U.S. patent application number 09/996040 was filed with the patent office on 2002-07-04 for methods of use of quinolone compounds against atypical upper respiratory pathogenic bacteria.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Dubois, Jacques, St-Pierre, Claude.
Application Number | 20020086867 09/996040 |
Document ID | / |
Family ID | 31720085 |
Filed Date | 2002-07-04 |
United States Patent
Application |
20020086867 |
Kind Code |
A1 |
Dubois, Jacques ; et
al. |
July 4, 2002 |
Methods of use of quinolone compounds against atypical upper
respiratory pathogenic bacteria
Abstract
This invention relates, in part, to newly identified methods of
using quinolone antibiotics, particularly a gemifloxacin compound
against atypical upper respiratory pathogenic bacteria
Inventors: |
Dubois, Jacques;
(Fleuramont, CA) ; St-Pierre, Claude; (St-Elie
d'Orford, CA) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
31720085 |
Appl. No.: |
09/996040 |
Filed: |
November 28, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09996040 |
Nov 28, 2001 |
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09395851 |
Sep 14, 1999 |
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60141409 |
Jun 29, 1999 |
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60141457 |
Jun 29, 1999 |
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Current U.S.
Class: |
514/253.08 |
Current CPC
Class: |
A61K 31/47 20130101;
Y02A 50/30 20180101; Y02A 50/478 20180101 |
Class at
Publication: |
514/253.08 |
International
Class: |
A61K 031/496 |
Claims
What is claimed is:
1. A method for modulating metabolism of atypical upper respiratory
pathogenic bacteria comprising the step of contacting atypical
upper respiratory pathogenic 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 atypical upper respiratory
pathogenic bacteria is selected from the group consisting of: a
member of the genus Legionella, a member of the genus, Pseudomonas,
Pseudomonas aeruginosa strain, a L. pneumophila strain, a L.
Pneumophila serogroup 1, a L. Pneumophila serogroup 2, a L.
pneumophila serogroup 3, a L. pneumophila serogroup 4, a L.
Pneumophila serogroup 5, a L. pneumophila serogroup 6, a L.
pneumophila serogroup 7, a L. pneumophila serogroup 8, a L.
dumoffii strain, a L. longbeacheae strain, a L. micdadei strain, a
L. oakridgensis strain, a L. feelei strain, a L. anisa strain, a L.
sainthelensi strain, a L. bozemanii strain, a L. gormanii strain, a
L. wadsworthii strain, a L. jordanis; strain and a L. gormanii
strain.
3. A method of treating or preventing a bacterial infection by
atypical upper respiratory pathogenic 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
atypical upper respiratory pathogenic bacteria.
4. The method of claim 3 wherein said atypical upper respiratory
pathogenic bacteria is selected from the group consisting of: a
member of the genus Legionella, a member of the genus, Pseudomonas,
Pseudomonas aeruginosa strain, a L. pneumophila strain, a L.
pneumophila serogroup 1, a L. pneumophila serogroup 2, a L.
pneumophila serogroup 3, a L. pneumophila serogroup 4, a L.
pneumophila serogroup 5, a L. pneumophila serogroup 6, a L.
pneumophila serogroup 7, a L. pneumophila serogroup 8, a L.
dumoffii strain, a L. longbeacheae strain, a L. micdadei strain, a
L. oakridgensis strain, a L. feelei strain, a L. anisa strain, a L.
sainthelensi strain, a L. bozemanii strain, a L. gormanii strain, a
L. wadsworthii strain, a L. jordanis; strain and a L. gormanii
strain.
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: a member of the genus Legionella, a member
of the genus, Pseudomonas, Pseudomonas aeruginosa strain, a L.
pneumophila strain, a L. pneumophila serogroup 1, a L. pneumophila
serogroup 2, a L. pneumophila serogroup 3, a L. pneumophila
serogroup 4, a L. pneumophila serogroup 5, a L. pneumophila
serogroup 6, a L. Pneumophila serogroup 7, a L. pneumophila
serogroup 8, a L. dumoffii strain, a L. longbeacheae strain, a L.
micdadei strain, a L. oakridgensis strain, a L. feelei strain, a L.
anisa strain, a L. sainthelensi strain, a L. bozemanii strain, a L.
gormanii strain, a L. wadsworthii strain, a L. jordanis; strain and
a L. gormanii strain.
11. The method of claim 1 wherein said bacteria is selected from
the group consisting of: a member of the genus Legionella, a member
of the genus, Pseudomonas, Pseudomonas aeruginosa strain, a L.
pneumophila strain, a L. pneumophila serogroup 1, a L. pneumophila
serogroup 2, a L. pneumophila serogroup 3, a L. pneumophila
serogroup 4, a L. pneumophila serogroup 5, a L. pneumophila
serogroup 6, a L. pneumophila serogroup 7, a L. pneumophila
serogroup 8, a L dumoffii strain, a L. longbeacheae strain, a L.
micdadei strain, a L. oakridgensis strain, a L. feelei strain, a L.
anisa strain, a L. sainthelensi strain, a L. bozemanii strain, a L.
gormanii strain, a L. wadsworthii strain, a L. jordanis; strain and
a L. gormanii strain.
12. A method for modulating metabolism of atypical upper
respiratory pathogenic bacteria comprising the step of contacting
atypical upper respiratory pathogenic bacteria with an
antibacterially effective amount of a composition comprising a
compound selected from the group consisting of: gemifloxacin,
ofloxacin, levofloxacin, trovafloxacin, azithromycin, moxifloxacin,
ciprofloxacin, clarithromycin, rifampicin and erythromycin; or an
antibacterially effective derivative of any of these compounds.
13. The method of claim 12 wherein said bacteria is selected from
the group consisting of: a member of the genus Legionella, a member
of the genus, Pseudomonas, Pseudomonas aeruginosa strain, a L.
pneumophila strain, a L. pneumophila serogroup 1, a L. pneumophila
serogroup 2, a L. pneumophila serogroup 3, a L. pneumophila
serogroup 4, a L. pneumophila serogroup 5, a L. pneumophila
serogroup 6, a L. pneumophila serogroup 7, a L. pneumophila
serogroup 8, a L. dumoffii strain, a L. longbeacheae strain, a L.
micdadei strain, a L. oakridgensis strain, a L. feelei strain, a L.
anisa strain, a L. sainthelensi strain, a L. bozemanii strain, a L.
gormanii strain, a L wadsworthii strain, a L. jordanis; strain and
a L. gormanii strain.
14. The method of claim 1 wherein said contacting is performed once
daily.
15. A method of treating or preventing a bacterial infection by
atypical upper respiratory pathogenic bacteria comprising the step
of administering an antibacterially effective amount of a
composition comprising a compound selected from the group
consisting of: gemifloxacin, ofloxacin, levofloxacin,
trovafloxacin, azithromycin, moxifloxacin, ciprofloxacin,
clarithromycin, rifampicin and erythromycin; or an antibacterially
effective derivative of any of these compounds, to a mammal
suspected of having or being at risk of having an infection with
atypical upper respiratory pathogenic bacteria.
16. The method of claim 15 wherein said bacteria is selected from
the group consisting of: a member of the genus Legionella, a member
of the genus, Pseudomonas, Pseudomonas aeruginosa strain, a L.
pneumophila strain, a L. pneumophila serogroup 1, a L. pneumophila
serogroup 2, a L. pneumophila serogroup 3, a L. pneumophila
serogroup 4, a L. pneumophila serogroup 5, a L. pneumophila
serogroup 6, a L. pneumophila serogroup 7, a L. pneumophila
serogroup 8, a L. dumoffii strain, a L. longbeacheae strain, a L.
micdadei strain, a L. oakridgensis strain, a L. feelei strain, a L.
anisa strain, a L sainthelensi strain, a L. bozemanii strain, a L.
gormanii strain, a L. wadsworthii strain, a L. jordanis; strain and
a L. gormanii strain.
Description
[0001] This invention relates, in part, to methods of using
quinolone antibiotics, particularly a gemifloxacin compound,
against atypical upper respiratory pathogenic bacteria.
BACKGROUND OF THE INVENTION
[0002] Quinolones have been shown to be effective to varying
degrees against a range of certain respiratory tract pathogens.
However, as diseases caused by these pathogens are on the rise,
there exists a need for antimicrobial compounds that are more
potent and that exhibit a longer post-antibiotic effect 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-1,8naph-
thyridine-3carboxylic acid of formula I 1
[0004] PCTIKR98/00051 discloses
(R,S)-7-(3-aminomethyl-4-syn-methoxyinino--
pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-
1,8-naphthyridine-3-acid methanesulfonate and hydrates thereof
including the sesquihydrate.
[0005] Provided herein is an invention based, in part, on a
significant discovery made using a gemifloxacin compound against a
range of variety of Legionella isolated from nosocomial or acquired
respiratory tract infections and from environmental sources,
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 diseases caused by or related to atypical respiratory
tract pathogens, thereby filling an unmet medical need.
SUMMARY OF THE INVENTION
[0006] An object of the invention is a method for modulating
metabolism of atypical upper respiratory pathogenic bacteria
comprising the step of contacting atypical upper respiratory
pathogenic bacteria with an antibacterially effective amount of a
composition comprising a gemifloxacin compound, or an
antibacterially effective derivative thereof.
[0007] A further object of the invention is a method wherein said
atypical upper respiratory pathogenic bacteria is selected from the
group consisting of: a member of the genus Legionella, a member of
the genus, Pseudomonas, Pseudomonas aeruginosa strain, a Legionella
pneumophila strain, a Legionella pnetimophila serogroup 1, a
Legionella pnetimophila serogroup 2, a Legionella pneumophila
serogroup 3, a Legionella pnetmophila serogroup 4, a Legionella
pneumophila serogroup 5, a Legionela pneumophila serogroup 6, a
Legionella pneumophila serogroup 7, a Legionella pneumophila
serogroup 8, a Legionella dumoffii strain, a Legionella
longbeacheae strain, a Legionella micdadei strain, a Legionella
oakridgensis strain, a Legionella feelei strain, a Legionella anisa
strain, a Legionella sainthelensi strain, a Legionella bozemanii
strain. a Legionella gormanii strain, a Legionella wadsworthii
strain, a Legionella jordanis strain and a Legionella gormanii
strain.
[0008] Also provided by the invention is a method of treating or
preventing a bacterial infection by atypical upper respiratory
pathogenic 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 atypical upper respiratory
pathogenic 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: a
member of the genus Legionella, a member of the genus, Pseudomonas,
Pseudomonas aeruginosa strain, a L pneumophila strain, a L.
pneumophila serogroup 1, a L. pneumophila serogroup 2, a L.
pneumophila serogroup 3, a L. pneumophila serogroup 4, a L.
pneumophila serogroup 5, a L. pneumophila serogroup 6, a L.
pnetimophila serogroup 7, a L. pneumophila serogroup 8, a L.
dumoffli strain, a L. longbeacheae strain, a L. micdadei strain, a
L. oakridgensis strain, a L. feelei strain, a L. anisa strain, a L.
sainthelensi strain, a L. bozemanii strain, a L. gorinanii strain,
a L. wadsworthii strain, a L. jordanis strain and a L. gormanii
strain.
[0012] A further embodiment of the invention is method for
modulating metabolism of atypical upper respiratory pathogenic
bacteria comprising the step of contacting atypical upper
respiratory pathogenic bacteria with an antibacterially effective
amount of a composition comprising a compound selected from the
group consisting of: gemifloxacin, ofloxacin, levofloxacin,
trovafloxacin, azithromycin, moxifloxacin, ciprofloxacin,
clarithromycin, rifampicin and erythromycin; or an antibacterially
effective derivative of any of these compounds.
[0013] A still further embodiment of the invention is a method of
treating or preventing a bacterial infection by atypical upper
respiratory pathogenic bacteria comprising the step of
administering an antibacterially effective amount of a composition
comprising a compound selected from the group consisting of:
gemifloxacin, ofloxacin, levofloxacin, trovafloxacin, azithromycin,
moxifloxacin, ciprofloxacin, clarithromycin, rifampicin and
erythromycin; or an antibacterially effective derivative of any of
these compounds, to a mammal suspected of having or being at risk
of having an infection with atypical upper respiratory pathogenic
bacteria.
[0014] It is preferred in the methods of the invention that said
contacting is performed once daily.
[0015] 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
[0016] The present invention provides, among other things, methods
for using a composition comprising a gemifloxacin compound against
atypical upper respiratory pathogenic bacteria, especially a member
of the genus Legionella, a member of the genus, Pseidomonas,
Pseudomonas aerilginosa strain, a L. pneiumophila strain, a L.
pnetimophila serogroup 1, a L. pneumophila serogroup 2, a L.
pneumophila serogroup 3, a L pneumophila serogroup 4, a L.
pneumophila serogroup 5, a L. pneumophila serogroup 6, a L.
pneutmophila serogroup 7, a L. pneumophila serogroup 8, a L.
dumoffii strain, a L. longbeacheae strain, a L. micdadei strain, a
L. oakridgensis strain, a L feelei strain, a L. anisa strain, a L.
sainthelensi strain, a L. bozemanii strain, a L. gormanii strain, a
L. wadsworthii strain, a L. jordanis strain or a L. gormanii
strain.
[0017] 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.
[0018] This invention was based, in part, on analyses evaluating
the in vitro activity and postantibiotic effect (herein "PAE") of
gemifloxacin compared with those of trovafloxacin, moxifloxacin,
grepafloxacin, levofloxacin, ofloxacin, ciprofloxacin,
azithromycin, clarithromycin, erythromycin and rifampicin against
isolates of Legionella pneumophila and other Legionella spp. Test
isolates included L. pneumophila serogroup 1-12 (204), L. dimoffii
(10), L. micdadei (10) and L. longbeacheae (7). The PAE was
determined by exposing the isolates to the test antimicrobials for
1 hour at four times the minimum inhibitory concentration (herein
"MIC"). The antimicrobial was removed by three consecutive
centrifugations into fresh broth. The PAE was calculated by
measuring bacterial growth kinetics in similar antimicrobial-free
cultures. Rifampicin and trovafloxacin were the most active agents
tested (MIC.sub.90.ltoreq.0.008 mg/L). Gemifloxacin displayed high
potency (MIC.sub.90 0.016 mg/L) which was comparable to
levofloxacin, grepafloxacin and moxifloxacin (MIC.sub.90 0.016
mg/L) and more active than ciprofloxacin and ofloxacin (MIC.sub.90
0.03 mg/L). Against L. dumoffii and L. longbeachae, gemifloxacin
(MIC.sub.90 0.06 mg/L) was as active than ciprofloxacin, ofloxacin,
grepafloxacin and moxifloxacin. Against erythromycin-resistant L.
pnetimophila, gemifloxacin showed the longest PAE at 4.65 hours,
compared with 4.18 hours for grepafloxacin, 3.38 hours for
moxifloxacin and 2.83 hours for trovafloxacin. The gemifloxacin PAE
was significantly superior to that of rifampicin (0.9 h),
clarithromycin (1.9 h) and levofloxacin (2.59 h). Against
erythromycin-susceptible L. pneeumophila only gemifloxacin,
moxifloxacin, levofloxacin, ofloxacin and ciprofloxacin had a PAE
over 3 hours. For erythromycin-resistant Legionella spp. other than
L. pneumophila, gemifloxacin, moxifloxacin, levofloxacin and
ofloxacin had PAEs in excess of 3 hour, which was significantly
longer than the PAE of ciprofloxacin grepafloxacin and
erythromycin. The half-life for gemifloxacin and the data presented
here indicate a significant PAE to support a once-daily
administration of this agent for the treatment of Legionella
infections, and this dosing is preferred in the methods of the
invention.
[0019] The MIC range of gemifloxacin against L. pneunmophila
serogroups 1-9 was 0.008-0.06 mg/L (Tables 2 and 3). Gemifloxacin
was 5-6-fold more active than erythromycin against L. pneumophila
strains tested. Gemifloxacin activity against L. Pneumophila
strains was higher than ciprofloxacin and ofloxacin but similar to
grepafloxacin and moxifloxacin.
[0020] L. pneumophila strains of serogroups 1-3 and 7-9 were more
susceptible to gemifloxacin than L. pneumophila serogroups 4-6.
Against the most frequent L. pnetimophila, such as serogroup 1,
gemifloxacin MlC.sub.90 (0.016 mg/L) was superior to azithromycin,
clarithromycin, erythromycin, ofloxacin and ciprofloxacin.
[0021] Against L. ditmoffii and L. longbeacheae, gemifloxacin,
grepafloxacin and clarithromycin showed superior activity to
azithromycin and erythromycin (Table 4). Against L. micdadei,
gemifloxacin, ciprofloxacin, ofloxacin and moxifloxacin MICs were
5-fold more active than erythromycin.
[0022] Against erythromycin-resistant L. pneumophila only
gemifloxacin, moxifloxacin and grepafloxacin displayed a mean PAE
of >3 hours (Table 5). Clarithromycin, erythromycin and
rifampicin showed a PAE of <2 hours against these strains.
Against erythromycin-resistant Legionella spp. other than
pneumophila, gemifloxacin, grepafloxacin, levofloxacin, ofloxacin
and rifampicin displayed a mean PAE of >3 hours, and
erythromycin and clarithromycin of <2 hours.
[0023] Against erythromycin-susceptible L. pneumophila,
gemifloxacin, moxifloxacin, ofloxacin and ciprofloxacin displayed a
mean PAE of >3hours. Gemifloxacin and ofloxacin were the only
quinolones showing a mean PAE of >2 hours against
erythromycin-susceptible Legionella spp. other than L.
pneumophila.
[0024] Gemifloxacin is an effective antimicrobial agent against
most Legionella spp. and was significantly superior to the commonly
used legionellosis therapy, erythromycin.
[0025] Against erythromycin-susceptible L. pneumophila, the mean
PAE of gemifloxacin (3.49 hours) was >1 h longer than that of
trovafloxacin, levofloxacin and clarithromycin.
[0026] Against erythromycin-susceptible Legionella spp. other than
pneumophila the mean PAE of gemifloxacin (2.27 hours) was >1 h
longer than that of trovafloxacin, moxifloxacin and
clarithromycin.
[0027] Against erythromycin-resistant L. pneumophila, the mean PAE
of gemifloxacin (4.65 hours) was significantly superior to the mean
PAE of trovafloxacin, levofloxacin, ciprofloxacin, azithromycin,
clarithromycin, erythromycin and rifampicin. A difference in mean
PAE was also noted between gemifloxacin and trovafloxacin against
Legionella spp. other than L. pneumophila.
[0028] The results of this study indicate that gemifloxacin should
be a promising agent for the treatment of lower respiratory tract
infections caused by Legionella spp.
1TABLE 1 Legionella Strains Tested Microrganism No. of strains
tested L. pneumophila 204* L. micdadei 10 L. dumoffli 10 L.
longbeacheae 7 Others.sup..dagger. 7 *10 different serogroups
.sup..dagger.oakridgensis, feelei, anisa, sainthelensi, bozemanii,
gormanii, wadsworthii
[0029]
2TABLE 2 Susceptibility of Legionella pneumophila Serogroups 1-4 L.
pneumophila serogroup 1 L. pneumophila serogroup 2 (n = 85) (n =
17) MIC (mg/L) MIC (mg/L) Antimicrobial Range 50% 90% Range 50% 90%
Gemifloxacin 0.008-0.06 0.016 .ltoreq.0.004 0.008-0.016 0.008 0.016
Trovafloxacin .ltoreq.0.004-0.016 .ltoreq.0.004 .ltoreq.0.004
.ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 Moxifloxacin
.ltoreq.0.004-0.03 0.016 0.016 .ltoreq.0.004-0.016 0.008 0.008
Grepafloxacin .ltoreq.0.004-0.06 0.016 0.016 .ltoreq.0.004-0.03
0.008 0.016 Levofloxacin .ltoreq.0.004-0.016 0.016 0.016
.ltoreq.0.004-0.016 0.008 0.008 Ofloxacin 0.008-0.03 0.03 0.03
0.008-0.03 0.016 0.03 Ciprofloxacin 0.016-0.25 0.03 0.03
.ltoreq.0.004-0.03 0.016 0.016 Azithromycin 0.008-1.0 0.06 0.5
0.008-0.12 0.06 0.12 Clarithromycin .ltoreq.0.004-0.12 0.06 0.06
.ltoreq.0.004-0.06 0.03 0.06 Erthromycin 0.03-1.0 0.25 1.0
0.008-0.5 0.25 0.25 Rifampicin .ltoreq.0.004-0.008 .ltoreq.0.004
0.008 .ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 L. pneumophila
serogroup 3 L. pneumophila serogroup 4 (n = 15) (n = 26) MIC (mg/L)
MIC (mg/L) Antimicrobial Range 50% 90% Range 50% 90% Gemifloxacin
0.008-0.016 0.016 0.016 0.008-0.03 0.016 0.03 Trovafloxacin
.ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004
.ltoreq.0.004 .ltoreq.0.004 Moxifloxacin .ltoreq.0.004-0.016 0.008
0.016 .ltoreq.0.004-0.016 0.016 0.016 Grepafloxacin
.ltoreq.0.004-0.016 0.008 0.016 0.008-0.016 0.008 0.016
Levofloxacin 0.008-0.016 0.008 0.016 0.004-0.016 0.016 0.016
Ofloxacin 0.016-0.03 0.016 0.03 0.008-0.03 0.03 0.03 Ciprofloxacin
.ltoreq.0.004-0.03 0.03 0.03 0.016-0.12 0.03 0.06 Azithromycin
0.016-0.25 0.12 0.25 0.008-0.25 0.12 0.12 Clarithromycin 0.016-0.06
0.03 0.06 0.004-0.06 0.03 0.06 Erthromycin 0.06-0.5 0.25 0.5
0.016-0.5 0.5 0.5 Rifampicin .ltoreq.0.004 .ltoreq.0.004
.ltoreq.0.004 .ltoreq.0.004-0.008 .ltoreq.0.004 .ltoreq.0.004
[0030]
3TABLE 3 Susceptibility of L. pneumophila Serogroups 5-12 L.
pneumophila serogroup 5 L. pneumophila serogroup 6 (n = 15) (n =
40) MIC (mg/L) MIC (mg/L) Antimicrobial Range 50% 90% Range 50% 90%
Gemifloxacin 0.03-0.06 0.03 0.03 0.008-0.03 0.016 0.03
Trovafloxacin .ltoreq.0.004-0.008 .ltoreq.0.004 .ltoreq.0.004
.ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 Moxifloxacin
.ltoreq.0.004-0.03 0.016 0.016 .ltoreq.0.004-0.016 0.008 0.016
Grepafloxacin .ltoreq.0.004-0.003 0.016 0.03 .ltoreq.0.004-0.016
0.008 0.016 Levofloxacin .ltoreq.0.004-0.016 0.008 0.016
0.008-0.016 0.008 0.016 Ofloxacin 0.008-0.03 0.016 0.03 0.008-0.03
0.03 0.03 Ciprofloxacin 0.016-0.06 0.03 0.03 .ltoreq.0.004-0.03
0.03 0.03 Azithromycin 0.008-0.5 0.03 0.25 0.016-0.25 0.06 0.12
Clarithromycin 0.03-0.06 0.03 0.06 .ltoreq.0.004-0.06 0.016 0.06
Erthromycin 0.06-1.0 0.25 0.5 0.008-0.25 0.12 0.25 Rifampicinl
.ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004-0.008
.ltoreq.0.004 .ltoreq.0.004 L. pneumophila serogroup 7 L.
pneumophila serogroup 8, 9 (n = 2) and 12 (n = 4) MIC (mg/L) MIC
(mg/L) Antimicrobial Range 50% 90% Range 50% 90% Gemifloxacin
0.008-0.016 0.008 0.016 0.016 0.016 0.016 Trovafloxacin
.ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004
.ltoreq.0.004 .ltoreq.0.004 Moxifloxacin .ltoreq.0.004-0.016
.ltoreq.0.004 0.016 0.016 0.016 0.016 Grepafloxacin
.ltoreq.0.004-0.008 .ltoreq.0.004 0.008 0.008 0.008 0.008
Levofloxacin 0.008-0.016 0.008 0.016 0.008-0.016 0.008 0.016
Ofloxacin 0.03 0.03 0.03 0.03 0.03 0.03 Ciprofloxacin 0.03 0.03
0.03 0.03 0.03 0.03 Azithromycin 0.06 0.06 0.06 0.06 0.06 0.06
Clarithromycin 0.016-0.06 0.016 0.06 0.06 0.06 0.06 Erthromycin
0.12-0.5 0.12 0.5 0.25 0.25 0.25 Rifampicinl .ltoreq.0.004
.ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004
.ltoreq.0.004
[0031]
4TABLE 4 Susceptibility of Legionella Other than pneumophila L.
dumoffii L. micdadei (n = 10) (n = 10) MIC (mg/L) MIC (mg/L)
Antimicrobial Range 50% 90% Range 50% 90% Gemifloxacin 0.06 0.06
0.06 0.008-0.03 0.016 0.03 Trovafloxacin .ltoreq.0.004-0.008 0.008
0.008 .ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 Moxifloxacin
0.008-0.03 0.03 0.03 0.008-0.03 0.016 0.03 Grepafloxacin 0.06 0.06
0.06 .ltoreq.0.004-0.016 0.008 0.016 Levofloxacin 0.016 0.016 0.016
0.008-0.016 0.016 0.016 Ofloxacin 0.03 0.03 0.03 0.03 0.03 0.03
Ciprofloxacin 0.016-0.03 0.016 0.03 0.016-0.03 0.016 0.03
Azithromycin 0.12-0.25 0.12 0.25 0.016-0.25 0.25 0.25
Clarithromycin 0.03-0.06 0.03 0.06 0.03-0.12 0.06 0.06 Erthromycin
0.25-0.5 0.25 0.5 0.25-1 0.5 1 Rifampicin .ltoreq.0.004-0.03 0.008
0.016 0.008 0.008 0.008 L. longbeacheae Other Legionella spp. (n =
7) (n = 7)* MIC (mg/L) MIC (mg/L) Antimicrobial Range 50% 90% Range
50% 90% Gemifloxacin 0.016-0.06 0.06 0.06 0.016-0.06 0.03 0.06
Trovafloxacin .ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004
.ltoreq.0.004 .ltoreq.0.004 .ltoreq.0.004 Moxifloxacin 0.008-0.03
0.016 0.03 0.008-0.03 0.008 0.03 Grepafloxacin .ltoreq.0.004-0.06
0.03 0.06 .ltoreq.0.004-0.03 0.03 0.03 Levofloxacin 0.008-0.016
0.016 0.016 0.008-0.06 0.016 0.016 Ofloxacin 0.016-0.03 0.03 0.03
.ltoreq.0.004-0.06 0.016 0.06 Ciprofloxacin .ltoreq.0.004-0.03
0.016 0.03 .ltoreq.0.004-0.03 0.016 0.03 Azithromycin 0.016-0.25
0.12 0.25 0.016-0.5 0.12 0.5 Clarithromycin 0.008-0.06 0.06 0.06
.ltoreq.0.004-0.12 0.03 0.12 Erthromycin 0.008-0.5 0.25 0.5 0.016-1
0.5 1 Rifampicin .ltoreq.0.004-0.06 .ltoreq.0.004 0.06
.ltoreq.0.004-0.008 .ltoreq.0.004 0.008 *Includes one isolates of
L. bozemanii, L. feelei, L. jordanis, L. gormanii, L. oakridgensis,
L. sainthelensi and L. wadsworthii.
[0032]
5TABLE 5 Mean PAE of Antimicrobials Against Erthromycin-resistant
and -susceptible Strains of Legionella Mean PAE (h)*
Erthromycin-resistant strains Erthromycin-susceptible strains
Antimicrobial L. pneumophila Legionella spp..sup..dagger. L.
pneumophila Legionella spp.** (4 .times. MIC) (n = 7) (n = 9) (n =
15) (n = 13) Gemifloxacin 4.65 .+-. 3 3.34 .+-. 2 3.49 .+-. 3 2.27
.+-. 2 Trovafloxacin 2.83 .+-. 2 2.25 .+-. 2 1.71 .+-. 1 1.22 .+-.
1 Moxifloxacin 3.38 .+-. 2 2.02 .+-. 1 3.59 .+-. 3 1.18 .+-. 2
Grepafloxacin 4.18 .+-. 3 3.67 .+-. 1 2.62 .+-. 3 1.67 .+-. 1
Levofloxacin 2.59 .+-. 2 3.24 .+-. 1 2.14 .+-. 2 1.35 .+-. 1
Ofloxacin 2.99 .+-. 1 4.13 .+-. 2 3.53 .+-. 3 3.04 .+-. 2
Ciprofloxacin 2.86 .+-. 2 2.13 .+-. 3 3.61 .+-. 2 1.86 .+-. 2
Azithromycin 2.16 .+-. 1 2.13 .+-. 1 2.91 .+-. 3 1.86 .+-. 2
Clarithromycin 1.90 .+-. 1 1.60 .+-. 2 0.72 .+-. 2 0.98 .+-. 2
Erythromycin 0.90 .+-. 1 0.44 .+-. 1 0.93 .+-. 1 2.06 .+-. 2
Rifampicin 0.93 .+-. 4 5.6 .+-. 3 2.86 .+-. 5 3.09 .+-. 4 *Means
are given .+-. SD .sup..dagger.L. micdadei (n = 1), L. dumofii (n =
3), L. bozeinanii (n = 1), L. wadsworthii (n = 1), L. longbeacheae
(n = 2) **L. micdadei (n = 4), L. dunzofii (n = 5), L. bozemanii (n
= 1), L. gormanii (n = 1), L. jordanis (n = 1), L. longbeacheae (n
= 1)
[0033] The invention provides a method for modulating metabolism of
atypical upper respiratory pathogenic bacteria. Skilled artisans
can readily choose atypical upper respiratory pathogenic 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.
[0034] 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
comprises provision of a composition comprising a gemifloxacin
compound to a mammal, particularly a human patient in need of such
composition or directly to bacteria in culture medium or buffer or
on a surface.
[0035] For example, when contacting a human patient or contacting
said bacteria in a human patient or in vitro, the compositions
comprising 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.
[0036] 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, 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.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] A gemifloxacin compound or composition of the invention may
be administered by injection to achieve a systemic effect against
relevant bacteria, preferably a atypical upper respiratory
pathogenic 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 atypical
upper respiratory pathogenic bacteria.
[0043] 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 atypical upper
respiratory pathogenic bacteria, exposed in wound tissue and for
prophylactic use in dental treatment as an alternative to, or in
conjunction with, antibiotic prophylaxis.
[0044] Alternatively, 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 10mg/ml for bathing of wounds or
indwelling devices.
[0045] Also provided by the invention is a method of treating or
preventing a bacterial infection by atypical upper respiratory
pathogenic bacteria comprising the step of administering an
antibacterially effective amount of a composition comprising a
gemifloxacin compound to a mammal, preferably a human, suspected of
having or being at risk of having an infection with atypical upper
respiratory pathogenic bacteria.
[0046] While a preferred object of the invention provides a method
wherein said atypical upper respiratory pathogenic bacteria is
selected from the group consisting of: a member of the genus
Legionella, a member of the genus, Pseudomonas, Pseudomonas
aeruginosa strain, a L. pneumophila strain, a L. pneumophila
serogroup 1, a L. pneumophila serogroup 2, a L. pneumophila
serogroup 3, a L. pneumophila serogroup 4, a L. pneumophila
serogroup 5, a L. Pneumophila serogroup 6, a L. pneumophila
serogroup 7, a L. pneumophila serogroup 8, a L. dumoffii strain, a
L. longbeacheae strain, a L. micdadei strain, a L. oakridgensis
strain, a L. feelei strain, a L. anisa strain, a L. sainthelensi
strain, a L. bozemanii strain, a L. gormanii strain, a L.
wadsworthii strain, a L. jordanis; strain and a L. gormanii strain.
Other atypical upper respiratory pathogenic 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.
[0047] Preferred embodiments of the invention include, among other
things, methods wherein said composition comprises gemifloxacin, or
a pharmaceutically acceptable derivative thereof.
EXAMPLES
[0048] The present invention is further described by the following
examples. The examples are provided solely to illustrate the
invention by reference to specific embodiments. This
exemplification's, while illustrating certain specific aspects of
the invention, do not portray the limitations or circumscribe the
scope of the disclosed invention.
[0049] All examples were carried out using standard techniques,
which are well known and routine to those of skill in the art,
except where otherwise described in detail.
[0050] All parts or amounts set out in the following examples are
by weight, unless otherwise specified.
Example 1 Bacterial Strains
[0051] A variety of Legionella were isolated from respiratory tract
and environmental sources. Identification of organisms was by
standard methods know in the art (for example, see, Washington, C.
W. Jr. Legionella. In: Murray et al., eds. Manual of Clinical
Microbiology. 6th ed. American Society of Microbiology
1995:533-544).
Example 2 Susceptibility Testing
[0052] MICs were determined by standard 2-fold agar dilution
procedure using Buffered Yeast Extract agar (herein "BYE")
(National Committee for Clinical Laboratory Standards: Methods for
antimicrobial susceptibility tests for bacteria that growth
aerobically, approved standards M 7-A4. National Committee for
Laboratory Standards, Villanova, Pa., 1997).
[0053] A final innoculum of about 10.sup.4 colony forming units
(herein "CFU") was inoculated onto the BYE containing doubling
dilutions of antibiotics (0.004-256 mg/L). Plates were incubated at
35.degree. C. for 48 hours. An MIC was defined as the lowest
concentration of antimicrobial that completely inhibited visible
growth. Strains of Pseudomonas aeruginosa ATCC 27853 and L.
Pneumophila ATCC 33152 were included as controls.
Example 3 Determination of PAE
[0054] The in vitro method using the broth technique (Craig, W. A.
Antibiotics in laboratory medicine. Williams & Wilkins
1986:515-536) was used to determine the PAE with Buffered Yeast
extract (BYE). Each strain was exposed to antimicrobial
concentration of four times the MIC. Fresh inoculum (1 ml, final
concentration of 10.sup.6-10.sup.7 CFU/ml) was added to 9 ml of
prepared antimicrobial containing medium and to 9 ml of drug-free
control medium and incubated at 37.degree. C. for 1-2 hours.
Antimicrobial agent was removed by three consecutive
centrifugations at 1200.times.g for 10 minutes. Counts of CFU/ml
were performed on all cultures at time zero, before and after
washing, and every 1 hour until turbidity develops. The counts of
CFU/ml were graphed and the duration of PAE was calculated by
equation:
PAE=T-C
[0055] where T is the time required for the count of CFU in the
test culture to increase 1 log.sub.10 above the count observed
immediately after drug removal, and C is the time required for the
count of untreated control culture to increase by 1 log.sub.10
above the count observed immediately after the completion of the
same procedure used on the test culture for drug removal.
[0056] 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.
* * * * *