Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, August 1999, p. 1895-1900, Vol. 43, No. 8
Antimicrobial Research Laboratory, Taiho
Pharmaceutical Co., Ltd. Tokushima 771-0194, Japan,1 and SynPhar Laboratories
Inc., Edmonton, Alberta T6E 5V2, Canada2
Received 19 October 1998/Returned for modification 10 February
1999/Accepted 20 May 1999
Syn2190, a monobactam derivative containing
1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor
of group 1 Expanded-spectrum cephalosporins
show good therapeutic efficacies against various infectious diseases
caused by gram-negative bacteria. However, due to long-term clinical
usage, the problem of resistance of gram-negative bacteria to
expanded-spectrum cephalosporins has occurred. This resistance is
principally associated with the hyperproduction of chromosomally
mediated cephalosporinases (16, 23), which are classified as
group 1 To overcome these clinical problems brought about by the increasing
incidence of
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro and In Vivo Activities of Syn2190, a Novel
-Lactamase Inhibitor
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactamase. The concentrations of inhibitor needed to
reduce the initial rate of hydrolysis of substrate by 50% for Syn2190 against these enzymes were in the range of 0.002 to 0.01 µM. These values were 220- to 850-fold lower than those of tazobactam. Syn2190 showed in vitro synergy with ceftazidime and cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1 -lactamase-producing strains, such as Pseudomonas
aeruginosa, Enterobacter cloacae, Citrobacter
freundii, and Morganella morganii. However, against
-lactamase-derepressed mutants of P. aeruginosa, the
MICs of ceftazidime plus Syn2190 were not affected by the amount of
-lactamase, and the values were the same for the parent strains. The
MICs at which 50% of isolates are inhibited (MIC50s) of
ceftazidime plus Syn2190 were 2- to 16-fold lower than those of
ceftazidime alone for ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC50s of cefpirome
plus Syn2190 were two- to eightfold lower for cefpirome-resistant
clinical isolates. The synergies of Syn2190 plus ceftazidime or
cefpirome observed in vitro were also reflected in vivo. Syn2190
improved the efficacies of both cephalosporins in both a murine
systemic infection model with cephalosporin-resistant rods and urinary tract infection models with cephalosporin-resistant P. aeruginosa.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactamases (4). The increased levels of
production of cephalosporinases among species of
Enterobacter, Citrobacter,
Serratia, Pseudomonas, and
Acinetobacter may be induced by broad-spectrum -lactams,
and spontaneous mutation to a stably derepressed constitutive state may
occur (1, 12). These cephalosporinases confer resistance to
all cephalosporins (7, 22). The resistance mechanism of
Pseudomonas aeruginosa is considered to be the combination
of -lactamase production and lower outer membrane (OM) permeability
(10).
-lactamase-producing organisms, three -lactamase inhibitors, clavulanic acid, sulbactam, and tazobactam, have been developed. These -lactamase inhibitors inactivate various types of
group 2 -lactamases, including extended- and broad-spectrum -lactamases. However, their inhibitory activities against
cephalosporinases are generally weak (2, 11). In our program
to identify potent inhibitors of group 1 cephalosporinases, Syn2190
(Fig. 1) was found to possess potent
inhibitory activity against cephalosporinases. This paper describes the
in vitro and in vivo activities of Syn2190 in combination with various
cephalosporins.
View larger version (11K):
[in a new window]
FIG. 1.
Chemical structure of Syn2190.
| |
MATERIALS AND METHODS |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
Antibacterial agents. Syn2190 and tazobactam were prepared by SynPhar Laboratories Inc. and Taiho Pharmaceutical Co., Ltd., respectively. Other antibiotics were obtained as commercial preparations.
Organisms.
Bacterial strains, listed in Tables 1 and 2, that
produce the characterized -lactamases were kindly provided by
R. T. Testa (15) for Escherichia coli TEM-1
and TEM-2 and Klebsiella pneumoniae CTX-1, J. F. Acar
for E. coli TEM-7 (8) and SHV-5 (9),
J. D. Williams for K. pneumoniae 366L (19),
and M. Galleni for Enterobacter cloacae P99 (13).
Other bacterial strains were clinical isolates collected from 1988 to
1995 from several hospitals in Japan, and their biological properties
were identified with the VITEK system (ASM III; Vitek System Inc.). All
of the strains used were stored at 
80°C as suspensions in 10% skim
milk. -Lactamase-derepressed mutants of P. aeruginosa
were obtained as follows. The parent organism was incubated in
Sensitivity Disk Agar (SDA-N; Nissui), which is a modified
Mueller-Hinton medium adjusted with divalent cations containing 2 to
8× the MIC of ceftazidime, and the colony obtained after incubation
for 48 h was used as a mutant. Alterations of penicillin-binding
proteins (25), outer membrane proteins (20), and
physiological characters were not observed for these mutants. The
-lactamases produced by the characterized -lactamase-producing strains, listed in Table 2, were identified by their
substrate-hydrolyzing profiles by using ampicillin and cephalothin.
Assay of -lactamase activity and -lactamase inhibitory
activity.
The enzymes were obtained as crude cell extracts
prepared by ultrasonication. -Lactamase activity was determined by
the UV method (5). The amount of protein was measured by
using the Bio-Rad Protein Assay. The concentration of inhibitor needed
to reduce the initial rate of hydrolysis of substrate by 50%
(I50) was recorded as the residual activity of
-lactamase. Substrates (100 µM cephalothin for group 1 -lactamases; 100 µM ampicillin or cefotaxime for group 2 -lactamases) were added to the reaction mixture after preincubation
of the enzyme with -lactamase inhibitor for 5 min at 30°C. The
reaction rate was measured by the UV method.
In vitro susceptibility tests.
A total of 106
cells of bacterial suspension per ml in broth cultures was spotted onto
SDA-N plates with a twofold serial dilution of antibiotic either alone
or in the presence of a -lactamase inhibitor. A total of 1 or 5 µg
of a -lactamase inhibitor per ml was combined with antibiotic for
the characterized -lactamase-producing strains or was combined with
antibiotic at a 1- to-1 ratio for the -lactamase-derepressed mutant
strains and clinical isolates. The MIC was defined as the lowest
antibiotic concentration that prevented visible growth of bacteria
after overnight incubation at 37°C.
Induction of -lactamase.
The bacteria were incubated with
each concentration of test compound for 2 h. The bacterial cells
were washed twice with 50 mM phosphate buffer (pH 7.0) and were
ultrasonicated. After centrifugation, the supernatant was used as the
crude enzyme extract. -Lactamase activity was determined with 100 µM cephalothin as the substrate by the UV method (5).
Therapeutic efficacy in mice systemic infection model.
A
bacterial suspension (106 to 107 cells/ml) was
mixed with an equal volume of 10% gastric mucin (Difco), and the
mixture was inoculated intraperitoneally into mice. Male ddY mice
weighing, on average, 21.5 g (age, 4 to weeks; Japan SLC Inc.,
Shizuoka, Japan) were used. The antibiotics, either alone or in the
presence of a -lactamase inhibitor at ratio of 1 to 1, were
administered subcutaneously at 1 and 3 h after the inoculation.
The 50% effective doses (ED50s) were calculated by the
Probit method from the survival rate at 5 days after infection.
Therapeutic efficacy in murine urinary tract infection
model.
A total of 0.1 ml of bacterial suspension (6.2 × 104 cells/mouse) was inoculated into the mouse urinary
tract. Female ddY mice weighing, on average, 19.2 g (age, 4 weeks)
were used. At 6 h postinoculation, the antibiotics, either alone
or in the presence of a -lactamase inhibitor at a ratio of 1 to 1, were administered twice daily for 2 days and once daily at 3 days after
infection. At 5 days after infection, the kidneys were removed and were
homogenized with 2 ml of saline, and the bacterial cells were counted
serially by the pour plate method. Statistical analysis was performed
by the Tukey method.
Plasma Syn2190 concentration. Syn2190 was administered intravenously at a dose of 20 mg/kg of body weight. Blood was obtained from the inferior mesenteric vein of the mice with a heparinized syringe. Plasma Syn2190 concentrations were determined by high-pressure liquid chromatography. The half-life in plasma was calculated by the compartment method with the WinNonlic computer program.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
-Lactamase inhibitory activity.
The inhibitory activity of
Syn2190 against -lactamases was compared to that of tazobactam
(Table 1). Tazobactam showed moderate inhibitory activity against group 1 -lactamases produced by P. aeruginosa, E. cloacae, Morganella morganii,
and Citrobacter freundii. The I50s of tazobactam
were in the range of 0.433 to 4.995 µM. Syn2190 had stronger
inhibitory activity against these enzymes. The I50s of
Syn2190 were in the range of 0.002 to 0.010 µM, and these values were
220- to 850-fold lower than those of tazobactam. Against
plasmid-mediated group 2b and 2be -lactamases and
chromosome-mediated group 2e -lactamases, tazobactam showed stronger
inhibition than Syn2190. The I50s of Syn2190 were
103- to 104-fold higher than those of
tazobactam.
|
Synergy in combination with cephalosporin.
The synergistic
activity of Syn2190 at 1.0 and 5.0 µg/ml with ceftazidime was tested
against -lactamase-producing bacteria (Table
2). Syn2190 plus ceftazidime showed
synergy against group 1 -lactamase-producing bacteria, but the
synergy depended on the concentration of the inhibitor. When 1.0 µg
of Syn2190 per ml was combined with ceftazidime, the MICs of
ceftazidime were decreased 2- to 64-fold in comparison with those of
ceftazidime alone against E. cloacae, Enterobacter
aerogenes, M. morganii, C. freundii, and
P. aeruginosa. However, with 5.0 µg of Syn2190 per ml, the
MICs of ceftazidime were decreased 8- to 128-fold in comparison with
those of ceftazidime alone. These synergistic activities of Syn2190
were 2- to 8-fold stronger at 1.0 µg/ml and 2- to 32-fold stronger at
5.0 µg/ml than those of tazobactam against all strains except
M. morganii. In contrast, tazobactam showed stronger synergy
than Syn2190 against group 2be -lactamase-producing bacteria. The
MICs of Syn2190 for all bacteria tested were 
100 µg/ml (data not
shown).
|
In vitro antibacterial activity of cephalosporin-Syn2190 against
derepressed mutants.
Table 3 shows
the antibacterial activities of ceftazidime-Syn2190 and
cefpirome-Syn2190 at combination ratios of 1 to 1 against -lactamase-derepressed mutants of P. aeruginosa. The MICs
of ceftazidime-Syn2190 were 1.56 to 3.13 µg/ml for
-lactamase-derepressed mutants, and the reductions in the MICs were
16- to 32-fold in comparison with those of ceftazidime alone. These
values were the same as the MICs of ceftazidime for the parent strains.
The MICs of cefpirome-Syn2190 against derepressed mutants were 1.56 to
6.25 µg/ml, and the reductions in the MICs were 16- to 64-fold in
comparison with those of cefpirome alone. These values were also the
same or lower than the MICs of cefpirome for the parent strains.
|
12.5 µg/ml) are shown in Table 4. Syn2190 showed synergy with
ceftazidime against all species tested. When the MIC at which 50% of
isolates are inhibited (MIC50) of ceftazidime alone was 25 µg/ml for P. aeruginosa, that of ceftazidime-Syn2190 was
reduced to 6.25 µg/ml. MIC50s of ceftazidime-Syn2190 were 12.5, 3.13, and 3.13 µg/ml and were reduced 8-, 8-, and 16-fold in
comparison with those of ceftazidime for E. cloacae,
E. aerogenes, and C. freundii, respectively. For
S. marcescens, the MIC50 of ceftazidime-Syn2190
was twofold lower than that of ceftazidime. MIC90s of
ceftazidime-Syn2190 were reduced one-eighth and one-half for P. aeruginosa and E. cloacae, respectively. The
MIC50s of cefpirome-Syn2190 were 12.5, 3.13, and 25 µg/ml
and were reduced one-eighth, one-eighth, and one-half in comparison
with those of cefpirome alone for cefpirome-resistant P. aeruginosa, E. cloacae, and C. freundii,
respectively. For S. marcescens, the MIC50 of cefpirome-Syn2190 was not reduced in comparison with that of cefpirome. The MIC90 of cefpirome-Syn2190 for E. cloacae
was reduced one-fourth.
|
Induction of -lactamase.
For P. aeruginosa,
treatment with 0.25 µg of imipenem per ml for 2 h induced a
higher level of -lactamase production: 2.16 U/mg of protein compared
to a control value of 0.016 U/mg of protein (Fig.
2). Treatment with 10 µg of ceftazidime
per ml induced a level of production of 0.166 U/mg of protein. This
activity was almost 10-fold higher than that for the no-treatment
control. On the other hand, Syn2190 and tazobactam did not induce
-lactamase production. In E. cloacae, treatment with 0.1 and 1.0 µg of imipenem per ml induced levels of -lactamase
production of 8.62 and 22.9 U/mg of protein, respectively, compared to
a control value of 0.016 U/mg of protein. These activities were 200- and 470-fold higher in comparison with those for the no-treatment
control. Treatment with 100 µg of ceftazidime per ml induced
-lactamase production that was almost 250-fold higher than that for
the no-treatment control. However, Syn2190 and tazobactam did not
induce -lactamase production in P. aeruginosa, and the
levels were only eight- and twofold higher, respectively, in comparison
with the control value for E. cloacae, even with the highest
concentrations tested.
|
In vivo antibacterial activity of cephalosporin-Syn2190.
Table
5 shows the in vivo activities of Syn2190
combined with cephalosporins against murine systemic infections caused
by group 1 -lactamase-producing strains. Therapeutic efficacy in terms of the ED50s of ceftazidime-Syn2190 was compared with
that of ceftazidime-tazobactam combined at a ratio of 1 to 1 against P. aeruginosa 94-46017 and P. aeruginosa
94-46209. The ED50s of ceftazidime-tazobactam of 190.2 and
54.9 mg/kg for these two strains, respectively, were similar to those
of ceftazidime alone (175.8 and 85.1 mg/kg, respectively), whereas the
ED50s of ceftazidime-Syn2190 of 37.2 and 31.2 mg/kg for
these two strains, respectively, were five- and threefold superior to
those of ceftazidime alone, respectively. For the combination of
Syn2190 with ceftazidime, the ED50 was 95.8 mg/kg, although
that of ceftazidime alone was >465 mg/kg against P. aeruginosa 46220 DR-2. Against E. cloacae, the
ED50 of ceftazidime-Syn2190 was 387.4 mg/kg, although that
of ceftazidime was >465 mg/kg. The ED50s of
ceftazidime-Syn2190 against C. freundii and S. marcescens were decreased about one-fifth in comparison with those
of ceftazidime alone. In combination with cefpirome, the
ED50 of cefpirome-Syn2190 was 40.5 mg/kg against P. aeruginosa 46220 DR-2, although that of cefpirome alone was 234.9 mg/kg. Against E. cloacae, the ED50 of
cefpirome-Syn2190 was 48.8 mg/kg, although that of cefpirome was 334.4 mg/kg. The ED50s of cefpirome-Syn2190 against C. freundii and S. marcescens were decreased about
one-half in comparison with those of cefpirome.
|
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
Three -lactamase inhibitors, clavulanic acid, sulbactam, and
tazobactam, have been developed and are marketed. These -lactamase inhibitors have strong inhibitory activities against plasmid- and
chromosome-mediated group 2 -lactamases (2, 11), mainly penicillinases (4), and their clinical efficacies in
combination with various penicillins such as ampicillin, ticarcillin,
and piperacillin have been confirmed. On the other hand, the main factor related to resistance to cephalosporins was the high-level production of group 1 -lactamases, mainly cephalosporinases
(4). These -lactamases are not satisfactorily inhibited
by clavulanic acid, sulbactam, or even tazobactam. Syn2190 showed
stronger inhibitory activity than tazobactam against group 1 -lactamases from P. aeruginosa, E. cloacae,
M. morganii, and C. freundii. Therefore, the
combination of Syn2190 with a cephalosporin is considered effective and
useful for the treatment of infections caused by cephalosporin-resistant bacteria.
In this study we found that the MICs of ceftazidime combined with
Syn2190 were reduced to 1/2 to 1/128 in comparison with those of
ceftazidime alone against group 1 -lactamase-producing bacteria.
This synergy was dependent on the concentration of the inhibitor.
However, the synergy was not observed when ceftazidime-Syn2190 was
tested against group 2 -lactamase-producing strains. This finding
may be of little importance, because most expanded-spectrum and
"fourth-generation" cephalosporins are stable against this group of
-lactamases (3, 14).
The resistance of P. aeruginosa to cephalosporins is
attributed to a number of mechanisms. Of note are the lower level of OM
permeability and the increased level of production of -lactamases (10). The limited OM permeability of P. aeruginosa is attributed to increases in cephalosporin MICs. To
increase the rate of penetration across the OM as well as to increase
stability against -lactamases, we designed our inhibitor (Syn2190)
to harbor a 1,5-dihydroxy-4-pyridone moiety at the 3-C position on the
monobactam ring. Use of this moiety, which is able to use the
tonB-dependent iron transport system, is believed to
increase the rate of permeation across the OM (6, 17, 18,
24). We have demonstrated the ability of Syn2190 both to bind to
free iron and to have a fast penetration rate (unpublished data). The
inhibitory activity of Syn2190, combined with its improved penetration
through the OM, might explain its ability to show synergy with
ceftazidime against derepressed mutants of P. aeruginosa
strains (Table 3).
The synergy of Syn2190 was also observed among clinical isolates of cephalosporin-resistant gram-negative bacteria (Table 4). The level of reduction was more prominent at the MIC50 rather than at the MIC90. A possible cause is the involvement of more than one mechanism of resistance, e.g., low-level affinity of binding of the cephalosporins combined with Syn2190 to the penicillin-binding proteins or the reversible nature of Syn2190.
Syn2190 combined with ceftazidime or cefpirome at a ratio of 1 to 1 was observed to have efficacy in vivo; in contrast, tazobactam showed little efficacy against systemic infections caused by P. aeruginosa. This efficacy occurred even though both ceftazidime (21) and cefpirome (26) possess longer half-lives in plasma than Syn2190. The half-lives of ceftazidime, cefpirome, and Syn2190 were 8.3, 11.4, and 4.5 min, respectively. The data presented above have therefore shown that the combination of Syn2190 plus a cephalosporin antibiotic, e.g., ceftazidime or cefpirome, may provide an effective treatment for drug-resistant infections caused by P. aeruginosa, E. cloacae, and M. morganii, among others.
Resistant gram-negative bacteria, such as P. aeruginosa and
Enterobacter, Citrobacter, Morganella,
and Serratia spp., that inducibly or constitutively produce
large amounts of -lactamase have recently been isolated in response
to the frequent clinical use of expanded-spectrum cephalosporins, which
are stable to -lactamases (16, 23). The combination of a
cephalosporin with the -lactamase inhibitor Syn2190 is considered to
be promising for the treatment of infections caused by these resistant
strains and should be evaluated further. It is also expected to
diminish the prevalence of resistant strains.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Antimicrobial Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno Hiraishi Kawauchi-cho, Tokushima 771-0194, Japan. Phone: 088-665-5327. Fax: 088-665-6554.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
| 1. |
Aronoff, S. C., and D. M. Shlaes.
1987.
Factors that influence the evolution of -lactam resistance in -lactamase-inducible strains of Enterobacter cloacae and Pseudomonas aeruginosa.
J. Infect. Dis.
155:936-941[Medline].
|
| 2. |
Aronoff, S. C.,
M. R. Jacobs,
S. Johenning, and S. Yamabe.
1984.
Comparative activities of the -lactamase inhibitors YTR830, sodium clavulanate, and sulbactam combined with amoxicillin or ampicillin.
Antimicrob. Agents Chemother.
26:580-582 |
| 3. |
Bush, K.
1989.
Classification of -lactamases: group 1, 2a, 2b, and 2b'.
Antimicrob. Agents Chemother.
33:264-270 |
| 4. |
Bush, K.,
G. A. Jacoby, and A. A. Medeiros.
1995.
A functional classification scheme for -lactamases and its correlation with molecular structure.
Antimicrob. Agents Chemother.
39:1211-1233[Medline].
|
| 5. |
Bush, K., and R. B. Sykes.
1986.
Methodology for the study of -lactamases.
Antimicrob. Agents Chemother.
30:6-10 |
| 6. | Choi, K. I., J. H. Cha, A. N. Pae, Y. S. Cho, H. Y. Kho, M. H. Chang, H. Y. Kang, and B. Y. Chung. 1997. Studies on new catechol containing cephalosporins. III. Synthesis and structure-activity relationships of cephalosporins having a pyridone moiety at C-7 position. J. Antibiot. 50:279-282. |
| 7. |
Doren, G. V.,
M. A. Pfaller,
R. N. Jones, and The National Broad Spectrum -Lactam Surveillance Group.
1997.
In vitro surveillance study of the antimicrobial spectrum of newer cephalosporins and other -lactam tested against non-enteric gram-negative bacilli 1997 result, abstr. E-95, p. 130.
In
Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 8. |
Gutmann, L.,
M. D. Kitzis,
D. Billot-Klein,
F. Goldstein,
G. Tran Van Nhieu,
T. Lu,
J. Carlet, and R. Williamson.
1988.
Plasmid-mediated -lactamase (TEM-7) involved in resistance to ceftazidime and aztreonam.
Rev. Infect. Dis.
10:860-866[Medline].
|
| 9. |
Gutmann, L.,
B. Ferre,
F. W. Goldstein,
N. Rizk,
E. Pint-Schuster,
J. F. Acar, and E. Collatz.
1989.
SHV-5, a novel SHV-type -lactamase that hydrolyzes broad-spectrum cephalosporins and monobactams.
Antimicrob. Agents Chemother.
33:951-956 |
| 10. |
Hancock, R. E. W., and W. A. Woodruff.
1988.
Roles of porin and -lactamase in -lactam resistance of Pseudomonas aeruginosa.
Rev. Infect. Dis.
10:770-775[Medline].
|
| 11. |
Higashitani, F.,
A. Hyodo,
N. Ishida,
M. Inoue, and S. Mitsuhashi.
1990.
Inhibition of -lactamases by tazobactam and in-vitro antibacterial activity of tazobactam combined with piperacillin.
J. Antimicrob. Chemother.
25:567-574 |
| 12. | Higashitani, F., K. Nishida, and A. Hyodo. 1995. Effects of tazobactam on the frequency of the emergence of resistant strains from Enterobacter cloacae, Citrobacter freundii and Proteus vulgaris. J. Antibiot. 48:1027-1033[Medline]. |
| 13. | Joris, B., F. De Meester, M. Galleni, G. Reckinger, J. Coyette, J. M. Frere, and J. Van Beeuman. 1985. The beta-lactamase of Enterobacter cloacae P99. Chemical properties, N-terminal sequence and interaction with 6 beta-halogenopenicillinates. Biochem. J. 228:241-248[Medline]. |
| 14. |
Kobayashi, S.,
S. Arai,
S. Hayashi, and K. Fujimoto.
1986.
-Lactamase stability of cefpirome (HR 810), a new cephalosporin with a broad antimicrobial spectrum.
Antimicrob. Agents Chemother.
30:713-718 |
| 15. |
Kuck, H. A.,
N. V. Jacobus,
P. J. Petersen,
W. J. Weiss, and R. T. Testa.
1989.
Comparative in vitro and in vivo activities of piperacillin combined with the -lactamase inhibitors tazobactam, clavulanic acid, and sulbactam.
Antimicrob. Agents Chemother.
33:1964-1969 |
| 16. | Livermore, D. M. 1987. Clinical significance of beta-lactamase induction and stable derepression in gram-negative rods. Eur. J. Clin. Microbiol. 6:439-445[Medline]. |
| 17. |
Maejima, T.,
M. Inoue, and S. Mitsuhashi.
1991.
In vitro antibacterial activity of KP-736, a new antibiotic.
Antimicrob. Agents Chemother.
35:104-110 |
| 18. |
Mochizuki, H.,
H. Yamada,
Y. Oikawa,
K. Murakami,
J. Ishiguro,
H. Kosuzume,
N. Aizawa, and E. Mochida.
1988.
Bactericidal activity of M14659 enhanced in low-iron environments.
Antimicrob. Agents Chemother.
32:1648-1654 |
| 19. | Moosdeen, F., J. Makell, J. Philpott-Howard, and J. D. Williams. 1983. Cefotetan activity against gram-negative aerobes and anaerobes. J. Antimicrob. Chemother. 11(Suppl.):59-65. |
| 20. |
Nicas, T. I., and R. E. W. Hancock.
1983.
Pseudomonas aeruginosa outer membrane permeability: isolation of a porin F-deficient mutant.
J. Bacteriol.
153:281-285 |
| 21. | Okumura, K., H. Tsuji, K. Takeda, I. Fukuda, T. Nagaki, M. Takano, K. Higo, and J. Kinami. 1983. Absorption, distribution metabolism and excretion of ceftazidime in mice, rats and rabbits. Chemotherapy (Tokyo) 31(Suppl. 3):188-198. |
| 22. |
Pfaller, M. A.,
G. V. Dosen,
R. N. Jones, and The National Broad Spectrum -Lactam Surveillance Group.
1997.
Activity of broad-spectrum -lactam antimicrobials versus Bush group 1 enzyme producing species, abstr. E-150, p. 141.
In
Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 23. |
Schryvers, A. B.,
J. Ogunariwo,
S. Chamberland,
A. J. Godfrey,
H. R. Rabin, and L. E. Bryan.
1987.
Mechanism of Pseudomonas aeruginosa persistence during treatment with broad-spectrum cephalosporins of lung infections in patients with cystic fibrosis.
Antimicrob. Agents Chemother.
31:1438-1439 |
| 24. |
Silley, P.,
J. W. Griffiths,
D. Monsey, and A. M. Harris.
1990.
Mode of action of GR69153, a novel catechol-substituted cephalosporin, and its interaction with the tonB-dependent iron transport system.
Antimicrob. Agents Chemother.
34:1806-1808 |
| 25. |
Spratt, R. G.
1975.
Distinct penicillin-binding proteins involved in the division, and shape of Escherichia coli.
Proc. Natl. Acad. Sci. USA
72:2999-3003 |
| 26. | Tabata, S., T. Ogawa, M. Inazu, and S. Hayashi. 1991. Cefpirome sulfate: pharmacokinetics and mechanism of excretion in rats with experimentally induced renal and hepatic injuries. Chemotherapy (Tokyo) 39(Suppl. 1):100-104. |
Antimicrobial Agents and Chemotherapy, August 1999, p. 1895-1900, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Paukner, S., Hesse, L., Prezelj, A., Solmajer, T., Urleb, U.
(2009). In Vitro Activity of LK-157, a Novel Tricyclic Carbapenem As Broad-Spectrum {beta}-Lactamase Inhibitor. Antimicrob. Agents Chemother.
53: 505-511
[Abstract] [Full Text] -
Black, J. A., Thomson, K. S., Buynak, J. D., Pitout, J. D. D.
(2005). Evaluation of {beta}-Lactamase Inhibitors in Disk Tests for Detection of Plasmid-Mediated AmpC {beta}-Lactamases in Well-Characterized Clinical Strains of Klebsiella spp.. J. Clin. Microbiol.
43: 4168-4171
[Abstract] [Full Text] -
Ribera, A., Fernandez-Cuenca, F., Beceiro, A., Bou, G., Martinez-Martinez, L., Pascual, A., Cisneros, J. M., Rodriguez-Bano, J., Pachon, J., Vila, J.
(2004). Antimicrobial Susceptibility and Mechanisms of Resistance to Quinolones and {beta}-Lactams in Acinetobacter Genospecies 3. Antimicrob. Agents Chemother.
48: 1430-1432
[Abstract] [Full Text] -
Jamieson, C. E., Lambert, P. A., Simpson, I. N.
(2003). In Vitro Activities of Novel Oxapenems, Alone and in Combination with Ceftazidime, against Gram-Positive and Gram-Negative Organisms. Antimicrob. Agents Chemother.
47: 2615-2618
[Abstract] [Full Text] -
Jamieson, C. E., Lambert, P. A., Simpson, I. N.
(2003). In Vitro and In Vivo Activities of AM-112, a Novel Oxapenem. Antimicrob. Agents Chemother.
47: 1652-1657
[Abstract] [Full Text] -
Coudron, P. E., Hanson, N. D., Climo, M. W.
(2003). Occurrence of Extended-Spectrum and AmpC Beta-Lactamases in Bloodstream Isolates of Klebsiella pneumoniae: Isolates Harbor Plasmid-Mediated FOX-5 and ACT-1 AmpC Beta-Lactamases. J. Clin. Microbiol.
41: 772-777
[Abstract] [Full Text] -
Danes, C., Navia, M. M., Ruiz, J., Marco, F., Jurado, A., Jimenez de Anta, M. T., Vila, J.
(2002). Distribution of {beta}-lactamases in Acinetobacter baumannii clinical isolates and the effect of Syn 2190 (AmpC inhibitor) on the MICs of different {beta}-lactam antibiotics. J Antimicrob Chemother
50: 261-264
[Abstract] [Full Text] -
Masuda, N., Sakagawa, E., Ohya, S., Gotoh, N., Nishino, T.
(2001). Hypersusceptibility of the Pseudomonas aeruginosa nfxB Mutant to {beta}-Lactams Due to Reduced Expression of the AmpC {beta}-Lactamase. Antimicrob. Agents Chemother.
45: 1284-1286
[Abstract] [Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»