Gepotidacin and vancomycin for use in the treatment of infections caused by Staphylococcus saprophyticus

Abstract

The present invention relates to a method for treating bacterial infections caused by Staphylococcus saprophyticus, comprising administering gepotidacin or a pharma- ceutically acceptable salt thereof and vancomycin or a pharma-ceutically acceptable salt thereof to a human in need thereof. Novel combination pharmaceuticals, compositions, resistance-guided therapies and / or corresponding uses thereof are also disclosed.

Description

[Technical field]

[0001] STATEMENT REGARDING FEDERALLY FUNDED RESEARCH This invention was made with Government support under the Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, U.S. Department of Health and Human Services, within Contract No. HHSO100201300011C. The Government has certain rights in this invention.

[0002] FIELD OF THEINVENTION The present invention relates to a method of treatment, a pharmaceutical combination or composition, a combination or resistance-guided therapy and / or their corresponding uses for treating bacterial infections caused by Staphylococcus saprophyticus comprising the administration of gepotidacin or a pharma- ceutical acceptable salt thereof and vancomycin or a pharma- ceutical acceptable salt thereof. [Background technology]

[0003] Misuse and overuse of antibiotics has led to worrying levels of overall resistance rates across diseases, resulting in a global call to action. Infections caused by multidrug-resistant organisms pose a major public health burden, not only in terms of morbidity and mortality, but also in terms of increased expenditure on patient management and implementation of infection control measures. The problem of antimicrobial resistance is complicated by the existence of bacterial strains that are resistant to multiple antimicrobial agents.

[0004] Antibiotics are routinely used to treat urinary tract infections (UTIs), which are very common, with approximately 11% of women over the age of 18 experiencing at least one episode per year. Of these, half will experience more than one recurrent episode over their lifetime. UTIs are caused by a variety of uropathogenic bacteria, including Staphylococcus saprophyticus, which is estimated to be the causative agent in 5% to 15% of community-acquired UTIs.

[0005] Vancomycin is a glycopeptide antibiotic with activity against aerobic and anaerobic Gram-positive bacteria. Vancomycin is often used in patients with UTIs caused by Gram-positive bacterial infections. However, bacterial resistance to vancomycin, especially by enterococci, has increased in recent years, presenting a serious medical and public health risk.

[0006] So far, various antibacterial drugs have been developed, which have become clinically very important antimicrobial drugs. Researchers at GlaxoSmithKline described a novel class of antibacterial agents targeting type IIA topoisomerase [see Nature, Vol. 466, pp. 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], which showed activity against a wide range of Gram-positive and Gram-negative bacteria. WO 2008 / 128942 and U.S. Patent No. 8,389,524, which are incorporated herein by reference in their entirety, disclose tricyclic nitrogen-containing compounds, pharmaceutical compositions and their corresponding uses as antibacterial compounds. Summary of the Invention [Problem to be solved by the invention]

[0007] There is a need for the development of novel combination pharmaceuticals or compositions containing combinations of antibiotics or antimicrobial agents with different mechanisms of action, resistance-guided therapies and / or their uses for treating bacterial infections that demonstrate synergistic and bactericidal effects leading to less resistance development. However, any combination of agents should not have antagonistic interactions.

[0008] The present invention is directed to overcoming these and other problems encountered in the art. [Means for solving the problem]

[0009] It has now been unexpectedly found that gepotidacin is synergistically effective against Staphylococcus saprophyticus when acting together with the antibiotic vancomycin, without any negative interactions.

[0010] Thus, the present invention provides a method for treating an infection caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to the human a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, together with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof.

[0011] The present invention also provides vancomycin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of infections in humans caused by Staphylococcus saprophyticus, by co-administration with gepotidacin, or a pharma- ceutically acceptable salt thereof.

[0012] The present invention also provides gepotidacin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of infections in humans caused by Staphylococcus saprophyticus, by co-administration with vancomycin, or a pharma- ceutically acceptable salt thereof.

[0013] The present invention also provides the use of gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection in humans caused by Staphylococcus saprophyticus.

[0014] The present invention also provides the use of vancomycin, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection in a human caused by Staphylococcus saprophyticus, by co-administration with gepotidacin, or a pharma- ceutical acceptable salt thereof.

[0015] The present invention also provides the use of gepotidacin, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection in a human caused by Staphylococcus saprophyticus, by co-administration with vancomycin, or a pharma- ceutical acceptable salt thereof.

[0016] The present invention also provides a kit comprising gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of infection in humans caused by Staphylococcus saprophyticus.

[0017] The present invention also provides a combination drug comprising gepotidacin or a pharma- ceutically acceptable salt thereof and vancomycin or a pharma- ceutically acceptable salt thereof.

[0018] The present invention also provides a pharmaceutical composition comprising gepotidacin or a pharma- ceutically acceptable salt thereof, vancomycin or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0019] Figures 1-5 show the bactericidal time-kill curves for each of the five isolates of Staphylococcus saprophyticus tested in the Examples herein. In each figure, A shows the kill curves for 1 / 4x MIC gepotidacin and 1 / 2x MIC vancomycin, and B shows the kill curves for 1x MIC gepotidacin and 1x MIC vancomycin. [Brief description of the drawings]

[0020] [Figure 1] Figure 1 shows the killing time-kill curves for Staphylococcus saprophyticus 1106006 (WT). Figure 1A shows the killing curves at 1 / 4x MIC gepotidacin and 1 / 2x MIC vancomycin. Figure 1B shows the killing curves at 1x MIC gepotidacin and 1x MIC vancomycin. [Diagram 2] Figure 2 shows the killing time-kill curves for Staphylococcus saprophyticus 1113726 (WT). Figure 2A shows the killing curves at 1 / 4x MIC gepotidacin and 1 / 2x MIC vancomycin. Figure 2B shows the killing curves at 1x MIC gepotidacin and 1x MIC vancomycin. [Diagram 3] Figure 3 shows the killing time-kill curves for Staphylococcus saprophyticus 1115244 (WT). Figure 3A shows the killing curves at 1 / 4x MIC gepotidacin and 1 / 2x MIC vancomycin. Figure 3B shows the killing curves at 1x MIC gepotidacin and 1x MIC vancomycin. [Figure 4] Figure 4 shows the killing time-kill curves for Staphylococcus saprophyticus 1125669 (WT). Figure 4A shows the killing curves at 1 / 4x MIC gepotidacin and 1 / 2x MIC vancomycin. Figure 4B shows the killing curves at 1x MIC gepotidacin and 1x MIC vancomycin. [Diagram 5] Figure 5 shows the killing time-kill curves for Staphylococcus saprophyticus 1129086 (WT). Figure 5A shows the killing curves at 1 / 4x MIC gepotidacin and 1 / 2x MIC vancomycin. Figure 5B shows the killing curves at 1x MIC gepotidacin and 1x MIC vancomycin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The terms "antimicrobial," "antibiotic," and "antimicrobial agent" refer to any natural or synthetic compound that kills or inhibits the growth of microorganisms.

[0022] Antibiotic resistance occurs when bacteria change in response to antibiotic use, making the antibiotic less effective.

[0023] As would be understood by one of skill in the art, the term "vancomycin," as used herein, encompasses all forms of vancomycin, including vancomycin hydrochloride.

[0024] Gepotidacin is a novel triazaacenaphthylene antibiotic, the first of its class, with the ability to selectively inhibit bacterial DNA replication by means not utilized by any currently approved human therapeutics, thus providing an opportunity to address an unmet medical need. Gepotidacin and its racemic form are disclosed in WO 2008 / 128942, which is incorporated herein in its entirety. 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-triazaacenaphthylene-3,8-dione.

[0025] [ka]

[0026] The methods and combinations of the present invention are based on the combination of gepotidacin or its pharma- ceutically acceptable salt and vancomycin or its pharma- ceutically acceptable salt. Combination therapy is a treatment in which two or more drugs (or other therapeutic agents) are administered to a patient for a single disease or when multiple diseases or pathogens are suspected or known to be present. Combination antibiotic therapy is used in patients due to the widespread emergence of multidrug-resistant (MDR) organisms. Multidrug resistance can be defined as the lack of susceptibility to at least one agent in three or more antibiotic classes. Antimicrobial or antibacterial agents are frequently used in combination, so inhibitor interactions between the agents are undesirable.

[0027] Combination therapy may have the advantage of broadening the antibacterial spectrum, providing synergistic effects, and preventing the emergence of resistance.

[0028] The studies in this application demonstrate a synergistic effect of combining gepotidacin and vancomycin against Staphylococcus saprophyticus.

[0029] Thus, in a first aspect, the present invention provides a method for treating an infection caused by Staphylococcus saprophyticus in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, together with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof.

[0030] As used herein, a "therapeutically effective amount" means a nontoxic but sufficient amount of active ingredient to provide the desired effect.

[0031] As used herein, "caused by Staphylococcus saprophyticus" can mean that Staphylococcus saprophyticus has been identified as causing or being part of the cause of the infection (i.e., associated with the infection) or it can mean that Staphylococcus saprophyticus is suspected or strongly suspected to be causing or being part of the cause of the infection based on identification of symptoms and other factors such as patient history or local epidemiology.

[0032] In any of the aspects of the invention, in one embodiment, the infection is a urinary tract infection (UTI). A urinary tract infection is an infection of the bladder (also known as "cystitis"). In one embodiment, the infection is an uncomplicated urinary tract infection (uUTI), which is defined in the "Guidelines on Urological Infections" (European Urological Society), https: / / uroweb.org / guideline / urological-infections, as "an acute, sporadic or recurrent lower (uncomplicated cystitis) and / or upper (uncomplicated pyelonephritis) UTI restricted to non-pregnant women with no known associated anatomical and functional abnormalities or comorbidities in the urinary tract." Symptoms of uUTI may occur suddenly and may include: frequent and strong urgency to urinate even after emptying the bladder; dysuria, pain or burning sensation when urinating; foul-smelling or strong-smelling urine; cloudy urine; pressure, fullness of the bladder, or cramps in the lower abdomen or middle of the back; low-grade fever; chills; and / or the presence of blood in the urine. uUTI is generally seen in otherwise healthy subjects, mostly women, who have no associated structural or functional abnormalities in the urinary tract, kidney disease, or comorbidities that may lead to more severe outcomes and require further attention.

[0033] In one embodiment, the present invention provides a method for treating UTI in a human in need thereof, comprising administering to the human a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, together with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof.

[0034] In one embodiment, the present invention provides a method for treating a UTI caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to the human a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, together with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof.

[0035] In any embodiment of the invention, gepotidacin or a pharma- ceutically acceptable salt thereof and vancomycin or a pharma- ceutically acceptable salt thereof may be administered in separate or combined pharmaceutical formulations by any convenient route, either sequentially (i.e., sequential administration), concurrently (i.e., co-administration), or simultaneously (i.e., simultaneous administration).

[0036] In one embodiment, gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma- ceutically acceptable salt thereof, are administered sequentially.

[0037] Vancomycin administration may conform to recommended treatment guidelines.

[0038] Thus, for example, vancomycin or a pharma- ceutically acceptable salt thereof (such as vancomycin HCl) may be administered orally at 125 mg every 6 hours for 10 days, or 500 mg every 6 hours for 10 days.

[0039] Given the synergistic effects of vancomycin and gepotidacin demonstrated in the present application, the length of time for vancomycin administration may be reduced from 10 days to, for example, 1, 2, 3, 4, 5, 6, 7, 8 or 9 days.

[0040] In one embodiment, for any aspect of the invention, a human is administered gepotidacin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In one embodiment, for any aspect of the invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered at 1500 mg (measured as the free base), bid (total daily dose of 3000 mg measured as the free base) for 5 days. In another embodiment, for any aspect of the invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered once at 3000 mg. In another embodiment, for any aspect of the invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3000 mg each (measured as the free base), 6-12 or 10-12 hours apart.

[0041] In another aspect, the present invention provides a method for the treatment of an infection caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to the human a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof, followed by a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof.

[0042] In one embodiment, the human is administered vancomycin or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, followed by gepotidacin or a pharma- ceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In one embodiment, the human is administered vancomycin or a pharma- ceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13, or 14 days, followed by gepotidacin or a pharma- ceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0043] In another aspect, the present invention provides a method for the treatment of an infection caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to the human a therapeutically effective amount of gepotidacin or a pharma- ceutical acceptable salt thereof, followed by a therapeutically effective amount of vancomycin or a pharma- ceutical acceptable salt thereof.

[0044] In one embodiment, the human is administered gepotidacin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days followed by vancomycin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In one embodiment, the human is administered gepotidacin or a pharmaceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13, or 14 days followed by vancomycin or a pharmaceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0045] In one embodiment, for any aspect of the invention, the total duration of treatment is no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0046] In another aspect, the present invention provides a method of treating an infection caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to the human a pharmaceutical composition comprising: (a) a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof; and (b) a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof.

[0047] In one aspect, the present invention relates to a combination therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof, to a human being in need thereof.

[0048] In one embodiment, the infection is a UTI, hi another embodiment, the infection is a uUTI.

[0049] In one embodiment, the present invention provides a combination therapy for treating UTI comprising administering a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof, to a human being in need thereof.

[0050] In one embodiment, the present invention provides a combination therapy for treating UTI comprising administering a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof, to a human being in need thereof.

[0051] In one embodiment, the present invention provides a combination therapy for treating UTI caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof, to a human being in need thereof.

[0052] In one embodiment, the present invention provides a combination therapy for treating UTI caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof, to a human being in need thereof.

[0053] Gepotidacin or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition comprising gepotidacin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.Similarly, vancomycin or a pharmaceutically acceptable salt thereof may be present in a corresponding pharmaceutical composition of vancomycin or a pharmaceutically acceptable salt thereof comprising vancomycin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0054] In another aspect, the present invention relates to a combination or resistance-guided therapy for treating bacterial infections caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of vancomycin or a pharma- ceutically acceptable salt thereof to a human in need thereof. Gepotidacin or a pharma- ceutically acceptable salt thereof may be present in a pharmaceutical composition comprising gepotidacin or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient. Similarly, vancomycin or a pharma- ceutically acceptable salt thereof may be present in a corresponding pharmaceutical composition of vancomycin or a pharma- ceutically acceptable salt thereof comprising vancomycin or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient. In one embodiment, the infection is a UTI. In one embodiment, the infection is a uUTI.

[0055] As will be understood by those skilled in the art, as used herein, "resistance guided therapy" refers to a course of treatment whose instructions are guided by knowledge of the phenotypic or genotypic susceptibility of a microorganism to a given antibiotic, as described, for example, in Bradshaw et al., The Journal of Infectious Diseases, Vol. 216, Supplementary Issue 2, July 15, 2017, pp. S412-S419. Detecting Staphylococcus saprophyticus in an infection before or during a treatment course, and then detecting the resistance of Staphylococcus saprophyticus strains to certain antibiotics, has the advantage of potentially reducing the patient's exposure to ineffective antibiotics that may lead to resistance. Identification of Staphylococcus saprophyticus can be performed by any suitable genotypic or phenotypic means, such as by NAAT.

[0056] Thus, in one aspect, the present invention provides a resistance-guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin, or a pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin, or a pharma- ceutical acceptable salt thereof, to a human in need thereof.

[0057] The combination or resistance-guided therapy of the present invention may be achieved by simultaneous, co-administration or sequential administration of the two components.

[0058] In one aspect, the present invention relates to combination or resistance-guided therapies for treating a bacterial infection caused by Staphylococcus saprophyticus, wherein the bacterial infection is a UTI.

[0059] In one aspect, the invention relates to combination or resistance-guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, wherein the UTI is a uUTI.

[0060] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating bacterial infections caused by Staphylococcus saprophyticus, where each component is administered orally.

[0061] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, comprising simultaneous, co-administration or sequential administration of therapeutically effective amounts of gepotidacin or a pharmaceutically acceptable salt thereof and vancomycin or a pharmaceutically acceptable salt thereof to a human in need thereof, wherein the use of vancomycin or a pharmaceutically acceptable salt thereof provides a synergistic effect and / or aids in protecting against the development of resistance to either gepotidacin or a pharmaceutically acceptable salt thereof or vancomycin or a pharmaceutically acceptable salt thereof without interfering with the activity of each.

[0062] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating bacterial infections caused by Staphylococcus saprophyticus, comprising the simultaneous, co-administration or sequential administration of a therapeutically effective amount of a pharmaceutical composition comprising gepotidacin or a pharmaceutically acceptable salt thereof and at least one or more pharmaceutically acceptable excipients, and vancomycin or a pharmaceutically acceptable salt thereof to a human in need thereof, wherein the use of vancomycin or a pharmaceutically acceptable salt thereof provides a synergistic effect and / or helps to protect against the development of resistance to either gepotidacin or a pharmaceutically acceptable salt thereof or vancomycin or a pharmaceutically acceptable salt thereof without interfering with the activity of each.

[0063] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating UTI, comprising administration of therapeutically effective amounts of gepotidacin and vancomycin or a pharma- ceutically acceptable salt thereof to a human in need thereof, wherein the use of vancomycin or a pharma- ceutically acceptable salt thereof provides a synergistic effect and / or helps protect against the development of resistance to either gepotidacin or a pharma- ceutically acceptable salt thereof or vancomycin or a pharma- ceutically acceptable salt thereof without interfering with the activity of each. In one embodiment, the UTI is uUTI.

[0064] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating UTI caused by Staphylococcus saprophyticus, comprising administration of a therapeutically effective amount of gepotidacin and vancomycin or a pharmaceutically acceptable salt thereof to a human in need thereof, wherein the use of vancomycin or a pharmaceutically acceptable salt thereof provides a synergistic effect and / or helps to protect against the development of resistance to either gepotidacin or a pharmaceutically acceptable salt thereof or vancomycin or a pharmaceutically acceptable salt thereof without interfering with the activity of each. In one embodiment, the UTI is uUTI.

[0065] In one aspect, the invention relates to a resistance-guided therapy for treating bacterial infections caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin or a pharma- ceutically acceptable salt thereof to a human in need thereof, and administering vancomycin or a pharma- ceutically acceptable salt thereof to a human in need thereof, wherein the use of vancomycin or a pharma- ceutically acceptable salt thereof provides a synergistic effect and / or helps to protect against the development of resistance to either gepotidacin or a pharma- ceutically acceptable salt thereof or vancomycin or a pharma- ceutically acceptable salt thereof without interfering with the activity of each. In any of the above aspects and embodiments of the invention, in one embodiment, the human is male, and in one embodiment, the human is female.

[0066] In another aspect, the present invention provides vancomycin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of an infection caused by Staphylococcus saprophyticus by co-administration with gepotidacin, or a pharma- ceutically acceptable salt thereof.

[0067] In another aspect, the present invention provides gepotidacin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of infections caused by Staphylococcus saprophyticus by co-administration with vancomycin, or a pharma- ceutically acceptable salt thereof.

[0068] In another aspect, the present invention provides the use of gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection caused by Staphylococcus saprophyticus.

[0069] Thus, in one embodiment, the present invention provides vancomycin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of UTIs caused by Staphylococcus saprophyticus by co-administration with gepotidacin, or a pharma- ceutically acceptable salt thereof.

[0070] In another aspect, the present invention provides gepotidacin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of UTIs caused by Staphylococcus saprophyticus by co-administration with vancomycin, or a pharma- ceutically acceptable salt thereof.

[0071] In another aspect, the present invention provides the use of vancomycin, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection caused by Staphylococcus saprophyticus by co-administration with gepotidacin, or a pharma- ceutical acceptable salt thereof.

[0072] In another aspect, the present invention provides the use of gepotidacin, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection caused by Staphylococcus saprophyticus by co-administration with vancomycin, or a pharma-ceutical acceptable salt thereof.

[0073] Gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma- ceutically acceptable salt thereof, may be administered in separate or combined pharmaceutical formulations, sequentially or simultaneously, by any convenient route.

[0074] In another aspect, the present invention provides a kit comprising gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of an infection caused by Staphylococcus saprophyticus.

[0075] In another aspect, the present invention provides a pharmaceutical combination comprising gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma- ceutically acceptable salt thereof.

[0076] In another aspect, the present invention provides a pharmaceutical composition comprising gepotidacin or a pharma- ceutically acceptable salt thereof, vancomycin or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0077] In another aspect, the present invention provides a pharmaceutical combination of gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma- ceutically acceptable salt thereof.

[0078] In another aspect, the present invention relates to a pharmaceutical combination comprising gepotidacin, or a pharma- ceutical acceptable salt thereof, and vancomycin, or a pharma- ceutical acceptable salt thereof, for use in a combination or resistance-guided therapy as described in the present invention.

[0079] In another aspect, the present invention relates to a pharmaceutical composition comprising gepotidacin or a pharma- ceutical acceptable salt thereof, vancomycin or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use in a combination or resistance-guided therapy as described in the present invention.

[0080] In another aspect, the present invention provides a combination of gepotidacin, or a pharma- ceutically acceptable salt thereof, and vancomycin, or a pharma-ceutically acceptable salt thereof, for use in the treatment of an infection caused by Staphylococcus saprophyticus.

[0081] In another aspect, the present invention provides a pharmaceutical composition comprising gepotidacin, or a pharma- ceutical acceptable salt thereof, and vancomycin, or a pharma- ceutical acceptable salt thereof, for use in the treatment of an infection caused by Staphylococcus saprophyticus.

[0082] In another aspect the present invention relates to the use of a pharmaceutical combination or a pharmaceutical composition as defined in the present invention for the manufacture of a medicament for the treatment of an infection caused by Staphylococcus saprophyticus, such as UTI.

[0083] In another aspect, the invention relates to the use of a pharmaceutical combination or a pharmaceutical composition as described herein for the manufacture of a medicament for treating UTI.

[0084] In another aspect, the invention relates to the use of a pharmaceutical combination or a pharmaceutical composition as described herein for the manufacture of a medicament for treating a UTI caused by Staphylococcus saprophyticus.

[0085] In another aspect, the present invention relates to the use of a pharmaceutical combination or a pharmaceutical composition as described herein for the manufacture of a medicament for treating uUTI caused by Staphylococcus saprophyticus.

[0086] In another aspect, the present invention relates to the use of a pharmaceutical combination or a pharmaceutical composition as defined in the present invention for resistance-guided therapy for the treatment of a bacterial infection caused by Staphylococcus saprophyticus in a human in need thereof.

[0087] In another aspect, the present invention relates to the use of a medicament combination or a pharmaceutical composition as defined in the present invention for combination therapy for the treatment of a bacterial infection caused by Staphylococcus saprophyticus in a human in need thereof.

[0088] In another aspect, the present invention relates to the use as defined in the present invention, wherein the bacterial infection is a UTI, such as a uUTI.

[0089] Compounds used in the present invention WO 2008 / 128942 discloses the preparation of the free base and hydrochloride salt of gepotidacin.

[0090] It will be understood that the phrase "gepotidacin or a pharma- ceutically acceptable salt thereof" is intended to encompass gepotidacin, a pharma- ceutically acceptable salt of gepotidacin, a solvate of gepotidacin, or any pharma- ceutically acceptable combination thereof. Thus, as a non-limiting example used herein for illustrative purposes, "gepotidacin or a pharma- ceutically acceptable salt thereof" may include a pharma- ceutically acceptable salt of gepotidacin that further exists as a solvate.

[0091] It will be understood that the phrase "vancomycin or a pharma- ceutically acceptable salt thereof" is intended to encompass vancomycin, a pharma- ceutically acceptable salt of vancomycin, a solvate of vancomycin, or any pharma- ceutically acceptable combination thereof. Thus, as a non-limiting example used herein for illustrative purposes, "vancomycin or a pharma- ceutically acceptable salt thereof" can include a pharma- ceutically acceptable salt of vancomycin that further exists as a solvate.

[0092] As used herein, vancomycin or gepotidacin (or any pharma- ceutically acceptable salt thereof) may be in any of its physical forms, including non-solid forms, such as liquid or semi-solid forms, solid forms, such as amorphous or crystalline forms, particular polymorphic forms, and solvates, including hydrates.

[0093] Suitable pharma- ceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci (1977) 66, pp. 1-19.

[0094] For both gepotidacin and vancomycin, the desired salt forms may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with 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 acids such as glucuronic acid or galacturonic acid, alpha hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like. Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chloroate, chloroform ... These include the salts of benzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, mandelates, and sulfonates such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and naphthalene-2-sulfonates.

[0095] Pharmaceutically acceptable salts of gepotidacin include acid addition salts, such as those salts with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic acids, such as acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid or tartaric acid. In one embodiment, in any aspect of the invention, the gepotidacin is gepotidacin free base or gepotidacin methanesulfonate (mesylate).

[0096] Pharmaceutically acceptable salts of vancomycin include acid addition salts, such as those salts with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or with organic acids, such as acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, or tartaric acid. In one embodiment, in any aspect of the invention, the vancomycin is vancomycin hydrochloride.

[0097] The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0098] Pharmaceutical Compositions and Formulations Pharmaceutical compositions and formulations acceptable and adapted for use in the methods and / or uses of the present invention are prepared using conventional pharmaceutical compositions, formulations or chemical materials, formulation excipients, preparation means, processes and / or methods and conventional techniques, etc., known in the art.

[0099] In particular, gepotidacin or a pharma- ceutically acceptable salt used in the present invention, by analogy with other antibacterial / antituberculous compounds, may be formulated for administration in any convenient manner for use in human or veterinary medicine.

[0100] The pharmaceutical compositions used in the present invention may be formulated for administration by any route, including those in a form adapted for oral, topical or parenteral use, and may be used in mammals, including humans.

[0101] The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, creams or liquid preparations such as oral or sterile parenteral solutions or suspensions.

[0102] In one embodiment, the gepotidacin or its pharma- ceutically acceptable salt of the present invention is in tablet or capsule form. In one embodiment, it is in tablet form. In one embodiment, the tablet is a 750 mg tablet.

[0103] Vancomycin or a pharma- ceutically acceptable salt thereof may be administered in any suitable form, including oral capsules (such as 125 mg or 250 mg), oral tablets, delayed or extended release oral tablets, delayed or extended release oral capsules, oral suspensions (i.e., dry powder for reconstitution with water), or injectable solutions.

[0104] The tablets and capsules for oral administration in the present invention may be in unit dose presentation form and may contain conventional excipients such as binders, fillers, tableting lubricants, disintegrants or wetting agents.Tablets may be coated according to methods well known in normal pharmaceutical practice.Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as dry products for reconstitution with water or other suitable vehicles before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavorings or colorants.

[0105] Suppositories will contain conventional suppository bases such as cocoa butter or other glycerides.

[0106] For parenteral administration, fluid unit dosage forms are prepared by utilizing the compound and a sterile vehicle, preferably water.The compound can be either suspended or dissolved in the vehicle, depending on the vehicle and concentration used.When preparing liquid, the compound can be dissolved in water for injection, and filter sterilized before filling and sealing suitable vials or ampoules.

[0107] Advantageously, agents such as local anesthetics, preservatives and buffers may be dissolved in the vehicle. To enhance stability, the composition may be frozen after filling into the vial, and the water may be removed under vacuum. The dry lyophilized powder may then be sealed in the vial, and an accompanying vial of water for injection may be provided to reconstitute the liquid before use. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound may 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.

[0108] Moreover, the dosage of the compounds or pharmaceutical compositions used in the present invention to be administered will vary depending on the patient and the mode of administration, and may be any effective amount.

[0109] 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 the particular drug to which it refers to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on factors such as the patient's general health, the patient's age, etc.

[0110] Treatment regimens for administration of the compounds and / or pharmaceutical compositions used in the present invention can also be easily determined by those skilled in the art. The dosage of the compounds and / or pharmaceutical compositions used in the present invention to be administered can vary over a wide range so as to provide an effective amount per unit dose based on the patient's body weight per day to achieve the desired effect.

[0111] The composition may contain from 0.1% by weight, preferably 10% to 60% by weight, of active material, depending on the method of administration. If the composition contains dosage units, each unit will preferably contain 50 to 1000 mg of active ingredient. Unless otherwise noted, the amount of active ingredient (i.e., gepotidacin) refers to the amount of gepotidacin free base.

[0112] The dosage of gepotidacin or a pharma- ceutically acceptable salt used in the present invention for the treatment of adults will preferably range from 100 to 6000 mg per day, or from 100 to 3000 mg per day, for example 1500 mg per day or 3000 mg per day, depending on the route and frequency of administration. Such dosage amounts to about 1.5 to about 100 or 50 mg / kg per day. Suitably, the dosage is from 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, the dosage is 3000 mg twice a day (i.e., 6000 mg per day).

[0113] Any conventional method of administration may be suitable for use in the present invention.

[0114] Depending on the treatment being performed, the compounds and / or compositions of the present invention may be administered orally, intravenously, intraperitoneally, subcutaneously, intramuscularly or topically. Preferably, the compositions are adapted for oral administration. In any of the above aspects of the present invention, in one embodiment, gepotidacin or a pharmaceutically acceptable salt thereof and vancomycin or a pharmaceutically acceptable salt thereof are administered orally.

[0115] Synergy may help reduce the patient's exposure to the first drug (whether vancomycin or gepotidacin) to a few days rather than a long period before switching to or adding other drugs to the treatment regimen. This dual therapy may help protect gepotidacin from the selection and / or spread of resistance and increase the efficacy of both compounds.

[0116] It should be understood that the present invention is not limited to the above exemplified aspects or embodiments, and that the right to the exemplified aspects or embodiments and all modifications that come within the scope of the following claims are reserved.

[0117] Various references to journals, patents and other publications cited herein contain the state of the art and are incorporated herein by reference as if fully set forth. EXAMPLES

[0118] The examples set forth below are illustrative of the present invention and are not intended to limit the scope of the invention in any way.

[0119] The examples herein describe the synergistic, promiscuous and antagonistic interactions between gepotidacin and vancomycin determined using reference in vitro broth microdilution checkerboards. Recent clinical isolates of Enterococcus faecalis and Staphylococcus saprophyticus (five isolates per species) were tested against the checkerboards of gepotidacin in combination with vancomycin. Synergy was observed for gepotidacin and vancomycin against four of the five Staphylococcus saprophyticus isolates. In cases where the observation of synergy was common (>50% of isolates) for a species / drug combination, a time-kill assay was performed. Only gepotidacin and vancomycin met this criterion against S. saprophyticus. This synergistic activity between gepotidacin and vancomycin against S. saprophyticus was confirmed by time-kill at 1× MIC concentrations of the two drugs for all five isolates.

[0120] method Baseline Broth Microdilutions Consensus median baseline MIC values ​​were determined for each isolate and each compound by CLSI M07 (2018) reference broth microdilution (BMD) using cation-adjusted Mueller-Hinton broth (CAMHB) in triplicate. As required by CLSI M100 (2021), quality control (QC) strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus 29213, and Enterococcus faecalis ATCC 29212 were tested concomitantly with the clinical isolates (QC data not shown).

[0121] Checkerboard Panel Broth microdilution panels were prepared according to the methods described in Chapter 5.16 of the Clinical Microbiology Procedure Handbook, 4th ed., 2016. To assess interactions, gepotidacin was tested alone and in combination with other antimicrobial agents using cation-adjusted Mueller-Hinton broth (CAMHB).

[0122] Time-Death Method If synergy was observed in 50% of the isolates within a species via the checkerboard assay (FIC ≤ 0.5), a follow-up time-kill kinetic study was performed for all of the compound combinations. CAMHB was used for the follow-up time-kill kinetic study. Each organism was tested in media containing either compound alone or both (MICs of each compound were 1 / 2x, 1 / 4x and 1x). Samples were taken from the time-kill enrichment tubes at time point 0 (T0), T2, T4, T8 and T24. Samples were serially diluted from 10-fold to 8-fold in tubes with 0.15 mL of 0.85% saline solution. Volumes of 0.1 mL from the original sample and subsequent dilutions were then plated on tryptic soy agar with 5% sheep blood. Plates were incubated at 35°C for 24 hours, after which viable cell counts were quantified for each tube at the indicated time points (T0-T24).

[0123] Data analysis Interpretation of antimicrobial combination interactions for the checkerboard follows that outlined in the Clinical Microbiology Procedures Handbook, 4th Edition (2016). Antimicrobial interaction categorical characterization was defined as synergistic if the fractional inhibitory concentration (FIC) index was 0.5 or less, indifferent if the FIC index was greater than 0.5 and less than 4.0, and antagonistic if the FIC index was greater than 4.0 in the checkerboard assay. Interactions other than synergistic or antagonistic are referred to as indifferent or withheld.

[0124] If the observation of synergy for a species / drug combination was common (>50% of isolates tested for that species), a time-kill assay was performed. To confirm synergy via time-kill, recorded cell counts were entered into an Excel spreadsheet and plotted against time to demonstrate time-kill curve kinetics. As described in the CLSI M26-A instruction manual, bactericidal activity was measured as a 3-log decrease in CFU / mL below the initial inoculum, maintained over 24 hours. 10 Synergy via time-kill assay was defined as a > 2 log reduction between the combination and the most active agent alone at 24 hours. 10 A reduction in the number of organisms surviving in the presence of the combination was defined as a CFU / mL reduction of ≥ 2 log below the initial inoculum. 10 CFU / mL and at least one of the drugs should not affect the growth curve of the tested organism. Promiscuity and antagonism are measured as ±1 log agonist growth compared to the most active agent alone at 24 hours, respectively. 10 ~<2log 10 Killing and >1 log compared to less active single agents 10 was defined as proliferation.

[0125] result Activity against Enterococcus faecalis No cases of synergy or antagonism were observed for gepotidacin and vancomycin tested against Enterococcus faecalis isolates (Table 1 ).

[0126] Activity against Staphylococcus saprophyticus Gepotidacin demonstrated synergy with vancomycin for four of the five isolates. The four isolates that showed synergy in the checkerboard assay had ΣFICmin values ​​ranging from >0.25 to 0.31 (Table 1).

[0127] [Table 1]

[0128] All five S. saprophyticus isolates were further evaluated via time-kill assays. A difference of > 2 log between the combination and the most active agent alone at 24 hours was 10 Synergy between gepotidacin and vancomycin, defined as a CFU / mL reduction, was observed for all five isolates when both agents were tested at their respective 1× MIC concentrations (Figures 1-5). Time-kill under these conditions was consistent with the definition of bactericidal activity (a 3-log reduction in CFU / mL below the initial inoculum sustained over 24 hours). 10 The synergistic activity observed at 1 / 4x and 1 / 2x MIC conditions in the checkerboard assay was not confirmed in the time-kill study.

[0129] No cases of antagonism were observed for the combinations tested against Staphylococcus saprophyticus isolates.

Claims

1. 1. A pharmaceutical for use in the treatment of infections in humans caused by Staphylococcus saprophyticus by co-administration with gepotidacin or a pharmaceutically acceptable salt thereof, said pharmaceutical comprising vancomycin or a pharmaceutically acceptable salt thereof.

2. 1. A pharmaceutical for use in the treatment of infections in humans caused by Staphylococcus saprophyticus by co-administration with vancomycin or a pharmaceutically acceptable salt thereof, said pharmaceutical comprising gepotidacin or a pharmaceutically acceptable salt thereof.

3. 1. Use of gepotidacin, or a pharmaceutically acceptable salt thereof, and vancomycin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of infections in humans caused by Staphylococcus saprophyticus.

4. 1. Use of vancomycin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of infections in humans caused by Staphylococcus saprophyticus by co-administration with gepotidacin, or a pharmaceutically acceptable salt thereof.

5. 1. Use of gepotidacin, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of infections in humans caused by Staphylococcus saprophyticus by co-administration with vancomycin, or a pharmaceutically acceptable salt thereof.

6. A kit comprising gepotidacin, or a pharmaceutically acceptable salt thereof, and vancomycin, or a pharmaceutically acceptable salt thereof, for use in treating infections in humans caused by Staphylococcus saprophyticus.

7. A combination drug comprising gepotidacin or a pharmaceutically acceptable salt thereof and vancomycin or a pharmaceutically acceptable salt thereof.

8. 8. The pharmaceutical combination according to claim 7 for use in the treatment of infections in humans caused by Staphylococcus saprophyticus.

9. The combination medicine described in claim 8, wherein the infection is a urinary tract infection.

10. The combination medicine described in claim 9, wherein the infection is a simple urinary tract infection.

11. The combination pharmaceutical of any one of claims 7 to 10, wherein the gepotidacin or a pharmaceutically acceptable salt thereof and the vancomycin or a pharmaceutically acceptable salt thereof are administered sequentially.

12. The combination pharmaceutical of any one of claims 7 to 10, wherein the gepotidacin is gepotidacin methanesulfonate.

13. The combination pharmaceutical of any one of claims 7 to 10, wherein the vancomycin is vancomycin hydrochloride.

14. The combination pharmaceutical of any one of claims 7 to 10, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.

15. The combination pharmaceutical of any one of claims 7 to 10, wherein the vancomycin or a pharmaceutically acceptable salt thereof is administered orally.

16. A pharmaceutical composition comprising gepotidacin or a pharmaceutically acceptable salt thereof, vancomycin or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

17. 17. A pharmaceutical composition according to claim 16 for use in the treatment of infections in humans caused by Staphylococcus saprophyticus.

18. 17. Use of the pharmaceutical combination according to claim 7 or the pharmaceutical composition according to claim 16 for the manufacture of a medicament for the treatment of infections in humans caused by Staphylococcus saprophyticus.

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