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Antimicrobial Agents and Chemotherapy, January 2001, p. 312-315, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.312-315.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
In Vitro and In Vivo Efficacies of T-3811ME
(BMS-284756) against Mycoplasma pneumoniae
Masahiro
Takahata,*
Masako
Shimakura,
Ritsuko
Hori,
Kazuo
Kizawa,
Yozo
Todo,
Shinzaburo
Minami,
Yasuo
Watanabe, and
Hirokazu
Narita
Research Laboratories, Toyama Chemical Co.,
Ltd., Toyama, Japan
Received 20 March 2000/Returned for modification 15 July
2000/Accepted 12 October 2000
 |
ABSTRACT |
T-3811, the free base of T-3811ME (BMS-284756), a new
des-F(6)-quinolone, showed a potent in vitro activity (MIC at which 90% of the isolates tested are inhibited [MIC90], 0.0313 µg/ml) against Mycoplasma pneumoniae. The
MIC90 of T-3811 was 4-fold higher than that of
clarithromycin but was 4- to 8-fold lower than those of trovafloxacin,
gatifloxacin, gemifloxacin, and moxifloxacin and was 16- to 32-fold
lower than those of levofloxacin, ciprofloxacin, and minocycline. In an
experimental M. pneumoniae pneumonia model in hamsters,
after the administration of T-3811ME (20 mg/kg of body weight as
T-3811, once daily, orally) for 5 days, the reduction of viable cells
of M. pneumoniae in bronchoalveolar lavage fluid was
greater than those of trovafloxacin, levofloxacin, and clarithromycin (20 and 40 mg/kg, orally) (P < 0.05).
| |
TEXT |
Mycoplasma pneumoniae is
a major causative organism of pneumonia and accounts for as many as 20 to 30% of pneumonia cases (20). For the clinical
treatment of M. pneumoniae infections, macrolides and
tetracyclines are commonly used (9, 18, 25). However,
mutants resistant to macrolides have been reported over the last 10 years (17, 21, 23). Thus, a viable alternative to
macrolides in the treatment of pneumonia caused by M. pneumoniae is needed. New quinolones developed recently, such as
moxifloxacin and gatifloxacin (5, 10), possess a wide
antimicrobial spectrum and potent activity against various pathogens,
including M. pneumoniae, and are expected to be useful in
the treatment of this organism (4, 5, 6). T-3811ME
(BMS-284756), a new des-F (6)-quinolone, which exhibits excellent
activity against respiratory pathogens such as Streptococcus
pneumoniae, Chlamydia pneumoniae, and M. pneumoniae, is under development for both oral and parenteral administration (24). In the present study, we studied in
vitro and in vivo antimycoplasma activity of T-3811ME. The in
vivo efficacy of T-3811ME was evaluated in hamsters with
experimental pneumonia caused by M. pneumoniae and compared
with those of trovafloxacin, levofloxacin, and clarithromycin.
Determination of MIC.
The following agents were employed:
T-3811ME (T-3811 methanesulfonate monohydrate, also known as
BMS-284756), T-3811 (the free base of T-3811ME), ciprofloxacin,
levofloxacin, trovafloxacin, gatifloxacin, gemifloxacin,
moxifloxacin, clarithromycin, and minocycline; T-3811, T-3811ME,
trovafloxacin, gatifloxacin, gemifloxacin, and moxifloxacin were
synthesized at Research Laboratories, Toyama Chemical Co., Ltd., Tokyo,
Japan. Ciprofloxacin, levofloxacin, and clarithromycin were extracted
from commercially available tablets. The purity of each of these three
agents was above 99.8% as measured by high-performance liquid
chromatography (HPLC). Minocycline was purchased from Lederle-Japan
Ltd., Tokyo, Japan. T-3811, the free base of T-3811ME, was used for all
in vitro studies.
M. pneumoniae FH, a standard strain, was used for
experimental pneumonia studies with hamsters. Fifty clinical isolates
of M. pneumoniae were used for MIC determination of nine
antimicrobial agents. MICs were determined using a microdilution method
(phenol red method) in 96-well microplates (12). A broth
microdilution procedure was used according to the method of Whithear et
al. (26). The medium used for MIC determination and
dilution of agents was PPLO (Difco Inc., Detroit, Mich.) broth
supplemented with 30% Mycoplasma Supplement S (Difco), 0.5% glucose
(Wako Pure Chemicals Industries, Ltd., Osaka, Japan), and 0.002%
phenol red (Tokyo Kasei Co., Ltd., Tokyo, Japan). Preculture was
carried out with the same medium for 6 to 9 days of incubation at
37°C. Then, 10 µl of suspension (106 CFU/ml) was
inoculated into 96-well microplates containing 90 µl of the
antibiotic solution. The MICs were determined after 5 days of
incubation at 37°C by color change from red to yellow. Phenol red
indicated a yellow color (acidification) after cell growth resulting in
consumption of glucose.
Therapeutic efficacies of T-3811ME, trovafloxacin, levofloxacin,
and clarithromycin. (i) Experimental pneumonia model in hamsters.
For the experimental pneumonia model, hamsters were used as in previous
reports (2, 3, 11). Four-week-old male Syrian hamsters
were purchased from Japan SLC Inc., Shizuoka, Japan, and were assigned
to the study after an acclimation period of 3 days. On the day of
infection, the hamsters were randomly allocated to each group (control,
n = 11; treated groups, n = 5 to 6).
M. pneumoniae FH was cultured in PPLO broth at 37°C for 7 days and stored at 
40°C (approximately 108 CFU/ml). The
frozen cells were thawed at 37°C before use. Pulmonary infections
were induced in hamsters anesthetized with sodium pentobarbital (Dainippon Pharmaceutical Co., Ltd., Osaka, Japan) by intratracheally injecting 0.1 ml of the suspension of M. pneumoniae.
(ii) Administration of antimicrobial agents.
T-3811ME,
levofloxacin, trovafloxacin, and clarithromycin were suspended in 0.5%
methylcellulose SM-400 (Shin-Etsu Chemical Co., Ltd., Tokyo, Japan).
Oral administration of antimicrobial agents at 20 mg/kg of body weight
(T-3811ME-treated groups) and 20 and 40 mg/kg (all other groups) was
initiated on the 7th day after infection by M. pneumoniae
and continued once daily for 2 and 5 days.
(iii) Evaluation of therapeutic effects of antimicrobial
agents.
Animals were sacrificed at 24 h after final
administration following anesthetization with ether. Bronchoalveolar
lavage fluid (BALF) was obtained by injection into and subsequent
suction of 2 ml of Hanks solution (Nissui Pharmaceutical Co., Ltd.,
Tokyo, Japan) from the trachea. This BALF and its 10-fold serial
dilutions were used for viable cell count. The viable cell counts were
measured on the plate of PPLO agar containing supplements. The limit of assay of CFUs in BALF by this method was 2.30 log CFU/ml.
(iv) Statistical analysis.
The significance of each group in
terms of the viable cell count in BALF was analyzed by Tukey's
multiple comparisons procedures in an imbalanced two-way ANOVA (SAS
version 6.12 software).
The concentrations in serum, BALF, and lung tissue after administration
at a dose of 20 mg/kg orally were studied for T-3811ME,
trovafloxacin,
levofloxacin, and clarithromycin (each group,
n = 3 to
4). At 0.25, 0.5, 1, 2, 4, and 6 h after drug administration,
blood, BALF, and lung tissue samples were collected. Animals were
sacrificed by exsanguination from the cephalic vein under ether
anesthesia at each sampling time. The blood serum (collected from
the
cephalic vein) was measured for drug concentrations. After
blood was
kept in Sepaclen-A-5 (Eiken Kizai Co., Ltd., Tokyo,
Japan) at room
temperature for more than 30 min, serum was obtained
by centrifugation.
Lung tissue was removed and homogenized in
fourfold volumes of of
phosphate-buffered solution (PBS) (pH 7.0,
1/15 mol/liter). BALF was
obtained by injection into and subsequent
suction of PBS (1 ml) from
the trachea. We used this method because
the volume of BALF was very
small. However the actual concentration
of BALF would be much higher if
corrected for dilution. The homogenized
tissue and BALF were
centrifuged. The supernatants and serum were
frozen at
40°C until
required for HPLC assay. An equal volume
of methanol was added to each
of the samples, which were then
mixed and centrifuged. Supernatants
were used for measurement
of T-3811, trovafloxacin, and levofloxacin
concentrations by HPLC
(LC series device [Shimadzu Co., Ltd., Tokyo,
Japan] or L series
device [Hitachi Co., Ltd., Tokyo, Japan]). The
concentration of
clarithromycin was measured by a bioassay method
(paper disk method)
using
Micrococcus luteus ATCC 9341 as a
test strain and heart
infusion agar (Eiken Kagaku Co., Ltd., Tokyo,
Japan) as a medium.
Area under the plasma concentration-time curve from
0 h to
(AUC
0-
)
and the terminal half-life were
calculated from the mean concentrations
in plasma by noncompartmental
analysis with WinNonlin software
(Scientific Consulting, Inc.). The
maximum plasma concentration
(
Cmax) and the time
to reach
Cmax were obtained directly from
the
actual mean concentrations in
plasma.
The MIC at which 90% of the isolates tested are inhibited
(MIC
90) of T-3811 against 50 clinical isolates was 0.0313 µg/ml
and was 4-fold higher than that of clarithromycin but was 4- to
8-fold lower than those of trovafloxacin, gatifloxacin, gemifloxacin,
and moxifloxacin and was 16- to 32-fold lower than those of
levofloxacin,
ciprofloxacin, and minocycline. The MIC of T-3811 for
M. pneumoniae FH was 0.0313 µg/ml and was 2- to 32-fold
lower than those of
other quinolones tested (Table
1).
Figure
1 shows the viable cell counts in
BALF from hamsters with experimental pneumonia caused by
M. pneumoniae FH. The viable
cells of
M. pneumoniae in the
nontreated group were 10
5 to 10
6 CFU/ml from 7 days (start of administration) through 12 days
(1 day after
administration over 5 days) after infection. After
the administration
of trovafloxacin (20 and 40 mg/kg), levofloxacin
(20 and 40 mg/kg), and
clarithromycin (20 mg/kg) once daily for
2 days, the viable cells of
M. pneumoniae in BALF were comparable
to those of the
nontreated group. On the other hand, T-3811ME
(20 mg/kg as T-3811) and
clarithromycin (40 mg/kg) reduced the
viable cell count in BALF, and
the viable cells of
M. pneumoniae in these groups were
significantly fewer than in the nontreated
group (
P < 0.05). The viable cells of
M. pneumoniae in BALF after
administration of T-3811ME (20 mg/kg as T-3811) once daily for
5 days
were significantly fewer than those in the clarithromycin-,
trovafloxacin-, and levofloxacin-treated groups (20 and 40 mg/kg)
and
the nontreated groups (
P < 0.05).
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FIG. 1.
In vivo efficacy of T-3811ME and other antibacterial
agents against experimental pneumonia caused by M. pneumoniae FH in hamsters. For results at 2 days an asterisk
indicates a P of <0.05 for T-3811ME versus control,
trovafloxacin, levofloxacin, and clarithromycin (except clarithromycin
at 40 mg/kg), or for clarithromycin (40 mg/kg) versus control. For
results at 5 days, an asterisk indicates a P of <0.05 for
T-3811ME versus control, trovafloxacin, levofloxacin, and
clarithromycin. Results are presented as Means + standard
deviations (error bars) (untreated group, n = 11;
treated groups, n = 5 to 6), for 2 or 5 days of
therapy.
|
|
Table
2 shows the pharmacokinetic
parameters. The
Cmax of T-3811 in serum was 0.85 µg/ml and was lower than that of levofloxacin
and comparable to those
of trovafloxacin and clarithromycin. The
Cmax of
T-3811 in lung tissue was 2.1 µg/g and was lower than
that of
clarithromycin and comparable to those of levofloxacin
and
trovafloxacin. The
Cmax of T-3811 in BALF was
0.09 µg/ml and
was lower than that of levofloxacin and comparable to
that of
trovafloxacin. The
Cmax of
clarithromycin in BALF was lower than
the limit of assay. The
AUC
0- of T-3811 in lung tissue
was 7.7 µg·h/g and
was greater than that of trovafloxacin and
lower than those of
levofloxacin and clarithromycin. The
Cmax/MIC
and AUC
0-/MIC of T-3811 in lung tissue were 67.1
and
246, respectively and were greater than those of trovafloxacin
and
levofloxacin. Clarithromycin possessed a potent in vitro activity
against
M. pneumoniae and showed a significant therapeutic
effect
(40 mg/kg, for 2 days) in the present study. However, the
therapeutic
effect of clarithromycin was inferior to that of T-3811ME
in other
cases. Because
M. pneumoniae is an extracellular
parasite (
19),
it was considered that the low distribution
in BALF and weak bactericidal
activity of clarithromycin compared with
T-3811 (data not shown)
resulted in low efficacy.
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|
TABLE 2.
Pharmacokinetic parameters after oral administration of
antibacterial agents (20 mg/kg) to hamsters with experimental pneumonia
caused by M. pneumoniae FH
|
|
Macrolides and tetracyclines are the most-active antibiotics against
mycoplasmas in vitro (
1,
16,
22,
25). However,
improvements in therapy are needed to accommodate specific
characteristics
of the microorganism or unusual manifestations of the
illness.
Until now, it was reported that quinolones are less effective
in mycoplasmal and chlamydial infection (
16). The newer
fluoroquinolones,
such as moxifloxacin and gatifloxacin, which have
recently undergone
substantial development, exhibit in vitro activity
against a broadened
spectrum, including
M. pneumoniae
(
5,
6,
7,
8,
10,
15). T-3811, the free base of T-3811ME
(BMS-284756), also showed
excellent in vitro activity against
M. pneumoniae. The in vitro
activity of T-3811 was four- to
eight-fold greater than those
of other new quinolones tested. Also, the
in vivo efficacy of
T-3811ME against experimental pneumonia caused by
M. pneumoniae was superior to those of trovafloxacin,
levofloxacin, and clarithromycin.
Although the existing data on in vivo
efficacy are only preliminary
(
11,
13,
14), the newer
fluoroquinolones are promising agents
for the treatment of
M. pneumoniae infection and, more generally,
for that of
community-acquired pneumonia. Newer quinolones have
attracted interest
as potential therapy for community-acquired
pneumonia because they are
active against a wide range of pathogens,
including
M. pneumoniae.
In conclusion, T-3811ME possessed potent in vitro antimycoplasma
activity and had a significantly superior therapeutic effect
compared
to clarithromycin, trovafloxacin, and levofloxacin on
experimental
pneumonia caused by
M. pneumoniae FH. These data
indicate
that T-3811ME (BMS-284756) could be a viable alternative
to macrolides,
such as clarithromycin, in the treatment of pneumonia
caused by
M. pneumoniae.
| |
ACKNOWLEDGMENTS |
We express our thanks to Mitsuo Kaku, Department of Molecular
Diagnostics, Department of Laboratory Medicine, Tohoku University Graduate School of Medicine, for providing us with the M. pneumoniae strains and to Helen Lavin for reviewing the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Research
Laboratories, Toyama Chemical Co., Ltd., 4-1, Shimookui 2-chome, Toyama
930-8508, Japan. Phone: 81-76-431-8268. Fax: 81-76-431-8208. E-mail:
MASAHIRO_TAKAHATA{at}toyama-chemical.co.jp.
| |
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Antimicrobial Agents and Chemotherapy, January 2001, p. 312-315, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.312-315.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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