Treatment of bacterial infections in the central nervous system and associated neurological disorders in animals

Abstract

The present disclosure relates to methods of control, treatment and / or prevention of a neurological disease or disorder in animals, optionally livestock, comprising administering a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate or hydrate of salt thereof, wherein the neurological disease or disorder is caused by a bacterial infection in the central nervous system. The present disclosure further provides a method of control, treatment and / or prevention of a bacterial infection in the central nervous system in animals, optionally livestock, comprising administering a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate or hydrate of salt thereof.

Description

MMV Ref.: 2920951-543977TREATMENT OF BACTERIAL INFECTIONS IN THE CENTRAL NERVOUS SYSTEM AND ASSOCIATED NEUROLOGICAL DISORFERS IN ANIMALS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This International Patent Application claims the benefit of U. S. Provisional Patent Application No. 63 / 729,675. filed 09 December 2024, which is hereby incorporated by reference in its entirety.FIELD

[0002] The present disclosure relates to methods of control, treatment and / or prevention of bacterial infections in the central nervous system in animals, for example livestock, for example swine, using fluoroquinolone antibiotics and associated compositions thereof. In preferred aspects, pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof are used in methods of treatment and / or prevention of bacterial infections in central nervous system in livestock, for example, in swine. The present disclosure further relates to methods of treatment and / or prevention of neurological diseases or disorders in animals, for example livestock, for example in swine, using fluoroquinolone antibiotics and associated compositions thereof.BACKGROUND

[0003] A bacterial infection can spread from an infected organ to other organs of the body causing multiple systemic diseases. For example, a bacterial infection can affect the brain when bacteria enter the bloodstream and travel to the brain. This can lead to serious consequences for example bacterial infection in the brain such as meningitis or encephalitis or other neurological diseases or disorders.

[0004] Streptococcus suis (5. suis) is regarded as one of the major swine bacterial pathogens and an emerging zoonotic agent. S. suis is commonly found in the respiratory, gastrointestinal, and reproductive tracts of healthy pigs. It is considered a commensal bacterium in the natural microbiota of pigs. The nasal cavities and tonsils of pigs serve as reservoirs for S. suis and other pathogenic microorganisms, establishing a niche within the upper respiratory' tract. Once inside the host, S. suis can spread through the bloodstream to various organs. After spread to different organs and tissues, S. suis can cause arthritis and / or other multiple systemic diseases such as septic shock, polyserositis, and endocarditis. S. suisMMV Ref.: 2920951-543977can also cross the blood-brain barrier, leading to bacterial infections in the central nervous system, for example, meningitis.

[0005] Vertical transmission is common from sow to piglet during birth. Additionally, transmission can occur through close contact between pigs, such as nose-to-nose contact or via contaminated environments. The bacterium poses not only a threat to swine health but also to public health, as it can be transmitted to humans, particularly individuals in close contact with infected pigs or pork-derived products, resulting in zoonotic infections. S. suis is a gram-positive bacterium possessing a polysaccharide capsule that provides protection against the host immune system. Based on capsular polysaccharide (CPS) antigens, 33 serotypes (types 1 to 31, 33, and 1 / 2) have been identified for S. suis. Among them, serotype 2 is the most frequently isolated serotype from diseased pigs in most countries and is most commonly involved in human infections. S. suis infections cause great economic losses in the swine industry worldwide.

[0006] Penicillin has traditionally been a mainstay in the treatment and control of S. suis infections; however, the emergence of penicillin-resistant strains necessitates the exploration of alternative therapeutic treatment options to combat infections effectively. Pradofloxacin, Pradalex™, a third-generation fluoroquinolone, was recently approved in the United States for treatment of S. suis respiratory infections in growing swine. Pradofloxacin is a highly effective quinolone antibiotic in veterinary medicine. Its antibacterial action and indications, application forms and suitable preparations are described, for example, in WO 1997 / 031001 Al, WO 2000 / 031076 Al, WO 2003 / 007995 Al, WO 2003 / 101422 Al, WO 2004 / 082658 Al, WO 2005 / 018641 Al. WO 2005 / 044271 Al. WO 2005 / 097789 Al, WO 2006 / 061156 Al, and WO 2018 / 146194 Al, the contents of each of these applications is herein incorporated by reference in their entireties.

[0007] Bacterial infections of the central nervous system, for example, meningitis, can lead to devastating neurological diseases and disorders. As such, there is a need to develop new methods and associated compositions capable of treating, for example, bacterial infections of the central nervous system, or neurological diseases or disorders caused by such bacterial infections of the central nervous system in livestock.SUMMARYMMV Ref.: 2920951-543977

[0008] In an aspect, the disclosure provides for a method of control, treatment and / or prevention of an infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound or a pharmaceutically acceptable salt, solvate, hydrate or hydrate of salt thereof. In an aspect, the disclosure provides for a method of control, treatment and / or prevention of an infection, optionally a bacterial infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound or a pharmaceutically acceptable salt, solvate, hydrate or hydrate of salt thereof. In an aspect, the disclosure provides for a method of control, treatment and / or prevention of a bacterial infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound or a pharmaceutically acceptable salt, solvate, hydrate or hydrate of salt thereof.

[0009] In an aspect, the disclosure provides for a method of control and / or treatment of a bacterial infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the fluoroquinolone compound, optionally pradofloxacin, is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system after at least about 2 hours of the administration.

[0010] In an aspect, the disclosure provides a method of treatment of a bacterial infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the fluoroquinolone compound, optionally pradofloxacin, is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system after at least about 2 hours of the administration.

[0011] In an aspect, the disclosure provides for a method of control and / or treatment of a bacterial infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the fluoroquinolone compound, optionally pradofloxacin, is effective inMMV Ref.: 2920951-543977alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system from about 2 hours - about 48 hours of the administration.

[0012] In some aspects, the disclosure provides a method of treatment of a bacterial infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, wherein the fluoroquinolone compound is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system from about 2 hours to about 48 hours of the administration, wherein the fluoroquinolone compound comprisesOor pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0013] In some aspects, the present disclosure provides methods for control, treatment and / or prevention of a bacterial infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the fluoroquinolone compound, optionally pradofloxacin, is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system after at least about 2 hours of the administration.

[0014] In additional aspects, the disclosure provides for methods of control, treatment and / or prevention of a bacterial infection in the central nervous system in livestock, wherein the bacterial infection originates from the respiratory tract, optionally lungs, the method comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.MMV Ref.: 2920951-543977

[0015] In some aspects, the present disclosure provides methods of control, treatment and / or prevention of a bacterial infection in the central nervous system in livestock, wherein the bacterial infection originates from the respiratory tract, optionally lungs, the method comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the treatment is effective in alleviation, amelioration and / or reduction of severity of symptoms after about 2 hours of the administration.

[0016] In some aspects, the present disclosure provides a method of treatment and / or prevention of a bacterial infection in central nervous system in livestock, wherein the bacterial infection originates from the respiratory tract, optionally lungs, the method comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the fluoroquinolone compound, optionally pradofloxacin, is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system after at least about 2 hours of the administration.

[0017] In some aspects, the present disclosure provides methods of control, treatment and / or prevention of a bacterial infection in the central nervous system in livestock, wherein the bacterial infection originates from the respiratory tract, optionally lungs, the method comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the treatment is effective in alleviation, amelioration and / or reduction of severity of symptoms from about 2 hours –about 48 hours of the administration of the fluoroquinolone compound, optionally pradofloxacin.

[0018] In some aspects, the fluoroquinolone compound, optionally pradofloxacin, is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system from about 2 hours - about 48 hours of the administration.

[0019] In some aspects, the present disclosure provides a method of treatment of a bacterial infection in the central nervous system in livestock comprising administering to the livestockMMV Ref.: 2920951-543977a therapeutically effective amount of a fluoroquinolone compound, wherein the fluoroquinolone compound is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system from about 2 hours to about 48 hours of the administration, wherein the fluoroquinolone compound comprisesor pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0020] In aspects, the fluoroquinolone compound has Cmaxof about 1 – 5 μg / mL, optionally from about 2 – 3 μg / mL, a t1 / 2from about 5 to about 12 hours, optionally from about 8 to about 9 hours, and Tmaxfrom about 15 minutes – about 90 minutes, optionally from about 30 – 60 minutes upon administration.

[0021] In some aspects, the bacterial infection is in the brain. In some aspects, the bacterial infection is of the brain. In some aspects, the bacterial infection is in the meninges. In some aspects, the bacterial infection is meningitis.

[0022] In some aspects, the bacterial infection disseminated systemically from the respiratory tract to the central nervous system.

[0023] In some aspects, the bacterial infection disseminated systemically from the respiratory tract to the brain. In some aspects, the bacterial infection disseminated systemically from the respiratory tract to the meninges.

[0024] In aspects, the fluoroquinolone compound comprises pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0025] In some aspects, the livestock is pig or swine. In some aspects, the livestock is cattle.MMV Ref.: 2920951-543977

[0026] In some aspects, the administration is oral. In some aspects, the administration is parenteral.

[0027] In some aspects, the administration is parenteral, optionally intravenous, subcutaneous, intramuscular or intrathecal. In some aspects, the administration is subcutaneous. In some aspects, the administration is intramuscular.

[0028] In additional aspects, the disclosure provides for methods of treatment and / or prevention of a neurological disease or disorder in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some aspects, the disclosure provides a method of treatment of a neurological disease or disorder in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0029] In some aspects, the neurological disease or disorder is caused by a bacterial infection.

[0030] In some aspects, the neurological disease or disorder is caused by a bacterial infection in central nervous system.

[0031] In some aspects, the neurological disease or disorder is caused by a bacterial infection in the brain. In some aspects, the neurological disease or disorder is caused by a bacterial infection in the meninges.

[0032] In some aspects, the bacterial infection originates from the respiratory tract, optionally lungs. In some aspects, the neurological disease or disorder is caused by a bacterial infection in central nervous system, wherein the bacterial infection disseminated systemically from the respiratory tract to the central nervous system. In some aspects, the neurological disease or disorder is caused by a bacterial infection in the brain, wherein the bacterial infection disseminated systemically from the respiratory tract to the brain.

[0033] In some aspects, the neurological disease or disorder is caused by a bacterial infection in the brain, wherein the bacterial infection disseminated systemically from the respiratory- tract to the meninges.MMV Ref.: 2920951-543977

[0034] In some aspects, the neurological disease or disorder is caused by meningitis. In some aspects, the neurological disease or disorder is meningitis.

[0035] In some aspects, the bacterial infection is caused by one or more bacteria of the genus Streptococcus, Bordetella, Glaesserella (Haemophilus), Mycoplasma, Pasteurella, or Histophilus. In additional aspects, the bacterial infection is caused by one or more bacteria Streptococcus suis (S. suis), Bordetella bronchiseptica (B. bronchiseptica), Glaesserella (Haemophilus) parasuis (G. parasuis), Mycoplasma hyopneumoniae (M. hyopneumoniae), Pasteurella multocida (P. multocida), or Histophilus somni.

[0036] In some aspects, the bacterial infection is caused by Streptococcus suis.

[0037] In additional aspects, the disclosure provides for pharmaceutical compositions comprising a fluoroquinolone compound, optionally pradofloxacin. or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some aspects, the composition further comprises at least one pharmaceutically acceptable excipient.

[0038] In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a neurological disease or disorder in livestock.

[0039] In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a neurological disease or disorder in livestock, wherein the neurological disease or disorder is caused by a bacterial infection in the central nervous system of the livestock.

[0040] In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a bacterial infection in the central nervous system in livestock. In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a bacterial infection of the central nervous system in livestock.MMV Ref.: 2920951-543977

[0041] In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a bacterial infection in livestock, wherein the bacterial infection is of the central nervous system. In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a bacterial infection in livestock, wherein the bacterial infection is of the brain.

[0042] In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a bacterial infection in the central nervous system in livestock, wherein the bacterial infection is of the brain, wherein the bacterial infection originates from the respiratory tract, optionally lungs. In some aspects, the bacterial infection originates from the lungs. In some aspects the livestock is pig or swine.

[0043] In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a bacterial infection in the central nervous system in livestock, wherein the bacterial infection is of the brain.

[0044] In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a bacterial infection in the central nervous system in livestock, wherein the bacterial infection is of the brain, optionally wherein the bacterial infection disseminated systemically from the respiratory tract, optionally lungs, to the central nervous system. In some aspects, the disclosure provides use of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, for the manufacture of a medicament for treatment and / or prevention of a bacterial infection in the central nervous system in livestock, wherein the bacterial infection is of the brain, optionally wherein the bacterial infection disseminated systemically from the respiratory tract, optionally lungs, to the central nervous system, wherein the neurological disease or disorderMMV Ref.: 2920951-543977is caused by a bacterial infection in central nervous system of the livestock. In some aspects the livestock is pig or swine.

[0045] In some aspects, the bacterial infection is caused by one or more bacteria of the genus Streptococcus, Bordetella, Glaesserella (Haemophilus), Mycoplasma, Pasteurella, or Histophilus. In additional aspects, the bacterial infection is caused by one or more bacteria Streptococcus suis (S. suis), Bordetella bronchiseptica (B. bronchiseptica), Glaesserella (Haemophilus) parasuis (G. parasuis), Mycoplasma hyopneumoniae (M. hyopneumoniae), Pasteurella multocida (P. multocida), or Histophilus somni. In some aspects, the bacterial infection is caused by Streptococcus suis.

[0046] In some aspects, the fluoroquinolone compound comprises pradofloxacin. In some aspects, the fluoroquinolone compound comprisesor pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1. Schematic representation of a custom plate with a range of concentrations of pradofloxacin. POS: Positive Control; NEG: Negative Control; PRA: Pradofloxacin. The numbers under PRA represent the concentration of pradofloxacin in pg / mL.DETAILED DESCRIPTION

[0048] The inventors have surprisingly found that pradofloxacin (for example. Formula I) is effective in the control, treatment and / or prevention of bacterial infections of the central nervous system in animals, optionally livestock, optionally pigs (swine). Pradofloxacin is effective in the control, treatment and / or prevention of bacterial infections of the brain. Further, pradofloxacin is effective in the treatment and / or prevention of neurological diseases or disorders in livestock. Specifically, pradofloxacin is effective in the treatment and / orMMV Ref.: 2920951-543977prevention of neurological disorders caused by bacterial infection in the central nervous system in livestock.

[0049] In some aspects, the present disclosure is directed toward the use of pradofloxacin for control, treatment and / or prevention of central nervous system infections in livestock. More specifically, the present disclosure is directed toward the use of pradofloxacin for the control, treatment and / or prevention of bacterial infections of the brain originating from the respiratory tract, optionally lungs.

[0050] The fluoroquinolone class of antibacterial, or antibiotic, compounds are known to be effective in controlling, treating or preventing systemic peripheral bacterial infections in livestock. The fluoroquinolone class of antibacterial compounds includes Enrofloxacin, Ciprofloxacin, Marbofloxacin, Danofloxacin, Difloxacin, Norfloxacin, Pradofloxacin, Orbifloxacin and the like.

[0051] Pradofloxacin is a fluoroquinolone antibiotic, 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (pradofloxacin), and represented by Formula IO

[0052] As described herein, in aspects the disclosure provides for pradofloxacin which include esters, salts, solvates, hydrates and hydrates of the salts. Pradofloxacin, being solid, can, under certain circumstances, form various crystal modifications; see, US Patent No. 6,664,268 (crystal modification B), US Patent No. 6,436,955 (crystal modification A), US Patent No. 6,492,391 (crystal modification C), US Patent No. 6,492,391 (crystal modification D), US Patent No. 6,995,170 (semi hydrochloride), the contents of each of these applications is herein incorporated by reference in their entireties.

[0053] In aspects described herein, optically active pradofloxacin can exist in the form of its racemates or in enantiomeric forms. Not only the pure enantiomers, but also their mixturesMMV Ref.: 2920951-543977can be employed in accordance with the invention. Pradofloxacin that is usually used for pharmaceutical purposes is the isomer with the S, S-pyrrolidino-piperidine substituent.Suitable salts are pharmaceutically useful acid addition salts and basic salts.

[0054] Pradofloxacin has unique PK / PD properties, among fluoroquinolone antibiotics, with a higher maximum concentration (Cmax) of 2.5 μg / mL, shorter time to reach maximum concentration (Tmax) of 45 minutes, and a half-life (T1 / 2) of 8.5 hours. These properties aid in achieving and maintaining drug concentrations above the MIC for sufficient durations to inhibit bacterial growth effectively and limit the selection of resistant mutants. Further, the effects of the treatment can be observed faster when using pradofloxacin as compared to other fluoroquinolone antibiotics.

[0055] In some embodiments, the present disclosure provides a method of control, treatment and / or prevention of bacterial infections of the central nervous system, in animals, optionally livestock. In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain, in animals, optionally livestock. In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain originating from the respiratory' tract, for example lungs, in animals, optionally livestock. In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain originating from the lungs, in animals, optionally livestock.

[0056] In some embodiments, the present disclosure provides method of control, treatment and / or prevention of a bacterial infection of central nervous system in animals, optionally livestock, wherein the method comprises administering to the animals, optionally livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides method of control treatment and / or prevention of abacterial infection of central nervous system in animals, optionally livestock, wherein the method comprises administering to the animals, optionally livestock a therapeutically effective amount of pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0057] In some embodiments, the fluoroquinolone compound has Cmaxfrom about 1-5 μg / mL, optionally from about 1.5 μg / mL – about 4.5 μg / mL, optionally from about 2.0MMV Ref.: 2920951-543977μg / mL – about 4.5 μg / mL, optionally from about 2.0 μg / mL – about 4.0 μg / mL, optionally from about 2.0 μg / mL – about 3.5 μg / mL, optionally from about 2.0 μg / mL – about 3.0 μg / mL, optionally from about 2.0 μg / mL – about 2.5 μg / mL; t1 / 2from about 5 to about 12 hours, optionally from about 6 hours to about 11 hours, optionally from about 6 hours to about 10 hours, optionally from about 7 hours to 10 hours, optionally from about 8 hours to 10 hours, optionally from about 8 hours to about 9 hours; and Tmaxfrom about 15 min – about 90 min, optionally from about 30 min – about 75 min, optionally from about 30 min – about 60 min, optionally from about 40 min – about 60 min; upon administration.

[0058] In some embodiments, the present disclosure provides a method of control, treatment and / or prevention of a bacterial infection in central nervous system in animals, optionally livestock comprising administering to the animals, optionally livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the treatment is effective in alleviation, amelioration and / or reduction of severity of symptoms from about 2 hours - about 48 hours, optionally from about 2 hours - about 46 hours, optionally from about 2 hours - about 44 hours, optionally from about 2 hours - about 42 hours, optionally from about 2 hours - about 40 hours, optionally from about 2 hours - about 38 hours, optionally from about 2 hours - about 36 hours, optionally from about 2 hours -about 34 hours, optionally from about 2 hours - about 32 hours, optionally from about 2 hours - about 30 hours, optionally from about 2 hours - about 28 hours, optionally from about 2 hours - about 26 hours, optionally from about 2 hours - about 24 hours, optionally from about 2 hours - about 22 hours, optionally from about 2 hours - about 20 hours, optionally from about 2 hours - about 18 hours, optionally from about 2 hours - about 16 hours, optionally from about 2 hours - about 14 hours, optionally from about 2 hours - about 12 hours, optionally from about 2 hours - about 10 hours, optionally from about 2 hours -about 8 hours, optionally from about 2 hours - about 6 hours, optionally from about 24 hours - about 48 hours, optionally from about 26 hours - about 48 hours, optionally from about 28 hours - about 48 hours, optionally from about 30 hours - about 48 hours, optionally from about 32 hours - about 48 hours, optionally from about 34 hours - about 48 hours, optionally from about 36 hours - about 48 hours, optionally from about 38 hours - about 48 hours, optionally from about 40 hours - about 48 hours, optionally from about 42 hours - about 48 hours, optionally from about 44 hours - about 48 hours, optionally from about 46 hours -MMV Ref.: 2920951-543977about 48 hours from the administration of the fluoroquinolone compound, optionally pradofloxacin.

[0059] In some embodiments, the present disclosure provides a method of control, treatment and / or prevention of a bacterial infection in central nervous system in animals, optionally livestock comprising administering to the animals, optionally livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the treatment is effective in alleviation, amelioration and / or reduction of severity' of symptoms from about 2 hours - about 10 hours from the administration of the fluoroquinolone compound, wherein the fluoroquinolone compound has Cmaxfrom about 1 - 5 μg / mL, optionally from about 2 - 3 μg / mL, t1 / 2from about 5 hours to about 12 hours, optionally from about 8 hours to about 9 hours, and Tmaxfrom about 15 minutes – about 90 minutes, optionally from about 30 minutes – about 60 minutes upon administration.

[0060] In some embodiments, the present disclosure provides method of control, treatment and / or prevention of a bacterial infection of the brain in animals, optionally livestock, wherein the method comprises administering to the animals, optionally livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides method of control, treatment and / or prevention of a bacterial infection of the brain in animals, optionally livestock, wherein the method comprises administering to the animals, optionally livestock a therapeutically effective amount of pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0061] In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain in swine, wherein the method comprises administering to the swine a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain originating from the respiratory tract, optionally lungs in swine, wherein the method comprises administering to the swine a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of saltMMV Ref.: 2920951-543977thereof. In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain originating from the lungs in swine, wherein the method comprises administering to the swine a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0062] In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain in cattle, wherein the method comprises administering to the cattle a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain originating from the respiratory tract, optionally lungs in cattle, wherein the method comprises administering to the cattle a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides method of control, treatment and / or prevention of bacterial infections of the brain originating from the lungs in cattle, wherein the method comprises administering to the cattle a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0063] In some embodiments, the present disclosure provides methods of control, treatment and / or prevention of bacterial infections of the brain in cat, wherein the method comprises administering to the cat a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides methods of control, treatment and / or prevention of bacterial infections of the brain originating from the respiratory tract, optionally lungs in cat. wherein the method comprises administering to the cat a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides methods of control, treatment and / or prevention of bacterial infections of the brain originating from the lungs in cat, wherein the method comprises administering to the cat a therapeutically effective amount of aMMV Ref.: 2920951-543977fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0064] In some embodiments, the present disclosure provides methods of control, treatment and / or prevention of bacterial infections of the brain in dog, wherein the method comprises administering to the dog a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides methods of control, treatment and / or prevention of bacterial infections of the brain originating from the respiratory tract, optionally lungs in dog, wherein the method comprises administering to the dog a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides methods of control, treatment and / or prevention of bacterial infections of the brain originating from the lungs in dog, wherein the method comprises administering to the dog a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

[0065] In some embodiments, the bacterial infection is caused by one or more bacteria of the genus Streptococcus, Bordetella, Glaesserella (Haemophilus), Mycoplasma, Histophilus or Pasteurella. In some embodiments, the infection is caused by one or bacteria Streptococcus suis (S. suis), Bordetella bronchiseptica (B. bronchiseptica), Glaesserella (Haemophilus) parasuis (G. parasuis), Mycoplasma hyopneumoniae (M. hyopneumoniae). Histophilus somni (H. somni) ox Pasteurella multocida (P. multocida). In some embodiments, the bacterial infection is caused by Streptococcus suis (S. suis).

[0066] In some embodiments, the present disclosure provides methods of treatment and / or prevention of neurological disease or disorder caused by bacterial infection in the central nervous system, in animals, optionally livestock. In some embodiments, the present disclosure provides methods of treatment and / or prevention of neurological disease or disorder caused by bacterial infection in the central nervous system originating from the respiratory tract, optionally lungs. In some embodiments, the neurological disease or disorder is caused by the bacterial infection disseminated systemically from the respiratory tract to the central nervous system. In some embodiments, the neurological disease or disorder is caused by the bacterial infection disseminated systemically from the respiratory tract to the brain.MMV Ref.: 2920951-543977

[0067] In some embodiments, the present disclosure provides methods of treatment and / or prevention of a neurological disease or disorder in animals, optionally livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof. In some embodiments, the present disclosure provides methods of treatment and / or prevention of a neurological disease or disorder in animals, optionally livestock comprising administering to the livestock a therapeutically effective amount pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof

[0068] Preferred features, embodiments and variations of the invention may be discerned from the following detailed description which provides sufficient information for those skilled in the art to perform the invention. The detailed description is not to be regarded as limiting the scope of the preceding summary of the invention in any way.

[0069] Throughout the specification and claims, unless the context requires otherwise, the term '‘substantially” or “about” will be understood to not be limited to the value for the range qualified by the terms.

[0070] In this specification and the appended claims, the singular forms “a,” '‘an,” and “the” include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

[0071] “Treatment,” as used herein, refers broadly to alleviating signs and / or symptoms of a disease or injury condition. For example, treatment of a bacterial infection means alleviating, ameliorating, or relieving at least to some extent the symptoms of the bacterial infection, and / or reducing at least to some extent, the amount of pathogenic bacteria in the location of the infection. The treatment of a neurological disease of disorder means alleviating, ameliorating, or relieving at least to some extent the symptoms of the neurological disease or disorder as defined by the attending medical or veterinary officer attending to the subject in need thereof. “Prevention” means prophylactic measures, where the therapeutic composition is administered prior to the development of signs and / or symptoms or exposure to the disease condition to lessen the development of signs and / or symptoms of a disease condition.MMV Ref.: 2920951-543977

[0072] The term “control’' as used herein refers to management of the disease, or infection, after exposure to the disease condition, for example the pathogen, but prior to the development of signs and / or symptoms in an effort to reduce the probability of development and / or severity of signs and / or symptoms of a disease condition.

[0073] The term “effects of the treatment” means alleviation, amelioration, and / or reduction of severity at least to some extent the symptoms of the bacterial infection, and / or reducing at least to some extent, the amount of pathogenic bacteria in the location of the infection. The alleviation, amelioration and / or reduction of severity of symptoms may be determined by any of the known techniques in the art, for example, visible signs of illness, rectal temperature, or extending the lifetime of affected animals by about 2 - about 24 hours.

[0074] In some embodiments, the treatment is effective in alleviation, amelioration and / or reduction of severity of symptoms after at least about 2 hours of the administration. In some embodiments, the treatment is effective in alleviation, amelioration and / or reduction of severity of symptoms after about 3 hours, optionally after about 4 hours, optionally after about 5 hours, optionally after about 6 hours, optionally after about 7 hours, optionally after about 8 hours, optionally after about 9 hours, optionally after about 10 hours, optionally after about 12 hours, optionally after about 14 hours, optionally after about 16 hours, optionally after about 18 hours, optionally after about 20 hours, optionally after about 22 hours, optionally after about 24 hours, optionally after about 25 hours, optionally after about 26 hours, optionally after about 27 hours, optionally after about 28 hours, optionally after about 29 hours, optionally after about 30 hours, optionally after about 31 hours, optionally after about 32 hours, optionally after about 33 hours, optionally after about 34 hours, optionally after about 36 hours, optionally after about 38 hours, optionally after about 40 hours, optionally after about 42 hours, optionally after about 44 hours, optionally after about 46 hours of the administration.

[0075] In some embodiments, the treatment is effective in alleviation, amelioration and / or reduction of severity of symptoms from about 2 hours - about 48 hours from administration of the fluoroquinolone compound, optionally pradofloxacin. In some embodiments, the treatment is effective in alleviation, amelioration and / or reduction of severity of symptoms from about 2 hours - about 46 hours, optionally from about 2 hours - about 44 hours, optionally from about 2 hours - about 42 hours, optionally from about 2 hours - about 40 hours, optionally from about 2 hours - about 38 hours, optionally from about 2 hours - aboutMMV Ref.: 2920951-54397736 hours, optionally from about 2 hours - about 34 hours, optionally from about 2 hours -about 32 hours, optionally from about 2 hours - about 30 hours, optionally from about 2 hours - about 28 hours, optionally from about 2 hours - about 26 hours, optionally from about 2 hours - about 24 hours, optionally from about 2 hours - about 22 hours, optionally from about 2 hours - about 20 hours optionally from about 2 hours - about 18 hours, optionally from about 2 hours - about 16 hours optionally from about 2 hours - about 14 hours, optionally from about 2 hours - about 12 hours, optionally from about 24 hours -about 48 hours, optionally from about 25 hours - about 48 hours, optionally from about 26 hours - about 48 hours, optionally from about 27 hours - about 48 hours, optionally from about 28 hours - about 48 hours, optionally from about 29 hours - about 48 hours, optionally from about 30 hours - about 48 hours, optionally from about 31 hours - about 48 hours, optionally from about 32 hours - about 48 hours, optionally from about 33 hours - about 48 hours, optionally from about 34 hours - about 48 hours, optionally from about 35 hours -about 48 hours, optionally from about 36 hours - about 48 hours, optionally from about 37 hours - about 48 hours, optionally from about 39 hours - about 48 hours, optionally from about 39 hours - about 48 hours, optionally from about 40 hours - about 48 hours, optionally from about 41 hours - about 48 hours, optionally from about 42 hours - about 48 hours, optionally from about 43 hours - about 48 hours, optionally from about 44 hours - about 48 hours, optionally from about 45 hours - about 48 hours, optionally from about 46 hours -about 48 hours, optionally from about 47 hours - about 48 hours, from the administration of the fluoroquinolone compound, for example, pradofloxacin.

[0076] In some embodiments, the method of control and / or treatment of the present disclosure is more effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system relative to other fluoroquinolone antibacterial compounds in a similar dosage conditions. In some embodiments, the method of control and / or treatment of the present disclosure is more effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system relative to enrofloxacin in a similar dosage conditions. In some embodiments, the method of control and / or treatment of the present disclosure is more effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system relative to beta-lactam antibacterial compounds in a similar dosage conditions. In some embodiments, the method of control and / or treatment of the present disclosure is more effective in alleviation, amelioration and / orMMV Ref.: 2920951-543977reduction of severity of symptoms of the bacterial infection of the central nervous system faster relative to penicillin in a similar dosage conditions. In some embodiments, the method of control and / or treatment of the present disclosure is more effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system faster relative to macrolide antibacterial compounds in a similar dose conditions.

[0077] In some embodiments, the method of control and / or treatment of the present disclosure is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system faster than other fluoroquinolone antibacterial compounds in a similar dosage conditions. In some embodiments, the method of control and / or treatment of the present disclosure is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system faster than enrofloxacin in a similar dosage conditions. In some embodiments, the method of control and / or treatment of the present disclosure is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system faster than beta-lactam antibacterial compounds in a similar dosage conditions. In some embodiments, the method of control and / or treatment of the present disclosure is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system faster than penicillin in a similar dosage conditions. In some embodiments, the method of control and / or treatment of the present disclosure is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection of the central nervous system faster than macrolide antibacterial compounds in a similar dose conditions.

[0078] “Pharmaceutically acceptable salts” are taken to mean, for example, the salts of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulphonic acid. 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. Furthermore, the compounds according to the present disclosure can be bound to acidic or basic ion exchangers.Pharmaceutically useful basic salts which may be mentioned are the alkali metal salts, for example the sodium or potassium salts, the alkaline earth metal salts, for example the magnesium or calcium salts; the zinc salts, the silver salts and the guanidinium salts.MMV Ref.: 2920951-543977

[0079] “Hydrates” are taken to mean not only the hydrates of the fluoroquinolone itself, but also the hydrates of its salts. A particular example which may be mentioned is the stable pradofloxacin trihydrate (see US Patent No. 7,977,484, incorporated herein by reference in its entirety).

[0080] The term “active ingredient” or “antibacterial compound” as used herein means the fluoroquinolone compound, for example, pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof.

[0081] “Central nervous system” refers to the brain and its surrounding tissues, for example the meninges, the brain stem, and the interstitial fluid; and the spinal column including the spinal cord and the cerebrospinal fluid. “Respiratory tract” refers to the respiratory system, for example, the upper respiratory tract, the lower respiratory tract, the nose, sinuses, mouth, throat, windpipe, bronchi, bronchioles and lungs.

[0082] '‘Neurological disease or disorder” means conditions that affect the brain as well as the nerves found throughout the body and the spinal cord. Non-limiting examples of neurological diseases and disorders in pigs include meningitis, trembling, incoordination, ataxia, paddling, recumbency, convulsions, nystagmus, opisthotonos and seizures, including severe epileptiform-like seizures. The terms “neurological disease or disorder” and “neurologic disease or disorder” are used interchangeably in this disclosure.

[0083] The terms “therapeutically effective amount” or “pharmaceutically effective amount” or “effective amount” are used interchangeably herein and mean an amount, which has a therapeutic effect or is the amount required to produce a therapeutic effect, or “effect of the treatment” in the subject. For example, a “therapeutically effective amount” or “pharmaceutically effective amount” or “effective amount” of an antibacterial agent or a pharmaceutical composition is the amount of the antibacterial agent or a pharmaceutical composition comprising the antibacterial agent, or the active ingredient, required to produce a desired therapeutic effect as may be judged by the attending medical officer in a subject in need of therapy, or by clinical trial results, model animal infection studies, and / or in vitro studies. For prophylactic treatments, for example, for the prevention of a bacterial infection, the therapeutically effective amount is that amount which would be effective in preventing the bacterial infection. Further, the “therapeutically effective amount” or “pharmaceutically effective amount” or “effective amount” for the treatment of a neurological disease orMMV Ref.: 2920951-543977disorder means that amount of the active ingredient which results in at least one of prevention or delay of onset or amelioration, and / or reduction in severity of symptoms of a neurological disorder in a subject or an attainment of a desired biological outcome.

[0084] The term “Cmax” refers to the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is administered. The term “Tmax” refers to the time it takes for a drug to reach the maximum concentration (Cmax) after administration. The term “ti / 2” refers to the half-life of the drug, which means the amount of time required for the drug concentration measured in plasma (or other biological matrices) to be reduced to exactly half of its starting concentration or amount.

[0085] The term “pharmaceutically inert ingredient” or “carrier” or “excipient” refers to a compound or material used to facilitate administration of a compound, for example, to increase the solubility of the compound. Typical, non-limiting examples of such carriers or excipients include bulking agents, solubilizing agents, stabilizing agents, buffering agents. pH adjusting agents, tonicity adjustors, hydrotropic agent, chelating agents, antioxidants, preservatives and the like. Typical, non-limiting examples of solid excipients include, starch, lactose, dicalcium phosphate, sucrose, and kaolin. Typical, non-limiting examples of liquid excipients include sterile water and edible oils such as peanut oil and sesame oil. In addition, various adjuvants commonly used in the art may also be included. These and other such excipients are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N. J. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g.. in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press., which is incorporated herein by reference in its entirety.

[0086] “Unit dosage form,” as used herein, refers broadly to physically discrete units suitable as unitary dosages for subjects in need thereof, each unit containing a predetermined quantity of the composition of the present invention, alone or in combination with other active agents, calculated in an amount sufficient to produce the desired effect, in association with one or more pharmaceutically acceptable excipient, for example diluent, carrier, or vehicle, where appropriate.

[0087] “Subject” means a non-human animal such as companion animals or livestock.“Animal” as used herein means companion animals or livestock. “Livestock” meansMMV Ref.: 2920951-543977mammals such as, for example, cattle, horses, sheep, pigs (also referred to as swine), goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur bearers such as. for example, minks, chinchilla, racoons and birds such as, for example, chickens, geese, turkeys, ducks, pigeons and bird species for keeping on domestic premises and in zoos. In some embodiments, the subject is cattle or swine. In some embodiments the subject is swine. In some embodiments the subject is cattle. “Companion animal” means a pet or other domestic animal, for example cats, dogs, horses, guinea pigs and mice. In some embodiments, the subject is cat or dog. In some embodiments, the subject is cat. In some embodiments, the subject is dog.

[0088] “Serotype” means an antigenic property of a cell (for example bacteria or virus) identified by molecular methods”.

[0089] As used herein, the terms “bacterial infection in the central nervous system” and “bacterial infection of the central nervous system” are used interchangeably. Similarly, the terms “bacterial infection in the brain” and “bacterial infection of the brain” are used interchangeably. In some embodiments, the present disclosure provides methods of treatment and / or prevention of bacterial infection in the central nervous system originating from the lungs. “Bacterial infection in the central nervous system originating from the lungs” means an infection that initially impacts the respiratory system, specifically the lungs, and progressively spreads to the central nervous system. Accordingly, “bacterial infection in the brain originating from the lungs” means an infection that initially impacts the respiratory system, specifically the lungs, and progressively spreads to the brain. Without being bound to a theory, it is believed that the main route of 5. suis infection in pigs is the upper respiratory tract. Once inside the host, S. suis can spread through the bloodstream to various organs. S. suis can also cross the blood-brain barrier, causing the bacterial infection to be disseminated systemically from the respiratory tract to the central nervous system, leading to bacterial infections in the central nervous system, for example, the brain, or the meninges, causing for example, meningitis.

[0090] In some embodiments, the present disclosure provides methods of treatment and / or prevention of neurological disease or disorder caused by bacterial infection in livestock. In some embodiments, the present disclosure provides methods of treatment and / or prevention of neurological disease or disorder caused by bacterial infection in the central nervous system, in livestock. In some embodiments, the present disclosure provides methods ofMMV Ref.: 2920951-543977treatment and / or prevention of neurological disease or disorder caused by bacterial infection in the central nervous system originating from the lungs, in livestock. In some embodiments, the neurological disease or disorder is caused by the bacterial infection disseminated systemically from the respiratory tract to the central nervous system. In some embodiments, the neurological disease or disorder is caused by the bacterial infection disseminated systemically from the respiratory’ tract to the brain.

[0091] In some embodiments, the present disclosure provides a method of treatment and / or prevention of a neurological disease or disorder in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate or hydrate of salt thereof. In some embodiments, the present disclosure provides a method of treatment and / or prevention of a neurological disease or disorder in livestock comprising administering to the livestock a therapeutically effective amount pradofloxacin, or a pharmaceutically acceptable salt, solvate, hydrate or hydrate of salt thereof

[0092] In some embodiments, the method of present disclosure comprises administering to a subject in need thereof, a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate, or hydrate of salt thereof. In some embodiments, the method of present disclosure comprises administering to a subject in need thereof, a therapeutically effective amount of pradofloxacin or a pharmaceutically acceptable salt, hydrate, or hydrate of salt thereof.

[0093] In some embodiments, the method of the present disclosure comprises administering to a subject in need thereof, a composition comprising a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate, or hydrate of salt thereof. In some embodiments, the method of the present disclosure comprises administering to a subject in need thereof, a composition comprising pradofloxacin or a pharmaceutically acceptable salt, hydrate, or hydrate of salt thereof.

[0094] The terms “administration"’ or “administering"’ mean delivery of a composition or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate methods, which serves to deliver the composition or its active ingredients or other pharmaceutically active ingredients to the site of the infection. The method of administration may vary depending on various factors, such as for example, the components of theMMV Ref.: 2920951-543977pharmaceutical composition or the type / nature of the pharmaceutically active or inert ingredients, the site of the potential or actual infection, the microorganism involved, severity of the infection, age and physical condition of the subject and a like.

[0095] In principle the compositions described herein can be administered to the subject via different routes, for example oral, or parenteral. In some embodiments, the composition is administered orally. Non-limiting examples of oral dosage forms include ablets, dragees, capsules, pills, granules, suppositories, injections and orally administrable solutions, suspensions and emulsions, as well as pastes, ointments, gels, creams, lotions, powders and sprays. In some embodiments the composition is administered orally as a solution, suspension or emulsion. In some embodiments, the composition is administered parenterally, for example subcutaneously, intramuscularly, intravenously, intramammarily, intraperitoneally, or intrathecally. In some embodiments, the composition is administered via subcutaneous or intramuscular injection. In some embodiments the composition is administered intravenously. In some embodiments, the composition is injected into the subject via an injection.

[0096] Typical dosages are in the range of about 1 to 50 mg / kg target animal. In some embodiments, the dosage of a fluoroquinolone compound, optionally pradofloxacin ranges from about 1 to 40 mg / kg, optionally from about 1 to about 35 mg / kg, optionally from about 1 to about 30 mg / kg, optionally from about 1 to about 25 mg / kg, optionally from about 1 to about 20 mg / kg, optionally from about 1 to about 15 mg / kg, optionally from about 1 to about 10 mg / kg, optionally from about 2 to about 20 mg / kg, optionally from about 2 to about 15 mg / kg, optionally from about 2 to about 10 mg / kg, optionally from about 5 to about 20 mg / kg. optionally from about 5 to about 15 mg / kg. and optionally from about 5 to about 10 mg / kg.

[0097] The dosage may be administered via one or more unit dosage forms. With regard to the treatment scheme one application may be sufficient but application on two or more days may be required depending on the circumstances and the disease. Usually the application is on consecutive days.

[0098] In some embodiments, the method of the present disclosure comprises administration of a single dose of a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin or a composition comprising a fluoroquinolone compound, optionally pradofloxacin to a subject in need thereof.MMV Ref.: 2920951-543977

[0099] In some embodiments, the method of the present disclosure comprises administration of multiple doses of a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin or a composition comprising a fluoroquinolone compound, optionally pradofloxacin to a subject in need thereof.

[0100] In some embodiments, the method comprises administering the composition daily. In some embodiments, the method comprises administering the composition weekly. In some embodiments, the method comprises administering the composition once, twice, thrice, four times, five times, or six times per week.

[0101] In some embodiments, the administration is a single dose. In some embodiments, the composition is administered for a duration of at least 28 days. In some embodiments, the composition is administered for at least 14 days. In some embodiments, the composition is administered for at least 7 days. In some embodiments, the composition is administered for at least 3 days. In some embodiments, the composition is administered for at least 1 day.

[0102] In some embodiments, the present disclosure provides compositions comprising a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin, or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof. The composition may be in a solid or liquid form. In some embodiments, the composition is a liquid composition. In some embodiments, the composition of the present disclosure comprise pradofloxacin in a concentration of 3 to 30 %, optionally from about 10 to 25 %, optionally from about 15 to 25 %. Unless indicated otherwise, the data in percentages are given in each case as w / v (i.e. in g / 100 ml of solution), and - in case of salts or hydrates - are calculated to refer to the content of pure pradofloxacin.

[0103] In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the treatment of bacterial infection in the central nervous system in livestock. In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the treatment and / or prevention of bacterial infection in the central nervous system originating from the lungs in livestock. In some embodiments, the bacterial infection is disseminated systemically from the respiratory tract to the central nervous system.MMV Ref.: 2920951-543977

[0104] In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the control, treatment and / or prevention of bacterial infection in the brain in animals, optionally livestock. In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the control, treatment and / or prevention of bacterial infection in the brain originating from the respiratory tract, optionally lungs in animals, optionally livestock. In a preferred embodiment, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the control, treatment and / or prevention of bacterial infection in the brain originating from the respiratory tract, optionally lungs in swine. In some embodiments, the bacterial infection is disseminated systemically from the respiratory tract to the central nervous system, optionally brain.

[0105] In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hy drate of salt thereof, in the manufacture of a medicament for the control, treatment and / or prevention of neurological disease or disorder caused by bacterial infection in animals, optionally livestock. In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the control, treatment and / or prevention of neurological disease or disorder caused by bacterial infection in the central nervous system, in animals, optionally livestock. In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the control, treatment and / or prevention of neurological disease or disorder caused by bacterial infection in the central nervous system originating from the respiratory tract, optionally lungs, in livestock. In some embodiments, the neurological disease or disorder is caused by the bacterial infection disseminated systemically from the respiratory tract to the central nervous system, optionally brain in livestock, optionally swine.MMV Ref.: 2920951-543977

[0106] In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the control, treatment and / or prevention of neurological disease or disorder caused by bacterial infection in the brain, in animals, optionally livestock. In some embodiments, the present disclosure provides a use of a fluoroquinolone compound, optionally pradofloxacin or a pharmaceutically acceptable salt, hydrate or hydrate of salt thereof, in the manufacture of a medicament for the control, treatment and / or prevention of neurological disease or disorder caused by bacterial infection in the brain originating from the respiratory tract, optionally lungs, in livestock. In some embodiments, the neurological disease or disorder is caused by the bacterial infection disseminated systemically from the respiratory tract to the central nervous system, optionally brain in livestock, optionally swine.

[0107] EXAMPLES

[0108] Example 1

[0109] Pradofloxacin minimum inhibitory concentration (MIC) of Streptococcus suis associated with central nervous system (CNS) disease in swine was reviewed. This review was conducted in accordance with Good Scientific Practice (GSP); Good Documentation Practice (GDP); and Relevant laboratory SOPs or study-specific procedures (SSPs).

[0110] Thirty well-characterized, central nervous system (CNS) disease-associated, Streptococcus suis isolates recovered from pigs at different farms or if at the same farm, recovered at least 3 months apart, were tested in this study. The demographics of the isolates tested are summarized below.Table 1: Streptococcus suis Isolate Demographics Sorted by various US StatesMLSTState AgeSample ID Organ Serotype Sequence Isolate (week)Type1 AR 4 Brain Swab 17 7782 IA 4 Brain _* 977MMV Ref.: 2920951-5439773 IA 5 Brain 7 32 4 IA 7 Brain 4 977 5 IA < 11 Brain 7 29 6 IA 10 Brain 2 28 7 IA 10 Brain 2 1 8 IA 4 Brain 1 1 9 IA 5 Brain 10 1170 10 IA 4 Brain 7 373 11 IA 5.7 Brain 3 108 12 IL 10 Brain 24 94 13 IL 6 Brain 33 1381 14 IL 2.7 Brain 23 108 15 IN 5 Brain 1 1 16 IN 8 Brain 7 108 17 IN 5 Brain Swab 5 977 18 MI 5 Brain 4 485 19 MI 2 Brain 1 1 20 MN 6 Brain 3 94 21 MN 2.3 Brain Swab 1 1 22 MN 6 Brain 5 977MMV Ref.: 2920951-54397723 MO 3 Brain 5 97724 MO 4 Brain 1 125 OH 5 Brain 5 97726 OH 7 Brain 23 10827 OK 2.8 Brain 1 128 PA 3 Brain 1 / 2 2829 SD 4 Brain 1 / 2 2830 SD 7 Brain 4 977*Isolate did not react to any of the antisera tested. This isolate’s serotype is unknown. MLST: Multilocus sequence typing; AR: Arkansas; IA: Iowa; IL: Illinois; IN: Indiana; MI: Michigan; MN: Minnesota; MO: Missouri; OH: Ohio; OK: Oklahoma; PA: Pennsylvania; SD: South Dakota

[0111] Streptococcus suis isolates were recovered from the brains of 2 to 11-week-old pigs from farms across eleven U. S. states. Isolates were collected from pigs that had a known, documented history of meningitis or meningoencephalitis. The antimicrobial susceptibility testing was in the format of a broth microdilution method. Isolates selected for this study were tested using 96-well Sensititre™ plates (Thermo Scientific™), customized to include a known concentration of Pradofloxacin within each well. The range of the antibiotic concentration (0.00012 - 8 pg / mL) included in the custom plate is shown in Figure l. Up to four isolates were tested per plate. The preparation and inoculation of each plate (including media prep and isolate prep) was conducted according to the manufacturer's instructions and Iowa State University (ISU) diagnostic lab’s internal procedures. Quality control tests were included within each plate. For initial QC testing of the custom panel, Enterococcus faecalis (ATCC 29212) and Escherichia coli (ATCC 25922) were used following ISU diagnostic lab’s internal procedure. The MIC results were found to be within the acceptable ranges for both QC organisms for all plates used in this study.MMV Ref.: 2920951-543977

[0112] In addition, positive and negative control wells were included in every plate and a test was deemed "‘acceptable" only if the expected results for the positive and control wells were visible. Also, confirmation checks were performed for the positive control well for each test isolate to ensure the inoculum was pure culture.

[0113] Pradofloxacin MIC results, including minimum and maximum MICs. MICmode, MICso, and MIC90 for the Streptococcus suis isolates selected for this study are presented in the table below.Table 2: Streptococcus suis-Pradofloxacin Minimum Inhibitory Concentration (MIC) Results (µg / mL)Pradofloxacin AgeSample ID StateMIC (week)Isolate(week)30 0.015 SD 71 0.03 AR 44 0.03 IA 720 0.03 MN 617 0.03 IN 527 0.06 OK 2.82 0.06 IA 43 0.06 IA 515 0.06 IN 56 0.06 IA 1018 0.06 MI 529 0.06 SD 412 0.06 IL 108 0.06 IA 49 0.06 IA 5MMV Ref.: 2920951-54397714 0.06 IL 2.7 10 0.06 IA 425 0.06 OH 516 0.06 IN 821 0.06 MN 2.3 23 0.06 MO 322 0.06 MN 626 0.06 OH 719 0.06 MI 224 0.06 MO 45 0.12 IA nursery 7 0.12 IA 10 13 0.12 IL 611 0.12 IA 5.7 28 0.12 PA 3Total Tested 30Min MIC 0.015Max MIC 0.12MICmode 0.06MIC50 0.06MIC90 0.12AR: Arkansas; IA: Iowa; IL: Illinois; IN: Indiana; MI: Michigan; MN: Minnesota; MO: Missouri; OH: Ohio; OK: Oklahoma; PA: Pennsylvania; SD: South Dakota; MIC: minimum inhibitory concentration; MIC50: concentration that inhibits 50% of the isolates; MIC90: concentration that inhibits 90% of the isolates; MICmode: MIC value appearing the greatest number of times in the results.MMV Ref.: 2920951-543977

[0114] The minimum inhibitory concentration (MIC) for the isolates tested ranged from 0.015 g / mL to 0.12 pg / mL. The majority of the Streptococcus suis isolates tested had an MIC of 0.06 pg / mL for Pradofloxacin. Therefore, pradofloxacin is likely to be effective in the treatment of Streptococcus suis infection in the central nervous system.

[0115] Example 2

[0116] Pradofloxacin's efficacy against S'. suis infection in swine brain is described.

[0117] The pathogenic strains that disseminated systemically from the respiratory tract to the brain in infected swine were analyzed.Table 3: MIC of Pradofloxacin for S. suis isolated from swine brainPathogen Origin of No. of MICmode** MIC50* MIC90* MIC Sample Isolates (pg / mL) (pg / mL) (pg / mL) range (pg / mL) S. suis Brain / Brain 30 0.06 0.06 0.12 0.015 to Swab 0.12* The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively. ** MICmode: MIC value appearing the greatest number of times in the results.

[0118] The pathogenic S. suis strains that had become systemic, migrating from the respiratory tract to the brain to cause meningitis were selected. This selection criterion aimed to ensure that the isolates were representative of severe, invasive infections. The MIC values for the 30 S', suis isolates ranged from 0.015 pg / mL to 0.12 pg / mL. underscoring the variability' in susceptibility among the S', suis isolates tested. The MIC50, which represents the concentration that inhibits 50% of the isolates, and the MIC90, which inhibits 90% of the isolates, were found to be 0.06 pg / mL and 0.12 pg / mL, respectively. This suggests that a majority of the isolates tested (90%) were inhibited by a relatively low concentration of pradofloxacin. The pradofloxacin MIC results for these pathogenic isolates closely mirrored those of the initial phase. While the MICmode and MICso were identical, the MICs>o was one doubling dilution less for the isolates originating in the brain (0.25 pg / mL versus 0.12 pg / mL).MMV Ref.: 2920951-543977

[0119] The low MIC values witnessed in this study emphasizes pradofloxacin's potential as a viable treatment option for S. suis infections in swine.

Claims

1. MMV Ref.: 2920951-5439772.CLAIMS1. A method of treatment of a bacterial infection in the central nervous system in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin.

5.

6. (Formula I), or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof, wherein the fluoroquinolone compound, optionally pradofloxacin, is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system after at least about 2 hours of the administration.

2. The method of claim 1, wherein the bacterial infection originates from the respiratory tract, optionally lungs.

3. The method of claim 1 or 2, wherein the fluoroquinolone compound, optionally pradofloxacin, is effective in alleviation, amelioration and / or reduction of severity of symptoms of the bacterial infection in the central nervous system from about 2 hours - about 48 hours of the administration.

4. The method of any one of claims 1 to 2, wherein the fluoroquinolone compound comprises pradofloxacin.

5. The method of any one of claims 1 to 4, wherein the fluoroquinolone compound has a Cmax of 1-5 pg / mL, optionally from about 2-3 pg / mL, ti / 2 from about 5 to about 12 hours, optionally from about 8 to about 9 hours, and Tmax from about 15 minutes - about 90 minutes, optionally from about 30 minutes - about 60 minutes upon administration.MMV Ref.: 2920951-5439776. A method of treatment of a neurological disease or disorder in livestock comprising administering to the livestock a therapeutically effective amount of a fluoroquinolone compound, optionally pradofloxacin.12.H H13.\ 1 N14.N—16.

17. (Formula I), or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof.

7. The method of claim 6, wherein the fluoroquinolone compound has a Cmax of 1-5 pg / mL, optionally between 2-3 pg / mL, ti / 2 between 5 to 12 h, optionally between 8 to 9h, and Tmax between 15 min - 90 min, optionally between 30 - 60min upon administration.19.8 The method of claim 6 or 7, wherein the neurological disease or disorder is caused by a bacterial infection, optionally meningitis.

9. The method of claim 8, wherein the neurological disease or disorder is caused by a bacterial infection in central nervous system, optionally in the brain or the meninges.

10. The method of any one of claims 1 to 9, wherein the bacterial infection originates from the respiratory tract, optionally lungs.

11. The method of any one of claims 1 to 10, wherein the bacterial infection disseminated systemically from the respiratory tract to the central nervous system, optionally to the brain or the meninges.

12. The method of any one of claims 1 to 11, wherein the livestock is swine.

13. The method of any one of claims 1 to 12, wherein the bacterial infection is caused by one or more bacteria of the genus Streptococcus, Bordetella, Glaesserella {Haemophilus), Mycoplasma, Pasteurella, or Histophilus, optionally Streptococcus suis (S. suis), Bordetella bronchiseptica (B. bronchiseptica), Glaesserella {Haemophilus) parasuis (G. parasuis),MMV Ref.: 2920951-54397725.Mycoplasma hyopneumoniae (M. hyopneumoniae), Pasteurella multocida (P. multocida), or Histophilus somni.26.optionally the bacterial infection is caused by Streptococcus suis.

14. A composition for use in the method of any one of claims 1 - 13 comprising pradofloxacin,29.

30. (Formula I), or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt.

15. Use of a fluoroquinolone compound, optionally pradofloxacin,33.

34. (Formula I), or a pharmaceutically acceptable salt, solvate, hydrate, or hydrate of salt thereof for the manufacture of a medicament for treatment and / or prevention of a neurological disease or disorder in livestock.

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