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Antimicrobial Agents and Chemotherapy, January 1998, p. 23-27, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Efficacy of CS-834 against Experimental Pneumonia
Caused by Penicillin-Susceptible and -Resistant
Streptococcus pneumoniae in Mice
Takashi
Fukuoka,1
Harumi
Kawada,1
Akiko
Kitayama,1
Tetsufumi
Koga,1
Mikie
Kubota,1
Tamako
Harasaki,1
Yasuki
Kamai,1
Satoshi
Ohya,1,*
Hiroshi
Yasuda,1
Masayuki
Iwata,1 and
Shogo
Kuwahara2
Biological Research Laboratories, Sankyo Co.,
Ltd., Shinagawa-ku, Tokyo 140,1 and
Department of Microbiology, School of Medicine, Toho
University, Tokyo 143,2 Japan
Received 25 March 1997/Returned for modification 11 August
1997/Accepted 17 October 1997
 |
ABSTRACT |
The efficacy of CS-834, a novel oral carbapenem, was assessed by
using a murine model of pneumonia caused by penicillin-susceptible and
penicillin-resistant Streptococcus pneumoniae and was
compared with those of oral cephems, i.e., cefteram pivoxil,
cefpodoxime proxetil, cefdinir, and cefditoren pivoxil. Intranasal
inoculation of 106 CFU of penicillin-susceptible or
penicillin-resistant S. pneumoniae in the exponential
growth phase induced pneumonia and bacteremia in ddY mice within
48 h. For the treatment of infections caused by the
penicillin-susceptible strain the antibiotics were administered orally
at 0.4, 2, and 10 mg/kg of body weight twice daily for 2 days beginning
at 24 h after bacterial inoculation, and for the treatment of
infections caused by a penicillin-resistant strain the antibiotics were
administered at 2, 10, and 50 mg/kg twice daily for 2 days beginning at
24 h after bacterial inoculation. Among the antibiotics tested,
CS-834 exhibited the most potent efficacy against both types of
strains. Against infections caused by penicillin-susceptible S. pneumoniae, CS-834 at all doses significantly reduced the numbers
of viable cells in both the lungs and blood. Cefpodoxime proxetil at
all doses and cefteram pivoxil and cefditoren pivoxil at doses of 2 and
10 mg/kg showed comparable efficacies. Against infections caused by
penicillin-resistant S. pneumoniae, CS-834 at doses of 10 and 50 mg/kg showed the most potent efficacy among the antibiotics
tested, resulting in the maximum decrease in the numbers of viable
cells in the lungs. Comparable efficacies were observed with cefteram
pivoxil and cefpodoxime proxetil at doses of 50 mg/kg each. The
concentration of CS-834 in the lungs and blood was higher than that of
cefdinir and was lower than those of the other antibiotics tested,
suggesting that the potent therapeutic efficacy of CS-834 reflects its
strong activity against S. pneumoniae.
| |
INTRODUCTION |
Streptococcus pneumoniae
is one of the most common pathogens, causing community-acquired
pneumonia accompanied by high rates of morbidity and mortality,
particularly in children, elderly people, and immunocompromised hosts
(2, 9). The increase in the incidence of infections caused
by penicillin-resistant S. pneumoniae has become a serious
clinical problem in many countries (1, 4, 6, 8, 11, 15, 17).
It has been reported that the frequency of isolation of
penicillin-resistant S. pneumoniae strains was one-third
among isolates from patients with severe infections, such as pneumonia
and meningitis, in Japan (8).
Several new oral cephem antibiotics (cefdinir and the prodrugs, such as
cefteram pivoxil, cefpodoxime proxetil, and cefditoren pivoxil) were
reported to have very potent antibacterial activity against various
species of gram-positive and gram-negative bacteria (12, 14, 18,
20). They showed only moderate activities against
penicillin-resistant S. pneumoniae, however.
CS-834 is a novel orally absorbable carbapenem; its active metabolite
is R-95867 (Fig. 1). This antibiotic
showed a broad spectrum of activity, covering both gram-positive and
gram-negative aerobes and anaerobes, including penicillin-susceptible
and penicillin-resistant S. pneumoniae (21). In
this study, we developed a murine pneumonia model of
penicillin-susceptible and penicillin-resistant S. pneumoniae and investigated the therapeutic efficacy of CS-834 in
this model.
(This work was presented in part at the 36th Interscience Conference on
Antimicrobial Agents and Chemotherapy, New Orleans, La., 15 to 18 September 1996 [13].)
| |
MATERIALS AND METHODS |
Antibiotics.
The following compounds were synthesized at
Sankyo Research Laboratories, Tokyo, Japan: CS-834, sodium salt of
R-95867, cefpodoxime proxetil, cefpodoxime, cefteram, and cefditoren.
The other compounds were obtained from the indicated sources: cefteram
pivoxil, Toyama Chemical Co., Ltd., Tokyo, Japan; cefdinir, Fujisawa
Pharmaceutical Co., Ltd., Osaka, Japan; and cefditoren pivoxil, Meiji
Seika Kaisha, Ltd., Tokyo, Japan.
Bacterial strains.
Penicillin-susceptible strain 2132 (MIC
of benzylpenicillin, 0.012 µg/ml) and penicillin-resistant strains
9605 and 9601 (MICs of benzylpenicillin, 1.56 µg/ml for both strains)
of S. pneumoniae, originally isolated from patients with
pneumonia in 1983 and 1993 in Japan, were used in this study.
Susceptibility testing.
MICs were determined by the usual
twofold agar dilution method (5) with Pearlcore heart
infusion agar (Eiken Chemical Co., Ltd., Tokyo, Japan) supplemented
with 5% defibrinated horse blood. The inoculum size was
104 CFU per spot (5 µl). The inoculated plates were
incubated at 37°C for 18 h.
Pneumonia caused by S. pneumoniae in mice.
After
overnight incubation on brain heart infusion agar (Difco Laboratories,
Detroit, Mich.) supplemented with 5% defibrinated horse blood
(BHIA-B), freshly grown colonies were suspended in heart infusion broth
(Difco Laboratories) supplemented with 10% heat-treated horse serum
(HIB-S) at an optical density at 550 nm of 0.12 (JUNIOR II
Spectrophotometer; Coleman Instruments Corp., Maywood, Ill.). The
bacterial suspension was diluted 100-fold with fresh HIB-S and was
incubated, with shaking, to yield an optical density at 550 nm of 0.12. This culture, which was in the exponential growth phase, was diluted
5-fold (for strain 9601), 10-fold (for strain 2132), and 25-fold (for
strain 9605) with the same medium and was used for inoculation.
Experimental pneumonia was induced in male ddY mice weighing 19 to
21 g (SLC Japan Inc.) with penicillin-susceptible strain 2132 or
penicillin-resistant strain 9605 or 9601. Mice were anesthetized lightly by intravenous injection of ketamine (Sankyo, Co., Ltd., Tokyo,
Japan) at 1 mg/kg of body weight, and 50 µl (for strains 2132 and
9605) or 75 µl (for strain 9601) of a bacterial suspension (approximately 106 CFU) was inoculated through the nares
into the lungs. To investigate the change in viable cell numbers in the
lungs and blood, infected mice were killed at 24, 48, and 72 h
after infection and their lungs and blood were removed. The lungs were
homogenized in 2 ml of saline, and the homogenates and blood were
serially diluted 10-fold with saline. One hundred microliters of the
diluent was spread onto BHIA-B plates, and the plates were incubated at
37°C for 24 h. The viable cell numbers were determined by
counting the numbers of colonies on the plates.
Histopathological examination.
The lung tissues were removed
from unmedicated mice infected with strain 9605 at 24 h after
infection and were immediately fixed in 10% neutral buffered formalin.
The fixed tissues were embedded in paraffin wax, sectioned, and then
stained with hematoxylin-eosin for histological examination or with
methylene blue for the identification of bacteria.
Therapeutic efficacy.
Drugs were administered orally at 24, 32, 48, and 56 h after the bacterial challenge. Doses of 0.4, 2, and 10 mg/kg of body weight were used against infections caused by
strain 2132; doses of 2, 10, and 50 mg/kg were used against infections
caused by strain 9605; and a dose of 10 mg/kg was used against
infections caused by strain 9601. At 72 h after infection the mice
were killed, and their lungs and blood were removed. The lungs were
homogenized in saline, and the homogenates and blood were serially
diluted 10-fold with saline. One hundred microliters of the diluent was spread onto BHIA-B plates, and the plates were incubated at 37°C for
24 h. The viable cell numbers in the lungs and blood were determined by counting the numbers of colonies on the plates. The means
and standard errors were calculated for each group. The detection
limits for lungs infected with penicillin-susceptible and -resistant
S. pneumoniae strains were 2.3 and 1.3 log10 CFU per lung, respectively, to avoid significant drug carryover. The detection limit for blood was 2.0 log10 CFU per ml for both
infections caused by the penicillin-susceptible S. pneumoniae strain and infections caused by penicillin-resistant
S. pneumoniae strains.
Pharmacokinetic studies.
Pharmacokinetic studies were done
with mice of the same strain used for the pneumonia model, but the mice
were not infected. At 15, 30, 60, 120, and 240 min after oral
administration of antibiotics at 100 mg/kg of body weight, the mice
were exsanguinated, and their blood and lungs were collected.
Antibiotic concentrations in serum and lung homogenates were determined
by the paper disc diffusion method by using Bacillus
subtilis ATCC 6699 as the bioassay indicator (7). Four
mice were used for each datum point.
Statistical analysis.
The statistical significance of the
differences between the numbers of viable organisms recovered from the
lungs and blood were evaluated by the Student t test. A
difference between two groups was considered to be statistically
significant if the P value was <0.05.
| |
RESULTS |
Antibacterial activity.
Table 1
presents the antibacterial activities of R-95867, cefteram,
cefpodoxime, cefdinir, and cefditoren against the strains used in this
study, penicillin-susceptible S. pneumoniae 2132 and
penicillin-resistant S. pneumoniae 9605 and 9601. R-95867, as well as cefteram and cefditoren, showed potent activity against penicillin-susceptible strain 2132. The activity of R-95867 was stronger than those of cefpodoxime and cefdinir. Against
penicillin-resistant strains 9605 and 9601, R-95867 exhibited the most
potent activity, and it was 4- to 16-fold stronger than the reference
antibiotics.
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TABLE 1.
Antibacterial activities of R-95867 and reference
antibiotics against penicillin-susceptible and -resistant S. pneumoniae strains used for experimental infections
|
|
Murine pneumonia model.
Figure 2
shows the changes in bacterial viability in the lungs and blood of mice
after infection with penicillin-susceptible (Fig. 2A) and
penicillin-resistant (Fig. 2B) strains. Both penicillin-susceptible and
-resistant strains induced pneumonia and bacteremia in mice within
48 h after infection. The pneumonias were not fatal during a 72-h
observation period after infection. The numbers of viable cells of
penicillin-susceptible strain 2132 in the lungs and blood were
approximately 105 CFU/lung and below 102 CFU/ml
of blood, respectively, at 24 h after infection, and they increased to approximately 109 CFU/lung and
approximately 106 CFU/ml of blood, respectively, at
72 h after infection. On the other hand, the numbers of viable
cells of the penicillin-resistant strains in the lungs decreased to
approximately 104 CFU/lung at 48 h after infection.
The numbers of viable cells of strain 9601 increased to approximately
105 CFU/lung at 72 h, while the level of viable cells
of strain 9605 remained almost unchanged until 72 h after
infection. The numbers of viable cells of penicillin-resistant strains
in blood increased to approximately 105 CFU/ml at 24 h, and the levels remained almost unchanged until 72 h after
infection. Microscopic observation showed typical histopathological findings in the lung tissues of mice infected with penicillin-resistant strain 9605. The lung tissue was invaded by large numbers of
inflammatory cells, mainly neutrophils, and cocci were present in
alveolar spaces (data not shown).
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FIG. 2.
Viable cell counts for penicillin-susceptible strain
2132 (A) and penicillin-resistant strains 9605 and 9601 (B) in the
lungs and blood of mice at 24, 48, and 72 h after infection.
Symbols:  , strain 2132;  , strain 9605;  , strain 9601. Each
point represents the mean ± standard error (n = 5 to 7).
|
|
Therapeutic efficacy against experimental pneumonia in mice.
Figure 3 shows the therapeutic efficacies
of CS-834 and the reference antibiotics against pneumonia caused by the
penicillin-susceptible strain. At doses of 0.4, 2, and 10 mg/kg, all
antibiotics exhibited dose-dependent efficacies against the infection.
CS-834 was the most active among the antibiotics tested, and its use
resulted in significant reductions in the numbers of viable cells in
both the lungs and blood at all doses in comparison with the numbers of
viable cells in the lungs and blood of the control group. Cefpodoxime proxetil at all doses and cefteram pivoxil and cefditoren pivoxil at
doses of 2 and 10 mg/kg showed efficacies comparable to that of CS-834.
The therapeutic efficacy of cefdinir was inferior to those of the other
antibiotics tested, and its use resulted in significant reductions in
bacterial numbers in the lungs and blood only when it was used at a
dose of 10 mg/kg.
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FIG. 3.
Efficacies of CS-834 and reference antibiotics against
pneumonia caused by penicillin-susceptible strain 2132. Each column and
bar represents the mean ± standard error, respectively
(n = 4 to 6). The indicated doses of each drug were
administered orally twice daily for 2 days beginning at 24 h after
infection, and the numbers of viable cells in the lungs (A) and blood
(B) of mice were determined at 72 h after infection. CFTM-PI,
cefteram pivoxil; CPDX-PR, cefpodoxime proxetil; CFDN, cefdinir;
CDTR-PI, cefditoren pivoxil. The asterisks indicate a significant
difference (P < 0.05) compared with the results for
the control group.
|
|
The efficacy of CS-834 was compared with those of the reference
antibiotics against experimental pneumonia caused by
penicillin-resistant
strains 9605 (Fig.
4A) and 9601 (Fig.
4B). CS-834 at a dose
of
2 mg/kg exhibited modest efficacy against infections caused by
strain 9605, as did the other antibiotics tested. CS-834 at doses
of 10 and 50 mg/kg, however, resulted in large reductions in the
numbers of
viable cells in both the lungs and blood. This effect
was superior to
the effects of the other antibiotics tested. Cefteram
pivoxil and
cefpodoxime proxetil showed potent efficacies at doses
of 50 mg/kg, and
their efficacies were comparable to the efficacy
of CS-834. Cefditoren
pivoxil and cefdinir exhibited modest efficacies
at all doses, although
their use at doses of 10 and 50 mg/kg resulted
in significant
reductions in the numbers of viable cells in the
lungs and blood in
comparison with the numbers of viable cells
in the lungs and blood of
the control group. At a dose of 10 mg/kg,
CS-834 was the most active
drug against pneumonia caused by strain
9601 when its activity was
compared with those of the other antibiotics
used at the same dose.
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FIG. 4.
Efficacies of CS-834 and reference antibiotics against
pneumonia caused by penicillin-resistant strains 9605 (A) and 9601 (B).
Each column and bar represents the mean ± standard error
(n = 8 to 10). The indicated doses of each drug were
administered orally twice daily for 2 days beginning at 24 h after
infection, and the numbers of viable cells in the lungs and blood of
mice were determined at 72 h after infection. CFTM-PI, cefteram
pivoxil; CPDX-PR, cefpodoxime proxetil; CFDN, cefdinir; CDTR-PI,
cefditoren pivoxil. The asterisks indicate a significant difference
(P < 0.05) compared with the results for the control
group.
|
|
Pharmacokinetics of drugs in serum and lung.
Table
2 presents the values of the
pharmacokinetic parameters for R-95867 and the reference antibiotics in
the serum and lungs of mice after the administration of a single oral
dose of 100 mg/kg of body weight. The concentrations of R-95867 in the serum and lungs were higher than those of cefdinir and lower than those
of the other antibiotics tested. The mean ± standard error peak
levels of R-95867 were 43.8 ± 5.4 µg/ml and 9.1 ± 0.75 µg/g in the serum and lungs, respectively, at 30 min after
administration. At 120 min after administration the concentration of
R-95867 in the lungs was below the detection limit (0.2 µg/ml). At
all time points at which values were determined, the concentrations of cefdinir in the lungs were below the detection limit.
| |
DISCUSSION |
It has been difficult to develop animal models of pneumonia caused
by penicillin-resistant S. pneumoniae, since
penicillin-resistant strains are less pathogenic than
penicillin-susceptible ones for the induction of pneumonia in healthy
animals (3, 10, 16, 19). Our model also showed that in the
lungs the numbers of cells of the penicillin-resistant strain were
lower than the numbers of cells of the penicillin-susceptible strain.
For this reason, some investigators used models of pneumonia caused by
penicillin-resistant pneumococci and induced in immunocompromised
animals or by using foreign bodies, such as melted agar (3, 10,
16). We, however, successfully constructed with healthy mice a
model of pneumonia caused by penicillin-resistant S. pneumoniae.
The reason that we used pathogens in the exponential growth phase is
that they were more pathogenic than pathogens in other growth phases
for the induction of pneumonia in mice (data not shown). In our
pneumonia model, the numbers of viable cells of penicillin-resistant
S. pneumoniae remained approximately 104 to
106 CFU in the lungs of mice with bacteremia from 24 to
72 h after infection, and this infection was not fatal until
72 h after infection. In addition, the histological changes, such
as the inflammatory reaction, could be observed in infected lungs
within 24 h, and higher doses of the antibiotics resulted in
better therapeutic efficacy, suggesting that this experimental model of
infection in ddY mice is reliable for evaluating the in vivo efficacies of antibiotics.
CS-834 showed the most potent activity among the antibiotics tested, in
particular, against pneumonia caused by penicillin-resistant S. pneumoniae strains, although the concentrations of its active metabolite were lower than those of cefteram, cefpodoxime, and cefditoren in the lungs and blood of mice. These results suggest that
the excellent therapeutic efficacy of CS-834 reflects the potent in
vitro activity of R-95867, which was 4- to 16-fold greater than those
of the other antibiotics against the penicillin-resistant strains.
Against clinical isolates of penicillin-susceptible and -resistant
S. pneumoniae, R-95867 also exhibited more potent activity than the cephem antibiotics: the MICs of R-95867 for 90% of strains of
penicillin-susceptible and -resistant isolates were 0.05 and 0.39 µg/ml, respectively (21).
In conclusion, the new orally administered carbapenem CS-834 has been
considered to be an extremely promising compound for further
evaluation. Its antibacterial activity would cover not only pneumonia
caused by penicillin-susceptible S. pneumoniae but also the
pneumonia caused by penicillin-resistant S. pneumoniae encountered in general practice and could be used for the treatment of
hospital outpatients. Clinical studies with CS-834 are in progress in
Japan and the United States.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Biological
Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome,
Shinagawa-ku, Tokyo, 140, Japan. Phone: 81-3-3492-3131. Fax:
81-3-5436-8565. E-mail: ohya{at}shina.sankyo.co.jp.
| |
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Antimicrobial Agents and Chemotherapy, January 1998, p. 23-27, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
