Methods of use of antimicrobial compounds against pathogenic amycoplasma bacteria

This invention relates, in part, to newly identified methods of using quinolone antibiotics, particularly a gemifloxacin compound against certain pathogenic bacteria.

This invention relates, in part, to newly identified methods of using
 quinolone antibiotics, particularly a gemifloxacin compound against
 Mycoplasma bacteria, such as Mycolplasma pneumoniae.
 BACKGROUND OF THE INVENTION
 Quinolones have been shown to be effective to varying degrees against a
 range of bacterial pathogens. However, as diseases caused by these
 pathogens are on the rise, there exists a need for antimicrobial compounds
 that are more potent than the present group of quinolones.
 Gemifloxacin mesylate (SB-265805) is a novel fluoroquinolone useful as a
 potent antibacterial agent. Gemifloxacin compounds are described in detail
 in patent application PCT/KR98/00051 published as WO 98/42705. Patent
 application EP 688772 discloses novel quinoline(naphthyridine)carboxylic
 acid derivatives, including anhydrous
 (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluo
 ro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of formula I.
 ##STR1##
 PCT/KR98/00051 discloses
 (R,S)-7-(3-aminomethyl-4-syn-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-
 fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
 methanesulfonate and hydrates thereof including the sesquihydrate.
 Provided herein is a significant discovery made using a gemifloxacin
 compound against Mycoplasma, demonstrating the activity of the
 gemifloxacin compound used was superior to a number of quinolones as
 described in more detail herein. Germifloxacin compounds are valuable
 compounds for the treatment of bacterial infection caused by a range of
 Mycoplasma pathogens, including those resistant to usual oral therapy,
 thereby filling an unmet medical need.
 SUMMARY OF THE INVENTION
 An object of the invention is a method for modulating metabolism of
 pathogenic Mycoplasma bacteria comprising the step of contacting
 pathogenic Mycoplasma bacteria with an antibacterially effective amount of
 a composition comprising a quinolone, particularly a gemifloxacin
 compound, or an antibacterially effective derivative thereof.
 A further object of the invention is a method wherein said pathogenic
 Mycoplasma bacteria is selected from the group consisting of: Mycoplasma
 pneumoniae, M. hominis, M. fermentans, M. genitaliun, M. penetrans and
 Ureaplasma urealyticum.
 Also provided by the invention is a method of treating or preventing a
 bacterial infection by pathogenic Mycoplasma bacteria comprising the step
 of administering an antibacterially effective amount of a composition
 comprising a quinolone, particularly a gemifloxacin compound to a mammal
 suspected of having or being at risk of having an infection with
 pathogenic Mycoplasma bacteria.
 A preferred method is provided wherein said modulating metabolism is
 inhibiting growth of said bacteria or killing said bacteria.
 A further preferred method is provided wherein said contacting said
 bacteria comprises the further step of introducing said composition into a
 mammal, particularly a human.
 Further preferred methods are provided by the invention wherein said
 bacteria is selected from the group consisting of: Mycoplasma pneumoniae,
 M. hominis, M. fermentans, M. genitalium, M. penetrans and Ureaplasma
 urealyticum.
 Various changes and modifications within the spirit and scope of the
 disclosed invention will become readily apparent to those skilled in the
 art from reading the following descriptions and from reading the other
 parts of the present disclosure.

DESCRIPTION OF THE INVENTION
 The present invention provides, among other things, methods for using a
 composition comprising a quinolone, particularly a gemifloxacin compound
 against a range of pathogenic bacteria.
 As used herein "gemifloxacin compound(s)" means a compound having
 antibacterial activity described in patent application PCT/KR98/00051
 published as WO 98/42705, or patent application EP 688772.
 This invention was based, in part, on analyses evaluating the in vitro
 activity of a gemifloxacin compound, as well as other new quinolones and
 macrolides using low-passaged clinical isolates and type strains of
 Mycoplasma species commonly found in the respiratory and urogenital tract
 of humans. Organisms used in the analyses included Mycoplasma pneumoniae
 (MPN), M. homonis (Mh), M. fermentans (Mf), M. genitalium (Mg), M.
 penetrans (Mp) and Ureaplasma urealyticum (Uu). Minimum Inhibitory
 Concentrations (MICs) were determined using a micro-broth dilution method.
 Assays for Ureaplasma urealyticum were performed in 10B media and all
 other mycoplasma assays were carried out in SP4 medium. Comparator drugs,
 to which gemifloxacin was compared, as well as also being useful in the
 methods of the invention, include levofloxacin (Lev), trovafloxacin (Tro),
 grepafloxacin (Gre), azithromycin (Azi), clarithromycin (Cla),
 tetracycline (Tet) and clindamycin (Cli). The results of these MIC assays
 are shown in Table 1.
 TABLE 1
 MIC 90 (ug/ml)
 Isolates (number) Gem Lev Trov Grep Azith Clar Tet Clin
 MPN (103) 0.125 0.5 0.25 0.125 .ltoreq.0.008 .ltoreq.0.008
 0.25 --
 Mh (49) .ltoreq.0.008 0.25 0.031 0.031 -- -- 32
 .ltoreq.0.008
 Mf (19) .ltoreq.0.008 0.031 0.016 0.016 2 64
 0.063 0.031
 Uu (99) 0.25 1 0.125 1 4 0.063 1 --
 MICs for Mg (2) 0.063 1 0.063 0.125 .ltoreq.0.008 .ltoreq.0.008
 0.125 0.25
 0.063 0.5 0.063 0.125 .ltoreq.0.008 .ltoreq.0.008
 0.063 0.25
 MICs for Mp (1) .ltoreq.0.008 0.031 .ltoreq.0.008 0.016 .ltoreq.0.008
 .ltoreq.0.008 0.125 .ltoreq.0.008
 Depending on the species tested, gemifloxacin had variable results when
 compared to the macrolides. Gemifloxacin was equally as active or more
 active in vitro when compared to tetracycline, clindamycin and the other
 quinolones.
 The invention provides a method for modulating metabolism of pathogenic
 Mycoplasma bacteria. Skilled artisans can readily choose pathogenic
 Mycoplasma bacteria or patients infected with or suspected to be infected
 with these organisms to practice the methods of the invention.
 Alternatively, the bacteria useful in the methods of the invention may be
 those described herein.
 The contacting step in any of the methods of the invention may be performed
 in many ways that will be readily apparent to the skilled artisan.
 However, it is preferred that the contacting step is a provision of a
 composition comprising a gemifloxacin compound to a human patient in need
 of such composition or directly to bacteria in culture medium or buffer.
 For example, when contacting a human patient or contacting said bacteria in
 a human patient or in vitro, the compositions comprising a quinolone,
 particularly a gemifloxacin compound, preferably pharmaceutical
 compositions may be administered in any effective, convenient manner
 including, for instance, administration by topical, oral, anal, vaginal,
 intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal or
 intradermal routes among others.
 It is also preferred that these compositions be employed in combination
 with a non-sterile or sterile carrier or carriers for use with cells,
 tissues or organisms, such as a pharmaceutical carrier suitable for
 administration to a subject. Such compositions comprise, for instance, a
 media additive or a therapeutically effective amount of a compound of the
 invention, a quinolone, preferably a gemifloxacin compound, and a
 pharmaceutically acceptable carrier or excipient. Such carriers may
 include, but are not limited to, saline, buffered saline, dextrose, water,
 glycerol, ethanol and combinations thereof. The formulation should suit
 the mode of administration.
 Quinolone compounds, particularly gemifloxacin compounds and compostions of
 the methods of the invention may be employed alone or in conjunction with
 other compounds, such as bacterial efflux pump inhibtor compounds or
 antibiotic compounds, particularly non-quinolone compounds, e.g.,
 beta-lactam antibiotic compounds.
 In therapy or as a prophylactic, the active agent of a method of the
 invention is preferably administered to an individual as an injectable
 composition, for example as a sterile aqueous dispersion, preferably an
 isotonic one.
 Alternatively, the gemifloxacin compounds or compositions in the methods of
 the invention may be formulated for topical application for example in the
 form of ointments, creams, lotions, eye ointments, eye drops, ear drops,
 mouthwash, impregnated dressings and sutures and aerosols, and may contain
 appropriate conventional additives, including, for example, preservatives,
 solvents to assist drug penetration, and emollients in ointments and
 creams. Such topical formulations may also contain compatible conventional
 carriers, for example cream or ointment bases, and ethanol or oleyl
 alcohol for lotions. Such carriers may constitute from about 1% to about
 98% by weight of the formulation; more usually they will constitute up to
 about 80% by weight of the formulation.
 For administration to mammals, and particularly humans, it is expected that
 the antibacterially effective amount is a daily dosage level of the active
 agent from 0.001 mg/kg to 10 mg/kg, typically around 0.1 mg/kg to 1 mg/kg,
 preferably about 1 mg/kg. A physician, in any event, will determine an
 actual dosage that is most suitable for an individual and will vary with
 the age, weight and response of the particular individual. The above
 dosages are exemplary of the average case. There can, of course, be
 individual instances where higher or lower dosage ranges are merited, and
 such are within the scope of this invention. It is preferred that the
 dosage is selected to modulate metabolism of the bacteria in such a way as
 to inhibit or stop growth of said bacteria or by killing said bacteria.
 The skilled artisan may identify this amount as provided herein as well as
 using other methods known in the art, e.g. by the application MIC tests.
 A further embodiment of the invention provides for the contacting step of
 the methods to further comprise contacting an in-dwelling device in a
 patient. In-dwelling devices include, but are not limited to, surgical
 implants, prosthetic devices and catheters, i.e., devices that are
 introduced to the body of an individual and remain in position for an
 extended time. Such devices include, for example, artificial joints, heart
 valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal
 fluid shunts, urinary catheters, and continuous ambulatory peritoneal
 dialysis (CAPD) catheters.
 A quinolone, particularly a gemifloxacin compound or composition of the
 invention may be administered by injection to achieve a systemic effect
 against relevant bacteria, preferably a pathogenic Mycoplasma bacteria,
 shortly before insertion of an in-dwelling device. Treatment may be
 continued after surgery during the in-body time of the device. In
 addition, the composition could also be used to broaden perioperative
 cover for any surgical technique to prevent bacterial wound infections
 caused by or related to pathogenic Mycoplasma bacteria.
 In addition to the therapy described above, a gemifloxacin compound or
 composition used in the methods of this invention may be used generally as
 a wound treatment agent to prevent adhesion of bacteria to matrix
 proteins, particularly pathogenic Mycoplasma bacteria, exposed in wound
 tissue and for prophylactic use in dental treatment as an alternative to,
 or in conjunction with, antibiotic prophylaxis.
 Alternatively, a quinolone, particularly a gemifloxacin compound or
 composition of the invention may be used to bathe an indwelling device
 immediately before insertion. The active agent will preferably be present
 at a concentration of 1 .mu.g/ml to 10 mg/ml for bathing of wounds or
 indwelling devices.
 Also provided by the invention is a method of treating or preventing a
 bacterial infection by pathogenic Mycoplasma bacteria comprising the step
 of administering an antibacterially effective amount of a composition
 comprising a quinolone, particularly a gemifloxacin compound to a mammal,
 preferably a human, suspected of having or being at risk of having an
 infection with pathogenic Mycoplasma bacteria.
 While a preferred object of the invention provides a method wherein said
 pathogenic Mycoplasma bacteria is selected from the group consisting of:
 Mycoplasma pneumoniae, M. hominis, M. fermentans, M. genitalium, M.
 penetrans and Ureaplasma urealyticum. Other pathogenic Mycoplasma bacteria
 may also be included in the methods. The skilled artisan may identify
 these organisms as provided herein as well as using other methods known in
 the art, e.g. MIC tests.
 Preferred embodiments of the invention include, among other things, methods
 wherein said composition comprises gemifloxacin, or a pharmaceutically
 acceptable derivative thereof.
 Each reference cited herein is hereby incorporated by reference in its
 entirety. Moreover, each patent application to which this application
 claims priority is hereby incorporated by reference in its entirety.