Combinations for the treatment of infections caused by Mycoplasma genitalium

Abstract

The present invention relates to a method for treating a bacterial infection caused by or associated with Mycoplasma genitalium, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof and doxycycline to a human in need thereof. Novel pharmaceutical combinations, compositions, resistance-guided therapies and / or corresponding uses thereof are also disclosed.

Description

[Technical field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA), U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response Agreement No. HHS0100201300011C. The Government has certain rights in this invention.

[0002] FIELD OF THEINVENTION The present invention relates to a therapeutic method, pharmaceutical combination or composition, combination therapy or resistance guided therapy, and / or corresponding uses thereof for treating bacterial infections caused by Mycoplasma genitalium comprising administration of jepotidacin or a pharma- ceutical acceptable salt thereof and doxycycline. [Background technology]

[0003] 2. Background of the Invention Misuse and overuse of antibiotics have led to worrying levels of global resistance rates for all diseases, resulting in a global call to action. Infections caused by multidrug-resistant organisms pose a huge public health burden, not only from morbidity and mortality but also in terms of increased expenditures for patient management and implementation of infection control measures. The problem of antimicrobial resistance is compounded by the existence of bacterial strains resistant to multiple antimicrobial agents. Antibiotic resistance, especially in sexually transmitted infections (STIs), is an ever-increasing public health problem. STIs may become the first incurable bacterial infections since the introduction of antibiotics. Mycoplasma genitalium is an important cause of sexually transmitted infections (STIs). Mycoplasma genitalium was first identified in the early 1980s and has come to be recognized as a cause of male urethritis, accounting for approximately 15%-20% of cases of nongonococcal urethritis (NGU), 20%-25% of nonchlamydial NGU, and approximately 30% of persistent or recurrent urethritis (Sexually Transmitted Diseases Treatment Guidelines 2015, Centers for Disease Control and Prevention). Mycoplasma genitalium has been detected in human urogenital, respiratory, and rectal specimens, with the human urogenital tract appearing to be its preferred colonization site. As M. genitalium grows slowly, detection is usually achieved by nucleic acid amplification tests (NAATs).

[0004] Mycoplasma genitalium is associated with acute and chronic urethritis in men. Although existing data on infections in women are limited and inconsistent, it has been suggested that M. genitalium is associated with urethritis, cervicitis, endometritis, pelvic inflammatory disease (PID), and possibly female infertility. Because M. genitalium lacks a cell wall, common antibiotics that target cell wall biosynthesis (e.g., β-lactams, including penicillins and cephalosporins) are ineffective against this organism. Because most M. genitalium cases are asymptomatic and difficult to diagnose, treatment of most infections caused by M. genitalium is focused on symptomatic management of urethritis, cervicitis, endometritis, and PID.

[0005] Successful treatment is difficult due to the increasing reports of Mycoplasma genitalium resistance to conventional antimicrobials such as macrolides and fluoroquinolones. In the "Sexually Transmitted Disease Treatment Guidelines 2015," the Centers for Disease Control and Prevention, azithromycin is the preferred first-line treatment for infections caused by Mycoplasma genitalium, but resistance rates are increasing worldwide. Moxifloxacin is also used, but the probability of mutations in the quinolone resistance determining region (QRDR) of ParC is as high as 88%, and dual resistance has been reported. Pristinamycin, another option, is difficult to supply and is only 80% effective. In cases of dual resistance to macrolides and fluoroquinolones, treatment options are extremely limited.

[0006] Thus, there is a need for the development of novel pharmaceutical combinations or compositions, combination therapies or resistance-guided therapies and / or uses containing antibiotics or combinations of antimicrobial agents with different mechanisms of action for treating bacterial infections, which exhibit synergistic bactericidal effects and result in a lower incidence of antimicrobial or antimicrobial resistance, however, any drug combination should not have antagonistic interactions.

[0007] The present invention is directed to overcoming these and other problems encountered in the art. Summary of the Invention

[0008] The novel mechanism-based antibiotic jepotidacin has now unexpectedly been found to be synergistically effective against Mycoplasma genitalium when acting without negative interactions with the tetracycline antibiotic doxycycline.

[0009] Thus, the present invention provides a method for treating an infection caused by Mycoplasma genitalium 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 doxycycline.

[0010] The present invention also provides doxycycline for use in the treatment of infection caused by Mycoplasma genitalium by co-administration with jepotidacin or a pharma- ceutical acceptable salt thereof.

[0011] The present invention also provides jepotidacin or a pharma- ceutically acceptable salt thereof for use in the treatment of an infection caused by Mycoplasma genitalium by co-administration with doxycycline.

[0012] The present invention also provides gepotidacin, or a pharma- ceutical acceptable salt thereof, and doxycycline in the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium.

[0013] The present invention also provides the use of doxycycline in the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium by co-administration with jepotidacin or a pharma- ceutical acceptable salt thereof.

[0014] The present invention also provides the use of jepotidacin or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium by co-administration with doxycycline.

[0015] The present invention also provides a kit comprising jepotidacin or a pharma- ceutically acceptable salt thereof, and doxycycline for use in the treatment of an infection caused by Mycoplasma genitalium.

[0016] The present invention also provides a pharmaceutical combination comprising jepotidacin or a pharma- ceutically acceptable salt thereof and doxycycline.

[0017] The present invention also provides a pharmaceutical composition comprising jepotidacin or a pharma- ceutically acceptable salt thereof, doxycycline, and at least one pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 shows the distribution of minimum inhibitory concentrations (MICs) (μg / mL) of gepotidacin (GEP), azithromycin (AZM), moxifloxacin (MXF) and doxycycline (DOX) against the 54 Mycoplasma genitalium strains shown in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description of the Invention The terms "antimicrobial," "antibiotic," and "antibacterial" are used interchangeably herein and refer to any natural or synthetic compound that kills or inhibits the growth of microorganisms.

[0020] Furthermore, as understood in the present invention, antibiotic resistance occurs when bacteria change in response to the use of antibiotics, rendering them ineffective, and antimicrobial resistance is a broader term that also includes resistance to drugs that treat infections caused by other microorganisms, such as parasites (e.g., malaria or helminths), viruses (e.g., HIV) and fungi (e.g., Candida).

[0021] Doxycycline is a tetracycline antibiotic. It has been reported to show poor clinical efficacy in treating urogenital infections caused by Mycoplasma genitalium, with a cure rate of less than 50% (Manhart LE et al. Efficacy of antimicrobial therapy for infections by Mycoplasma genitalium. Clin Infect Dis 2015; 61 (suppl 8): S802-17). As will be understood by those skilled in the art, the term "doxycycline" as used herein encompasses all forms of doxycycline, including doxycycline hyclate (hydrochloride hemiethanolate hemihydrate) and doxycycline monohydrate.

[0022] Jeppotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that has the ability to selectively inhibit bacterial DNA replication by a mechanism not used by any currently approved human therapeutics, thus offering an opportunity to address an unmet medical need. Jeppotidacin and its racemate are disclosed in WO2008 / 128942, the entire contents of which are incorporated herein by reference. Jeppotidacin 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. [ka]

[0023] The method and combination of the present invention is based on the combination of jepotidacin or its pharma- ceutically acceptable salt with doxycycline. Combination therapy is a treatment in which two or more drugs (or other therapeutic agents) are given to a patient for a single disease or when multiple diseases or pathogens are suspected or known to be present. Due to the widespread emergence of multi-drug resistant (MDR) organisms, combination antibiotic therapy is used in patients. Multi-drug resistance can be defined as the lack of susceptibility to at least one drug in three or more antibiotic categories. Antimicrobial or antibacterial drugs are often used in combination, and therefore inhibitory drug interactions between the drugs are undesirable.

[0024] Combination therapy may have the advantage of broadening the antibacterial spectrum, providing synergy, and preventing the emergence of resistance.

[0025] The studies in this application demonstrate synergistic or additive effects against Mycoplasma genitalium when jepotidacin is combined with doxycycline.

[0026] Thus, in a first aspect, the present invention provides a method for treating an infection caused by Mycoplasma genitalium in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharma- ceutical acceptable salt thereof together with a therapeutically effective amount of doxycycline.

[0027] As used herein, "caused by Mycoplasma genitalium" can mean that Mycoplasma genitalium has been identified (e.g., by NAAT) as causing or being part of the cause of (i.e., associated with) an infection; or it can mean that Mycoplasma genitalium is suspected or strongly suspected to be causing or being part of the cause of an infection based on identification of symptoms and other factors, such as patient history or area epidemiology.

[0028] In any of the aspects of the invention, in one embodiment, the Mycoplasma genitalium causing the infection is resistant to a macrolide or fluoroquinolone. Although "resistant" is recognized as a subgroup of "non-susceptible," as used herein, "resistant" is used synonymously with "non-susceptible" to refer to a form of bacteria that resists the effects of antibiotics or has low or no susceptibility to antibiotics. In one embodiment, drug resistance in Mycoplasma genitalium may be suspected (e.g., from local epidemiology or susceptibility patterns or patient history, e.g., findings of recurrent urethritis). In another embodiment, drug resistance may be demonstrated by established techniques, including phenotypic or genotypic determinations. In the present invention, in one embodiment, "resistant" means resistant or non-susceptible as defined by Performance Standards for Antimicrobial Susceptibility Testing, Clinical and Laboratory Standards Institute (CLSI) Supplement M100 and / or Methods for Antimicrobial Susceptibility Testing for Human Mycoplasma; Approved Guideline, CLSI document M43-A: CLSI 2011. In one embodiment, the Mycoplasma genitalium causing the infection is azithromycin resistant. In one embodiment, the Mycoplasma genitalium causing the infection is moxifloxacin resistant.

[0029] In any of the aspects of the invention, in one embodiment, the infection is selected from a sexually transmitted infection or disease (STI or STD), bacterial female infertility, reproductive tract infection, and superinfection-associated urinary tract infection. In one embodiment, the infection is urethritis. In one embodiment, the infection is acute urethritis, chronic urethritis, nongonococcal urethritis, or nonchlamydial nongonococcal urethritis. In one embodiment, the infection is selected from urethritis, cervicitis, endometritis, and pelvic inflammatory disease (PID).

[0030] In one embodiment, the present invention provides a method for treating urethritis caused by Mycoplasma genitalium in a human in need thereof, comprising administering to the human a therapeutically effective amount of gepotidacin or a pharma- ceutically acceptable salt thereof together with a therapeutically effective amount of doxycycline.

[0031] In one embodiment, the present invention provides a method for treating acute urethritis caused by Mycoplasma genitalium in a human in need thereof, comprising administering to the human a therapeutically effective amount of gepotidacin or a pharma- ceutically acceptable salt thereof together with a therapeutically effective amount of doxycycline.

[0032] In one embodiment, the present invention provides a method for treating nongonococcal urethritis caused by Mycoplasma genitalium 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 doxycycline.

[0033] In any embodiment of the present invention, jepotidacin or a pharma- ceutically acceptable salt thereof, and doxycycline may be administered sequentially (i.e., administered consecutively), in parallel (i.e., administered concomitantly) or simultaneously (i.e., administered simultaneously) in separate or combined pharmaceutical formulations by any convenient route.

[0034] In one embodiment, jepotidacin or a pharma- ceutically acceptable salt thereof and doxycycline are administered sequentially.

[0035] Doxycycline administration may follow recommended treatment guidelines such as those set forth in the "Sexually Transmitted Disease Treatment Guidelines 2015," Centers for Disease Control and Prevention, or the "2016 European Guidelines for Mycoplasma genitalium Infection," Jensen et al, Journal of the European Academy of Dermatology and Venereology, DOI: 10.1111 / jdv.13849. Thus, for example, doxycycline may be administered as 200 mg orally once daily for 7 days, 100 mg orally twice daily for 7 days, or 100 mg orally twice daily for 14 days. Other possible treatment regimens include oral doxycycline 200 mg (as 100 mg every 12 hours) on the first day of treatment, followed by a maintenance dose of 100 mg / day (which may be a single dose or 50 mg every 12 hours); or 100 mg every 12 hours.

[0036] Given the synergistic effect of doxycycline and jepotidacin as demonstrated herein, the length of time for doxycycline administration may be reduced from 7-14 days to, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 days.

[0037] For any aspect of the invention, in one embodiment, doxycycline is administered for 5 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 6 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 7 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 8 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 9 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 10 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 11 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 12 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 13 days. For any aspect of the invention, in one embodiment, doxycycline is administered for 14 days.

[0038] For any aspect of the invention, in one embodiment, a human is administered 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. For any aspect of the invention, in one embodiment, gepotidacin or a pharma- ceutically acceptable salt thereof is administered at 1500 mg bid (total daily dose of 3000 mg) for 5 days. For any aspect of the invention, in another embodiment, gepotidacin or a pharma- ceutically acceptable salt thereof is administered at 3000 mg once. For any aspect of the invention, in another embodiment, gepotidacin or a pharma- ceutically acceptable salt thereof is administered in two doses of 3000 mg each, 6 to 12 hours apart.

[0039] For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 5 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 6 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 7 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 8 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 9 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 10 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 11 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 12 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 13 days. For any aspect of the invention, in one embodiment, the human is administered gepotidacin or a pharma- ceutically acceptable salt thereof for 14 days.

[0040] In another aspect, the present invention provides a method for treatment of an infection caused by Mycoplasma genitalium in a human in need thereof, comprising administering to said human a therapeutically effective amount of doxycycline followed by a therapeutically effective amount of gepotidacin or a pharmacologic acceptable salt thereof.

[0041] In one embodiment, the human is administered doxycycline for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, followed by jepotidacin 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 doxycycline for 7, 8, 9, 10, 11, 12, 13, or 14 days, followed by jepotidacin or a pharmaceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0042] In another aspect, the present invention provides a method for treatment of an infection caused by Mycoplasma genitalium in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharma- ceutical acceptable salt thereof, followed by a therapeutically effective amount of doxycycline.

[0043] In one embodiment, the human is administered jepotidacin 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 doxycycline for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In one embodiment, the human is administered jepotidacin or a pharma- ceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13, or 14 days, followed by doxycycline for 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0044] For any aspect of the invention, in one embodiment the total length of treatment is no more than 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days.

[0045] In another aspect, the present invention provides a method of treating an infection caused by Mycoplasma genitalium 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 doxycycline.

[0046] In one aspect, the present invention provides a method for treating an infection caused by Mycoplasma genitalium 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 doxycycline, when the human has failed at least one prior treatment.

[0047] In one embodiment, the prior treatment may be an antibiotic, such as a macrolide (e.g., azithromycin) or a fluoroquinolone (e.g., moxifloxacin). Treatment failure may be defined according to established guidelines, for example, failure may be considered if there is no improvement in symptoms after 3, 4, 5, 6, or 7 days of antibiotic treatment.

[0048] In another aspect, the present invention provides a method for treating an infection caused by Mycoplasma genitalium in a human in need thereof, comprising: a) determining whether the Mycoplasma genitalium strain causing the infection is resistant to a macrolide or a fluoroquinolone; b) administering said human therapeutically effective amount of gepotidacin or a pharma- ceutical acceptable salt thereof together with a therapeutically effective amount of doxycycline if the Mycoplasma genitalium strain is found to be resistant to a macrolide or a fluoroquinolone. The present invention provides a method comprising:

[0049] Examples of macrolides include azithromycin, clarithromycin, erythromycin, and josamycin. Examples of fluoroquinolones include ciprofloxacin, gemifloxacin, moxifloxacin, and levofloxacin.

[0050] As used herein, "determining whether the Mycoplasma genitalium strain causing the infection is resistant to a macrolide or fluoroquinolone" can mean that a skilled artisan considers local epidemiology, susceptibility patterns, or patient history to determine the likelihood of resistance. Additionally, genotypic and phenotypic methods known to those skilled in the art can also be used.

[0051] In one embodiment, in step a), the Mycoplasma genitalium strain is tested for azithromycin resistance.In another embodiment, in step a), the Mycoplasma genitalium strain is tested for moxifloxacin resistance.

[0052] In one aspect, the present invention relates to a combination therapy for treating a bacterial infection caused by Mycoplasma genitalium, comprising administering a therapeutically effective amount of jepotidacin or a pharma- ceutical acceptable salt thereof in combination with a therapeutically effective amount of doxycycline to a human in need thereof.

[0053] In one embodiment, the infectious disease is selected from a sexually transmitted infection or disease (STI or STD), bacterial female infertility, reproductive tract infection, and superinfection-associated urinary tract infection. In one embodiment, the infectious disease is urethritis. In one embodiment, the infectious disease is acute urethritis, chronic urethritis, or nongonococcal urethritis, or nonchlamydial nongonococcal urethritis. In one embodiment, the infectious disease is selected from urethritis, cervicitis, endometritis, and pelvic inflammatory disease (PID).

[0054] In one embodiment, the present invention provides a combination therapy for treating urethritis caused by Mycoplasma genitalium, comprising administering a therapeutically effective amount of jepotidacin or a pharma- ceutical acceptable salt thereof in combination with a therapeutically effective amount of doxycycline to a human in need thereof.

[0055] In one embodiment, the present invention provides a combination therapy for treating nongonococcal urethritis caused by Mycoplasma genitalium, comprising administering a therapeutically effective amount of jepotidacin or a pharma- ceutical acceptable salt thereof in combination with a therapeutically effective amount of doxycycline to a human in need thereof.

[0056] 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, doxycycline may be present in a corresponding pharmaceutical composition of doxycycline comprising doxycycline and at least one pharmaceutically acceptable excipient.

[0057] In another aspect, the present invention relates to a combination or resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium, comprising administering to a human in need thereof a therapeutically effective amount of jepotidacin or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of doxycycline. The jepotidacin or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition comprising jepotidacin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Similarly, the doxycycline may be present in a corresponding pharmaceutical composition of doxycycline comprising doxycycline and at least one pharmaceutically acceptable excipient. In one embodiment, the infection is urethritis. In one embodiment, the infection is acute urethritis, chronic urethritis or nongonococcal urethritis.

[0058] As will be understood by those skilled in the art, as used herein, "resistance-guided therapy" refers to a course of treatment whose direction is 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, Volume 216, Issue suppl_2, 15 July 2017, Pages S412-S419. Detecting Mycoplasma genitalium in an infection and then detecting resistance of Mycoplasma genitalium strains to a particular antibiotic before or during the course of treatment has the advantage of potentially reducing the patient's exposure to ineffective antibiotics that may lead to resistance. Identification of Mycoplasma genitalium may be by any suitable means, such as by NAAT. Various assays capable of detecting resistance (phenotypic or genotypic) to macrolides are also known.

[0059] Thus, in one aspect, the present invention provides a resistance-guided therapy for treating a bacterial infection caused by Mycoplasma genitalium, comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharma- ceutical acceptable salt thereof in combination with a therapeutically effective amount of doxycycline.

[0060] The combination therapy or resistance-guided therapy of the present invention may be achieved by simultaneous, concomitant or sequential administration of the two components.

[0061] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium, wherein the bacterial infection is selected from a sexually transmitted infection or disease (STI or STD), bacterial female infertility, reproductive tract infections and superinfection-associated urinary tract infections.

[0062] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium, wherein the reproductive tract infection or superinfection-associated urinary tract infection is selected from urethritis, cervicitis, endometritis, cervicitis, endometritis, endometritis or pelvic inflammatory disease (PID), respectively.

[0063] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium, wherein the urethritis is selected from acute urethritis, chronic urethritis or nongonococcal urethritis.

[0064] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium, wherein each of the components is administered orally.

[0065] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium; comprising simultaneous, concomitant or sequential administration of therapeutically effective amounts of jepotidacin or a pharmacologic acceptable salt thereof and doxycycline to a human in need thereof; wherein the use of doxycycline provides a synergistic and / or additive effect and / or also helps protect against the development of resistance to either jepotidacin or a pharmacologic acceptable salt thereof or doxycycline without interfering with their individual activities.

[0066] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium; comprising simultaneous, concomitant or sequential administration to a human in need thereof of a therapeutically effective amount of a pharmaceutical composition comprising jepotidacin or a pharmacopoeitic salt thereof and at least one or more pharmacopoeitic excipients; and doxycycline; wherein the use of doxycycline provides a synergistic and / or additive effect and / or also helps protect against the development of resistance to either jepotidacin or a pharmacopoeitic salt thereof or doxycycline without interfering with their individual activities.

[0067] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating genital tract infections or superinfection-associated urinary tract infections caused by or associated with Mycoplasma genitalium, comprising administration of therapeutically effective amounts of gepotidacin or a pharmacologic acceptable salt thereof and doxycycline to a human in need thereof, wherein the use of doxycycline results in a synergistic and / or additive effect and / or also helps protect against the development of resistance to either gepotidacin or a pharmacologic acceptable salt thereof or doxycycline without interfering with their individual activities.

[0068] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating urethritis caused by or associated with Mycoplasma genitalium, comprising the administration to a human in need thereof of a therapeutically effective amount of jepotidacin; and doxycycline, wherein the use of doxycycline provides a synergistic and / or additive effect; and / or also aids in protection against the development of resistance to either jepotidacin or a pharma-ceutically acceptable salt thereof or doxycycline without interfering with their individual activities. In one embodiment, the urethritis is acute urethritis, chronic urethritis or nongonococcal urethritis.

[0069] In one aspect, the present invention relates to a combination or resistance-guided therapy for treating non-gonococcal urethritis caused by or associated with Mycoplasma genitalium, comprising administration of a therapeutically effective amount of jepotidacin or a pharmaceutically acceptable salt thereof to a human in need thereof; and doxycycline to a human in need thereof, wherein the use of doxycycline as a second antimicrobial or antibacterial agent results in a synergistic and / or additive effect; and / or also aids in protection against the development of resistance to either jepotidacin or a pharmaceutically acceptable salt thereof or doxycycline, without interfering with their individual activities.

[0070] In one aspect, the present invention relates to a resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium, comprising administering to a human in need thereof a therapeutically effective amount of jepotidacin or a pharma- ceutically acceptable salt thereof; and doxycycline to a human in need thereof; wherein the use of doxycycline provides a synergistic and / or additive effect; and / or also aids in protecting against the development of resistance to either jepotidacin or a pharma- ceutically acceptable salt thereof or doxycycline without interfering with their individual activities. In any of the above aspects and embodiments of the invention, in one embodiment, the human is male. In one embodiment, the human is female.

[0071] In another aspect, the present invention provides doxycycline for use in the treatment of infection caused by Mycoplasma genitalium by co-administration with jepotidacin or a pharma-ceutically acceptable salt thereof.

[0072] In another aspect, the present invention provides jepotidacin or a pharma- ceutically acceptable salt thereof for use in the treatment of an infection caused by Mycoplasma genitalium by co-administration with doxycycline.

[0073] In another aspect, the present invention provides the use of jepotidacin, or a pharma- ceutical acceptable salt thereof, and doxycycline in the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium.

[0074] In one embodiment, the infection is selected from a sexually transmitted infection (STI), bacterial female infertility, a reproductive tract infection or a urinary tract infection associated with a superinfection. In one embodiment, the reproductive tract infection or a urinary tract infection associated with a superinfection is selected from urethritis, cervicitis, endometritis or pelvic inflammatory disease (PID). In one embodiment, the urethritis is selected from acute urethritis, chronic urethritis or nongonococcal urethritis.

[0075] Thus, in one embodiment, the present invention provides doxycycline for use in the treatment of urethritis caused by Mycoplasma genitalium by co-administration with jepotidacin or a pharma-ceutically acceptable salt thereof.

[0076] In another aspect, the present invention provides jepotidacin or a pharma- ceutically acceptable salt thereof for use in the treatment of urethritis caused by Mycoplasma genitalium by co-administration with doxycycline.

[0077] In another aspect, the present invention provides the use of doxycycline in the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium by co-administration with jepotidacin or a pharma-ceutically acceptable salt thereof.

[0078] In another aspect, the present invention provides the use of gepotidacin or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium by co-administration with doxycycline.

[0079] The gepotidacin or a pharma- ceutically acceptable salt thereof and doxycycline may be administered in separate or combined pharmaceutical formulations, sequentially or simultaneously, by any suitable route.

[0080] In one embodiment, the infection is selected from a sexually transmitted infection (STI), bacterial female infertility, a reproductive tract infection or a urinary tract infection associated with a superinfection. In one embodiment, the reproductive tract infection or a urinary tract infection associated with a superinfection is selected from urethritis, cervicitis, endometritis or pelvic inflammatory disease (PID). In one embodiment, the urethritis is selected from acute urethritis, chronic urethritis or nongonococcal urethritis.

[0081] In another aspect, the present invention provides a kit comprising jepotidacin or a pharma- ceutically acceptable salt thereof, and doxycycline for use in the treatment of an infection caused by Mycoplasma genitalium.

[0082] In another embodiment, the present invention provides a pharmaceutical combination (pharmaceutical combination) comprising jepotidacin or a pharma- ceutically acceptable salt thereof; and doxycycline.

[0083] In another embodiment, the present invention provides a pharmaceutical composition comprising jepotidacin or a pharma- ceutically acceptable salt thereof, doxycycline, and at least one pharma- ceutically acceptable excipient.

[0084] In another embodiment, the present invention provides a pharmaceutical combination of jepotidacin, or a pharma- ceutically acceptable salt thereof, and doxycycline.

[0085] In another aspect, the present invention relates to a pharmaceutical combination comprising jepotidacin or a pharma- ceutically acceptable salt thereof and doxycycline for use in combination therapy or resistance-guided therapy as described in the present invention.

[0086] In another aspect, the present invention relates to a pharmaceutical composition comprising jepotidacin or a pharma- ceutical acceptable salt thereof, doxycycline, and at least one pharma- ceutical acceptable excipient for use in combination therapy or resistance-guided therapy as described in the present invention.

[0087] In another aspect, the present invention provides a combination of jepotidacin, or a pharma- ceutically acceptable salt thereof, and doxycycline for use in the treatment of an infection caused by Mycoplasma genitalium.

[0088] In another aspect, the present invention provides a pharmaceutical composition comprising jepotidacin or a pharma- ceutically acceptable salt thereof, and doxycycline for use in the treatment of an infection caused by Mycoplasma genitalium.

[0089] 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 Mycoplasma genitalium.

[0090] In another aspect, the present invention relates to the use of a pharmaceutical combination or composition as described herein for the manufacture of a medicament for treating a genital tract infection or superinfection-associated urinary tract infection caused by Mycoplasma genitalium.

[0091] 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 the treatment of urethritis caused by Mycoplasma genitalium.

[0092] In another aspect, the present invention relates to the use of a pharmaceutical combination or composition as described herein for the manufacture of a medicament for the treatment of non-gonococcal urethritis caused by Mycoplasma genitalium.

[0093] 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 or associated with Mycoplasma genitalium in a human in need thereof.

[0094] 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 combination therapy for the treatment of a bacterial infection caused by or associated with Mycoplasma genitalium in a human in need thereof.

[0095] In another embodiment the invention relates to the use as defined in the invention, wherein the bacterial infection is selected from a sexually transmitted infection (STI), bacterial female infertility, a reproductive tract infection or a urinary tract infection associated with superinfection.

[0096] In another embodiment, the present invention relates to the use as defined in the present invention, wherein the genital tract infection or superinfection associated urinary tract infection is selected from urethritis, cervicitis, endometritis or pelvic inflammatory disease (PID).

[0097] In another embodiment, the invention relates to the use as defined in the present invention, wherein the urethritis is selected from acute urethritis, chronic urethritis or nongonococcal urethritis.

[0098] The present invention provides the following embodiments: 1. A therapeutically effective amount of [a] a first antimicrobial or antibacterial agent, which is jepotidacin or a pharma- ceutically acceptable salt thereof; or [b] A corresponding pharmaceutical composition comprising: [1][a] or a pharma- ceutically acceptable salt thereof; [2] at least one pharma- ceutically acceptable excipient; [c] a second antimicrobial or antibacterial agent, which is doxycycline; or [d] the corresponding pharmaceutical composition of [c], comprising: A second antimicrobial or antibacterial agent as defined in [1][c]; [2] at least one pharma- ceutically acceptable excipient; to a patient or subject in need thereof in combination with Combination therapy for treating bacterial infections caused by or associated with Mycoplasma genitalium.

[0099] 2. A combination therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium as described in embodiment 1, wherein the administration of each of the components defined in [a] or [b] in combination with [c] or [d] is achieved by simultaneous, concomitant or sequential administration.

[0100] 3. A combination therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium according to embodiment 1 or 2, wherein the combination therapy is defined as resistance-guided therapy.

[0101] 4. The use of a second antimicrobial or antibacterial agent in combination with a first antimicrobial or antibacterial agent is provide synergistic and / or additive effects; and / or also helps protect against the development of resistance to either [a] or [b] without interfering with their individual activities; 2. A combination therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium according to embodiment 1.

[0102] 5. A combination therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium according to embodiment 1, wherein the bacterial infection is selected from a sexually transmitted infection (STI), bacterial female infertility, bloodstream infection, upper respiratory tract infection, lower respiratory tract infection, skin infection, soft tissue infection, intra-abdominal infection, gastrointestinal infection, genital tract infection or urinary tract infection associated with superinfection.

[0103] 6. The combination therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium according to embodiment 5, wherein the genital tract infection or superinfection-associated urinary tract infection is selected from urethritis, cervicitis or pelvic inflammatory disease (PID), respectively.

[0104] 7. The combination therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium according to embodiment 6, wherein the urethritis is selected from acute urethritis, chronic urethritis or nongonococcal urethritis.

[0105] 8. A combination therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium according to embodiment 1, wherein each of the components [a] or [b] and [c] or [d], respectively, is administered orally.

[0106] 9. A therapeutically effective amount of [a] a first antimicrobial or antibacterial agent for a patient in need thereof, comprising the compound: (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; or Pharmacologically acceptable salts thereof; and [b] a second antimicrobial or antibacterial agent selected from doxycycline for patients or subjects in need thereof; including simultaneous, concomitant, or sequential administration of; Wherein the use of doxycycline as a second antimicrobial or antibacterial agent is: provide synergistic and / or additive effects; and / or also helps protect against the development of resistance to either [a] or [b] without interfering with their individual activities; Combination therapy for treating bacterial infections caused by or associated with Mycoplasma genitalium.

[0107] 10. A therapeutically effective amount of [a] a pharmaceutical composition comprising: [1] A first antimicrobial or antibacterial agent for a patient in need thereof, comprising the compound: (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: or a pharma- ceutically acceptable salt thereof; and [2] at least one or more pharma- ceutically acceptable excipients; and [b] a second antimicrobial or antibacterial agent selected from doxycycline for patients or subjects in need thereof; including simultaneous, concomitant, or sequential administration of; Wherein the use of doxycycline as a second antimicrobial or antibacterial agent is: provide synergistic and / or additive effects; and / or also helps protect against the development of resistance to either [a] or [b] without interfering with their individual activities; Combination therapy for treating bacterial infections caused by or associated with Mycoplasma genitalium.

[0108] 11. [a] a first pharmaceutical composition comprising: [1] a first antimicrobial or antibacterial agent to a patient in need thereof, the first antimicrobial or antibacterial agent being the compound (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; or a pharma-ceutically acceptable salt thereof; and [2] at least one or more pharma- ceutically acceptable excipients; and [b] a second pharmaceutical composition to a patient or subject in need thereof, comprising: [1] A second antimicrobial or antibacterial agent selected from doxycycline; and [2] at least one or more pharma- ceutically acceptable excipients; including simultaneous, concomitant, or sequential administration of a therapeutically effective combination of components consisting of: Wherein the use of doxycycline as a second antimicrobial or antibacterial agent is: provide synergistic and / or additive effects; and / or also helps protect against the development of resistance to either [a] or [b] without interfering with their individual activities; Combination therapy for treating bacterial infections caused by or associated with Mycoplasma genitalium.

[0109] 12. A therapeutically effective amount of [a] a first antimicrobial or antibacterial agent for a patient in need thereof, comprising the compound: (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: or a pharma- ceutically acceptable salt thereof; and [b] a second antimicrobial or antibacterial agent selected from doxycycline for patients or subjects in need thereof; including administration of; Wherein the use of doxycycline as a second antimicrobial or antibacterial agent is: provide synergistic and / or additive effects; and / or also helps protect against the development of resistance to either [a] or [b] without interfering with their individual activities; Combination therapy for treating genital tract infections or superinfection-associated urinary tract infections caused by or associated with Mycoplasma genitalium.

[0110] 13. A therapeutically effective amount of [a] a first antimicrobial or antibacterial agent for a patient in need thereof, comprising the compound: (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: or a pharma- ceutically acceptable salt thereof; and [b] a second antimicrobial or antibacterial agent selected from doxycycline for patients or subjects in need thereof; including administration of; Wherein the use of doxycycline as a second antimicrobial or antibacterial agent is: provide synergistic and / or additive effects; and / or also helps protect against the development of resistance to either [a] or [b] without interfering with their individual activities; Combination therapy for treating urethritis caused by or associated with Mycoplasma genitalium.

[0111] 14. The combination therapy for treating urethritis caused by or associated with Mycoplasma genitalium according to embodiment 13, wherein the urethritis is selected from acute urethritis, chronic urethritis or nongonococcal urethritis.

[0112] 15. A therapeutically effective amount of [a] a first antimicrobial or antibacterial agent for a patient in need thereof, comprising the compound: (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: or a pharma- ceutically acceptable salt thereof; and [b] a second antimicrobial or antibacterial agent selected from doxycycline for patients or subjects in need thereof; including administration of; Wherein the use of doxycycline as a second antimicrobial or antibacterial agent is: provide synergistic and / or additive effects; and / or also helps protect against the development of resistance to either [a] or [b] without interfering with their individual activities; Combination therapy for treating nongonococcal urethritis caused by or associated with Mycoplasma genitalium.

[0113] 16. A combination therapy caused by or associated with Mycoplasma genitalium according to any one of embodiments 12, 13, 14 or 15, wherein the administration of each of the components [a] or [b] is achieved by simultaneous, concomitant or sequential administration.

[0114] 17. A therapeutically effective amount of [a] a first antimicrobial or antibacterial agent for a patient in need thereof, comprising the compound: (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: or a pharma- ceutically acceptable salt thereof; and [b] a second antimicrobial or antibacterial agent selected from doxycycline for patients or subjects in need thereof; Dosage includes: Wherein the use of doxycycline as a second antimicrobial or antibacterial agent is: provide synergistic and / or additive effects; and / or also helps protect against the development of resistance to either [a] or [b] without interfering with their individual activities; Resistance-guided therapy for treating bacterial infections caused by or associated with Mycoplasma genitalium.

[0115] 18. [a] a first antimicrobial or antibacterial agent, which is jepotidacin or a pharma- ceutically acceptable salt thereof; and [b] A second antimicrobial or antibacterial agent, such as doxycycline 23. A pharmaceutical combination comprising:

[0116] 19. [a] a first antimicrobial or antibacterial agent, which is jepotidacin or a pharma- ceutically acceptable salt thereof; and [b] a second antimicrobial or antibacterial agent, which is doxycycline; and [c] at least one pharma- ceutically acceptable excipient 13. A pharmaceutical composition comprising:

[0117] 20. The pharmaceutical combination according to embodiment 18, for use in combination therapy or resistance-guided therapy.

[0118] 21. The pharmaceutical composition according to embodiment 19, for use in combination therapy or resistance-guided therapy.

[0119] 22. Use of a pharmaceutical combination according to embodiment 18 or a pharmaceutical composition according to embodiment 19 for the manufacture of a medicament for the treatment of a bacterial infection caused by or associated with Mycoplasma genitalium in a patient or subject in need thereof.

[0120] 23. The use according to embodiment 22, wherein the bacterial infection is selected from a sexually transmitted infection (STI), bacterial female infertility, bloodstream infection, upper respiratory tract infection, lower respiratory tract infection, skin infection, soft tissue infection, intraperitoneal infection, gastrointestinal infection, genital tract infection or urinary tract infection associated with superinfection.

[0121] 24. The use according to embodiment 23, wherein the genital tract infection or superinfection-associated urinary tract infection is selected from urethritis, cervicitis or pelvic inflammatory disease (PID).

[0122] 25. The use according to embodiment 24, wherein the urethritis is selected from acute urethritis, chronic urethritis or nongonococcal urethritis.

[0123] 26. Use of the pharmaceutical combination according to embodiment 18 or the pharmaceutical composition according to embodiment 19 for the manufacture of a medicament for treating a genital tract infection or a superinfection-associated urinary tract infection caused by or associated with Mycoplasma genitalium in a patient or subject in need thereof.

[0124] 27. Use of a pharmaceutical combination according to embodiment 18 or a pharmaceutical composition according to embodiment 19 for the manufacture of a medicament for the treatment of urethritis caused by or associated with Mycoplasma genitalium in a patient or subject in need thereof.

[0125] 28. Use of a pharmaceutical combination according to embodiment 18 or a pharmaceutical composition according to embodiment 19 for the manufacture of a medicament for the treatment of nongonococcal urethritis caused by or associated with Mycoplasma genitalium in a patient or subject in need thereof.

[0126] 29. Use of the pharmaceutical combination according to embodiment 18 or the pharmaceutical composition according to embodiment 19 for resistance-guided therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium in a patient or subject in need thereof.

[0127] 30. Use of a pharmaceutical combination according to embodiment 18 or a pharmaceutical composition according to embodiment 19 for combination therapy for treating a bacterial infection caused by or associated with Mycoplasma genitalium in a patient or subject in need thereof.

[0128] 31. The use according to embodiment 28 or 29, wherein the bacterial infection is selected from a sexually transmitted infection (STI), bacterial female infertility, bloodstream infection, upper respiratory tract infection, lower respiratory tract infection, skin infection, soft tissue infection, intraperitoneal infection, gastrointestinal infection, genital tract infection or urinary tract infection associated with superinfection.

[0129] 32. The use according to embodiment 31, wherein the genital tract infection or superinfection-associated urinary tract infection is selected from urethritis, cervicitis or pelvic inflammatory disease (PID).

[0130] 33. The use according to embodiment 32, wherein the urethritis is selected from acute urethritis, chronic urethritis or nongonococcal urethritis.

[0131] Compounds used in the present invention WO2008 / 128942 discloses the preparation of the free base and hydrochloride salt of jepotidacin.

[0132] It will be understood that the phrase "jepotidacin or a pharma- ceutically acceptable salt thereof" is intended to encompass jepotidacin, a pharma- ceutically acceptable salt of jepotidacin, a solvate of jepotidacin, or any pharma- ceutically acceptable combination thereof. Thus, as a non-limiting example used herein for illustrative purposes, "jepotidacin or a pharma- ceutically acceptable salt thereof" may further include a pharma- ceutical acceptable salt of jepotidacin, which exists as a solvate.

[0133] As used herein, doxycycline or gepotidacin (or any pharma- ceutically acceptable salt thereof) may be in any physical form, including non-solid forms, such as liquid or semi-solid forms, solid forms, such as amorphous or crystalline forms, certain polymorphic forms and solvates (including hydrates, e.g., doxycycline monohydrate and doxycycline hyclate (hydrochloride hemiethanolate hemihydrate)), and mixtures of various forms.

[0134] Suitable pharma- ceutically acceptable salts include those described by Berge, Bighley and Monkhouse J. Pharm. Sci (1977) 66, pp 1-19.

[0135] For both jepotidacin and doxycycline, the desired salt forms may be prepared by any suitable method known in the art, such as by treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 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 acids (e.g., glucuronic acid or galacturonic acid), alpha-hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), or 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, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, and the like. These include benzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, mandelates, and sulfonates (e.g., xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and naphthalene-2-sulfonates).

[0136] Pharmaceutically acceptable salts of jepotidacin 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 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 of any aspect of the invention, jepotidacin is jepotidacin free base or jepotidacin methanesulfonate (mesylate).

[0137] The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0138] Pharmaceutical Compositions and Formulations Pharmaceutical compositions and formulations acceptable and compatible for use in the methods and / or uses of the present invention are prepared using pharmaceutical compositions, formulations or chemical materials, formulation excipients, preparation means, processes and / or methods and techniques known in the art.

[0139] In particular, jepotidacin or a pharma- ceutically acceptable salt thereof for use in the present invention may, by analogy with other antibacterial / antituberculous compounds, be formulated for administration in any suitable manner for use in human or veterinary medicine.

[0140] 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.

[0141] The compositions may be in the form of tablets, capsules, powders, granules, troches, suppositories, creams or liquid preparations such as oral or sterile parenteral solutions or suspensions.

[0142] In one embodiment, the jepotidacin 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.

[0143] Doxycycline may be administered in any suitable form, including oral capsules, 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.

[0144] The tablets and capsules for oral administration in the present invention may be in unit dose 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 prepared as a dry product 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 (e.g., lecithin, sorbitan monooleate, or gum arabic), non-aqueous vehicles (which may include edible oils) (e.g., almond oil), oily esters (e.g., glycerin, propylene glycol, or ethyl alcohol), preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), and, optionally, conventional flavorings or colorings.

[0145] Suppositories will contain conventional suppository bases such as cocoa butter or other glycerides.

[0146] For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle (preferably water).Depending on the vehicle and concentration used, the compound can be suspended or dissolved in the vehicle.When preparing a solution, the compound can be dissolved in water for injection, and then filtered and sterilized, and then filled into suitable vials or ampoules and sealed.

[0147] Advantageously, agents such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. To enhance stability, the composition can be frozen after filling into a vial and the water 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 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 achieved by filtration. The compound can be sterilized by exposure to ethylene oxide and then suspended in a sterile vehicle. Advantageously, the composition contains a surfactant or wetting agent to aid in uniform distribution of the compound.

[0148] Furthermore, the dosage of the compound or pharmaceutical composition used in the present invention will vary depending on the patient and the mode of administration, and may be any effective amount.

[0149] In any of the administration methods 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 it is said to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on factors such as the patient's health status, the patient's age, and the like.

[0150] The treatment regimen for administration of the compound and / or pharmaceutical composition used in the present invention can also be easily determined by those skilled in the art. The dosage of the compound and / or pharmaceutical composition used in the present invention can be varied over a wide range to provide an effective amount based on the patient's body weight per day in a unit dosage form to achieve the desired effect.

[0151] The composition may contain 0.1% by weight, preferably 10% to 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 active ingredient (i.e., jepotidacin) refers to the amount of jepotidacin free base.

[0152] The dose of jepotidacin or a pharma- ceutically acceptable salt used in the present invention for the treatment of adults is preferably in the range of 100 or 6000 mg / day, or 100-3000 mg / day, e.g., 1500 mg / day or 3000 mg / day, depending on the route and frequency of administration. Such a dose corresponds to about 1.5 to about 100 or 50 mg / kg / day. Suitably, the dose is 5-30 mg / kg / day. In one embodiment, the dose is 1500 mg twice daily (i.e., 3000 mg / day). In one embodiment, the dose is 3000 mg twice daily (i.e., 6000 mg / day).

[0153] Conventional methods of administration may be suitable for use in the present invention.

[0154] Depending on the treatment to be achieved, the compounds and / or compositions of the present invention can be administered orally, intravascularly, 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, jepotidacin or a pharma- ceutically acceptable salt thereof and doxycycline are administered orally.

[0155] The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention in any way. EXAMPLES

[0156] Example 1: In vitro evaluation of the oral antimicrobial drug jepotidacin against drug-resistant Mycoplasma genitalium overview Gepotidacin minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined for 54 Mycoplasma genitalium isolates by the Vero cell culture method. Macrolide resistance was present in 31 isolates, fluoroquinolone resistance was present in 18 (33%) isolates, and 17 isolates were dual resistant.

[0157] Synergy testing for jepotidacin and doxycycline was performed by checkerboard analysis against two macrolide-resistant and two double-resistant isolates.

[0158] Jeppotidacin was active against all 54 Mycoplasma genitalium isolates with median and modal MICs of 0.125 mg / L and MIC 90 was 0.25 mg / L (range ≤0.016-0.5 mg / L). No differences were noted in gepotidacin MICs between macrolide-resistant and susceptible isolates (p=0.24) or between fluoroquinolone-resistant, dual-resistant and susceptible isolates (p=0.2).

[0159] Gepotidacin MBCs were obtained for 44 Mycoplasma genitalium isolates, with a median MIC of 0.064 mg / L and a median MBC of 0.125 mg / L, with all isolates having a difference between MIC and MBC not exceeding 4-fold, suggesting bactericidal activity.

[0160] Checkerboard analysis showed synergy when jepotidacin was combined with doxycycline, with a FIC count (Fractional Inhibitory Concentration Index) of 0.5 for two isolates (one macrolide-resistant and one dual-resistant), and no additive / differential effect (FICs of 0.62 and 0.75) for the macrolide-resistant and dual-resistant isolates, respectively.

[0161] method Mycoplasma genitalium isolates A collection of 54 Mycoplasma genitalium isolates derived from 51 patients were tested. Thirty-one strains were macrolide resistant, with azithromycin MICs ≥ 16 μg / mL, and had mutations at the 23S rRNA gene A2058 (n = 17) or A2059 (n = 14, E. coli numbering) positions. Eighteen strains were moxifloxacin resistant (MIC ≥ 1 μg / mL); 17 strains were dual resistant, resistant to both moxifloxacin and azithromycin. The geographic origins of the isolates are shown in Table 1.

[0162] [Table 1]

[0163] Determination of minimum inhibitory concentration (MIC) Gepotidacin minimum inhibitory concentrations (MICs) were determined by the Vero cell culture method for all 54 isolates, and minimum bactericidal concentrations (MBCs) were determined for 44 M. genitalium strains. Gepotidacin, azithromycin, doxycycline, and moxifloxacin MICs were determined by inoculating Vero cell cultures containing two-fold dilutions of the test antibiotics with 5000 genome equivalents (geq) as determined by quantitative PCR (qPCR) (Hamasuna et al., Antimicrob. Agents Chemother 49, 4993-4998 (2005)). After a 3-week incubation period, cells and supernatants were harvested and M. genitalium growth was determined by qPCR. The MIC was defined as the lowest concentration of the test antibiotic that caused 99% growth inhibition when compared to the mean of control cultures grown without antibiotics.

[0164] Determination of minimum bactericidal concentration (MBC) After incubation for MIC determination, 15 μL of culture medium was transferred from the MIC plate to 135 μL of fresh Vero cell suspension to obtain a 10-fold dilution of gepotidacin. Plates were sealed and incubated for 4 weeks before Mycoplasma genitalium growth was determined by qPCR. The MBC was defined as the lowest concentration of antibiotic test substance that caused 99% growth inhibition when compared to the average of control culture wells grown without antibiotic.

[0165] Determination of synergy between jepotidacin and doxycycline Synergy testing was performed by checkerboard analysis for jepotidacin and doxycycline against two macrolide-resistant and two dual-resistant isolates. Checkerboards representing 8 × 8 doubling dilutions of jepotidacin and doxycycline, with midpoint concentrations representing doxycycline and jepotidacin MICs, respectively, were made in Vero cell suspensions and Mycoplasma genitalium was incubated for 3 weeks before growth was determined by qPCR. Results were expressed as fractional inhibitory concentration index (FICI). Synergy was assumed when FICI ≤ 0.5 and antagonism when FICI > 4.

[0166] Results and Discussion Jeppotidacin was active against all 54 Mycoplasma genitalium isolates with median and modal MICs of 0.125 mg / L and MIC 90The MICs were 0.25 mg / L (range ≤0.016–0.5 mg / L) and were significantly more active than the comparator antibiotics against the M. genitalium isolates tested (see Figure 1, which shows the distribution of MICs (μg / mL) of gepotidacin (GEP), azithromycin (AZM), moxifloxacin (MXF) and doxycycline (DOX) against 54 M. genitalium strains). These included geographically, temporally and genetically diverse reference strains as well as clinical M. genitalium isolates with a high proportion of fluoroquinolone-resistant isolates (33%) and macrolide-resistant isolates (57%).

[0167] Importantly, no differences in gepotidacin MICs were demonstrated between macrolide-resistant and susceptible isolates (p=0.24) or between fluoroquinolone-resistant, dual-resistant or susceptible isolates (p=0.2).

[0168] In this selected collection of isolates, jepotidacin was the most active compound (Table 2), followed by azithromycin (MIC 90 >64μg / mL), moxifloxacin (MIC 90 4 μg / mL), and doxycycline (MIC 90 1 μg / mL), its MIC 90 was 0.25 μg / mL (p<0.001 for all comparisons).

[0169] Table 2: MICs of 36 moxifloxacin-susceptible and 18 moxifloxacin-resistant isolates of Mycoplasma genitalium. Gepotidacin MBCs were obtained for 44 Mycoplasma genitalium isolates, with a median MIC of 0.064 and a median MBC of 0.125 mg / L; all isolates had a greater than four-fold difference between MIC and MBC, suggesting bactericidal activity.

[0170] [Table 2]

[0171] Checkerboard analysis of gepotidacin and doxycycline showed synergy with FIC 0.5 for two isolates (one macrolide-resistant and one double-resistant) and additivity / no difference (FIC 0.62 and 0.75) for the macrolide-resistant and double-resistant isolates, respectively (Table 3). Importantly, no antagonistic interaction was demonstrated between gepotidacin and doxycycline.

[0172] For the purposes of this study, synergy was defined as FICI ≤ 0.5 and antagonism as FICI > 4 in Table 3, mutations in the 23S rRNA gene that mediate macrolide resistance follow the Escherichia coli numbering, and ParC mutations that result in moxifloxacin resistance follow the Mycoplasma genitalium numbering.

[0173] [Table 3]

[0174] These results indicate that gepotidacin was active against all M. genitalium isolates tested, including fluoroquinolone- and macrolide-resistant isolates, and there was no cross-resistance to the comparators tested. MIC values ​​for gepotidacin were higher using the Vero cell culture method than those seen using the CLSI method for testing moxifloxacin-susceptible M. genitalium isolates, but bactericidal concentrations were comparable. Furthermore, these results indicate that doxycycline had additive or synergistic activity with gepotidacin, even in dual-resistant M. genitalium isolates.

[0175] Synergy or additivity may help to reduce the patient's exposure to the first drug (which may be doxycycline or jepotidacin) from a long period to a few days before switching to the other drug or adding the other drug to the treatment regimen. This dual therapy may help protect jepotidacin from the selection and / or spread of resistance while enhancing the efficacy of both compounds.

[0176] It should be understood that the present invention is not limited to the above-described aspects or embodiments, but reserves the right to any modifications that fall within the scope of the described aspects or embodiments and the following claims.

[0177] Various references to journals, patents, and other publications cited herein contain the state of the art and are incorporated by reference as if fully set forth.

Claims

1. 1. A composition for use in a method for treating an infection caused by Mycoplasma genitalium in a human in need thereof, comprising: the method comprising administering to the human a therapeutically effective amount of jepotidacin or a pharma- ceutical acceptable salt thereof together with a therapeutically effective amount of doxycycline; composition.

2. 2. The composition of claim 1, wherein the infection is selected from a sexually transmitted disease or disease, bacterial female infertility, reproductive tract infections and urinary tract infections associated with superinfection.

3. The composition of claim 1 , wherein the infection is urethritis.

4. The composition of claim 3, wherein the infection is nongonococcal urethritis.

5. The composition of any one of claims 1 to 4, wherein the Mycoplasma genitalium causing the infection is resistant to azithromycin or moxifloxacin.

6. The composition according to any one of claims 1 to 5, wherein said method comprises administering said jepotidacin or a pharma- ceutically acceptable salt thereof and said doxycycline sequentially.

7. The composition of any one of claims 1 to 6, wherein the jepotidacin is jepotidacin methanesulfonate.

8. The method according to any one of claims 1 to 7, wherein the jepotidacin or a pharma- ceutically acceptable salt thereof is administered orally.

9. The method of any one of claims 1 to 8, wherein the doxycycline is administered orally.

10. Use of gepotidacin or a pharma- ceutically acceptable salt thereof, and doxycycline in the manufacture of a medicament for the treatment of infection caused by Mycoplasma genitalium.

11. 13. Use of doxycycline in the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium by co-administration with doxycycline or a pharma- ceutical acceptable salt thereof.

12. 2. Use of gepotidacin or a pharma- ceutical acceptable salt thereof in the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium by co-administration with doxycycline.

13. A kit comprising gepotidacin or a pharma- ceutically acceptable salt thereof and doxycycline for use in the treatment of an infection caused by Mycoplasma genitalium.

14. A pharmaceutical combination comprising jepotidacin or a pharma- ceutically acceptable salt thereof and doxycycline for use in the treatment of infections caused by Mycoplasma genitalium.

15. A pharmaceutical composition for use in the treatment of infection caused by Mycoplasma genitalium, comprising jepotidacin or a pharma- ceutically acceptable salt thereof, doxycycline, and at least one pharma- ceutical acceptable excipient.

16. 16. Use of a pharmaceutical combination according to claim 14 or a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the treatment of an infection caused by Mycoplasma genitalium.

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