Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, April 1998, p. 785-788, Vol. 42, No. 4
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vivo Activity of HSR-903, a New Fluoroquinolone,
against Respiratory Pathogens
Satoshi
Yoshizumi,*
Haruki
Domon,
Shuichi
Miyazaki, and
Keizo
Yamaguchi
Department of Microbiology, Toho University
School of Medicine, 5-21-16 Omori-Nishi, Ota-Ku, Tokyo 143, Japan
Received 19 May 1997/Returned for modification 6 August
1997/Accepted 11 January 1998
 |
ABSTRACT |
The in vivo activity of HSR-903, a new fluoroquinolone, against
major bacteria which cause respiratory tract infections was evaluated.
HSR-903 was active against experimental respiratory tract infections in
mice challenged with penicillin-susceptible and penicillin-resistant
Streptococcus pneumoniae and Haemophilus influenzae strains. Treatment with HSR-903 reduced the bacterial numbers in infected murine lungs. In accord with the pulmonary clearance results, the rates of survival for mice treated with HSR-903,
sparfloxacin, levofloxacin, ciprofloxacin, and benzylpenicillin were
50, 30, 10, 0, and 0%, respectively, 14 days after being infected with
penicillin-resistant S. pneumoniae. A pharmacokinetic study
with pneumonic mice showed that the levels of HSR-903 in the lungs were
seven to eight times higher than those in the plasma. These results
indicate that clinical studies of HSR-903 against respiratory tract
infections may be warranted.
| |
INTRODUCTION |
Several fluoroquinolones with broad
antibacterial spectra, such as ciprofloxacin (22),
lomefloxacin (3), sparfloxacin (7), and
levofloxacin (17, 21), have been developed, and used in the
therapy of bacterial infections. However, many clinical isolates of
Streptococcus pneumoniae, a major respiratory pathogen, are
no longer susceptible to benzylpenicillin or the currently available
fluoroquinolones (1, 2).
HSR-903,
(S)-(
)-5-amino-7-(7-amino-5-azaspiro[2.4]hept-5 - yl) - 1 - cyclopropyl - 6 - fluoro - 1,4 - dihydro - 8 - methyl - 4 - oxoquinoline-3-carboxylic
acid methanesulfonate, is a new quinolone synthesized by Hokuriku
Seiyaku Co., Ltd., Fukui, Japan, that possesses potent antibacterial
activity (13, 15). In the study described here, we used in
vivo murine models to examine the activities of HSR-903 in comparison
with those of ciprofloxacin, sparfloxacin, and levofloxacin, against
the major respiratory pathogens S. pneumoniae and
Haemophilus influenzae.
| |
MATERIALS AND METHODS |
Antimicrobial agents.
The following antimicrobial agents
were used in this study and were obtained from the indicated sources:
HSR-903, Hokuriku Seiyaku Co., Ltd.; ciprofloxacin, Bayer Yakuhin
Ltd., Osaka, Japan; sparfloxacin, Dainippon Pharmaceutical Co., Ltd.,
Osaka, Japan; levofloxacin, Daiichi Pharmaceutical Co., Ltd., Tokyo,
Japan; and benzylpenicillin, Meiji Seika Kaisya, Tokyo, Japan.
Bacterial strains.
The bacterial strains used in this study
were maintained at the Department of Microbiology, Toho University
School of Medicine.
Experimental pulmonary infection caused by S. pneumoniae.
The in vivo activities of HSR-903 and the other drugs
tested against penicillin-susceptible S. pneumoniae (PSSP)
TUH39 were evaluated in 4-week-old male ICR mice (weight, about 20 g; SLC Japan Inc., Shizuoka, Japan). The bacteria were inoculated in Todd-Hewitt broth (Difco) supplemented with 30% horse serum, and the
mixture was incubated at 35°C until the culture became turbid to the
naked eye. When the bacteria were in the late logarithmic phase they
were harvested by centrifugation at 2,000 × g for 10 min at 4°C. The organisms were suspended in 0.9% saline to the desired concentration. The mice were placed under anesthesia with ketamine and xylazine, and each mouse was challenged with 3.7 × 106 CFU by intranasal instillation of 0.05 ml of bacterial
suspension. We did not determine the 50% lethal dose, but this
inoculum resulted in 100% mortality among the controls. The drugs were
administered orally 18 h after infection twice daily for 3 days.
We calculated the 50% effective dose (ED50), including
95% confidence limits, by the probit method (8) from the
survival rates on day 7 after infection. The efficacy of HSR-903
against penicillin-resistant S. pneumoniae (PRSP) TUM741 was
examined on the basis of pulmonary clearance and survival studies with
an established mouse model (9, 16, 18). To evaluate the
effects of HSR-903 and other drugs on the number of bacteria in the
lungs, CBA/J mice (Charles River Japan, Shizuoka, Japan), which are
susceptible to intranasal infection caused by PRSP, were used. The
bacterial suspension was prepared as mentioned above. Four-week-old
CBA/J mice (weight, 15 to 22 g) were placed under
ketamine-xylazine anesthesia, and each animal was challenged with
1.4 × 106 CFU, which resulted in 100% mortality
among the controls. A quinolone was administered orally or
benzylpenicillin was administered subcutaneously at 36 h after
infection to groups of four or five animals each three times a day for
3 days. The animals were killed 18 h after the last administration
of the drugs. The lungs and trachea were removed and were homogenized
in 0.9% saline, and 0.1-ml aliquots of serial 10-fold dilutions of the
homogenate were spread onto blood agar for the determination of viable
counts. The results are presented as the mean ± standard
deviation (SD) log CFU per set of lower respiratory tract organs.
Statistical analysis was done by the Bonferroni-Dunn multiple
comparison method. To compare the effects of HSR-903 and the reference
drugs on survival, groups of 10 mice each were infected with strain
TUM741, and 50 mg of each drug per kg of body weight was administered
as described above. Survival rates were recorded daily for 14 days
after infection.
Experimental respiratory tract infection caused by H. influenzae.
The effects of HSR-903 on a pulmonary infection caused
by H. influenzae were examined in a mouse model constructed
by Miyazaki et al. (10). Four-week-old male ICR mice
(weight, about 20 g) were used. For airway impairment, 40 µl of
1% formalin was instilled intranasally into mice while they were under
ketamine-xylazine anesthesia. An overnight culture of H. influenzae TMS8 was inoculated into brain heart infusion broth
(Difco) supplemented with hemin and NAD at a final concentration of
5%, and the culture was incubated at 35°C for 3 h. The
organisms in the culture were harvested by centrifugation and were
suspended in Eagle's minimal essential medium to make a volume similar
to that of the original culture. This bacterial suspension was added to
MFL cell monolayers, and the monolayers were incubated at 35°C for
1 h with gentle shaking. Free-floating bacteria were removed and
washed three times with saline. Then, cell-bound organisms were removed
from the flask and suspended in Eagle's minimal essential medium.
Three days after treatment of the mice with formalin as described
above, 50 µl of a cell-bound organism suspension (1.0 × 104 CFU/animal) was instilled intranasally into
anesthetized mice. We did not determine the minimum lethal dose for
this challenge. At 48 h after infection the drugs were
administered to each group (n = 5) orally twice daily
for 3 days. The viable counts of the organisms in the lungs and trachea
were determined by the same method used for the PRSP TUM741 model,
except that the tissue homogenates were spread onto chocolate agar. The
data are presented as the average ± SD log CFU per set of lower
respiratory tract organs, and the significance of intergroup
differences was calculated as described above.
Pharmacokinetics in pneumonic mice.
Four-week-old male ICR
mice (weight, about 20 g) were used for the analysis of
pharmacokinetics. Pneumonia caused by PSSP TUH39 was induced by the
method described above. At 18 h after infection the pneumonic mice
were orally given 0.2 ml of HSR-903 or another quinolone at a dose of
50 mg/kg. The animals were killed and the blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, and 6 h after administration of the drugs. The
lungs were removed, weighed, and stored at 80°C until they were
required for analysis. The blood samples were centrifuged to separate
the plasma. The plasma and tissue samples were analyzed by paper disk
methods, with Escherichia coli kp used as an indicator
organism (11, 12). Extraction of HSR-903 from tissues was
performed as follows. The tissue samples containing HSR-903 were
homogenized in a Polytron (Kinematica, Littau/Lucerne, Switzerland) in
4 volumes of 1/15 M phosphate buffer (pH 6.5). The homogenates were
heated at 80°C for 10 min and mixed with an equal volume of 0.2 N
HCl. After vigorous vortex mixing, the sample solutions were collected
by centrifugation at 2,000 × g for 20 min at room
temperature. Each sample solution was adjusted to neutral pH by adding
0.1 N NaOH, and the sample solutions were applied to paper disks.
| |
RESULTS AND DISCUSSION |
Efficacy against experimental pneumonia caused by S. pneumoniae in mice.
The protective effects of HSR-903 and
the other quinolones tested against experimental pneumonia caused by
PSSP TUH39 are summarized in Table 1.
HSR-903 was highly effective, with an ED50 of 9.94 mg/kg,
and it also had the highest in vitro activity against this strain. The
therapeutic effects of HSR-903 and the reference drugs in terms of the
pulmonary clearance of PRSP TUM741 are presented in Fig.
1. The mean viable count of the organisms recovered from the lungs of S. pneumoniae-infected mice was
8.09 ± 1.40 log CFU per lung. Treatment with HSR-903 at a dose of
50 mg/kg led to a significant reduction in the numbers of viable cells
in the lungs compared with those in the lungs of untreated (P < 0.01), benzylpenicillin-treated (P < 0.01), ciprofloxacin-treated (P < 0.01), or
levofloxacin-treated (P < 0.05) mice. Treatment with
sparfloxacin also led to a significant reduction in the viable counts in the lungs compared with those in the lungs of untreated (P < 0.01), benzylpenicillin-treated (P < 0.01), or ciprofloxacin-treated (P < 0.05) mice.
Treatment with levofloxacin afforded a significant reduction in the
viable counts in the lungs compared with those in the lungs of
untreated mice (P < 0.05), but a significant
reduction was not found for ciprofloxacin-treated mice compared
with that for untreated mice. The therapeutic effects of HSR-903,
ciprofloxacin, sparfloxacin, levofloxacin, and benzylpenicillin in
terms of survival are presented in Fig.
2. All control mice died by 6 days after infection. All ciprofloxacin- and benzylpenicillin-treated mice died
between 7 and 11 days after infection, while the survival rates for
mice treated with HSR-903, sparfloxacin, and levofloxacin were 50, 30, and 10%, respectively, at 14 days after infection.
View this table:
[in this window]
[in a new window]
|
TABLE 1.
Protective effects of HSR-903 and other drugs against
pulmonary infection caused by
S. pneumoniae TUH39a
|
|
View larger version (29K):
[in this window]
[in a new window]
|
FIG. 1.
Therapeutic effects of HSR-903 and other drugs in terms
of pulmonary clearance of S. pneumoniae TUM741. CBA/J mice
(n = 4 or 5) were infected intranasally with PRSP. A
drug (50 mg/kg) was administered three times a day for 3 days,
beginning 36 h after infection. The numbers of bacteria in the
lungs were determined 18 h after the last administration. The
results are presented as the mean ± SD log CFU (see text). The
MICs of HSR-903, ciprofloxacin, sparfloxacin, levofloxacin, and
benzylpenicillin were 0.063, 1, 0.25, 1, and 1 µg/ml, respectively.
*, P < 0.01 versus results for control,
ciprofloxacin, or benzylpenicillin treatment and P < 0.05 versus results for levofloxacin treatment;  , P < 0.01 versus results for control or benzylpenicillin treatment and
P < 0.05 versus results for ciprofloxacin treatment;
 , P < 0.05 versus results for control treatment.
|
|
View larger version (21K):
[in this window]
[in a new window]
|
FIG. 2.
Therapeutic effects of HSR-903, ciprofloxacin,
sparfloxacin, levofloxacin, and benzylpenicillin in terms of survival
following infection of CBA/J mice with PRSP TUM741. A drug (50 mg/kg)
was administered three times a day for 3 days, beginning 36 h
after infection.
|
|
Efficacy against experimental respiratory tract infection in mice
caused by H. influenzae.
The time course of the numbers of
viable bacteria in the lower respiratory tract organs during the
therapeutic period is presented in Fig.
3. The in vivo activity of HSR-903 in
this murine model was comparable to that of sparfloxacin and was
superior to those of ciprofloxacin and levofloxacin. The level of
recovery of viable cells from the lower respiratory tract organs of
mice treated with HSR-903 and sparfloxacin was significantly less than
that from the controls at all time points after drug administration. Levofloxacin showed a weak therapeutic effect (not significant) compared with the effect of no treatment (control) after therapy for 3 days, while ciprofloxacin was ineffective.
View larger version (20K):
[in this window]
[in a new window]
|
FIG. 3.
Time course of numbers of viable bacteria in the
respiratory tract during the therapeutic period. ICR mice were infected
intranasally with H. influenzae TMS8 (five mice in each
group). Drugs were administered orally at a dosage of 0.625 mg/kg twice
a day for 3 days, starting 18 h after infection. The numbers of
bacteria in the lungs were determined 18 h after the last
administration of the drugs. The data are presented as the mean ± SD log CFU (see text). The MICs of HSR-903, ciprofloxacin,
sparfloxacin, and levofloxacin were  0.001, 0.008, 0.002, and 0.016 µg/ml, respectively. *, P < 0.05 versus results
for control treatment; , P < 0.01 versus results for
control treatment and P < 0.05 versus results for
ciprofloxacin or levofloxacin treatment; , P < 0.01 versus results for control, ciprofloxacin, or levofloxacin treatment;
§, P < 0.01 versus results for control or
ciprofloxacin treatment.
|
|
Pharmacokinetics in pneumonic mice.
Figure
4 presents the pharmacokinetic profiles
of HSR-903, sparfloxacin, and levofloxacin in the plasma and lungs of
mice infected with S. pneumoniae TUH39. The pharmacokinetic
parameters of HSR-903 and the other drugs are presented in Table
2. The peak concentration of HSR-903 in
the lungs (10.12 µg/ml) was roughly two to three times greater than
those of sparfloxacin and levofloxacin. The area under the curve (AUC)
for HSR-903 in the lungs (53.82 µg · h/ml) was two to four
times greater than those for sparfloxacin and levofloxacin. The
half-life (t1/2) of HSR-903 in the lungs (3.41 h) was longer than that of levofloxacin but was shorter than that of
sparfloxacin. The best values of all parameters were for sparfloxacin
in plasma. The ratios of the maximum concentration (Cmax) and AUC for HSR-903 in the lungs to the
values of those parameters for HSR-903 in plasma were 7 and 8, respectively, whereas the ratios for sparfloxacin and levofloxacin were
close to 1.
View larger version (17K):
[in this window]
[in a new window]
|
FIG. 4.
Pharmacokinetics of HSR-903, sparfloxacin, and
levofloxacin in the plasma (a) and lungs (b) of infected mice. The
drugs were administered orally at a single dose of 50 mg/kg, 18 h
after infection. The results are presented as the mean ± SD.  ,
HSR-903;  , sparfloxacin;  , levofloxacin.
|
|
View this table:
[in this window]
[in a new window]
|
TABLE 2.
Values of pharmacokinetic parameters for HSR-903,
sparfloxacin, and levofloxacin in S. pneumoniae-infected micea
|
|
New oral fluoroquinolones and oral and injectable expanded-spectrum
cephems have played a key role in the clinical treatment
of respiratory
tract infections in the last decade. However, the
emergence of
resistant organisms is causing clinical problems
throughout the world;
various mutant strains with extended-spectrum
-lactamases have
appeared (
4,
14). In addition, the currently
available
fluoroquinolones have insufficient activity against
S. pneumoniae. HSR-903 is a new fluoroquinolone with potent
antibacterial
activity (
13,
15). The MIC of HSR-903 at which
90% of isolates
are inhibited (MIC
90), determined by the
broth microdilution method
(
5,
6) for recent clinical
isolates of
S. pneumoniae, including
PRSP (48 strains)
collected from Toho University Hospital between
1993 and 1995, was
0.063 µg/ml, and HSR-903 was 4 to 32 times
more active than
ciprofloxacin, sparfloxacin, and levofloxacin
(MIC
90s, 2.0, 0.25, and 1.0 µg/ml, respectively). Against
H. influenzae (44 strains), the MIC
90 of HSR-903 was 0.004 µg/ml, and
its activity
was two to four times greater than those of the other
quinolones
tested.
In an in vivo mouse model, HSR-903 showed good efficacy against both
S. pneumoniae and
H. influenzae, which are major
causes
of respiratory tract infections in humans. The frequency of
occurrence
of PRSP infections has increased in recent years
(
19). In patients
infected with PRSP, most
-lactams are
ineffective. In the present
study, the efficacy of HSR-903 was
evaluated with the nonimmunocompromised
CBA/J mouse model of
pneumococcal pneumonia since the histopathology
in this animal model
closely resembles that in humans with infection
(
18). The
results indicate that this drug may be effective against
pneumococcal
pneumonia in humans. In addition, HSR-903 was effective
against murine
pulmonary infection due to
H. influenzae, which
mimics
bronchitis in humans. These in vivo results are consistent
with the
potent in vitro activity of HSR-903. The AUC and
Cmax of HSR-903 in murine lungs were much higher
than would be expected
from the values in murine plasma. This feature
may be important
for the efficacy of HSR-903, although many host
factors may also
influence the in vivo activity of HSR-903. HSR-903
showed a long
elimination
t1/2 (18 h) in a
pharmacokinetic study with human
volunteers given a single dose of 200 mg (
20). This is far longer
than the
t1/2 in mice, so the drug may prove to be
particularly
effective against clinical respiratory tract infections in
humans.
In conclusion, HSR-903, a new fluoroquinolone, showed excellent
activity in in vivo experimental models. The present data,
in
conjunction with the potent in vitro activity and the long
t1/2 in humans, indicate that HSR-903 has
potential clinical utility
against respiratory tract infections.
| |
ACKNOWLEDGMENTS |
This work was supported by a grant from Hokuriku Seiyaku Co.,
Ltd.
We thank the staff of the Department of Microbiology, Toho University
School of Medicine, for helpful suggestions. We also thank Hideo Kato
and the researchers of the Microbiology Section of Hokuriku Seiyaku
Co., Ltd. for suggestions and skillful support.
| |
FOOTNOTES |
*
Corresponding author. Present address: Department of
Research, Hokuriku Seiyaku Co., Ltd., 37-1-1 Inokuchi, Katsuyama, Fukui 911-8555, Japan. Phone: 81 (779) 88-5121. Fax: 81 (779) 88-8021.
| |
REFERENCES |
| 1.
|
Appelbaum, P. C.
1992.
Antimicrobial resistance in Streptococcus pneumoniae: an overview.
Clin. Infect. Dis.
15:77-83[Medline].
|
| 2.
|
Azoulay-Dupuis, E.,
E. Vallee,
B. Veber,
J. P. Bedos,
J. Bauchet, and J. J. Pocidalo.
1992.
In vivo efficacy of a new fluoroquinolone, sparfloxacin, against penicillin-susceptible and -resistant and multiresistant strains of Streptococcus pneumoniae in a mouse model of pneumonia.
Antimicrob. Agents Chemother.
36:2698-2703[Abstract/Free Full Text].
|
| 3.
|
Hirose, T.,
E. Okezaki,
H. Kato,
Y. Ito,
M. Inoue, and S. Mitsuhashi.
1987.
In vitro and in vivo activity of NY-198, a new difluorinated quinolone.
Antimicrob. Agents Chemother.
31:854-859[Abstract/Free Full Text].
|
| 4.
|
Ishii, Y.,
A. Ohno,
H. Taguchi,
S. Imajo,
M. Ishiguro, and H. Matsuzawa.
1995.
Cloning and sequence of the gene encoding a cefotaxime-hydrolyzing class A -lactamase isolated from Escherichia coli.
Antimicrob. Agents Chemother.
39:2269-2275[Abstract].
|
| 5.
|
Japanese Society for Chemotherapy.
1990.
Method for the determination of minimum inhibitory concentration (MIC) of aerobic bacteria by microdilution method.
Chemotherapy (Tokyo)
38:102-105.
|
| 6.
|
Japanese Society for Chemotherapy.
1993.
Method for the determination of minimum inhibitory concentration (MIC) of fastidious bacteria and anaerobic bacteria by microdilution method.
Chemotherapy (Tokyo)
41:183-189.
|
| 7.
|
Kojima, T.,
M. Inoue, and S. Mitsuhashi.
1989.
In vitro activity of AT-4140 against clinical bacterial isolates.
Antimicrob. Agents Chemother.
33:1980-1988[Abstract/Free Full Text].
|
| 8.
|
Miller, L. C., and M. L. Tainter.
1944.
Estimation of ED50 and its error by means of logarithmic probit graph paper.
Proc. Soc. Exp. Biol. Med.
57:261-264.
|
| 9.
|
Miyazaki, H.,
K. Tateda,
T. Matsumoto,
S. Miyazaki, and K. Yamaguchi.
1996.
Therapeutic efficacies of penicillin G, cefotaxime, and imipenem/cilastatin against penicillin-resistant pneumococcal pneumonia in CBA/J mice.
J. Infect. Chemother.
2:34-39.
|
| 10.
|
Miyazaki, S.,
T. Nunoya,
T. Matsumoto,
K. Tateda, and K. Yamaguchi.
1997.
New murine model of bronchopneumonia due to cell-bound Haemophilus influenzae.
J. Infect. Dis.
175:205-209[Medline].
|
| 11.
| Nakamura, S., N. Kurobe, T. Ohue, M. Hashimoto, and M. Shimizu. 1991. Absorption, distribution, and excretion of
sparfloxacin in animals. Chemotherapy (Tokyo) 39(Suppl.
4):123-130. (In Japanese with English abstract.)
|
| 12.
| Okezaki, E., K. Ohmichi, S. Koike, Y. Takahashi, and E. Makino. 1988. Disposition and metabolism of NY-198, I. Bioassay
study of absorption, distribution, and excretion in various animals.
Chemotherapy (Tokyo) 36(Suppl. 2):132-137. (In
Japanese with English abstract.)
|
| 13.
|
Okezaki, E.,
Y. Watanabe,
T. Hirose,
T. Yoshida,
Y. Aoki, and H. Kato.
1995.
Antibacterial activity of HSR-903, a new novel quinolone, abstr. F202, p. 148.
In
Program and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 14.
|
Rice, L. B.,
S. H. Willey,
G. A. Papanicolaou,
A. A. Medeiros,
G. M. Eliopoulos,
R. C. Moellering, Jr., and G. A. Jacoby.
1990.
Outbreak of ceftazidime resistance caused by extended-spectrum -lactamases at a Massachusetts chronic-care facility.
Antimicrob. Agents Chemother.
34:2193-2199[Abstract/Free Full Text].
|
| 15.
|
Takahashi, Y.,
N. Masuda,
M. Otsuki,
M. Miki, and T. Nishino.
1997.
In vitro activity of HSR-903, a new quinolone.
Antimicrob. Agents Chemother.
41:1326-1330[Abstract].
|
| 16.
|
Takashima, K.,
K. Tateda,
T. Matsumoto,
T. Ito,
Y. Iizawa, and K. Yamaguchi.
1995.
Experimental respiratory tract infection caused by penicillin-resistant Streptococcus pneumoniae in CBA/J mice.
Ther. Res.
16:433-436. (In Japanese with English abstract.)
|
| 17.
|
Tanaka, M.,
M. Otsuki,
T. Une, and T. Nishino.
1990.
In-vitro and in-vivo activity of DR-3355, an optically active isomer of ofloxacin.
J. Antimicrob. Chemother.
26:659-666[Abstract/Free Full Text].
|
| 18.
|
Tatede, K.,
K. Takashima,
H. Miyazaki,
T. Matsumoto,
T. Hatori, and K. Yamaguchi.
1996.
Noncompromised penicillin-resistant pneumococcal pneumonia CBA/J mouse model and comparative efficacies of antibiotics in this model.
Antimicrob. Agents Chemother.
40:1520-1525[Abstract].
|
| 19.
|
Ubukata, K.,
Y. Asahi,
K. Okuzumi,
M. Konno, and The Working Group for Penicillin-Resistant S. pneumoniae.
1996.
Incidence of penicillin-resistant Streptococcus pneumoniae in Japan, 1993-1995.
J. Infect. Chemother.
1:177-184.
|
| 20.
|
Umemura, K.,
A. Mizuno, and M. Nakashima.
1996.
Pharmacokinetics and safety of HSR-903 in healthy volunteers, abstr. F60, p. 110.
In
Program and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 21.
|
Une, T.,
T. Fujimoto,
K. Sato, and Y. Osada.
1988.
In vitro activity of DR-3355, an optically active ofloxacin.
Antimicrob. Agents Chemother.
32:1336-1340[Abstract/Free Full Text].
|
| 22.
|
Wise, R.,
J. M. Andrews, and L. J. Edwards.
1983.
In vitro activity of Bay 09867, a new quinolone derivative, compared with those of other antimicrobial agents.
Antimicrob. Agents Chemother.
23:559-564[Abstract/Free Full Text].
|
Antimicrobial Agents and Chemotherapy, April 1998, p. 785-788, Vol. 42, No. 4
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Higa, F., Arakaki, N., Tateyama, M., Koide, M., Shinzato, T., Kawakami, K., Saito, A.
(2003). In vitro and in vivo activity of olamufloxacin (HSR-903) against Legionella spp.. J Antimicrob Chemother
52: 920-924
[Abstract]
[Full Text]
-
Okamoto, H., Miyazaki, S., Tateda, K., Ishii, Y., Yamaguchi, K.
(2001). In Vivo Efficacy of Telithromycin (HMR3647) against Streptococcus pneumoniae and Haemophilus influenzae. Antimicrob. Agents Chemother.
45: 3250-3252
[Abstract]
[Full Text]
-
Yoshizumi, S., Takahashi, Y., Murata, M., Domon, H., Furuya, N., Ishii, Y., Matsumoto, T., Ohno, A., Tateda, K., Miyazaki, S., Yamaguchi, K.
(2001). The in vivo activity of olamufloxacin (HSR-903) in systemic and urinary tract infections in mice. J Antimicrob Chemother
48: 137-140
[Abstract]
[Full Text]
-
Tomioka, H., Sato, K., Akaki, T., Kajitani, H., Kawahara, S., Sakatani, M.
(1999). Comparative In Vitro Antimicrobial Activities of the Newly Synthesized Quinolone HSR-903, Sitafloxacin (DU-6859a), Gatifloxacin (AM-1155), and Levofloxacin against Mycobacterium tuberculosis and Mycobacterium avium Complex. Antimicrob. Agents Chemother.
43: 3001-3004
[Abstract]
[Full Text]
-
Watanabe, A., Tokue, Y., Takahashi, H., Kikuchi, T., Kobayashi, T., Gomi, K., Fujimura, S., Nukiwa, T.
(1999). In Vitro Activity of HSR-903, a New Oral Quinolone, against Bacteria Causing Respiratory Infections. Antimicrob. Agents Chemother.
43: 1767-1768
[Abstract]
[Full Text]
-
Murata, M., Tamai, I., Sai, Y., Nagata, O., Kato, H., Tsuji, A.
(1999). Carrier-Mediated Lung Distribution of HSR-903, a New Quinolone Antibacterial Agent. J. Pharmacol. Exp. Ther.
289: 79-84
[Abstract]
[Full Text]
Top
Abstract
Introduction
