U.S. patent application number 09/853854 was filed with the patent office on 2001-09-27 for methods of use of antimicrobial compounds against pathogenic mycoplasma bacteria.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Crabb, Donna M., Duffy, Lynn B., Searcy, Karen B..
Application Number | 20010025048 09/853854 |
Document ID | / |
Family ID | 26839139 |
Filed Date | 2001-09-27 |
United States Patent
Application |
20010025048 |
Kind Code |
A1 |
Crabb, Donna M. ; et
al. |
September 27, 2001 |
Methods of use of antimicrobial compounds against pathogenic
mycoplasma bacteria
Abstract
This invention relates, in part, to newly identified methods of
using quinolone antibiotics, particularly a gemifloxacin compound
against certain pathogenic bacteria.
Inventors: |
Crabb, Donna M.;
(Birmingham, AL) ; Duffy, Lynn B.; (Birmingham,
AL) ; Searcy, Karen B.; (Birmingham, AL) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
26839139 |
Appl. No.: |
09/853854 |
Filed: |
May 11, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09853854 |
May 11, 2001 |
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09399855 |
Sep 21, 1999 |
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6262071 |
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60141455 |
Jun 29, 1999 |
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Current U.S.
Class: |
514/312 |
Current CPC
Class: |
A61K 31/47 20130101 |
Class at
Publication: |
514/312 |
International
Class: |
A61K 031/47 |
Claims
What is claimed is:
1. 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 gemifloxacin compound, or antibacterially effective
derivatives thereof.
2. The method of claim 1 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.
3. 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
gemifloxacin compound to a mammal suspected of having or being at
risk of having an infection with pathogenic Mycoplasma
bacteria.
4. The method of claim 3 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.
5. The method of claim 1 wherein said modulating metabolism is
inhibiting growth of said bacteria.
6. The method of claim 1 wherein said modulating metabolism is
killing said bacteria.
7. The method of claim 1 wherein said contacting said bacteria
comprises the further step of introducing said composition into a
mammal.
8. The method of claim 3 wherein said mammal is a human.
9. The method of claim 7 wherein said mammal is a human.
10. The method of claim 1 wherein said bacteria is selected from
the group consisting of: Mycoplasma pneumoniae, M. hominis, M.
fermentans, M. genitalium, M. penetrans and Ureaplasma
urealyticum.
11. The method of claim 1 wherein said bacteria is selected from
the group consisting of: Mycoplasma pneumoniae, M. hominis, M.
fermentans, M. genitalium, M. penetrans and Ureaplasma urealyticum.
Description
[0001] This invention relates, in part, to newly identified methods
of using quinolone antibiotics, particularly a gemifloxacin
compound against Mycoplasma bacteria, such as Mycoplasma
pneumoniae.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] 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)carb- oxylic acid derivatives, including
anhydrous (R,S)-7-(3-aminomethyl-4-meth-
oxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylic acid of formula I. 1
[0004] PCT/KR98/0005 1 discloses
(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-
-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridi-
ne-3-carboxylic acid methanesulfonate and hydrates thereof
including the sesquihydrate.
[0005] 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. Gemifloxacin
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
[0006] 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.
[0007] 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.
genitalium, M. penetrans and Ureaplasma urealyticum.
[0008] 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.
[0009] A preferred method is provided wherein said modulating
metabolism is inhibiting growth of said bacteria or killing said
bacteria.
[0010] 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.
[0011] 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.
[0012] 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
[0013] 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.
[0014] As used herein "gemifloxacin compound(s)" means a compound
having antibacterial activity described in patent application
PCT/KR98/0005 1 published as WO 98/42705, or patent application EP
688772.
[0015] 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. hominis (Mh), M.
fernentans (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.
1TABLE 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 <0.008 .ltoreq.0.008 0.125 0.25 0.063 0.5 0.063
0.125 <0.008 .ltoreq.0.008 0.063 0.25 MICs for Mp (1)
.ltoreq.0.008 0.031 .ltoreq.0.008 0.016 <0.008 .ltoreq.0.008
0.125 .ltoreq.0.008
[0016] 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.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] Preferred embodiments of the invention include, among other
things, methods wherein said composition comprises gemifloxacin, or
a pharmaceutically acceptable derivative thereof.
[0032] 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.
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