[0081] In one embodiment, the bacterial infection is caused by one or more bacteria selected from Porphyromonas levii resistant to metronidazole, Sterela wadsworthensis resistant to metronidazole, Bifidobacterium pseudocatenulatum resistant to clindamycin, Clostridioides difficile resistant to ceftriaxone, clindamycin, imipenem or moxifloxacin, Eggerthella lenta resistant to ceftriaxone, clindamycin or moxifloxacin, Eubacterium nodatum resistant to metronidazole, and Peptostreptococcus anaerobius resistant to clindamycin or moxifloxacin.

[0082] In another aspect, the present invention relates to a method for treating a bacterial infection caused by a Gram-negative and / or Gram-positive anaerobic organism described herein, wherein the Gram-negative and / or Gram-positive anaerobic organism is non-drug resistant or drug resistant.

[0083] The present invention also provides a method for treating a bacterial infection caused by a Gram-positive and Gram-negative aerobic or anaerobic bacterium described herein, a compound for use in such treatment, and / or use for such treatment, which comprises administering to a patient in need thereof a pharmaceutical composition comprising gepotidacin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0084] In another aspect, the present invention is a method for treating a bacterial infection caused by a Gram-negative or Gram-positive aerobic or anaerobic organism, a compound for use in such treatment, and / or use for such treatment, wherein the Gram-negative aerobic organism is - an Acinetobacter species selected from Acinetobacter baumannii, Acinetobacter baumannii anitratus, and Acinetobacter pittii, - a Haemophilus species selected from Haemophilus parainfluenzae and Haemophilus paraaphrophilus, - a Klebsiella species selected from Klebsiella oxytoca and Klebsiella variicola, or - a Proteus species selected from Proteus hauseri and Proteus penneri relates to a method, compound, and / or use as described above.

[0085] Indications treated by the method / use In another aspect of the present invention, the urinary tract infections defined herein may include acute urinary tract infections, and such bacterial infections result from a sudden and severe onset, short-term or rapidly progressive onset, and require emergency treatment.

[0086] In another aspect, the present invention is a method for treating a bacterial infection caused by a Gram-negative or Gram-positive aerobic bacterium, or an aerobic or anaerobic organism, a compound for use in such treatment, and / or use for such treatment, wherein the bacterial infection is selected from common urinary tract infections which may include, but are not limited to, cystitis or acute cystitis, and which may include, but are not limited to, simple urinary tract infections and / or acute urinary tract infections, relates to a method, compound, and / or use as described above.

[0087] Cystitis is an infection of the bladder. According to the present invention, acute cystitis is a sudden inflammation of the bladder caused by a bacterial infection commonly referred to as a urinary tract infection (UTI). See, for example, "Guidelines on Urological Infections" (European Urological Society), https: / / uroweb.org / guideline / urological-infections. This reports that "uncomplicated UTI" is "acute sporadic or recurrent lower (uncomplicated cystitis) and / or upper (uncomplicated pyelonephritis) UTI limited to non-pregnant women without known associated anatomical and functional abnormalities within the urinary tract or co-morbidities". The symptoms of acute cystitis can start suddenly and common symptoms include frequent strong urges to urinate even after emptying the bladder; dysuria with pain or a burning sensation during urination; urine with a foul or strong odor; cloudy urine; a feeling of pressure, bladder fullness or muscle spasms in the mid-lower abdomen or back; low-grade fever; chills; and / or the presence of blood in the urine.

[0088] As used herein, "cystitis" generally refers to inflammation of the bladder and is the most common type of "UTI". As used herein, "acute uncomplicated cystitis" is synonymous with "uncomplicated UTI" or "uUTI".

[0089] uUTI is seen in otherwise healthy subjects without associated structural and functional abnormalities within the urinary tract, kidney disease or co-morbidities, which are mostly women and can lead to more serious outcomes and require additional attention.

[0090] As used herein, "recurrent uUTI" means recurrence of uncomplicated UTI, with a frequency of at least 3 episodes per year or at least 2 episodes in the most recent 6 months. Treatment of recurrent uUTI requires special consideration, such as diagnosis of the infection by urine culture, for example, identification of urinary tract pathogens in a midstream urine sample. For example, in one embodiment, a bacterial count of at least 10 3 CFU / mL indicates recurrent uUTI.

[0091] A UTI may be a "complicated UTI", which is an infection associated with a condition, such as a structural or functional abnormality of the urogenital tract or the presence of an underlying disease, and increases the risk of a more severe outcome or treatment failure compared to a UTI in an individual without identified risk factors. In the present invention, "treatment of UTI" includes treatment of uncomplicated UTI and treatment of complicated UTI.

[0092] In one embodiment, in any aspect of the present invention, the urinary tract infection is selected from uncomplicated urinary tract infection (uUTI), cystitis, and acute cystitis.

[0093] In one embodiment, in any aspect of the present invention, the UTI is an uncomplicated UTI.

[0094] In one embodiment, in any aspect of the present invention, the UTI is a complicated UTI.

[0095] In one embodiment, in any aspect of the present invention, the human is female.

[0096] In one embodiment, in any aspect of the present invention, gepotidacin is gepotidacin free base.

[0097] In one embodiment, in any aspect of the present invention, gepotidacin is gepotidacin methanesulfonate.

[0098] In one embodiment, in any aspect of the present invention, the UTI is a recurrent uncomplicated UTI.

[0099] In one embodiment, in any aspect of the present invention, the human is a pregnant woman, an adolescent, or a child. As used herein, "adolescent" means being 12, 13, 14, 15, 16, or 17 years of age (i.e., 12 to 17 years old, including 12 and 17 years old). As used herein, "child" means 11 years old or younger.

[0100] In one embodiment, in any aspect of the present invention, the human has failed at least once with a previously selected treatment. In one embodiment, the previously selected treatment can be an antibiotic, for example, cephalosporin, carbapenem, nitrofurantoin, trimethoprim alone or in combination with sulfonamide, amoxicillin / clavulanic acid, fosfomycin, or a fluoroquinolone, for example, ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, norfloxacin or ofloxacin. Treatment failure can be defined according to established guidelines. For example, if there is no improvement in symptoms after treatment with an antibiotic for 3, 4, 5, 6 or 7 days, it can be considered a failure.

[0101] In another aspect, the present invention relates to a method for treating a bacterial infection caused by Staphylococcus corrodens, a compound for use in such treatment, and / or use thereof, wherein the pharmaceutically acceptable salt of gepotidacin is an acid addition salt.

[0102] In another aspect, the present invention relates to a method for treating a bacterial infection caused by Staphylococcus corrodens, a compound for use in such treatment, and / or use thereof, wherein the gepotidacin acid addition salt is formed from [a] a mineral acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or [b] an organic acid selected from acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid and tartaric acid.

[0103] In another aspect, the present invention relates to a method for treating a bacterial infection caused by Staphylococcus corrodens, a compound for use in such treatment, and / or use thereof, wherein the gepotidacin acid addition salt is a methanesulfonate.

[0104] In another aspect, the present invention relates to a method for treating a bacterial infection caused by Staphylococcus corrodens, a compound for use in such treatment, and / or use for such treatment, which comprises administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0105] In another aspect, the present invention relates to a method for treating a bacterial infection caused by Staphylococcus corrodens infection, a compound for use in such treatment, and / or use for such treatment, [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] a pharmaceutically acceptable excipient(s) which comprises administering a pharmaceutical composition comprising the same to a patient in need thereof.

[0106] In another aspect, the present invention relates to a method for treating a urinary tract infection caused by Staphylococcus corrodens, a compound for use in such treatment, and / or use in such treatment, which comprises administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0107] In another aspect, the present invention relates to a method for treating a urinary tract infection caused by Staphylococcus corrodens and / or Gram-negative aerobic bacteria, which comprises administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the Gram-negative aerobic organisms are selected from Acinetobacter baumannii anitratus, Acinetobacter pittii, Parainfluenzae sp., Haemophilus parafluphilus, Klebsiella oxytoca or Klebsiella variicola, Proteus hauseri or Proteus penneri.

[0108] In another aspect, the present invention relates to a method for treating urinary tract infections caused by Staphylococcus saprophyticus, drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, a compound for use in such treatment, and / or use for such treatment, which comprises administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0109] In another aspect, the present invention relates to a method for treating cystitis caused by Staphylococcus saprophyticus, drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, a compound for use in such treatment, and / or use for such treatment, which comprises administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0110] In another aspect, the present invention relates to a method for treating acute cystitis caused by Staphylococcus saprophyticus, drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, a compound for use in such treatment, and / or use for such treatment, which comprises administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0111] In another aspect, the present invention as described herein relates to methods for treating bacterial infections caused by the organisms defined in this application, and urinary tract infections (UTIs) including, but not limited to, uncomplicated urinary tract infections (uUTIs) as defined herein, and / or cystitis including, but not limited to, acute cystitis, and more specific infections including, but not limited to, compounds for use in such treatment, and / or use for such treatment.

[0112] In another aspect, the present invention also relates to - methods for treating bacterial infection(s) caused by Gram-positive aerobic bacteria and / or Gram-negative aerobic bacteria, compounds for use in such treatment, and / or use for such treatment, - Methods for treating bacterial infections (including but not limited to those caused by Gram-positive aerobic organisms such as Staphylococcus saprophyticus), compounds for use in such treatment, and / or uses for such treatment, - The following: · Uncomplicated urinary tract infections (uUTIs), · Cystitis, · Acute cystitis, · Complicated UTI Methods for treating urinary tract infections, including but not limited to these, compounds for use in such treatment, and / or uses for such treatment, - Methods for treating cystitis, which may include but are not limited to uncomplicated urinary tract infections (uUTIs) and / or acute cystitis caused by bacterial infections such as drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, compounds for use in such treatment, and / or uses for such treatment, - Methods for treating cystitis, which may include but are not limited to uncomplicated urinary tract infections (uUTIs) and / or acute cystitis caused by bacterial infections such as Staphylococcus saprophyticus, compounds for use in such treatment, and / or uses for such treatment, - Methods for treating cystitis, which may include but are not limited to uncomplicated urinary tract infections (uUTIs) and / or acute cystitis caused by bacterial infections such as Gram-negative aerobic bacteria, compounds for use in such treatment, and / or uses for such treatment Regarding Here, Each of the methods or uses described above or specified above respectively includes the administration of gepotidacin or a pharmaceutically acceptable salt thereof and / or its corresponding pharmaceutical composition as defined herein throughout the present application.

[0113] In another aspect, the present invention relates to a method for treating cystitis caused by Staphylococcus saprophyticus, a compound for use in such treatment, and / or a use for such treatment, wherein the cystitis is acute cystitis.

[0114] In another aspect, the present invention relates to the use of a compound as defined throughout this specification and this application, wherein the cystitis caused by Staphylococcus saprophyticus, drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae is acute cystitis, and relates to the use of said compound.

[0115] In one embodiment, the present invention provides a method for treating cystitis caused by Staphylococcus saprophyticus, comprising the step of administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0116] In one embodiment, the present invention provides a method for treating uncomplicated urinary tract infection, cystitis or acute cystitis, comprising the step of administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0117] In one embodiment, the present invention provides a method for treating uncomplicated urinary tract infection, cystitis or acute cystitis, comprising the step of administering gepotidacin to a patient in need thereof.

[0118] In one embodiment, the present invention is a method for treating uncomplicated urinary tract infection, cystitis or acute cystitis, [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] a pharmaceutically acceptable excipient(s) and comprising the step of administering the pharmaceutical composition comprising the same to a patient in need thereof.

[0119] In one embodiment, the present invention provides a method for treating urinary tract infection caused by Gram-negative aerobic bacteria, comprising the step of administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0120] In one embodiment, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for the treatment of simple urinary tract infection, cystitis or acute cystitis caused by Staphylococcus saprophyticus, drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae.

[0121] In one embodiment, the present invention provides the use of gepotidacin or a pharmaceutically acceptable salt thereof for the treatment of simple urinary tract infection, cystitis or acute cystitis caused by Staphylococcus saprophyticus, drug-resistant Escherichia coli, drug-resistant Klebsiella pneumoniae or Gram-negative aerobic bacteria.

[0122] In another aspect, the present invention relates to the use of gepotidacin or a pharmaceutically acceptable salt thereof for the treatment of urinary tract infection caused by Staphylococcus saprophyticus.

[0123] In another aspect, the present invention relates to the use of gepotidacin or a pharmaceutically acceptable salt thereof for the treatment of cystitis caused by Staphylococcus saprophyticus.

[0124] In another aspect, the present invention relates to the use of gepotidacin or a pharmaceutically acceptable salt thereof for the treatment of acute cystitis caused by Staphylococcus saprophyticus.

[0125] In another aspect, the present invention relates to the use of gepotidacin or a pharmaceutically acceptable salt thereof for the treatment of urinary tract infection caused by Gram-negative aerobic bacteria.

[0126] In another aspect, the present invention is - a Gram-positive organism selected from Staphylococcus saprophyticus, or - a Gram-negative aerobic organism selected from Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Parainfluenzae spp., Haemophilus parafluenzae, Klebsiella oxytoca, Klebsiella variicola, Raoultella ornithinolytica, Proteus hauseri, Proteus penneri and Serratia marcescens A method for treating an infectious disease caused thereby, a compound for use in such treatment, and / or use for such treatment, comprising: [a] a pharmaceutical composition comprising gepotidacin or a pharmaceutically acceptable salt thereof, and [b] a pharmaceutically acceptable excipient(s) administering the same to a patient in need thereof, relates to a method, a compound, and / or use.

[0127] In another aspect, the present invention relates to a method for treating uncomplicated urinary tract infection (uUTI), cystitis or acute cystitis caused by drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, a compound for use in such treatment, and / or use for such treatment, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof, relates to a method, a compound, and / or use.

[0128] In another aspect, the present invention relates to a method for treating uncomplicated urinary tract infection (uUTI), cystitis or acute cystitis caused by drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, a compound for use in such treatment, and / or use for such treatment, comprising administering gepotidacin to a patient in need thereof, relates to a method, a compound, and / or use.

[0129] In another aspect, the present invention relates to a method for treating uncomplicated urinary tract infection (uUTI), cystitis or acute cystitis caused by drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, a compound for use in such treatment, and / or use for such treatment, comprising: [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] a pharmaceutically acceptable excipient(s) administering a pharmaceutical composition comprising the same to a patient in need thereof, relates to a method, a compound, and / or use.

[0130] In another aspect, the present invention relates to a method for treating cystitis caused by Staphylococcus saprophyticus, drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, a compound for use in such treatment, and / or use for such treatment, which comprises administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0131] In another aspect, the present invention relates to a method for treating a bacterial infection or other disease as defined in the present application caused by Gram-negative and / or Gram-positive aerobic bacteria, a compound for use in such treatment, and / or use for such treatment, wherein the Gram-negative and / or Gram-positive aerobic organisms are non-drug-resistant or drug-resistant.

[0132] In another aspect, the present invention relates to a method for treating a bacterial infection or other disease as defined in the present application caused by Gram-negative and / or Gram-positive aerobic organisms, a compound for use in such treatment, and / or use for such treatment, wherein the Gram-negative and / or Gram-positive aerobic organisms are drug-resistant to antibiotics selected from the group consisting of, but not limited to, fluoroquinolones (including ciprofloxacin), azithromycin, tetracycline, nitrofurantoin, trimethoprim / sulfamethoxazole and fosfomycin.

[0133] In another aspect, the present invention relates to a method for treating a bacterial infection or other disease as defined in the present application caused by Gram-negative and / or Gram-positive aerobic organisms, a compound for use in such treatment, and / or use for such treatment, wherein drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae, which are Gram-negative aerobic organisms, are resistant to antibiotics selected from the group consisting of, but not limited to, ampicillin, trimethoprim-sulfamethoxazole and ciprofloxacin / levofloxacin or cefazolin.

[0134] In another aspect, the present invention relates to gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of uncomplicated urinary tract infection (uUTI), cystitis or acute cystitis caused by drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae in a patient in need thereof.

[0135] In another aspect, the present invention [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] one or more pharmaceutically acceptable excipients relates to the use of a pharmaceutical composition comprising the same in the treatment of uncomplicated urinary tract infection (uUTI), cystitis or acute cystitis caused by drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae in a patient in need thereof.

[0136] In another aspect, the present invention relates to gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of cystitis caused by Staphylococcus saprophyticus, drug-resistant Escherichia coli or drug-resistant Klebsiella pneumoniae in a patient in need thereof.

[0137] In another aspect, the present invention - a Gram-positive organism selected from Staphylococcus saprophyticus, or - a Gram-negative aerobic organism selected from Acinetobacter species, Citrobacter species, Haemophilus species, Klebsiella species, Raoultella planticola, Proteus species and Serratia marcescens, where - Acinetobacter species are selected from Acinetobacter baumannii, Acinetobacter anitratus and Acinetobacter pittii, - Citrobacter species are selected from the Citrobacter freundii complex and Citrobacter koseri, - Haemophilus species are selected from Haemophilus parainfluenzae and Haemophilus paraprophilus, - Klebsiella species are selected from Klebsiella oxytoca and Klebsiella variicola, or - A method for treating urinary tract infections caused by (Proteus species selected from Proteus hauseri and Proteus penneri), a compound for use in such treatment, and / or use for such treatment, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a patient in need thereof, a method, compound, and / or use related thereto.

[0138] In another aspect, the present invention relates to - a Gram-positive organism selected from Staphylococcus saprophyticus, or - a Gram-negative aerobic organism selected from Acinetobacter species, Citrobacter species, Haemophilus species, Klebsiella species, Raoultella adecarboxylata, Proteus species or Serratia marcescens - where Acinetobacter species are selected from Acinetobacter baumannii, Acinetobacter anitratus and Acinetobacter pittii, - Citrobacter species are selected from the Citrobacter freundii complex and Citrobacter koseri, - Haemophilus species are selected from Haemophilus parainfluenzae and Haemophilus paraprophilus, - Klebsiella species are selected from Klebsiella oxytoca and Klebsiella variicola, - A method for treating urinary tract infections caused by (Proteus species selected from Proteus hauseri and Proteus penneri), a compound for use in such treatment, and / or use for such treatment, comprising [a] gepotidacin or a pharmaceutically acceptable salt thereof, and [b] a pharmaceutically acceptable excipient(s) administering a pharmaceutical composition comprising the same to a patient in need thereof, a method, compound, or use related thereto.

[0139] In one aspect, the present invention relates to an individual or each method(s) of treatment as defined herein, compound(s) for use in its treatment, and / or use(s) for its treatment of a bacterial infection caused by a Gram-positive aerobic organism, such as a UTI, wherein the Gram-positive aerobic organism is selected from Staphylococcus lugdunensis, Streptococcus agalactiae, group F streptococci, group G streptococci, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans or Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus oralis, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis and Streptococcus vestibularis, and provides a method(s), compound(s), and / or use(s).

[0140] The compounds used herein WO 2008 / 128942 discloses the preparation of the free base and hydrochloride salt of gepotidacin.

[0141] Furthermore, it should be understood that the phrase "gepotidacin or a pharmaceutically acceptable salt thereof" is intended to encompass gepotidacin, a pharmaceutically acceptable salt of gepotidacin, a solvate of gepotidacin, or any pharmaceutically acceptable combination thereof. Thus, for purposes of illustration and as a non-limiting example used herein, "gepotidacin or a pharmaceutically acceptable salt thereof" can include a pharmaceutically acceptable salt of gepotidacin that further exists as a solvate.

[0142] As used herein, the term "compound of the invention" means gepotidacin in any form, i.e., any salt or non-salt form (e.g., free base or a pharmaceutically acceptable salt thereof), and any of its physical forms including, for example, non-solid forms (e.g., liquid or semi-solid forms) and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates including hydrates), as well as mixtures of the various forms.

[0143] Suitable pharmaceutically acceptable salts include those described in Berge, Bighley and Monkhouse J. Pharm. Sci (1977) 66, pages 1 - 19.

[0144] The compounds of the present invention are bases (containing a basic moiety), and thus, the desired salt forms may be prepared by any suitable method known in the art, such methods including treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid, alpha-hydroxy acid such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, mandelate, and sulfonates such as xylenesulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate and naphthalene-2-sulfonate.

[0145] Pharmaceutically acceptable salts of gepotidacin include acid addition salts, such as salts with a mineral acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or an organic acid, such as acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid or tartaric acid.

[0146] The present invention encompasses within the scope all possible stoichiometric and non-stoichiometric salt forms.

[0147] The present invention also includes various deuterated forms of the compounds of the present invention or their pharmaceutically acceptable salts. Each available hydrogen atom bonded to a carbon atom may independently be replaced by a deuterium atom. For example, deuterated substances, such as alkyl groups, can be prepared by conventional techniques (see, for example, methyl-d3-amine available from Aldrich Chemical Co., Milwaukee, WI, catalog number 489,689-2).

[0148] Pharmaceutical Compositions and Formulations Pharmaceutical compositions and formulations that are acceptable and compatible for use in the methods and / or uses of the present invention are prepared using pharmaceutical compositions, formulations or chemical substances, prescription excipients, preparation means, processes and / or methods known in the prior art, and the like.

[0149] In particular, gepotidacin or its pharmaceutically acceptable salts used in the present invention can be formulated to be administered by any convenient method used for human or veterinary medications, similar to other antibacterial / antitubercular compounds.

[0150] The pharmaceutical compositions used in the present invention may be formulated to be administered by any route, including forms suitable for oral, topical or parenteral use, and can be used in mammals including humans.

[0151] The compositions can be in the form of tablets, capsules, powders, granules, lozenges, suppositories, creams, or liquid formulations, such as oral or sterile parenteral solutions or suspensions.

[0152] In one embodiment, gepotidacin or its pharmaceutically acceptable salts of the present invention are in the form of tablets or capsules. In one embodiment, it is in the form of tablets. In one embodiment, the tablets are 750 mg tablets.

[0153] The preparation can also contain suitable conventional carriers, such as a cream or ointment base and ethanol or oleyl alcohol for lotions.

[0154] Tablets or capsules for oral administration according to the present invention may be in the form of unit dosage formulations and may contain conventional excipients, such as binders, fillers, tableting lubricants, disintegrants or wetting agents. Tablets can be coated according to methods well known in the normal pharmaceutical practice. Oral liquid formulations may be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be present as dry products which are reconstituted with water or other suitable vehicle before use. Such liquid formulations may contain conventional additives, such as suspending agents, such as sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat, emulsifying agents, such as lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (for example, edible oils may be included), such as almond oil, oily esters, such as glycerin, propylene glycol or ethyl alcohol, preservatives, such as methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

[0155] Suppositories contain conventional suppository bases, such as cocoa butter or other glycerides.

[0156] For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle (water is preferred). The compound, depending on the vehicle and the concentration used, can be suspended or dissolved in the vehicle. In the preparation of solutions, the compound can be dissolved in water for injection and filter sterilized before filling and sealing in suitable vials or ampoules.

[0157] Advantageously, agents such as local anesthetics, preservatives, and buffers can be dissolved in the vehicle. To improve solubility, the composition can be frozen after filling into a vial, and the water can be removed under vacuum. The lyophilized dry powder can then be sealed in the vial, and an accompanying vial of water for injection can be provided to reconstitute it into a liquid before use. A parenteral suspension is prepared in substantially the same manner, except that the compound is suspended rather than dissolved in the vehicle and sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before being suspended in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

[0158] Furthermore, the dosage of the compound or pharmaceutical composition used in the present invention can vary depending on the patient and the mode of administration and can be any effective amount.

[0159] According to any of the methods of administration of the present invention, the term "therapeutically effective amount", as used herein, generally includes within its meaning a non-toxic but sufficient amount of a particular drug that is referred to as providing the desired therapeutic effect. The exact amount required varies from subject to subject depending on factors such as the general health of the patient, the age of the patient, etc.

[0160] The treatment regimen for administration of the compound and / or pharmaceutical composition used in the present invention can also be readily determined by those skilled in the art. The dosage of the compound and / or pharmaceutical composition used in the present invention can vary widely to provide an effective amount per unit dosage based on the patient's body weight per day to achieve the desired effect.

[0161] The composition can contain 0.1% by weight, preferably 10 - 60% by weight, of the active substance, depending on the method of administration. If the composition contains dosage units, each unit preferably contains 50 - 1000 mg of the active ingredient. Unless otherwise indicated, the amount of the active ingredient (i.e., gepotidacin) refers to the amount of the gepotidacin free base.

[0162] The dosage used for the treatment of adults in the present invention is preferably in the range of 100 to 3000 mg per day, for example 1500 mg per day, depending on the route and frequency of administration. Such a dosage corresponds to about 1.5 to about 50 mg / kg per day (mg of gepotidacin per 1 kg of the patient's body weight). Appropriately, the dosage is 5 to 30 mg / kg per day. In one embodiment, the dosage is 1500 mg twice a day (i.e., 3000 mg per day). In one embodiment, two doses are administered at intervals of 6 to 12 hours per day.

[0163] Accordingly, in one embodiment, the present invention provides a method for treating urinary tract infection (UTI), comprising administering gepotidacin or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a human in need thereof, wherein the UTI is caused by one or more bacteria defined in the first aspect of the present invention, and gepotidacin or a pharmaceutically acceptable salt thereof is administered at 1500 mg twice a day at intervals of 6 to 12 hours.

[0164] In particular, the composition of the present invention exists as a unit dosage and is preferably taken 1 to 5 times a day, for example once or twice a day, to achieve the desired effect. In one embodiment, gepotidacin or a pharmaceutically acceptable salt thereof is administered for any of 3, 4, 5, 6 or 7 consecutive days. In one embodiment, in any aspect of the present invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered for 5 consecutive days.

[0165] Conventional methods of administration may be appropriate for use in the present invention.

[0166] Depending on the treatment to be carried out, the compounds and / or compositions of the present invention may be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. Preferably, the composition is adapted for oral administration.

[0167] The gepotidacin or a pharmaceutically acceptable salt thereof used in the present invention can be the sole therapeutic agent in the composition of the present invention or can be a combination with other antibacterial agents. When the other antibacterial agent is a β-lactam, a β-lactamase inhibitor can also be used.

[0168] The examples described below are illustrative of the present invention and are not intended to limit the scope of the present invention in any way.

Examples

[0169] Unless otherwise specified, the Clinical and Laboratory Standards Institute (CLSI) recommended procedures are as described in the then-current edition of CLSI Approved Standard M07, "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically".

[0170] [Example 1] Biological activity assay (in vitro assay) Tests were conducted to evaluate the in vitro activities of the compounds of the present invention and specific comparative drug compounds identified in the following methods.

[0171] Method 1 Antimicrobial activity was determined by the microdilution method using the CLSI recommended procedure.

[0172] Gepotidacin was tested in serial two-fold dilutions and the minimum inhibitory concentration (MIC) was determined as the lowest concentration of the compound that inhibited visible growth.

[0173] Gepotidacin was tested against 28 strains of Staphylococcus corrodens collected from multiple hospitals.

[0174] Amoxicillin, azithromycin, levofloxacin and cefuroxime were included as comparative drugs. The MICs of gepotidacin and the comparative drugs were determined by the microdilution method according to the CLSI method.

[0175] The MIC90 of gepotidacin (the MIC that inhibited 90% of the isolates tested) was 0.125 μg / mL against 28 isolates of Staphylococcus saprophyticus. This MIC90 value was at least 2- to 512-fold lower than the comparator drugs tested.

[0176] In addition, gepotidacin and at least one comparator drug from the above list were evaluated against Gram-negative aerobic organisms selected from Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Parainfluenza spp., Haemophilus parafluenzae, Klebsiella oxytoca, Klebsiella variicola, Raoultella ornithinolytica, and Serratia marcescens.

[0177] At least one salt of gepotidacin (i.e., for example, the mesylate) was tested and found to have an MIC of ≤8 μg / mL against at least one strain of all the organisms listed above.

[0178] Method 2 Antimicrobial activity was determined in a second study by agar microdilution using the CLSI-recommended procedure with serial two-fold dilutions, and the minimum inhibitory concentration (MIC) was determined as the lowest concentration of the compound that inhibited visible growth.

[0179] In this study, gepotidacin was tested by CLSI agar dilution against 51 isolates of Staphylococcus saprophyticus collected from 2005 to 2018. The MIC90 of the compound against all isolates tested was 0.125 μg / mL.

[0180] Amikacin, ceftazidime, colistin, fosfomycin, levofloxacin, meropenem, nitrofurantoin, and trimethoprim-sulfamethoxazole were included as comparator drugs. The MICs of the comparator drugs were determined by agar dilution according to the CLSI method.

[0181] In addition, gepotidacin and all of the above-described comparator drugs identified by this method were evaluated against Gram-negative aerobic organisms selected from Proteus hauseri and Proteus penneri. Gepotidacin was tested with at least one of the exemplified salts.

[0182] Gepotidacin had an MIC of ≤8 μg / mL against at least one strain of all of the organisms listed above.

[0183] Conclusions for Methods 1 and 2 This study demonstrated the in vitro activity of gepotidacin against Staphylococcus corrodens (MIC90 = 0.12 μg / mL), as well as against Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter pittii, Citrobacter freundii complex, Citrobacter koseri, Haemophilus parainfluenzae, Haemophilus paraaphrophilus, Klebsiella oxytoca, Klebsiella variicola, Raoultella ornithinolytica, Proteus hauseri, Proteus penneri, and Serratia marcescens (MIC ≤8 μg / mL against at least one strain of all of the organisms listed).

[0184] Additional information for Method 2 Materials / Methods: The panel included 511 Enterobacterales (formerly known as the Enterobacteriaceae) enriched to include isolates with ESBL, AmpC or carbapenemase, including Escherichia coli, Klebsiella oxytoca, Klebsiella variicola, Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae complex, Proteus mirabilis, Proteus penneri, Proteus hauseri, and Shigella boydii, Shigella flexneri, and Sonne bacteria; 55 Pseudomonas aeruginosa selected to include isolates with carbapenemase, ESBL, or carbapenem resistance due to OprD deletion and / or efflux; 60 Acinetobacter baumannii with carbapenemase; 95 Neisseria gonorrhoeae including those resistant or with reduced susceptibility to beta-lactam drugs, ciprofloxacin, azithromycin, tetracycline, or spectinomycin; and 51 isolates of Staphylococcus saprophyticus.

[0185] MIC was determined according to the guidelines of the CLSI agar dilution method.

[0186] Results: The MIC of gepotidacin against Escherichia coli ranged from ≤0.06 to 64 mg / L, and 96.1% of the isolates tested were inhibited at a concentration of ≤8 mg / L. The activity of gepotidacin against Escherichia coli was not affected by levofloxacin non-susceptibility or amino acid substitutions in the QRDRs of GyrA and ParC associated with quinolone resistance (188 out of 254 isolates of Escherichia coli were available). The MIC distribution of gepotidacin was also not related to beta-lactamase resistance mechanisms, and 100% of NDM, 94.6% of KPC, and 92.1% of OXA-48-like producing Escherichia coli were inhibited by gepotidacin at ≤8 mg / L.

[0187] The MIC of gepotidacin against Shigella was in the range of 0.125 - 8 mg / L, with 95.6% of the test isolates inhibited at ≤2 mg / L and 100% inhibited at ≤8 mg / L. Specifically, the MIC of gepotidacin against Shigella boydii (n = 3) was 2 mg / L, the MIC90 of gepotidacin against Shigella flexneri (n = 24) was 2 mg / L, and the MIC90 against Shigella sonnei (n = 64) was 2 mg / L. The activity of gepotidacin was not affected by levofloxacin non-susceptibility or amino acid substitutions in the QRDRs of GyrA and ParC (data were available), and the MIC distribution of gepotidacin was also not related to beta-lactamase resistance mechanisms.

[0188] The MIC of gepotidacin was in a higher range against Klebsiella (Klebsiella oxytoca, Klebsiella variicola, Klebsiella pneumoniae), Enterobacter (Enterobacter aerogenes, Enterobacter cloacae complex) and Proteus (Proteus mirabilis, Proteus penneri, Proteus hauseri), with MIC90s of 64, 32 and 32 mg / L, respectively. Specifically, the MIC of gepotidacin against Klebsiella oxytoca, Klebsiella variicola, Proteus hauseri and Proteus penneri was at least 4 mg / L, and was for at least one isolate in each case.

[0189] The MIC against all Enterobacteriaceae tested was not related to levofloxacin resistance or amino acid substitutions in the QRDRs of GyrA and ParC.

[0190] The MIC90s of gepotidacin against Pseudomonas aeruginosa and Acinetobacter baumannii were 32 and 64 mg / L, respectively, and were not related to levofloxacin resistance.

[0191] The MIC against all coagulase-negative staphylococci was ≤0.125 mg / L (same data as shown in Method 2).

[0192]

Table 1

[0193] Conclusion: Gepotidacin was active in vitro against Staphylococcus saprophyticus (100% at ≤0.125 mg / L).

[0194] At 8 mg / L, gepotidacin was active against drug-resistant Escherichia coli (96.1%) and Shigella spp. (100%), but was less active against other Gram-negative genera tested.

[0195] Method 3 Antimicrobial activity was determined by the microbroth dilution method using CLSI-recommended procedures.

[0196] Compounds were tested in serial two-fold dilutions, and the minimum inhibitory concentration (MIC) was determined as the lowest concentration of the compound that inhibited visible growth.

[0197] Specifically, gepotidacin was tested against six strains of Staphylococcus saprophyticus from the isolate collection of Laboratory Specialists, Inc., Westlake, Ohio.

[0198] Levofloxacin was included in the study as a comparator drug to determine the effect of urine on the in vitro activity of gepotidacin against Staphylococcus saprophyticus. The MIC was determined by the microbroth dilution method according to the CLSI method.

[0199] The minimum inhibitory concentration (MIC) of gepotidacin was 0.03 - 0.5 μg / mL against three isolates of methicillin-susceptible Staphylococcus saprophyticus and in the range of 0.06 - 0.5 μg / mL against three isolates of methicillin-resistant Staphylococcus saprophyticus. The MIC values of gepotidacin were 1 / 8 to 1 / 32 of levofloxacin in methicillin-susceptible Staphylococcus saprophyticus and 1 / 4 of levofloxacin in each methicillin-resistant Staphylococcus saprophyticus.

[0200] At least one exemplary salt of gepotidacin was tested (e.g., mesylate).

[0201] Gepotidacin had an MIC of ≤0.5 μg / mL against at least one strain of methicillin-sensitive or methicillin-resistant Staphylococcus aureus.

[0202] The data shown in the following table are the results of an in vitro study conducted with the same isolates of Staphylococcus aureus as those described above to determine the effect of urine on the in vitro activity of gepotidacin and levofloxacin against Staphylococcus aureus. The study strains were tested for MIC (minimum inhibitory concentration) according to the reference CLSI microbroth dilution method using cation-adjusted Mueller-Hinton broth (CAMHB) and adding 25%, 50%, and 100% urine (unadjusted pH, pH 6.42), and 100% urine (adjusted pH, 7.31 and 8.07). The MIC results (mean dilution differences) were slightly higher for both gepotidacin and levofloxacin in 100% stored urine (mean dilution differences, 0.67 - 1.54), but did not appear to be a function of pH.

[0203] [Table 2]

[0204] In conclusion, these tests demonstrated the in vitro activity of gepotidacin against test isolates of methicillin-sensitive and methicillin-resistant Staphylococcus aureus with an MIC ≤0.5 μg / mL, and a slightly higher MIC (mean dilution differences of 1.18 - 1.54) in 100% urine. It is surprising that gepotidacin activity is not significantly affected by urine, making gepotidacin a suitable treatment option for UTI.

[0205] [Example 2] Distribution and exposure of gepotidacin in tissues and body fluids of healthy and infected participants Exposure of the antibiotic target site plays an important role because suboptimal levels can lead to treatment failure and resistance. Over multiple clinical trials, exposure to gepotidacin was evaluated in plasma and other matrices such as urine, saliva, epithelial lining fluid (ELF), and alveolar macrophages (AM).

[0206] Bronchoalveolar lavage samples were collected to determine gepotidacin exposure in ELF and AM following a single 1000 mg IV infusion over 2 hours in healthy subjects. Saliva exposure was evaluated in healthy volunteers after a single 1500 mg oral dose. Gepotidacin exposure in urine was evaluated in women with acute uUTI after 5 days of 1500 mg BID oral dosing.

[0207] The AUC(0 - 12) ratios of ELF and AM to unbound plasma were 1.84 and 178, respectively, demonstrating good ELF exposure and excellent cellular penetration. Saliva concentrations showed a linear relationship with plasma concentrations (R2 = 0.76). The ratio of saliva AUC to unbound plasma AUC was close to 1. Gepotidacin exposure (AUC[0 - tau]) in the urine of uUTI patients was high (3742 μg·h / mL on day 1 and 5973 μg·h / mL on day 4). Urine C-tau exposure was in the range of 322 - 352 μg / mL after day 3. The minimum gepotidacin urine concentration maintained a state above the 4 μg / mL MIC over the 12-hour dosing interval. Gepotidacin renal excretion in uUTI participants was higher than in healthy subjects (20% vs. 7.5% of the dose). Gepotidacin free drug concentrations were measured from swabs taken from women with acute uUTI.

[0208] In conclusion, gepotidacin demonstrates favorable distribution characteristics such as improved intracellular penetration, ELF levels superior to plasma, and saliva exposure similar to plasma. In addition, high urine exposure encompasses the targeted MIC values in the treatment of UTI.

[0209] [Example 3] Phase II Trial to Evaluate Gepotidacin in the Treatment of Simple Urinary Tract Infections Methods: This Phase IIa single-site trial evaluated the safety, tolerability, pharmacokinetics, and efficacy of 1500 mg of gepotidacin BID orally for 5 days in female subjects with acute cystitis. Clean catch midstream urine specimens were obtained by standard methods for quantitative culture. Urine samples were collected from all participants at pre-treatment (baseline) and at all post-baseline visits. All urine samples were sent to a central laboratory (PPD Global Clinical Laboratories, Highland Heights, KY, USA) for Gram stain, quantitative culture, pathogen identification, and susceptibility testing. See Figure 1 for participant characteristics and study outline.

[0210] A. Microbiological studies Susceptibility testing was performed by CLSI microbroth dilution and gradient diffusion (for fosfomycin only) (CLSI, 2015, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-tenth edition; and CLSI, 2018. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-seventh Informational Supplement M100~S28). For inclusion in the microbiological treatment intent population (micro-ITT), growth of an identified baseline urinary pathogen (≧10 5 CFU / mL) was required. See Figure 2 for the baseline algorithm. Microbiological success was defined as the eradication of an identified baseline urinary pathogen confirmed by culture (no growth, <10 3 CFU / mL) and was determined at the treatment of cure (TOC; days 10 - 13) and follow-up visit (day 28).

[0211] For the purposes of this study, multidrug resistance (MDR) was defined as urinary tract pathogens resistant to three or more related antibiotic classes, and extended-spectrum beta-lactamase (ESBL) production was defined as Escherichia coli and Klebsiella pneumoniae urinary tract pathogens with a minimum inhibitory concentration (MIC) of ceftazidime, aztreonam, cefotaxime, or ceftriaxone of ≥2 μg / mL.

[0212] Results: Eight (36%) of the 22 participants had baseline-identified urinary tract pathogens (5 had E. coli, 1 had Staphylococcus saprophyticus, 1 had Klebsiella pneumoniae, and 1 had Citrobacter koseri) and were included in the micro-ITT. Fourteen participants (64%) did not have baseline-identified urinary tract pathogens (Table 3).

[0213]

Table 3

[0214] The MICs of gepotidacin against the eight identified urinary tract pathogens ranged from 0.06 to 4 μg / mL. Two E. coli isolates were multidrug resistant (defined as resistance to three or more antibiotic classes) as they were resistant to ampicillin, trimethoprim-sulfamethoxazole, and ciprofloxacin / levofloxacin or cefazolin. One additional E. coli isolate was ampicillin-resistant. See Table 4.

[0215]

Table 4

[0216] Microbiological responses to identified urinary tract pathogens The cure determination (TOC) and microbiological responses at follow-up visits are shown in Table 5. One microbiological failure (E. coli) at TOC was not due to persistent growth of the urinary tract pathogen, but rather to a non-reportable (lost stability) urine specimen. In the micro-ITT population, growth was observed in only two isolates after treatment, one being an E. coli isolate on Day 3 and one being a Citrobacter koseri isolate at follow-up (Figure 3 shows the quantitative bacterial counts (CFU / mL) by the baseline-identified urinary tract pathogens over time (micro-ITT population)). Among the eight participants in the micro-ITT, seven (88%) and six (75%) were microbiologically successful at TOC and follow-up visits, respectively.

[0217]

Table 5

[0218] Antimicrobial susceptibility of the identified urinary tract pathogens Two other identified Gram-negative urinary tract pathogens (Citrobacter koseri and Klebsiella pneumoniae) were both resistant to ampicillin and susceptible to all other antimicrobial agents tested. One identified coagulase-negative staphylococcal urinary tract pathogen was susceptible to all antibacterial agents tested. None of the recovered baseline urinary tract pathogens were resistant to nitrofurantoin, fosfomycin, piperacillin / tazobactam, or meropenem. No phenotypic ESBL-producing urinary tract pathogens were recovered. There was no evidence of reduced susceptibility to gepotidacin (defined as a ≥4-fold increase in MIC) between the baseline urinary tract pathogens obtained and the same urinary tract pathogens at subsequent visits.

[0219] Steady-state PK was available, and in four participants with identified Enterobacteriaceae urinary tract pathogens who were microbiologically successful at TOC, plasma fAUC24h / MIC ranged from 7 to 90.5, and urine AUC24h / MIC ranged from 1292 to 121,698. The participant with the lowest plasma fAUC / MIC (7) and urine AUC24h / MIC (1292) had Klebsiella pneumoniae with a gepotidacin MIC of 4 μg / mL.

[0220] In addition to the above-identified urinary pathogens, gepotidacin MIC was also determined for two baseline urinary pathogens that were not considered for inclusion in the microbiologically intended treatment population because they were recovered at lower bacterial counts (<10 5 CFU / mL): Acinetobacter pittii (MIC 1 mg / L) and Citrobacter freundii complex (MIC 1 mg / L).

[0221] PK / PD: Steady-state PK was available, and in four participants with identified Enterobacteriaceae urinary pathogens who had microbiological success at TOC, plasma fAUC24h / MIC ranged from 6.99 to 90.5, and urinary AUC24h / MIC ranged from 1292 to 121,698 (Table 6). The participant with the lowest plasma fAUC / MIC (6.99) and urinary AUC24h / MIC (1292) had Klebsiella pneumoniae with a gepotidacin MIC of 4 μg / mL and had microbiological success (Table 6).

[0222]

Table 6

[0223] Conclusion In the micro-ITT population, microbiological success was achieved by 7 out of 8 participants (88%) and 6 out of 8 participants (75%) at TOC and follow-up, respectively. The gepotidacin MIC values ranged from 0.06 to 4 μg / mL for all baseline urinary pathogens recovered. There were no participants in whom urinary pathogens with reduced susceptibility to gepotidacin (i.e., MIC of gepotidacin increased by 4-fold or more) developed after treatment.

[0224] B. Clinical Efficacy and Safety Analysis of the Phase IIa Trial Methods: Continuous blood and urine PK samples were collected at the first dose on Day 1 of the study treatment and at the dose with the time matched on Day 4. Participants took all doses of gepotidacin with food and stayed at the clinic until they completed a total of 10 doses. Participants were instructed to visit the clinic for TOC (Days 10 - 13) and follow-up (Day 28 ± 3).

[0225] Results: Summary of Exploratory Endpoints (ITT Population) Clinical efficacy: All subjects had a significant improvement in clinical symptoms (dysuria, frequency, urgency, lower abdominal pain) within 24 - 48 hours of treatment. Most subjects (20 out of 22; 90.9%) achieved symptom resolution at the time of cure determination (ToC) and follow-up (F / U). Microbiological eradication was achieved independent of baseline CFU.

[0226] Safety evaluation items: Most common AEs were related to the GI tract (diarrhea in 18 out of 22 [82%] and nausea in 17 out of 22 [77%]). Tolerance to nausea was observed with repeated dosing according to the investigator's observation. There were no withdrawals due to AEs. There was no clinically relevant trend in safety labs, ECG, or vital signs.

[0227] Additional information Results For the box plots of individual clinical symptom scores and total scores over time (treatment intention population), see Figure 4. Note: The box represents the 25% - 75% percentiles. Inside the box, the horizontal line is the median and the square dot is the mean. The upper and lower whiskers represent 1.5 × the interquartile range. Hollow circles represent outlier scores of individual participants.

[0228] For the four categories of acute cystitis symptoms consisting of urinary disorders, frequency, urgency, and lower abdominal pain or suprapubic pain, the mean of the total clinical symptom scores at baseline in the ITT population was 7.9 (range: 4 - 12) (in each category, the score range was 0 - 3). Among the 22 participants enrolled in this Phase IIa trial, 19 (86%) and 18 (82%) participants achieved clinically successful clinical responses at the TOC visit and follow-up visit, respectively. At the TOC, symptom resolution (i.e., clinical signs and symptom score 0) was achieved in 19 participants (1 participant withdrew from the study, 1 participant's score was not reported, and 1 participant who did not complete the administration [6 doses] had a score of 2). Symptom resolution at the follow-up was achieved in 20 participants (2 participants withdrew from the study). Lower abdominal pain or suprapubic pain at baseline was the most variable symptom category, with half of the participants reporting low scores of 0 (27%) or 1 (23%), and the other half of the participants reporting high scores of 2 (41%) or 3 (9%). In the other symptom categories, most participants had a score of 2.

[0229]

Table 7

[0230] Participants were housed during the administration period, and the most frequent adverse events were gastrointestinal, and all GI AEs were mild or moderate, onset on day 1, and improved with repeated dosing. Episodes of vomiting were drug-related in 4 participants, mild or moderate, and not considered treatment-limiting. The use of antiemetics was rare and of short duration. The safety profile of gepotidacin was similar to that observed in previous studies, with mainly mild or moderate severity gastrointestinal events reported as the most frequent AEs.

[0231] Conclusion Safety: Overall, gepotidacin was well tolerated over 5 days at a dose of 1500 mg BID without dose-limiting AEs. The most reported AEs were gastrointestinal (e.g., mainly diarrhea and nausea). Tolerance to nausea was observed with repeated dosing according to the investigator's observation. There were no withdrawals or discontinuations of study treatment due to AEs. There were no clinically significant changes in safety test parameters, vital signs, or ECG intervals.

[0232] C. Plasma and Urine Pharmacokinetics Methods: For pharmacokinetic assessment, serial blood and urine samples for assessment of gepotidacin PK concentrations were collected 12 hours (τ) after the morning dose on Day 1 and Day 4. Cτ (trough) concentrations were collected on Days 1 to 5. PK concentrations of gepotidacin in plasma and urine were measured using a validated LC-MS / MS bioanalytical assay.

[0233] Results: Gepotidacin was rapidly absorbed with a median Tmax of 1.50 - 1.92 hours. Steady state was achieved on Day 3, with moderate (1.4-fold) accumulation in plasma after BID dosing, which is consistent with an effective elimination half-life of 6.6 hours. Steady state urine trough levels were high and remained above the minimum inhibitory concentration (MIC) of 4 μg / mL over 12 hours. Approximately 20% of the dose was excreted in urine at 12-hour dosing intervals on Day 1, increasing to 31% on Day 4. Urine AUC(0 - 24) (11,945 μg·hr / mL) was higher than free plasma AUC(0 - 24) (39.4 μg·hr / mL). Slightly higher gepotidacin plasma and urine exposure was observed in uUTI patients compared to Phase I healthy subjects.

[0234] Plasma After repeated oral administration of 1500 mg twice daily, the plasma concentration of gepotidacin rapidly reached a peak at median Tmax of 1.50 and 1.92 hours (on Day 1 and Day 4, respectively), and decreased in a multi-phasic manner. Based on the Cτ (trough) plasma concentration, steady state was achieved on Day 3. A moderate 1.4-fold accumulation of gepotidacin was observed based on AUC, which was consistent with an effective elimination half-life of 6.6 hours. Refer to Figure 5 for the median gepotidacin Cτ plasma concentration per day after BID oral administration of gepotidacin (1500 mg), and refer to Figure 6 for the median gepotidacin plasma concentration-time profile after single and BID oral administration (1500 mg).

[0235]

Table 8

[0236] urine After repeated oral administration of 1500 mg of gepotidacin twice daily, the steady-state urine trough concentration was high and remained above the MIC of 4 μg / mL at a 12-hour dosing interval. Approximately 20% of the gepotidacin dose was excreted in urine at a 12-hour dosing interval on Day 1, increasing to 31% on Day 4. The steady-state urine AUC(0-24) of gepotidacin (11,945 μg·hr / mL) was higher than the free plasma AUC(0-24) (39.3 μg·h / mL) on Day 4.

[0237]

Table 9

[0238] Refer to Figure 7 for the median urine concentration-time profile after single and BID oral administration of gepotidacin (1500 mg).

[0239] PK / PD After repeated oral administration of 1500 mg twice daily, the mean gepotidacin urinary AUC(0-24) / MIC ratio (15,914) was higher than the free plasma AUC(0-24) / MIC ratio (37.0) of gepotidacin in 4 participants who had identified Escherichia coli urinary pathogens at baseline visit.

[0240] Conclusion Steady-state gepotidacin plasma exposure was obtained on Day 3. There was moderate (1.4-fold) accumulation of gepotidacin in plasma after BID dosing. Steady-state urinary gepotidacin exposure (AUC[0-24]) exceeded free plasma exposure by approximately 300-fold. Urine concentrations were also higher than the gepotidacin MIC 90 value (MIC 90 = 4 μg / mL) of common uUTI pathogens such as Escherichia coli. Considering that the bladder is the main site of infection in acute cystitis, this supports the use of gepotidacin for the treatment of UTI as described in the present invention. The efficacy of gepotidacin demonstrated in this Phase IIa trial provides further support.

[0241] [Example 4] Pharmacokinetics-Pharmacodynamics (PK-PD) of Gepotidacin in a Mouse Pyelonephritis and Thigh Infection Model The objective of this study was to characterize the pharmacokinetics-pharmacodynamics (PK-PD) relationship of gepotidacin in neutropenic mouse thigh and pyelonephritis models against 5 isolates of Escherichia coli covering the range of MIC (1-4 μg / mL) in order to support potential dose selection for the urinary tract infection indication.

[0242] Methods: PK and PD studies using gepotidacin were conducted in mouse (male CD-1 mice) thigh and kidney infections. The dosing regimen started 1 hour after infection and ranged from 1-200 mg / kg SC every 6 hours. Infected tissues were evaluated for bacterial burden 24 hours after infection (baseline control was 1 hour after infection).

[0243] Plasma and tissue samples (kidney or thigh homogenate) were collected at 15, 30, 60, 120, 240, and 360 minutes. A population PK (PopPK) model was constructed using NONMEM with plasma exposure.

[0244] Efficacy was determined against Escherichia coli ALL, 997577, ATCC 25922, IR5, and NCTC 13441 (MICs of 1 - 4 μg / mL) in thigh - infected neutropenic (I -) mice and against Escherichia coli ALL in kidney - infected immunocompetent (I +) and I - mice. The PopPK model was used to determine the GEP exposure associated with efficacy. PK - PD analysis was performed using Phoenix WinNonLin 6.3 (Pharsight). The change in log 10 colony - forming units (CFU) from baseline was correlated with free - drug (f) AUC:MIC using an inhibition model from the Phoenix library, and the plasma fAUC:MIC associated with a static state, 1 - or 2 - log 10 reduction in CFU was calculated using the model parameter values for each isolate.

[0245] Results: Plasma PK data best fit a one - compartment IV model with first - order elimination and were similar in I + vs I - and thigh - vs kidney - infected mice.

[0246] The AUC of gepotidacin in the kidney 0~6 was approximately 4 - 5 times higher than that in plasma, while the AUC in the thigh 0~6 was approximately half that of plasma.

[0247] In the thigh model, the median plasma fAUC:MIC ratios for static state, 1 - or 2 - log 10 reduction in CFU were 11, 16, and 25 (ranges of 3 - 17, 4 - 25, and 7 - 40), respectively. Efficacy against Escherichia coli ALL was similar in I - mice with thigh or kidney infection. In I + mice, the PK - PD target was reduced by half.

[0248] Conclusions: Plasma fAUC:MIC target median values were in the range of 11 - 25. Higher drug levels in plasma or from thigh to kidney did not lead to improved efficacy in the pyelonephritis model compared to the thigh infection model.

[0249] Additional information for Example 4 Method Pharmacokinetic study Male CD-1 mice without specific pathogens weighing approximately 27 g were used through PK and PD studies. In most studies, mice were neutropenized with two IP doses of cyclophosphamide on day -4 (150 mg / kg) and day -1 (100 mg / kg). Plasma and tissue samples (kidney and / or thigh) were collected from competent or neutropenic infected mice (N = 3 mice / group) at 15, 30, 60, 120, 240, and 360 minutes after administration following a single subcutaneous (SC) dose of 6.25 - 200 mg / kg. Samples were assayed by LC / MS / MS. The lower limit of quantification was 0.05 μg / mL.

[0250] Pharmacodynamic study PD studies were performed using thigh and / or kidney infection models in neutropenic or competent mice (N = 5 mice / group). Mice were infected with a logarithmic phase bacterial suspension (100 μL in the left thigh muscle or 50 μL in each of both kidneys (total 100 μl)). The final inoculum for all isolates was 6.0 - 7.0 log 10 CFU / mouse. Dose range studies were performed with 5 isolates (see Table 1). Starting 1 hour after infection, GEP was given SC at 1 - 200 mg / kg in separate doses (total 4 doses) every 6 hours (q6) over 24 hours (0.2 mL / mouse). Mice were euthanized 24 hours after the start of treatment (6 hours after the final dose), and the infected thigh or kidney was processed to determine the viable bacterial count (CFU). Baseline CFU was obtained from untreated mice 1 hour after infection, and growth control CFU was obtained from saline-treated mice at 24 hours.

[0251] Data analysis: Non-compartmental analysis (NCA): Plasma NCA was performed using Phoenix WinNonLin 6.3 (Pharsight) with the linear up log down method.

[0252] Population pharmacokinetics (PopPK): · The total plasma drug concentration was converted to free drug values based on 24% protein binding in mice. · A PopPK model was constructed to describe plasma drug exposure over time using NONMEM (7.3) and software R (version 3.4.0) for diagnostic plots. · The final model was used to simulate exposure at multiple dose levels evaluated in the efficacy study.

[0253] The NCA analysis was performed on simulated data. Next, PK / PD parameters were calculated for drug exposure over 24 hours. The free drug area under the curve relative to MIC (fAUC / MIC), the time the free drug concentration was maintained above the MIC value (fT>MIC), and the free drug Cmax value relative to MIC (fCmax / MIC) were obtained.

[0254] The PK-PD analysis was performed using Phoenix WinNonLin 6.3 (Pharsight). · Log 10 Colony-forming units (CFUs) were correlated with PK-PD parameters using several inhibition models from the Phoenix library. · Using the model parameter values for each isolate, PK-PD parameter values related to stasis, 1-log, or 2-log reduction from the baseline 1-hour control were calculated.

[0255] Results The gepotidacin concentration was higher in the kidney than in plasma or thigh homogenate (see Figure 8 for plasma, kidney, and thigh concentrations vs. time profile). AUC and Cmax were approximately dose-proportional. There was no significant difference in PK between neutropenic animals and immunocompetent animals. The PopPK model that best described the properties of gepotidacin in plasma was a one-compartment intravenous absorption model with first-order elimination using a combined error model. The final parameter estimates were a clearance of 0.104 L / h, a volume of distribution of 0.151 L, and an infusion time of 0.262 h (parameter values were in accordance with NCA), a proportional error of 41%, and an additive error of 14.6 μg / mL. Diagnostic plots (Figure 9: dependent variable vs. prediction, and conditional weighted residuals vs. time and prediction) indicated the validity of the developed model.

[0256] The inhibitory effect S-shaped Imax model represented the optimal results in the PK-PD analysis.

[0257]

Number

[0258] Consistent with previous results from in vitro and in vivo PK / PD studies, fAUC / MIC was well correlated with the efficacy of gepotidacin when the data for all isolates were pooled together (Figure 10). Tables 10 and 11 show the fAUC / MIC in plasma associated with a static state, 1-log, or 2-log reduction from baseline over the study.

[0259]

Table 10

[0260]

Table 11

[0261] Conclusion The median fAUC / MIC target was 11, 16, and 25 for the static state, 1-log, and 2-log decreases, respectively. The fAUC / MIC target was very similar between thigh and kidney infections. The fAUC / MIC target was reduced by approximately half in non-neutropenic mice. Higher drug levels in renal homogenates than in plasma or thigh did not lead to improved efficacy in the pyelonephritis model compared to the thigh infection model.

[0262] [Example 5] In vitro assay against aerobic organisms Method 1 Gepotidacin was tested against 101 coagulase-negative staphylococci and 105 Streptococcus viridans by serial two-fold dilution, and the minimum inhibitory concentration (MIC) was determined as the lowest concentration of the compound that inhibited visible growth.

[0263] All clinical isolates were collected from patient infections at medical centers in North America, Europe, Latin America, and the Asia-Pacific from 2009 to 2012, mainly from patients with records of nosocomial and community-acquired respiratory infections, bloodstream infections, and skin and skin tissue infections.

[0264] Ceftriaxone, meropenem, penicillin, levofloxacin, moxifloxacin, and linezolid were included as comparative drugs when testing isolates of Streptococcus viridans. Oxacillin, levofloxacin, moxifloxacin, and linezolid were included as comparative drugs when testing isolates of coagulase-negative staphylococci. MIC was determined by the microbroth dilution method according to the CLSI method.

[0265] The MIC90 of gepotidacin against test isolates of all coagulase-negative staphylococci (including Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, and Staphylococcus warneri), as well as viridans group streptococci (including Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, and Streptococcus vestibularis) was 0.5 μg / mL. This MIC90 was at least 2- to 64-fold lower than the comparator drugs tested, except for meropenem and moxifloxacin (both with MIC90 of 0.25 μg / mL) against viridans group streptococci.

[0266] In addition, the MIC value of gepotidacin against Morganella was 4 mg / L and against Providencia rettgeri was 8 mg / L, each for at least one test isolate.

[0267] A second study tested gepotidacin by the CLSI microbroth dilution method against bacterial isolates recovered from patients with acute bacterial skin and soft tissue infections during 2013-2014.

[0268] The MIC90 of gepotidacin against 13 S. epidermidis, 10 S. anginosus, and 19 viridans group streptococci tested was 0.25, 1, and 0.5 μg / mL, respectively.

[0269] Amoxicillin / clavulanic acid, linezolid, fusidic acid, ceftriaxone, ceftaroline, vancomycin, penicillin, quinupristin / dalfopristin, erythromycin, clindamycin, meropenem, tetracycline, chloramphenicol, fulcloxacillin, telavancin, daptomycin, trimethoprim / sulfamethoxazole, gentamicin, levofloxacin, tigecycline, and cefuroxime were included as comparator drugs. The MIC was determined by the microbroth dilution method according to the CLSI method.

[0270] In addition, the MIC was determined by the microbroth dilution method according to the CLSI method, and all comparator drugs from the above listing were evaluated against Gram-positive aerobic organisms selected from Staphylococcus lugdunensis, Streptococcus agalactiae, Group G streptococci, and Group F streptococci.

[0271] Gepotidacin had an MIC of ≤2 μg / mL against at least one strain of all the organisms listed above.

[0272] Method 2 The compound was tested in serial two-fold dilutions and the minimum inhibitory concentration (MIC) was determined as the lowest concentration of the compound that inhibited visible growth.

[0273] Specifically, gepotidacin was tested against four strains of Staphylococcus epidermidis from the isolate collection of Laboratory Specialists, Inc., Westlake, Ohio.

[0274] Levofloxacin was included as a comparator drug in the study to determine the effect of urine on the in vitro activity of gepotidacin against Staphylococcus epidermidis. The MIC was determined by the microbroth dilution method according to the CLSI method.

[0275] The minimum inhibitory concentration (MIC) of gepotidacin against two isolates of methicillin-sensitive Staphylococcus epidermidis was 0.5 μg / mL, and the MIC range against two isolates of methicillin-resistant Staphylococcus epidermidis was 0.25 - 0.5 μg / mL. The MIC value of gepotidacin was two-fold greater than the levofloxacin MIC in methicillin-sensitive Staphylococcus epidermidis and four-fold greater than the levofloxacin MIC in each of the methicillin-resistant Staphylococcus epidermidis.

[0276] At least one exemplary salt of gepotidacin was tested (i.e., mesylate, for example).

[0277] Gepotidacin had an MIC of ≤ 0.5 μg / mL against at least one strain of methicillin-sensitive or methicillin-resistant Staphylococcus epidermidis.

[0278] The data shown in the table below are the results of an in vitro study performed on the same isolates of Staphylococcus epidermidis described above to determine the effect of urine on the in vitro activity of gepotidacin and levofloxacin against Staphylococcus epidermidis. The study strains were tested for MIC according to the reference CLSI microbroth dilution method using cation-adjusted Mueller-Hinton broth (CAMHB) and adding 25%, 50%, and 100% urine (unadjusted pH, pH 6.42), and 100% urine (adjusted pH, 7.31 and 8.07). The results of the MIC of gepotidacin (mean dilution difference) were not significantly affected by the addition of urine (mean dilution difference was 0 - 1.01). The results of the MIC of levofloxacin were more affected by 100% stored urine at pH 8.07, with a mean dilution difference of approximately 1.8.

[0279]

Table 12

[0280] In conclusion, these tests demonstrated the in vitro activity of gepotidacin against test isolates of methicillin-sensitive and methicillin-resistant Staphylococcus epidermidis with MIC ≤ 0.5 μg / mL, and demonstrated no significant change in MIC in 100% urine (average dilution difference of 0 - 0.26). The fact that gepotidacin activity is not significantly affected by urine makes gepotidacin a suitable treatment option for UTI.

[0281] [Example 6] In vitro assay against anaerobic organisms Tests were conducted to evaluate the in vitro activity of gepotidacin and specific comparator drug compounds identified in the following methods.

[0282] Method 1 Antimicrobial activity was determined by agar dilution method using Clinical and Laboratory Standards Institute (CLSI) recommended procedures.

[0283] Compounds were tested in serial two-fold dilutions and the minimum inhibitory concentration (MIC) was determined as the lowest concentration of the compound that inhibited visible growth. Gepotidacin was tested against 333 gram-negative anaerobic isolates and 203 gram-positive anaerobic isolates collected from clinical samples in North America and Europe from 2000 - 2017 (most collected from 2013 - 2016).

[0284] Ceftriaxone, clindamycin, imipenem, metronidazole, moxifloxacin and piperacillin / tazobactam were included as comparators.

[0285] The MIC90 of gepotidacin (MIC that inhibits 90% of the isolates tested) was ≤ 4 μg / mL against the gram-negative and gram-positive anaerobic bacteria tested and is shown in the following table.

[0286] [Table 13]

[0287]

Table 14

[0288] When all Gram-negative anaerobic organisms were combined, the gepotidacin MIC90 was 4 μg / mL. This MIC90 value was lower than those of ceftriaxone, clindamycin, moxifloxacin, and piperacillin / tazobactam (overall MIC90 values were 512, >8, 8, and 16 μg / mL, respectively), and higher than those of imipenem and metronidazole (overall MIC90 values were 0.5 and 2 μg / mL, respectively).

[0289] When Gram-positive anaerobic organisms were combined, the gepotidacin MIC90 was 2 μg / mL. Based on the MIC90, gepotidacin showed increased activity against Gram-positive anaerobic organisms compared to ceftriaxone (256 μg / mL), clindamycin (>8 μg / mL), imipenem (8 μg / mL), moxifloxacin (>8 μg / mL), and piperacillin-tazobactam (16 μg / mL), and decreased activity compared to metronidazole (0.5 μg / mL).

[0290] A second study tested gepotidacin by the CLSI agar dilution method against isolates of Gram-positive and Gram-negative anaerobic bacteria from the GlaxoSmithKline Upper Providence culture collection.

[0291] The MICs of gepotidacin against 10 Bacteroides species, 3 Fusobacterium species, 1 Prevotella species, 1 Clostridium bifermentans, and 4 Peptostreptococcus species tested were 0.0.12 - 16, 0.12 - 1, 4, 0.06, and 0.12 - 2 μg / mL, respectively.

[0292] Amoxicillin, azithromycin, levofloxacin, and cefuroxime were included as comparator drugs.

[0293] Conclusion of Method 1 These studies have demonstrated the in vitro activity of gepotidacin against Gram-negative anaerobic organisms (MIC90 = 4 μg / mL) and Gram-positive anaerobic organisms (MIC90 = 2 μg / mL) (MIC ≤ 2 μg / mL against at least 1 strain of all organisms listed).

[0294] Additional data from Method 1 Additional analyses were performed from the results of the studies described in Method 1 above to determine the in vitro activity of gepotidacin against Gram-negative and Gram-positive anaerobic organisms with resistance to ceftriaxone, clindamycin, imipenem, metronidazole, moxifloxacin, and piperacillin / tazobactam.

[0295] Table 15 shows the MIC ranges for drug-resistant Bacteroides species when tested by the agar dilution method. Since the number of isolates was low (n < 10) for most drug-resistant subsets, MIC 50 / MIC 90 was not calculated.

[0296]

Table 15

[0297] Table 16 shows the MIC ranges for drug-resistant Bacteroides species when tested by the microbroth dilution method. Since the number of isolates was low (n < 10) for most drug-resistant subsets, MIC 50 / MIC 90 was not calculated.

[0298]

Table 16

[0299] Table 17 shows the MIC ranges for drug-resistant Gram-negative anaerobic bacteria (other than Bacteroides species) when tested by the agar dilution method. Since the number of isolates was low (n < 10) for all drug-resistant subsets, MIC 50 / MIC 90was not calculated.

[0300]

Table 17

[0301] Table 18 shows the MIC ranges against drug-resistant Gram-positive anaerobic bacteria when tested by the agar dilution method. Since the number of isolates was small (n < 10) for most of the drug-resistant subsets, MIC 50 / MIC 90 was not calculated.

[0302]

Table 18

[0303] Conclusions for additional data from Method 1 This study demonstrates the in vitro activity of gepotidacin against drug-resistant Gram-negative and Gram-positive anaerobic organisms with an MIC of ≤ 4 μg / mL against at least one strain of all the drug-resistant phenotypes listed in the above table, except for one isolate of Bacteroides caccae that had an MIC = 8 mg / L when tested by the agar dilution method.

[0304] [Example 7] In vitro assay against Gram-negative aerobic organisms Gepotidacin was tested at serial two-fold dilutions against the following organisms obtained from UTI patients. The minimum inhibitory concentration (MIC) was determined by the microbroth dilution method according to the CLSI method. For Acidovorax temperans (n = 1), the MIC of gepotidacin was 1 μg / mL. For Citrobacter amalonaticus (n = 1), the MIC of gepotidacin was 2 μg / mL. For Providencia stuartii (n = 1), the MIC of gepotidacin was 32 μg / mL. For Peptidiphaga spp. (n = 4), the MIC of gepotidacin was 8 or 16 μg / mL.

[0305] It should be understood that the present invention is not limited to the embodiments or forms exemplified above in this specification, and that rights are held for all modifications within the exemplified embodiments or forms and the following claims.

[0306] The various references to academic journals, patents and other publications cited in this specification, including the state of the art, are hereby incorporated by reference as if fully set forth.

Claims

1. 1. A method of treating a urinary tract infection (UTI), comprising administering a therapeutically effective amount of gepotidacin or a pharma- ceutical acceptable salt thereof to a human in need thereof, wherein the UTI is Saprophytic Staphylococcus;Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter piti, Citrobacter freundii complex, Citrobacter koseri, Haemophilus parainfluenzae, Haemophilus paraphloophilus, Klebsiella oxytoca, Klebsiella variicola, Leclercsia adecarboxylata, Proteus hauseli, Proteus pennelli, Serratia marcescens, Shigella boydii, Shigella flexneri, Salmonella sonnei, Salmonella morganii, Providencia rettgeri, Drug-resistant Klebsiella pneumoniae, Drug-resistant Escherichia coli, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, Salmonella putida; Staphylococcus lugdunensis, Streptococcus agalactiae, Group F streptococci, Group G streptococci, Staphylococcus capitis, Staphylococcus capra, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus congenita stellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus bestibularis; Bilophila wadsworthia, Stellera wadsworthensis, Clostridium bifermentans, Clostridium difficile, Egassella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides starcoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somera E, Prevotella bivia, Prevotella bucca, Prevotella denticola, Prevotella diciens, Prevotella melaninogenica, Veillonella alcalescens disper, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium denticola, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus inellus, Lactobacillus jensenii, Lactobacillus plantarum and Lactobacillus rhamnosus. The method of claim 1, wherein the infection is caused by one or more bacteria selected from the group consisting of:

2. 2. The method of claim 1, wherein prior to administration of gepotidacin or a pharma- ceutically acceptable salt thereof, the UTI is determined to be caused by one or more of the bacteria listed in claim 1.

3. 1. A method of treating a urinary tract infection (UTI) in a human, comprising: a) a sample from a human suspected of having a UTI, Saprophytic Staphylococcus;Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter piti, Citrobacter freundii complex, Citrobacter koseri, Haemophilus parainfluenzae, Haemophilus paraphloophilus, Klebsiella oxytoca, Klebsiella variicola, Leclercsia adecarboxylata, Proteus hauseli, Proteus pennelli, Serratia marcescens, Shigella boydii, Shigella flexneri, Salmonella sonnei, Salmonella morganii, Providencia rettgeri, Drug-resistant Klebsiella pneumoniae, Drug-resistant Escherichia coli, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, Salmonella putida; Staphylococcus lugdunensis, Streptococcus agalactiae, Group F streptococci, Group G streptococci, Staphylococcus capitis, Staphylococcus capra, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus congenita stellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus bestibularis; Bilophila wadsworthia, Stellera wadsworthensis, Clostridium bifermentans, Clostridium difficile, Egassella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides starcoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somera E, Prevotella bivia, Prevotella bucca, Prevotella denticola, Prevotella diciens, Prevotella melaninogenica, Veillonella alcalescens disper, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium denticola, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus inellus, Lactobacillus jensenii, Lactobacillus plantarum and Lactobacillus rhamnosus. determining whether the sample contains one or more bacteria selected from the group consisting of: b) if one or more bacteria are identified in the sample of step (a) and determined to be the cause of the UTI, administering a therapeutically effective amount of gepotidacin or a pharma- ceutical acceptable salt thereof to the human. The method includes:

4. 4. The method according to any one of claims 1 to 3, wherein the UTI is an uncomplicated UTI.

5. 4. The method according to any one of claims 1 to 3, wherein the UTI is a recurrent uncomplicated UTI.

6. 4. The method according to any one of claims 1 to 3, wherein the UTI is complicated UTI.

7. 7. The method of any one of claims 1 to 6, wherein the human is a female.

8. 7. The method of any one of claims 1 to 6, wherein the human is a male.

9. 9. The method of any one of claims 1 to 8, wherein the human is a pregnant woman, an adolescent or a child.

10. A method for treating uncomplicated UTI, comprising the step of administering a therapeutically effective amount of gepotidacin or a pharma- ceutically acceptable salt thereof to a human in need thereof, wherein the uncomplicated UTI is caused by one or more bacteria selected from Staphylococcus saproliferative, drug-resistant Staphylococcus saproliferative, Proteus hauseli, Proteus pennellii, drug-resistant Klebsiella pneumoniae, and drug-resistant Escherichia coli.

11. The method according to claim 10, wherein, prior to administration of gepotidacin or a pharma- ceutically acceptable salt thereof, one or more bacteria selected from Staphylococcus saproliferative, drug-resistant Staphylococcus saproliferative, Proteus hauseli, Proteus pennellii, drug-resistant Klebsiella pneumoniae, and drug-resistant Escherichia coli are determined to be the cause of the uncomplicated UTI.

12. 1. Gepotidacin or a pharma- ceutical acceptable salt thereof for use in the treatment of UTI, the UTI being Saprophytic Staphylococcus;Acinetobacter baumannii, Acinetobacter baumannii anitratus, Acinetobacter piti, Citrobacter freundii complex, Citrobacter koseri, Haemophilus parainfluenzae, Haemophilus paraphloophilus, Klebsiella oxytoca, Klebsiella variicola, Leclercsia adecarboxylata, Proteus hauseli, Proteus pennelli, Serratia marcescens, Shigella boydii, Shigella flexneri, Salmonella sonnei, Salmonella morganii, Providencia rettgeri, Drug-resistant Klebsiella pneumoniae, Drug-resistant Escherichia coli, Acidovorax temperans, Citrobacter amalonaticus, Providencia stuartii, Salmonella putida; Staphylococcus lugdunensis, Streptococcus agalactiae, Group F streptococci, Group G streptococci, Staphylococcus capitis, Staphylococcus capra, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus anginosus, Streptococcus australis, Streptococcus congenita stellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus bestibularis; Bilophila wadsworthia, Stellera wadsworthensis, Clostridium bifermentans, Clostridium difficile, Egassella lenta, Peptostreptococcus anaerobius, Peptostreptococcus anaerobius, Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides starcoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas levii, Porphyromonas somera E, Prevotella bivia, Prevotella bucca, Prevotella denticola, Prevotella diciens, Prevotella melaninogenica, Veillonella alcalescens disper, Veillonella parvula, Bifidobacterium adolescentis, Bifidobacterium breve, Bifidobacterium denticola, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Collinsella (Eubacterium) aerofaciens, Eubacterium limosum, Eubacterium nodatum, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus inellus, Lactobacillus jensenii, Lactobacillus plantarum and Lactobacillus rhamnosus. Gepotidacin or a pharma- ceutically acceptable salt thereof, which is caused by one or more bacteria selected from the group consisting of:

13. 13. The method of claim 12, wherein the UTI is uncomplicated UTI.

14. 13. The method of claim 12, wherein the UTI is recurrent uncomplicated UTI.

15. 13. The method of claim 12, wherein the UTI is complicated UTI.

16. 16. Gepotidacin or a pharma- ceutically acceptable salt thereof according to any one of claims 12 to 15, wherein the human is a female.

17. 16. Gepotidacin or a pharma- ceutically acceptable salt thereof according to any one of claims 12 to 15, wherein the human is a male.

18. 18. Gepotidacin or a pharma- ceutically acceptable salt thereof according to any one of claims 12 to 17, wherein the human is a pregnant woman, an adolescent or a child.

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