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Antimicrobial Agents and Chemotherapy, August 1999, p. 2010-2016, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro Antibacterial Activity of LJC 11,036, an Active
Metabolite of L-084, a New Oral Carbapenem Antibiotic with
Potent Antipneumococcal Activity
Muneo
Hikida,*
Kouju
Itahashi,
Atsumi
Igarashi,
Toshiharu
Shiba, and
Masataka
Kitamura
Medical Research Laboratories, Lederle
(Japan), Ltd., Shiki-shi, Saitama-ken 353-8511, Japan
Received 31 December 1998/Returned for modification 19 April
1999/Accepted 4 June 1999
 |
ABSTRACT |
LJC 11,036 is the active metabolite of L-084, a novel oral
carbapenem that exhibits potent broad-spectrum activity. Antibacterial activities of LJC 11,036 against clinical isolates from respiratory infections, such as Streptococcus pneumoniae
(n = 52), Streptococcus pyogenes
(n = 19), Haemophilus influenzae
(n = 50), Klebsiella pneumoniae
(n = 53), and Moraxella catarrhalis
(n = 53), and from urinary-tract infections, such as
Escherichia coli (n = 53) (MICs at which
90% of the isolates were inhibited [MIC90s], 0.1, 
0.006, 0.39, 0.05, 0.05, and 0.05 µg/ml, respectively), were 2- to
64-fold higher than those of imipenem, cefdinir, and faropenem.
Moreover, against these bacterial species, except for H. influenzae, the MIC90s of LJC 11,036 were 4- to
512-fold lower than those of levofloxacin. LJC 11,036 showed
bactericidal activity equal or superior to that of imipenem.
Bactericidal activity against penicillin-resistant S. pneumoniae (PRSP) did not vary with the phase of growth. LJC 11,036 had potent activity against various
-lactamase-producing strains, excluding carbapenemase
producers. Against renal dehydropeptidase-I, LJC 11,036 was more stable
than imipenem. Furthermore, LJC 11,036 produced in vitro postantibiotic
sub-MIC effects against PRSP HSC-3 (6.0 h at one-fourth the MIC) and
H. influenzae LJ5 (9.2 h at one-half the MIC). LJC
11,036 showed high binding affinities for PBP1A, -1B, -2A/2X, -2B, and
-3 of PRSP and for PBP1B, -2, -3A, and -3B of H. influenzae.
| |
INTRODUCTION |
Carbapenems are well recognized to
have broad antibacterial activities, and many derivatives have been
synthesized (3, 4, 8, 12). Parenteral carbapenems such as
imipenem (8), panipenem (11), and meropenem
(5) have been introduced into the market; however, no oral
carbapenem has been marketed as yet. Several oral carbapenem
derivatives, such as GV 118819X (13), CS-834
(18), DZ-2640 (14), and CL191,121 (17)
are under development. For development of an oral carbapenem, a
compound should possess distinct features, e.g., broad and potent
activity, high stability to -lactamase and
dehydropeptidase-I (DHP-I), and postantibiotic effect, and should
achieve high oral absorption in order to prevent both ready acquisition
of drug resistance in enteric bacteria and the occurrence of diarrhea.
L-084 (1) is a novel oral carbapenem with a
1-(1,3-thiazolin-2-yl)azetidin-3-ylthio group at the C-2 position (Fig.
1). In this study, we evaluated the
following in vitro antibacterial properties of LJC 11,036, the active
metabolite of L-084, in comparison with those of imipenem, faropenem,
cefdinir, and levofloxacin: (i) activity against clinical isolates,
(ii) activity against -lactamase-producing strains, (iii) correlation between the MIC and the MBC, (iv) stability to DHP-I,
(v) in vitro postantibiotic sub-MIC effect, (vi) potency against
bacteria at various phases of growth, and (vii) binding affinity for
penicillin-binding proteins (PBPs).
(This work was presented in part at the 38th Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Diego, Calif., 24 to 27 September 1998 [1]).
| |
MATERIALS AND METHODS |
Drugs.
LJC 11,036, an active metabolite of L-084, was
synthesized at the Medical Research Laboratories, Lederle (Japan),
Ltd., Saitama, Japan. L-084 is not active in vitro, and all studies
were performed with LJC 11,036, the active metabolite. Imipenem (Banyu
Pharmaceutical Co., Ltd.), faropenem (Yamanouchi Pharmaceutical
Co., Ltd./Suntory Ltd.), cefdinir (Fujisawa Pharmaceutical Co., Ltd.),
and levofloxacin (Daiichi Pharmaceutical Co., Ltd.) were obtained commercially.
Organisms.
Twenty-six aerobic standard strains and 37 -lactamase-producing strains were obtained from the
stock culture collection of the Medical Research Laboratories, Lederle
(Japan), Ltd. A total of 652 clinical isolates collected between 1994 and 1998 from patients at various hospitals in Japan were used for MIC determinations.
Determination of MICs.
MICs were determined by the agar
dilution method (10) with Sensitivity Disk Agar-N (SDA;
Nissui). SDA supplemented with 5% horse blood was used for
streptococci and Moraxella catarrhalis, while SDA
supplemented with 5% Fildes enrichment was used for Haemophilus
influenzae. One loopful (5 µl) of an inoculum corresponding to
104 CFU per spot was inoculated on drug-containing agar
plates, and the plates were incubated for 18 h at 37°C. The MIC
was defined as the lowest drug concentration which inhibited visible
growth of bacteria. To examine the effects of different inoculum sizes (106 to 108 CFU/ml) on the antibacterial
activity of LJC 11,036, MIC tests were also performed by the agar
dilution method using SDA. The stabilities of LJC 11,036 to
-lactamases were determined by drug susceptibility by
using the agar dilution method against
-lactamase-producing strains.
Determination of MBCs.
MICs were determined by the broth
dilution method using serial twofold dilutions. Strains were grown
overnight in sensitivity test broth (STB; Nissui). Overnight cultures
were diluted in fresh STB to approximately 106 CFU/ml and
inoculated into STB containing various concentrations of each drug. For
H. influenzae, STB supplemented with 5% Fildes enrichment
was used, while STB supplemented with 5% horse serum was used for
Streptococcus pneumoniae. Five microliters of cultures used
for the determination of MICs from test tubes showing no visible growth
of bacteria were inoculated on SDA plates. The MBC was defined as the
lowest drug concentration which inhibited visible growth of bacteria.
Drug susceptibility in various phases of growth.
Growth
curves obtained by monitoring the batch culture in the presence of
drugs were examined. The period between the logarithmic and stationary
phases was divided into three growth periods, and at each phase drugs
were added. Viable counts were determined at the times indicated in
Fig. 2.
In vitro postantibiotic sub-MIC effect.
STB supplemented
with 5% horse serum was used as the growth medium for
penicillin-resistant S. pneumoniae (PRSP) HSC-3. Bacteria in
the logarithmic phase of growth (approximately 108 CFU/ml)
were exposed to the MIC of the test drug at 37°C for 2 h. The
drug was removed by a 10
2 dilution into fresh medium
containing different sub-MIC concentrations (1/16, 1/8, and 1/4 the
MIC). Viable counts were determined at 0, 2, 4, 6, and 8 h after
the addition of sub-MIC concentrations of drugs. The in vitro
postantibiotic sub-MIC effect was calculated according to the method of
Licata et al. (7). For H. influenzae LJ5, STB
supplemented with 5% Fildes enrichment was used. After exposure to the
drug at twice the MIC for 2 h, the drug was removed by the
dilution method. Sub-MIC concentrations of one-eighth, one-fourth, and
one-half the MIC were used. Viable counts were determined at 0, 2, 4, 6, 8, 10, and 12 h.
Stability to DHP-I.
The stability of LJC 11,036 to renal
DHP-I was compared with that of imipenem by using recombinant human
DHP-I (9). Test compounds at a final concentration of 3 mM
were incubated at 30°C with DHP-I (enzyme activity, 0.6 U/ml) in 50 mM 3-(N-morpholino)propanesulfonic acid buffer (pH 7.0).
After various times of incubation, the concentrations of the compounds
were determined by high-performance liquid chromatography (9).
Binding assays for PBPs.
Binding of LJC 11,036 to PBPs of
PRSP HSC-3 and H. influenzae LJ5 was determined by
previously described competition assays (2, 15). Solubilized
membrane fractions were preincubated for 10 min at 30°C with a
nonradioactive compound diluted to various concentrations and then
postincubated with [3H]benzylpenicillin for another 10 min at 30°C. PBPs were detected by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fluorography.
| |
RESULTS |
Activity against clinical isolates.
Table
1 shows the in vitro activity of LJC
11,036 against gram-positive bacteria compared with those of imipenem,
faropenem, cefdinir, and levofloxacin. The MICs at which 90% of the
isolates are inhibited (MIC90s) of LJC 11,036 for
methicillin-susceptible Staphylococcus aureus (MSSA),
methicillin-resistant S. aureus (MRSA) (MIC of
methicillin, 
12.5 µg/ml), and Staphylococcus epidermidis were 0.025, 12.5, and 6.25 µg/ml, respectively. The activity against MSSA (MIC90) was equal to that of imipenem and 8- to
16-fold higher than those of faropenem, cefdinir, and levofloxacin. LJC
11,036 showed the highest activity against MRSA and S. epidermidis among the drugs tested. MIC90s for
penicillin-susceptible S. pneumoniae (PSSP), PRSP, and
Streptococcus pyogenes were 0.006, 0.1, and 0.006
µg/ml, respectively. Of the compounds used in this study, LJC 11,036 was the most active against streptococci.
The in vitro activity of LJC 11,036 against gram-negative bacteria is
shown in Table
2. Against
Escherichia coli,
Klebsiella pneumoniae, and
M. catarrhalis, the MIC
90s of this compound were
0.05 µg/ml; thus, it was 2- to 512-fold more active than the other
drugs tested. Against
H. influenzae, the activity of LJC
11,036
(MIC
90s, 0.39 µg/ml) was four- to eightfold
greater than those
of the other
-lactams tested, but it was less
active than levofloxacin.
The MIC
90s of LJC 11,036 against
Enterobacter cloacae (0.2 µg/ml)
and
Proteus
mirabilis (0.39 µg/ml) were 4- to 64-fold lower than
those of
imipenem and faropenem. LJC 11,036 was moderately active
against
Serratia marcescens (MIC
50, 0.39 µg/ml;
MIC
90, 25 µg/ml).
The activity of LJC 11,036 against
Pseudomonas aeruginosa (MIC
50,
6.25 µg/ml;
MIC
90, 100 µg/ml) was lower than those of imipenem
and
levofloxacin but greater than those of faropenem and cefdinir.
Influence of the inoculum size on the MIC.
Increasing the
inoculum size from 106 to 108 CFU/ml had little
or no significant effect on the in vitro activities of LJC 11,036 or
imipenem against S. aureus, S. pneumoniae,
E. coli, H. influenzae, and K. pneumoniae (Table 3). However, the
activity of imipenem against extended-spectrum
-lactamase (ESBL)-producing K. pneumoniae (TOHO-1 type) was more affected by the inoculum size
than that of LJC 11,036.
Activity against -lactamase-producing strains.
The comparative activities of LJC 11,036 and the other drugs against
various -lactamase-producing strains are shown in Table 4. The MICs of LJC 11,036, imipenem,
faropenem, and cefdinir against strains producing various types of
-lactamases, except for carbapenemase and
cephalosporinase of P. aeruginosa, were 0.78, 6.25,
25, and 0.1 to >100 µg/ml, respectively, indicating that LJC
11,036 was the most stable among the -lactams tested. However, like
imipenem, LJC 11,036 was hydrolyzed by carbapenemase.
Correlation between the MIC and MBC.
In five of the eight
strains tested, there was no difference between the MIC and the MBC for
LJC 11,036 (Table 5); among the remaining
strains, only a twofold difference was noted. The bactericidal activity
of LJC 11,036 was the most potent, followed by those of imipenem and
cefdinir, in that order.
Bactericidal activity.
A decrease of approximately 2 log10 units in the viable count was observed with LJC
11,036 against PRSP at the three different phases of growth. In
contrast, cefdinir did not exhibit bactericidal activity at any of the
growth phases (Fig. 2).
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FIG. 2.
Influence of the growth phase of PRSP HSC-3 on its
susceptibility to LJC 11,036. The MIC of LJC 11,036 is 0.025 µg/ml,
and that of cefdinir is 1.56 µg/ml.
|
|
In vitro postantibiotic sub-MIC effect.
LJC 11,036, unlike
cefdinir, produced a strong drug concentration-dependent postantibiotic
sub-MIC effect in vitro against PRSP HSC-3 (Fig.
3). Significant postantibiotic effects
(>1 h) were observed at all concentrations tested; 1.6 h at
one-eighth the MIC and 6.1 h at one-fourth the MIC. Moreover, as
shown in Fig. 4, against H. influenzae LJ5, significant postantibiotic effects were observed
at both one-fourth the MIC (1.7 h) and one-half the MIC (9.2 h).
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FIG. 3.
In vitro postantibiotic sub-MIC effect (PAE) of LJC
11,036 against PRSP HSC-3. Bacteria were exposed to the MIC from 0 to
2 h and then diluted into fresh medium containing one-fourth or
one-eighth the MIC. Solid circles at 2 h represent the count of
viable bacteria after exposure to the MIC, before (higher) and after
(lower) 102 dilution. Open circles, control (no drug).
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FIG. 4.
In vitro postantibiotic sub-MIC effect (PAE) of LJC
11,036 against H. influenzae LJ5. Procedures and symbols are
as explained for Fig. 3, except that bacteria were exposed to twice the
MIC from 0 to 2 h.
|
|
Stability to DHP-I.
After incubation at 30°C for 4 h,
the residual amount of LJC 11,036 decreased by only about 11% of the
initial amount, while that of imipenem decreased by 50% after only
1 h of incubation.
Binding of PBPs.
LJC 11,036 showed strong binding to PBP1A,
-1B, -2A/2X, -2B, and -3 of PRSP HSC-3, with 50% inhibitory
concentrations (IC50) of 0.12, 0.08, 0.16, 0.05, and 0.01 µg/ml, respectively (Fig. 5). Binding
of LJC 11,036 to PBP1B, -2, -3A, and -3B of H. influenzae LJ5 was also high (IC50, 0.09, 0.01, 0.12, and 0.10 µg/ml, respectively). The MICs of LJC 11,036 against PRSP HSC-3 and
H. influenzae LJ5 were 0.025 and 0.1 µg/ml, respectively.
| |
DISCUSSION |
This study demonstrated that LJC 11,036 possesses greater
activities than imipenem, faropenem, and cefdinir against the main causative organisms of respiratory and urinary-tract infections, i.e.,
S. pneumoniae, S. pyogenes, H. influenzae, K. pneumoniae, M. catarrhalis,
and E. coli.
S. pneumoniae is well known to be a major causative agent of
community-acquired pneumonia, bacteremia, meningitis, and acute otitis
media. At present the prevalence of PRSP is increasing worldwide, which
complicates treatment of these infections. A concentration of 0.2 µg
of LJC 11,036/ml inhibited the growth of all S. pneumoniae
strains tested, including PRSP. When this result is compared with the
published antipneumococcal data for other recently developed oral
carbapenems, such as GV 118819X (MIC100, 2.0 µg/ml) (13), CS-834 (MIC100, 0.5 µg/ml) (18), DZ-2640 (MIC100, 0.78 µg/ml)
(14), and CL 191,121 (MIC100, 1.0 µg/ml)
(17), LJC 11,036 appears to have the most potent
antipneumococcal activity, which is one of its noteworthy features. As
with imipenem, no significant inoculum effect was detected with LJC
11,036 against any of the strains tested. However, the MIC of imipenem
against an ESBL producer, compared with those against other strains,
increased much more than that of LJC 11,036. The bactericidal activity
of LJC 11,036 was demonstrated by the following findings: (i) there was
a good correlation between the MIC and the MBC against various strains,
and (ii) the antibacterial activity against PRSP did not vary with the
phase of growth tested. In addition, this compound produced longer in
vitro postantibiotic sub-MIC effects against both PRSP and H. influenzae than cefdinir.
S. pneumoniae has at least five PBPs (1A, 1B, 2A, 2B, and
2X). According to Hakenbeck et al. (6), the development of
drug resistance in PRSP is considered to be due both to multiple
changes in PBP1A and PBP2B and to the appearance of PBP2X.
However, in strain HSC-3, used in this study, separation of PBP2A
and PBP2X could not be detected. As was pointed out by Hakenbeck et al. (6), this finding may be due to the lot of polyacrylamide
used for the preparation of SDS-PAGE.
It is of considerable interest that LJC 11,036 shows high binding
affinities for five PBPs, including 2B, which exhibits reduced affinity
for oral cephalosporins (16). For LJC 11,036, the first target PBP of H. influenzae is PBP2, as has been noted with
imipenem. The morphological change (induction of a spherical form)
associated with PBP2 was observed (data not shown). The stability of
LJC 11,036 to various -lactamases, excluding
carbapenemases, was demonstrated indirectly by way of
determination of the MICs against -lactamase-producing
strains. Although LJC 11,036 was less active against P. aeruginosa than imipenem and levofloxacin, this compound exhibits
strong binding to PBPs in P. aeruginosa (data not shown). Therefore, the decreased activity against P. aeruginosa may
be due to poor permeation through the outer membrane. According to the
results of a Phase Ia clinical study (single oral doses of 25 to 200 mg), L-084 showed a high urinary recovery rate (approximately 60 to
70%). Moreover, antibiotic-related diarrhea was not observed with any
doses of L-084 (unpublished data). It is considered that the high
stability of LJC 11,036 to renal DHP-I contributes to the high urinary
recovery. These findings may lead to the efficacious use of L-084
against complicated urinary-tract infections caused by P. aeruginosa.
In conclusion, the specific features of L-084 discussed above warrant
further investigation for its potential human clinical application.
L-084 may have a potential role in the oral treatment of infections
that are less responsive to the currently available oral agents,
especially -lactams.
| |
ACKNOWLEDGMENTS |
We thank M. Inoue (Kitasato University School of Medicine) for
support and helpful discussion on the classification of
-lactamases, K. Ubukata (Teikyo University
School of Medicine) for supplying S. pneumoniae HSC-3,
and R. Testa (Wyeth-Ayerst Research) for helpful advice and comments.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Medical Research
Laboratories, Lederle (Japan), Ltd., 1-6-34 Kashiwa-cho,
Shiki-shi, Saitama-ken 353-8511, Japan. Phone: (048)
487-6622. Fax: (048) 474-1598.
| |
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Antimicrobial Agents and Chemotherapy, August 1999, p. 2010-2016, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Top
Abstract
Introduction
