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Antimicrobial Agents and Chemotherapy, November 1998, p. 2943-2949, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro and In Vivo Antibacterial Activities of OPC-20011, a
Novel Parenteral Broad-Spectrum 2-Oxaisocephem Antibiotic
Makoto
Matsumoto,*
Hisashi
Tamaoka,
Hiroshi
Ishikawa, and
Mikio
Kikuchi
Microbiological Research Institute, Otsuka
Pharmaceutical Co., Ltd., Tokushima City, Tokushima Prefecture
771-0192, Japan
Received 17 March 1998/Returned for modification 23 July
1998/Accepted 25 August 1998
 |
ABSTRACT |
OPC-20011, a new parenteral 2-oxaisocephem antibiotic, has an
oxygen atom at the 2- position of the cephalosporin frame.
OPC-20011 had the best antibacterial activities against gram-positive
bacteria, including methicillin-resistant Staphylococcus
aureus (MRSA), Enterococcus faecalis, and
penicillin-resistant Streptococcus pneumoniae:
MICs at which 90% of the isolates were inhibited were 6.25, 6.25, and
0.05 µg/ml, respectively. Its activity is due to a high affinity of
the penicillin-binding protein 2' in MRSA, an affinity which was
approximately 1,050 times as high as that for flomoxef. Against
gram-negative bacteria, OPC-20011 also showed antibacterial activities similar to those of ceftazidime.
The in vivo activities of OPC-20011 were comparable to or
greater than those of reference compounds in murine models of
systemic infection caused by gram-positive and -negative
pathogens. OPC-20011 was up to 10 times as effective as vancomycin
against MRSA infections in mice. This better in vivo efficacy is
probably due to the bactericidal activity of OPC-20011, while
vancomycin showed bacteriostatic activity against MRSA. OPC-20011
produced a significant decrease of viable counts in lung tissue at
a dose of 2.5 mg/kg of body weight, an efficacy similar to that of
ampicillin at a dose of 10 to 20 mg/kg on an experimental murine model
of respiratory tract infection caused by non-ampicillin-susceptible
S. pneumoniae T-0005. The better therapeutic
efficacy of OPC-20011 was considered to be due to its potent
antibacterial activity and low affinity for serum proteins of
experimental animals (29% in mice and 6.4% in rats).
| |
INTRODUCTION |
-Lactam antibiotics are known to
have strong, broad-spectrum antibacterial activity against both
gram-positive and -negative bacteria and to be safe in clinical use.
There is, however, a worldwide increase in bacteria highly resistant to
-lactams (4, 8, 22, 23). Approximately 50 to 80% of
Staphylococcus aureus strains have become resistant
to many kinds of antibiotics, with a few exceptions, such as vancomycin
(VCM). Furthermore, resistance to penicillin among strains of
Streptococcus pneumoniae has been spreading worldwide
(9, 14, 15). In some regions, such as Spain, almost 50% of
S. pneumoniae clinical isolates are penicillin resistant. These facts suggest that there may be few antibiotics which
can be utilized against infections caused by these gram-positive pathogens in the future. Furthermore, the introduction of new antibiotics has been decreasing recently compared with the period from
1945 to 1970, when a variety of new antibiotics with new structures
were discovered (3). The time has come to attempt to develop
new agents which can solve the problem of resistant bacteria. Our
efforts have been focused on the development of new antibiotics to
solve these problems. In earlier work (6, 7),
2-oxaisocephem antibiotics were synthesized and
evaluated as a new class of antibiotics by Doyle et al. They reported
that 2-oxaisocephem lacked comprehensive antibacterial activity
(7). In the course of our research, we identified OPC-20011
from a novel series of 2-oxaisocephems that showed good
antibacterial activity against methicillin-resistant S. aureus (MRSA), Enterococcus faecalis, and
penicillin-resistant S. pneumoniae and had a broad spectrum of antibacterial activity (13, 24). In this study we evaluated the antibacterial activities in vitro and in vivo of
OPC-20011 and compared them with those of reference compounds. We also
compared OPC-20011 with a 1-sulfur analog with the same substituents as OPC-20011 to clarify the properties of
2-oxaisocephem antibiotics.
| |
MATERIALS AND METHODS |
Organisms.
The clinical isolates used in this study were
obtained from several hospitals in Japan from 1990 to 1995 and were
stocked in our laboratory. The other strains used in this study were
stock cultures from our laboratory.
Antimicrobial agents.
OPC-20011 and OPC-20026, a 1-sulfur
analog with the same substituents as OPC-20011 (Fig.
1), were synthesized at the
Microbiological Research Institute of Otsuka Pharmaceutical Co., Ltd.,
Tokushima, Japan. The other antibiotics, including cefotiam
(CTM), flomoxef (FMOX), ceftazidime (CAZ), cefpirome (CPR), ampicillin
(ABPC), imipenem (IPM), methicillin (DMPPC), and VCM, were
purchased from commercial sources.
Susceptibility testing.
MICs were determined by the twofold
agar dilution method with Mueller-Hinton agar (Difco Laboratories,
Detroit, Mich.), which was supplemented with 5% horse blood to support
the growth of S. pneumoniae, Streptococcus
pyogenes, and Haemophilus influenzae. The overnight
cultures were diluted to approximately 106 CFU/ml with
fresh broth, and an inoculum of 104 CFU per spot was
applied with an inoculating apparatus (Microplanter; Sakuma Seisakusho,
Tokyo, Japan) to agar plates containing graded concentrations of each
compound. The MICs were defined as the minimum drug concentrations
which completely inhibited the growth of bacteria after incubation at
37°C for 18 h.
Affinities of PBPs.
The affinities of
penicillin-binding proteins (PBPs) for OPC-20011 and the
reference compounds were determined by competition assay with
[14C]benzylpenicillin (Amersham Japan Co., Ltd.,
Tokyo, Japan) as described previously (20, 21). Membranes
were collected by differential centrifugations (5,000 × g for 15 min and 100,000 × g for 60 min) of
enzymatically (100 µg of lysostaphin/ml containing 10 µg of
DNase/ml) disrupted cells of S. aureus FDA 209-P and MRSA 5143 or sonically disrupted cells of S. pneumoniae
T0096 and Escherichia coli NIHJ JC-2 in 50 mM potassium
phosphate buffer (pH 7.0). The concentrations of membrane proteins,
based on 
-globulin levels, were adjusted to 8 mg/ml for
S. aureus FDA 209-P, MRSA 5143, and S. pneumoniae T0096 and to 20 mg/ml for E. coli NIHJ JC-2. The binding reactions were done for 10 min with test compounds at
each concentration followed by 15 min with
[14C]benzylpenicillin at 37°C. The binding affinities
of PBPs for the test compounds were expressed as the concentration
required to prevent 50% of the binding of
[14C]benzylpenicillin (50% inhibitory concentration
[IC50]) to each PBP, determined by the imaging analyzer
BAS 2000 (Fuji Chemical Co. Ltd.).
In vivo effects. (i) Systemic infections.
In vivo activities
against systemic infections caused by gram-positive and -negative
pathogens were determined. Ten male ICR mice weighing 20 ± 1 g were used for each dosage group. The mice were challenged
intraperitoneally with 0.5 ml of approximately 10 to 100 times the 50%
lethal doses of the respective pathogens. The bacterial suspensions,
which were prepared from overnight cultures on Tryptic soy broth
(Difco) for methicillin-susceptible S. aureus (MSSA)
and MRSA, on brain heart infusion broth (Nissui) for S. pneumoniae, and on Mueller-Hinton broth for other pathogens at
37°C, were suspended in the fresh broth of overnight cultures containing gastric mucin (Difco) (for the concentrations, see Table 6).
One hour after infection, various doses of each compound were
administered to the mice subcutaneously. The number of mice surviving
after each dose was determined on day 7 after infection, and the 50%
effective dose (ED50) was calculated by the probit method.
(ii) Respiratory tract infection.
Groups of five rats (SD
rats; age, 5 weeks), pretreated 3 days before infection with
cyclophosphamide, were anesthetized with diethyl ether and challenged
directly in the respiratory tract by instilling 0.2 ml of a suspension
of MRSA 5143. The challenge doses were 2.75 × 107
CFU/ml. Antibiotics were administered subcutaneously at doses of 2.5, 5, and 10 mg/kg of body weight for OPC-20011 or 5, 10, and 20 mg/kg for
VCM three times, at 24, 36, and 48 h following infection. The
lungs were then removed aseptically under diethyl ether anesthesia
24 h after the final treatment and homogenized in 2 ml of
distilled water, and the viable bacilli in the lungs of each rat were
counted on Mueller-Hinton agar plates.
Groups of five mice (ICR mice; age, 4 weeks) were anesthetized with
diethyl ether and challenged directly in the respiratory
tract by
instilling 0.1 ml of suspension of
S. pneumoniae T0005,
which is a pathogen insensitive to ABPC. The challenge doses were
2.75 × 10
4 CFU/ml. Antibiotics were administered
subcutaneously at doses
of 2.5, 5, and 10 mg/kg once at 24 h for
OPC-20011 or at doses
of 5, 10, and 20 mg/kg three times, at 24, 40, and 48 h after
infection, for ABPC and VCM. The lungs were then
removed aseptically
under diethyl ether anesthesia 24 h after the
final treatment
and homogenized in 2 ml of distilled water, and the
viable bacilli
in the lungs of each mouse were counted on
Mueller-Hinton agar
plates which were supplemented with 5% horse
blood. Statistical
analysis was done by the following procedures. The
viable count
of bacilli in the lungs of each animal was expressed as
log
10 CFU, and the differences among the groups was
determined by using
a two-tailed Dunnett's
test.
Time-kill curve.
The activities of OPC-20011 and VCM against
MRSA were determined by a time-kill study, as described previously
(27). An overnight culture of MRSA was diluted with fresh
Mueller-Hinton broth to a density of approximately 104
CFU/ml, and the dilution was preincubated in L-tubes at 37°C for
1 h with shaking. Various concentrations, close to the MICs, of
the test compounds were added to the culture. At fixed time intervals,
0.1-ml portions of the contents of each tube were removed to 0.9 ml of
fresh saline and spread on drug-free Mueller-Hinton agar plates after
being suitably diluted (101 to 107 times). The
colonies were counted after incubation for 18 h at 37°C.
Affinity for serum proteins of different animal species.
The
binding percentages of OPC-20011 to serum proteins of different
animal species were determined by the following procedure. Sera were
obtained from different species (ICR mice, SD rats, NEZ rabbits, beagle
dogs, cynomolgus monkeys, and healthy human donors). Each serum was
mixed with 1/10 volume of 500 µg of OPC-20011/ml and incubated
for 1 h at 37°C. The incubated samples were then ultrafiltered
with Centrisart Cutoff 20000 (Sartorius). The binding concentrations of
the compound in the filtrates were measured by high-performance liquid
chromatography (SPD-10A chromatograph [Shimadzu Co. Ltd.]; UV
wavelength, 300 nm; solvent, 25% solution of CH3CN
containing 0.05% trifluoroacetate).
| |
RESULTS |
Susceptibility of clinical isolates.
The activity of
OPC-20011 against clinical isolates was compared with that of
OPC-20026, CTM, CAZ, FMOX, CPR, ABPC, IPM, DMPPC, and VCM. The MICs
at which 90% of the isolates are inhibited (MIC90s) of
test compounds for the strains tested are shown in Tables
1 and
2. In the
first study, the MIC90s of OPC-20011 were 2 to 16 times
lower than those of OPC-20026. In particular, a 16-fold difference
was observed between the MIC90 of OPC-20011 and that of
OPC-20026 for E. faecalis (Table 1). The
MIC90s of OPC-20011 for MSSA, DMPPC-susceptible
Staphylococcus epidermidis, and
non-ABPC-susceptible S. pneumoniae were 0.78, 1.56, and
0.05 µg/ml, respectively, the lowest MICs among the test
compounds. For MRSA, the MIC90 of OPC-20011 was 6.25 µg/ml, which was lower than those of other -lactam
antibiotics tested but 2 dilutions higher than that of VCM. The
MIC90s of OPC-20011 for DMPPC-resistant S. epidermidis and E. faecalis were 3.13 and 6.25 µg/ml, respectively, which were almost equal to those for VCM and
ABPC, respectively, and 2 to 32 times lower than those of the other
reference antibiotics tested.
Against
E. coli and
Klebsiella pneumoniae,
OPC-20011 inhibited 90% of the strains at 1.56 and 3.13 µg/ml,
respectively, which
were 2 to 32 times higher than the
MIC
90s of the reference compounds.
Against
H. influenzae, OPC-20011 inhibited 90% of the strains
at
0.2 µg/ml, which was equal to or two to eight times lower than
the MIC
90s of the reference compounds. Against
Serratia marcescens,
Proteus mirabilis, and
Providencia rettgeri, OPC-20011 inhibited
90% of the
strains at 6.25, 1.56, and 1.56 µg/ml, respectively,
at least 64 times more active than CTM and FOMX. Weaker activity
was observed with
all of the test compounds against
Pseudomonas aeruginosa:
the MIC
90s were 50 to 100 µg/ml.
PBP affinity.
In order to explain the antibacterial activities
of OPC-20011, the binding of OPC-20011 to PBPs in S. aureus FDA 209-P, MRSA 5143, S. pneumoniae C0096,
and E. coli NIHJ JC-2 was compared with those of
the reference compounds. The results are shown in Tables 3 to
5.
The IC50s of OPC-20011 for PBP2, -3, and -4 in S. aureus FDA 209-P were generally 3 to >64 times
lower than those of CTM, CAZ, FMOX, and CPR. For PBP2' in MRSA 5143, the IC50 of OPC-20011 was 2.0 µg/ml, which was
approximately 370 and 1,050 times as high as those of CPR and FMOX,
respectively. The IC50s of OPC-20011 for PBP1A and -1B
in S. pneumoniae C0096 were 9 to 50 times lower than
those of ABPC. PBP1B, -2 and -3 in E. coli NIHJ
JC-2 showed the highest affinity for OPC-20011 compared with FMOX and CPR, but OPC-20011 did not bind to PBP1A, -4, and -5 at
concentrations as high as 62.5 µg/ml.
Protective effects in vivo.
The therapeutic effects of
OPC-20011 and the reference compounds against acute systemic
infections in mice are shown in Table 6.
The efficacies of OPC-20011 against S. aureus
Smith, MRSA 5120, S. pneumoniae Type III, and
S. pneumoniae C0096 were approximately 2 to over
100 times greater than those of the other compounds tested.
OPC-20011 showed protective effects equivalent to those of VCM
against MRSA 5143 and to those of ABPC against E. faecalis, and it was approximately 8 to over 40 times more
effective than the other reference compounds. OPC-20011 also had
ED50s ranging from 0.06 to 8.4 mg/kg for the infections
caused by gram-negative pathogens, except P. aeruginosa. Against P. aeruginosa T0017, the efficacy of OPC-20011 was nearly equal to that of aztreonam (AZT) but less than that of CAZ, though the other
-lactams, CTM and FMOX, did not exhibit any protective effects.
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TABLE 6.
Protective effects of OPC-20011 and reference
compounds against experimental systemic infection models in mice
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The therapeutic effects of OPC-20011 and VCM against
experimental respiratory tract infection caused by MRSA 5143 are shown
in Table
7. A significant decrease in the
number of viable cells
in the lungs was observed at concentrations of
5 mg/kg for OPC-20011
and
10 mg/kg for VCM. The
efficacy of OPC-20011 at 5 mg/kg was
almost equal to that of
VCM at 20 mg/kg.
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TABLE 7.
Therapeutic effects of OPC-20011 and VCM in an
experimental murine model of respiratory tract infection caused by
MRSA 5143a
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The therapeutic effects of OPC-20011, ABPC, and VCM against
experimental respiratory tract infection caused by
S. pneumoniae T0005 are shown in Table
8. A significant decrease in the number
of viable cells in the lungs was observed at concentrations of
2.5
mg/kg for OPC-20011 and 20 mg/kg for ABPC with a single
treatment.
The efficacy of OPC-20011 at 2.5 mg/kg was almost
equal to that
of ABPC at 10 to 20 mg/kg. When three doses were
given, no viable
bacilli were observed in any of the
OPC-20011-treated groups.
With VCM, a significant decrease was
observed when three doses
were given, though no decrease was observed
with a single treatment.
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TABLE 8.
Therapeutic effects of OPC-20011, ABPC, and VCM
in an experimental murine model of respiratory tract infection
caused by S. pneumoniae T0005a
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Bactericidal activity.
The bactericidal activity of
OPC-20011 was compared with that of VCM against MRSA 5143 and MRSA
5120 (Fig. 2 and
3). Against MRSA 5143, both OPC-20011
(at twice the MIC) and VCM (at four times the MIC) showed bactericidal
activity. Against MRSA 5120, however, OPC-20011 showed bactericidal
activity at one-fourth the MIC within 8 h and produced a
rapid decrease in the number of viable cells at the same concentration,
while VCM did not show any bactericidal activity even at a
concentration of eight times the MIC. The MICs against the obvious
regrowth of MRSA 5120 exposed to concentrations of OPC-20011 below
the MIC for 24 h were not changed.
Affinity for serum proteins of different animal species.
The
affinities of the filters (Centrisart Cutoff 20000) used in this
binding study for OPC-20011 were checked. The rate of binding of
OPC-20011 to the filters was less than 1%. The binding percentage
(± standard deviation [SD]) of OPC-20011 to serum proteins prepared from ICR mice, SD rats, NEZ rabbits, beagle dogs,
cynomolgus monkeys, and healthy human donors are shown in Table
9. The rates of binding of OPC-20011
to serum proteins from humans and mice were almost equal.
| |
DISCUSSION |
OPC-20011 is a 2-oxaisocephem antibiotic
that has never been introduced to clinical use. In a previous report
about 2-oxaisocephems, it was shown to have limited
antibacterial activity (7). Then what is the advantage of a
2-oxaisocephem? The answers were obtained in this
study. The antibacterial activities and binding to PBPs of
OPC-20011 and OPC-20026, a 1-sulfur analog with the same
substituents as OPC-20011, were compared. The antibacterial
activity of the 2-oxaisocephem was 2 to 16 times more
potent than that of the 1-sulfur cephem. This potency of the
2-oxaisocephem was considered to be due to the high
affinity of the PBP in S. aureus, including MRSA.
None of the commercially available cephem antibiotics that were tested
had any activity against E. faecalis; OPC-20011,
the oxaisocephem antibiotic, showed antibacterial activity
similar to that of ABPC, although the 1-sulfur analog with the same
substituents as OPC-20011 was not active against this organism.
MRSA has an additional PBP2', which is involved in resistance to
-lactams (26). There have also been many recent
reports about other factors related to DMPPC resistance (2, 5, 10, 11, 17). The mechanism of resistance in MRSA is more complex than
PBP2' alone. Some other factors, such as femA, the glycine content of peptidoglycan, and the enhancement of autolysis, have been
reported to be essential for expression of DMPPC resistance. However,
PBP2' is an essential factor for DMPPC resistance (16, 19,
25), and inhibiting the activity or the expression of PBP2' is
the best way to solve the resistance problem. PBP2' bound OPC-20011
approximately 370 to 1,050 times better than the other -lactams.
This may be the reason for the MIC for OPC-20011 against all of the
clinically isolated MRSAs, which was less than 6.25 µg/ml.
Although VCM is probably the best drug that can be used for MRSA
infections at present, VCM-intermediate MRSA has been isolated in Japan
(12). Though the in vitro anti-MRSA activity of
OPC-20011 was less than that of VCM, the in vivo efficacy of
OPC-20011 in MRSA infection models was almost equal to or greater
than that of VCM. In particular, OPC-20011 showed a therapeutic
effect two to four times as potent as that of VCM in the model of
respiratory tract infection, even though OPC-20011 showed activity
almost equal to that of VCM in systemic infection in mice caused by the same organism, MRSA 5143. One reason may be related to the
bactericidal activities of these compounds for MRSA. The
bactericidal activity of OPC-20011 for MRSA 5120 was greater than
that for MRSA 5143, and these bactericidal activities were well
correlated to the efficacy in vivo. Also, the distribution of
OPC-20011 in lung tissue was approximately 15 µg/ml after a
single administration at a dose of 20 mg/kg (data not shown). It is
possible that VCM cannot reach sufficient tissue concentrations due to
its poor distribution, as the sputum level of VCM in patients is 2 to 3 µg/ml. This is considered to be consistent with the results of our
study comparing the therapeutic effects of OPC-20011 and VCM on
respiratory tract infection in rats.
The rate of bacterial eradication by VCM in combination with other
-lactams was reported to be approximately 60% in polymicrobial infections (18). Furthermore, it has been reported that
during clinical use, VCM induces microbial substitution (1)
when used alone, because of its narrow spectrum. Since OPC-20011
has a broad antibacterial spectrum covering not only gram-positive but
also gram-negative pathogens, even if used alone, its induction rate of
microbial substitution may be less than that of VCM.
OPC-20011 was the most effective of the compounds tested in this
study against S. pneumoniae. The reason for this potent
activity was considered to be the high PBP affinity. Though
S. pneumoniae C0096 is insensitive to ABPC because of
the drug's weak binding to PBP1A, this PBP showed higher affinity for
OPC-20011. Although we tried to examine the therapeutic efficacy in
a respiratory tract infection model, to our disappointment, we could
not establish the model with this organism. However, the efficacy of
OPC-20011 was significantly better than those of ABPC and VCM in a
corresponding model with the non-ABPC-susceptible S. pneumoniae T0005.
In conclusion, OPC-20011 has broad-spectrum antibacterial activity,
not only against MRSA, but also against penicillin-resistant S. pneumoniae and E. faecalis. It is
expected to demonstrate activity against gram-negative pathogens
equivalent to those of the selected reference compounds.
OPC-20011 is thus considered to be an antibacterial agent which can
overcome the shortcomings of some of the existing -lactam antibiotics.
| |
ACKNOWLEDGMENTS |
We thank Yoshiki Obana, Norimitsu Hariguchi, Kaoru Yokomi, and
Azusa Tateishi for their superb technical assistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Microbiological
Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima City, 771-0192, Japan. Phone:
81-886-65-2126. Fax: 81-886-65-6286. E-mail:
m_matsumoto{at}research.otsuka.co.jp.
| |
REFERENCES |
| 1.
|
Aoki, Y.
1992.
MRSA infection.
Clinica
19:182-187. (In Japanese.)
|
| 2.
|
Berger-Bachi, B.,
L. Barberis-Maino,
A. Strassle, and F. H. S. Kayser.
1989.
FemA, a host-mediated factor essential for methicillin resistance in Staphylococcus aureus: molecular cloning and characterization.
Mol. Gen. Genet.
219:263-269[Medline].
|
| 3.
|
Chopra, I.,
J. Hodgson,
B. Metcalf, and G. Poste.
1997.
The search for antimicrobial agents effective against bacteria resistant to multiple antibiotics.
Antimicrob. Agents Chemother.
41:497-503[Medline].
|
| 4.
|
Cohen, M. L.
1992.
Epidemiology of drug resistance: implications for a post-antimicrobial era.
Science
257:1050-1055.
|
| 5.
|
De Jonge, B. L. M.,
H. de Lencastre, and A. Tomasz.
1991.
Suppression of autolysis and cell wall turnover in heterogeneous Tn551 mutants of a methicillin-resistant Staphylococcus aureus strain.
J. Bacteriol.
173:1105-1110[Abstract/Free Full Text].
|
| 6.
|
Doyle, T. W.,
B. Belleau,
B.-Y. Luh,
C. F. Ferrari, and M. P. Cunningham.
1977.
Nuclear analogs of -lactam antibiotics. I. Synthesis of O-2-isocephems.
Can. J. Chem.
55:468.
|
| 7.
|
Doyle, T. W.,
J. L. Douglas,
B. Belleau,
T. T. Conway,
C. F. Ferrari,
D. E. Horning,
G. Lim,
B.-Y. Luh,
A. Martel,
M. Menard, and L. R. Morris.
1980.
Nuclear analogs of -lactam antibiotics. XIII. Structure activity relationships in the isocephalosporin series.
Can. J. Chem.
58:2508.
|
| 8.
|
Glaser, V.
1996.
Therapeutic alternatives for drug-resistant bacterial infections. SPECTRUM therapy markets and emerging technologies, p. 104-114.
Decision Resources, Inc., Waltham, Mass.
|
| 9.
|
Goldstein, J. G.
1997.
30 years of penicillin-resistant S. pneumoniae: myth or reality?
Lancet
350:233-234[Medline].
|
| 10.
|
Gustafson, J. E.,
B. Berger-Bachi,
A. Strassle, and B. J. Wilkinson.
1992.
Autolysis of methicillin-resistant and -susceptible Staphylococcus aureus.
Antimicrob. Agents Chemother.
36:566-572[Abstract/Free Full Text].
|
| 11.
|
Hartman, B. J., and A. Tomasz.
1986.
Expression of methicillin resistance in heterogeneous strains of Staphylococcus aureus.
Antimicrob. Agents Chemother.
29:85-92[Abstract/Free Full Text].
|
| 12.
|
Hiramatsu, K.,
H. Hanaki,
T. Ino,
K. Yabuta,
T. Oguri, and F. C. Tenover.
1997.
Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility.
J. Antimicrob. Chemother.
40:135-136[Free Full Text].
|
| 13.
|
Ishikawa, H.,
H. Tsubouchi, and K. Yasumura.
1994.
Synthesis and biological activity of new optically active 2-oxaisocephems: 3-(N-alkylpyridinium-4'-thio) methyl derivatives.
Bioorg. Med. Chem. Lett.
4:1147-1152.
|
| 14.
|
Jacobs, M. R.
1992.
Treatment and diagnosis of infections caused by drug-resistant Streptococcus pneumoniae.
Clin. Infect. Dis.
15:119-127[Medline].
|
| 15.
|
Klugman, K. P.
1990.
Pneumococcal resistance to antibiotics.
Clin. Microbiol. Rev.
3:171-196[Abstract/Free Full Text].
|
| 16.
|
Kuwahara-Arai, K.,
N. Kondo,
S. Hori,
E. Tateda-Suzuki, and K. Hiramatsu.
1996.
Suppression of methicillin resistance in a mecA-containing pre-methicillin-resistant Staphylococcus aureus strain is caused by the mecI-mediated repression of PBP 2' production.
Antimicrob. Agents Chemother.
40:2680-2685[Abstract].
|
| 17.
| Maidhof, H., B. Reinicke, P. Blümel, B. Berger-Bächi, and H. Labischinski. femA, which encodes
a factor essential for expression of methicillin resistance, affects
glycine content of peptidoglycan in methicillin-resistant and
methicillin-susceptible Staphylococcus aureus strains. J. Bacteriol. 173:3507-3513.
|
| 18.
|
MRSA Infection Committee,
K. Shimizu,
M. Orizu,
H. Kanno,
S. Kitamura,
T. Konishi,
K. Soma,
H. Nishitani,
Y. Noguchi,
S. Hasegawa,
H. Hasegawa, and K. Wada.
1996.
Clinical studies on vancomycin in the treatment of MRSA infection.
Jpn. J. Antibiot.
49:782-799[Medline].
|
| 19.
|
Ryffel, C.,
F. H. Kayser, and B. Berger-Bächi.
1992.
Correlation between regulation of mecA transcription and expression of methicillin resistance in staphylococci.
Antimicrob. Agents Chemother.
36:25-31[Abstract/Free Full Text].
|
| 20.
|
Spratt, B. G.
1980.
Biochemical and genetical approaches to the mechanism of action of penicillin.
Philos. Trans. R. Soc. Lond.
289:273-283[Abstract/Free Full Text].
|
| 21.
|
Spratt, B. G., and A. B. Pardee.
1995.
Penicillin-binding proteins and cell shape in E. coli.
Nature
254:516-517.
|
| 22.
|
Tenover, F. C., and J. M. Hughes.
1996.
The challenges of emerging infectious diseases.
JAMA
275:300-304[Abstract/Free Full Text].
|
| 23.
|
Tomasz, A.
1994.
A report on the Rockefeller University workshop. Multiple-antibiotic-resistant pathogenic bacteria.
N. Engl. J. Med.
330:1247-1251[Free Full Text].
|
| 24.
|
Tsubouchi, H.,
K. Tsuji,
K. Yasumura,
M. Matsumoto,
T. Shitsuta, and H. Ishikawa.
1995.
Synthesis and biological evaluation of a series of new parenteral optically active 3-[[(N-alkylpyridinium-4'-yl)thio]methyl]-2-oxaisocephems.
J. Med. Chem.
38:2152-2157[Medline].
|
| 25.
|
Ubukata, K.,
R. Nonoguchi,
M. Matsuhashi, and M. Konno.
1989.
Expression and inducibility in Staphylococcus aureus of the mecA gene, which encodes a methicillin-resistant S. aureus-specific penicillin-binding protein.
J. Bacteriol.
171:2882-2885[Abstract/Free Full Text].
|
| 26.
|
Utsui, Y., and T. Yokota.
1985.
Role of an altered penicillin-binding protein in methicillin- and cephem-resistant Staphylococcus aureus.
Antimicrob. Agents Chemother.
28:397-403[Abstract/Free Full Text].
|
| 27.
|
Wakebe, H., and S. Mitsuhashi.
1992.
Comparative in vitro activities of a new quinolone, OPC-17116, possessing potent activity against gram-positive bacteria.
Antimicrob. Agents Chemother.
36:2185-2191[Abstract/Free Full Text].
|
Antimicrobial Agents and Chemotherapy, November 1998, p. 2943-2949, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
