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Antimicrobial Agents and Chemotherapy, March 2001, p. 825-836, Vol. 45, No. 3
Pharmaceutical Research, F. Hoffmann-La Roche
Ltd.,1 and Basilea
Pharmaceutica,2 CH-4070 Basel, Switzerland
Received 26 September 2000/Returned for modification 31 October
2000/Accepted 19 December 2000
Ro 63-9141 is a new member of the pyrrolidinone-3-ylidenemethyl
cephem series of cephalosporins. Its antibacterial spectrum was evaluated against significant gram-positive and gram-negative pathogens in comparison with those of reference drugs, including cefotaxime, cefepime, meropenem, and ciprofloxacin. Ro 63-9141 showed
high antibacterial in vitro activity against gram-positive bacteria
except ampicillin-resistant enterococci, particularly vancomycin-resistant strains of Enterococcus faecium. Its
MIC at which 90% of the isolates tested were inhibited
(MIC90) for methicillin-resistant Staphylococcus
aureus (MRSA) was 4 µg/ml. Ro 63-9141 was bactericidal against
MRSA. Development of resistance to the new compound in MRSA was not
observed. Ro 63-9141 was more potent than cefotaxime against
penicillin-resistant Streptococcus pneumoniae
(MIC90 = 2 µg/ml). It was active against
ceftazidime-susceptible strains of Pseudomonas aeruginosa
and against Enterobacteriaceae except Proteus
vulgaris and some isolates producing extended-spectrum Methicillin-resistant staphylococci
(MRS) have become a serious problem in many parts of the world.
Although the incidence of strains of methicillin-resistant
Staphylococcus aureus (MRSA), methicillin-resistant
Staphylococcus epidermidis (MRSE), and other MRS varies from
country to country and from hospital to hospital (3, 5),
it has been steadily increasing worldwide in the last decade (10,
18, 19). MRS are resistant not only to the available MRS are characterized by the expression of a special penicillin-binding
protein (PBP), PBP 2', that is not present in methicillin-susceptible staphylococci. This PBP is causally connected with methicillin resistance, as it functions as a transpeptidase and is not efficiently inhibited by commercially available Ro 63-9141, the active principle of the water-soluble prodrug Ro
65-5788, is a novel parenteral cephalosporin with broad-spectrum activity against gram-positive and gram-negative pathogens. It differs
from older, broad-spectrum cephalosporins in that it has antibacterial
activity against MRS isolates. Its in vitro and in vivo antimicrobial
properties and its mode of action are described below.
(Part of this work was presented previously [Abstr. 38th Conf.
Antimicrob. Agents Chemother., abstr. F-22 to F-24, 1998].)
Antimicrobial compounds.
Ro 63-9141, Ro 65-5788, ceftriaxone, and linezolid were prepared for this study in the research
laboratories of F. Hoffmann-La Roche Ltd., Basel, Switzerland. The
other compounds were purchased from commercial sources. The chemical
structures of Ro 63-9141 and its prodrug Ro 65-5788 are shown in Fig.
1.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.825-836.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
In Vitro and In Vivo Properties of Ro 63-9141, a
Novel Broad-Spectrum Cephalosporin with Activity against
Methicillin-Resistant Staphylococci
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactamases. The basis for the antibacterial spectrum of Ro 63-9141 lies in its affinity to essential penicillin-binding proteins, including PBP 2' of MRSA, and its stability towards
-lactamases. The in vivo findings were in accordance with the in
vitro susceptibilities of the pathogens. These data suggest the
potential utility of Ro 63-9141 for the therapy of
infections caused by susceptible pathogens, including MRSA. Since
insufficient solubility of Ro 63-9141 itself precludes
parenteral administration in humans, a water-soluble prodrug, Ro
65-5788, is considered for development.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactam
antibiotics, but also, in most instances, to structurally unrelated
classes of antibacterials (for mainly unknown reasons) and thus
represent a prime target in the current search for new antimicrobials.
-lactams, in contrast to the
other transpeptidases in staphylococci, PBP 1, PBP 2, and PBP 3. However, the poor affinity of PBP 2' for -lactam antibiotics does
not seem to be inherent in the -lactam structure since new carbapenems and cephalosporins that are good inhibitors of PBP 2' have
recently been described (1, 6, 11, 12, 14, 20).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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FIG. 1.
Chemical structures of Ro 63-9141 and its prodrug Ro
65-5788.
Bacterial strains.
Except for some standard strains
(American Type Culture Collection strains), the isolates used in the in
vitro experiments were clinical isolates obtained from various, mainly
European, Japanese, and American, hospitals over a 10-year period,
except MRS, for which fresh clinical isolates from 1996 were employed. They were identified by standard methods and kept as stock cultures at
70°C or below. The strains used in the in vivo experiments were
clinical isolates or standard strains that were adapted to the
respective models through animal passage before use.
MIC determination. MICs against aerobes were determined by an agar or broth dilution method as recommended by the NCCLS (15) and against Bacteroides fragilis by agar dilution on Wilkins-Chalgren medium (Difco Laboratories, Detroit, Mich.) supplemented with 5 mg of hemin chloride per liter and 0.5 mg of menadione per liter (16).
PBP affinity.
Penicillin binding was determined using
fluorescein isothiocyanate-labeled ampicillin (FAMP) (Fig.
2).
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20°C. After thawing, the
membranes were sonicated briefly before use in labeling experiments.
The membranes were used at a concentration of 10 mg of protein/ml, the
fluorescent penicillin was added in 0.1 M sodium phosphate buffer, and
the mixture was incubated at room temperature for 15 min before the
addition of an equal volume (usually 0.02 ml) of sample buffer for
sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The sample
was applied directly to a discontinuous sodium dodecyl
sulfate-polyacrylamide gel (stacking gel, 2% polyacrylamide; separating gel, 7.6% polyacrylamide) for analysis. After
electrophoresis, the unstained gels were placed in 70% ethanol to
remove unbound fluorescent penicillin and then scanned in a Fluorimager
(Molecular Devices) and the amount of fluorescence was determined using
ImageQuant software from the manufacturer.
Labeling of soluble recombinant PBP 2' (preparation described
elsewhere [B. Mensch et al., submitted for publication])
was performed with 0.1 to 0.5 mg of protein per liter in 0.1 M sodium phosphate buffer. The protein solution (0.01 ml) was mixed with an
equal volume of a solution of the test substance in the same buffer,
and the mixture was incubated for 15 min. Then, 0.1 ml of 10 mM FAMP in
0.1 M sodium phosphate was added and the reaction was allowed to
continue for a further 15 min. The reaction was stopped by the addition
of 0.1 ml of ice-cold 10% aqueous trichloroacetic acid solution. The
precipitate formed was collected by filtration through Whatman GF/F
glass fiber filter paper. The filters were washed with 70% ethanol and
air dried before reading of the fluorescence in a Cytofluor 2000 microtiter plate fluorimeter. For direct competition, the test
substance and fluorescent penicillin were added in the same solution
and the reaction mixture was incubated for 5 min before the
trichloroacetic acid solution was added.
Stability towards -lactamases.
-Lactamases were
purified to homogeneity, and their hydrolytic activities and
inhibition were studied by standard methods (17).
Bactericidal activity. Overnight cultures of the test strains (four MRSA strains and one MRSE, one methicillin-susceptible S. aureus [MSSA], and one Escherichia coli strain) grown in 30 ml of Mueller-Hinton broth (MHB; Remel, Lenexa, Kans.) were diluted into fresh medium to yield an inoculum of 106 CFU/ml or higher. Drug was added either with the inoculum or at intervals of 1.5 h (early log phase) and 3 h (log phase) after its addition. Drug concentrations of 0 (control), 0.5, 1, 2, or 5 times the MIC were used. Ten-microliter aliquots of appropriate dilutions were plated on Mueller-Hinton agar (MHA), and colonies were counted after 24 h of incubation. To check whether resistant clones had been selected, the MICs were determined for those cultures which showed growth after 24 h.
Population analysis. The standard procedure described by Tomasz et al. (21) was followed. Single colonies from staphylococcal plates were inoculated into 30 ml of MHB in 100-ml Erlenmeyer flasks and incubated overnight at 35°C. Dilutions of the fully grown cultures were prepared in phosphate-buffered saline, and aliquots of 100 µl were plated out on MHA plates containing increasing concentrations of the compound to be tested, including controls with no antibiotic. Each experiment was run in triplicate, and the the numbers of CFU per plate were averaged. Plates were read after 2 days of incubation at 35°C.
Resistance development. Development of resistance to Ro 63-9141, imipenem, linezolid, and ciprofloxacin was studied with three MRSA strains and one MSSA strain by serial passage over graded concentrations in 2 ml of MHB and application of an inoculum of 105 CFU/ml.
Since exposure to Ro 63-9141 at this inoculum did not lead to resistant mutants, a comparative study for Ro 63-9141, imipenem, ciprofloxacin, and linezolid was performed with an MRSA strain (S. aureus 745) using a much higher inoculum. MHA was used as the medium. The compounds were dissolved in water (imipenem) or in a small volume of dimethyl sulfoxide (Ro 63-9141, ciprofloxacin, and linezolid), diluted in water, and incorporated in twofold serial dilutions in the agar. An inoculum of about 2 × 108 CFU/plate was applied by plating aliquots of 0.1 ml of an overnight culture. The plates were incubated at 35°C for 48 h, and the MICs were recorded as the lowest concentrations that prevented visible growth of colonies. For the second and further passages, the inoculum was prepared from the highest concentration of each test compound that gave rise to growth. At least five colonies were suspended in 1 ml of MHB, and this suspension was adjusted to yield an inoculum of approximately 2 × 108 CFU/plate. The plates were incubated at 35°C for 48 h, and the MICs were read. A total of six passages were performed for Ro 63-9141, and a total of five each were performed for the comparator drugs.Experimental septicemia in mice.
Septicemia was induced in
outbred Swiss albino mice (Jbm MoRo; weight, 16 to 20 g). Mice
were infected by intraperitoneal (i.p.) injection of diluted overnight
cultures of the test organisms. All strains, with the exceptions of
Streptococcus pyogenes 15, E. coli 25922, Klebsiella pneumoniae 418, Enterobacter
cloacae MRW, Serratia marcescens 69438, and
Pseudomonas aeruginosa BA, were injected as suspensions in
4% hog gastric mucin (Fluka Chemie AG, Buchs, Switzerland). Bacterial
challenge doses were 4 to 10 times the number of organisms required to
kill 50% of infected, but unmedicated, animals within 48 h. The test
compounds were administered subcutaneously (s.c.) 1, 3, and 5 h
after bacterial challenge in the P. aeruginosa BA
infection and 1 and 3 h afterward in all other infections. The
test compounds were used as solutions in saline, except for Ro 63-9141, which was administered as a suspension together with 2% (vol/vol)
Tween 80 (Sigma Chemical Co., St. Louis, Mo.). Control and treatment
groups at each dose were composed of five mice each. The 50% effective
dose (ED50, in milligrams per kilogram of body weight) was
calculated by probit analysis as described by Finney (4)
from the survival rates on day 4 after infection.
Experimental s.c. abscesses in mice. The test strains S. aureus I-6 and S. aureus Mu50 were grown for 18 h in semisolid brain heart infusion (BHI) medium (Difco Laboratories, Detroit, Mich.) (supplemented with 0.25% agarose) and subsequently diluted 103-fold in the same medium. Samples of 0.5 ml of this dilution were used as inocula for infection.
Female Swiss albino mice (Jbm MoRo; weight, 27 to 30 g) were injected beneath the loose skin of the left groin. The test compounds were administered i.p. 1 and 3 h after infection. Vancomycin was given as an aqueous solution, and linezolid and Ro 63-9141 were given as suspensions with 2% (vol/vol) Tween 80. Unmedicated mice developed visible abscesses at the site of infection by the third day following bacterial challenge. Mice were killed on the third day after infection. The abscesses were excised, added to 2 ml of saline, and homogenized in a blender. Viable cell counts of the bacteria per abscess were determined in duplicate by a standard plate procedure on BHI agar.| |
RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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MIC determination.
The antibacterial activity of Ro 63-9141 was compared with those of cefotaxime, cefepime, meropenem, and
ciprofloxacin. For gram-positive organisms vancomycin was also used as
a comparator, as were ampicillin for enterococci, ceftazidime for
P. aeruginosa, and metronidazole for B. fragilis.
The results are presented in Table 1.
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4 µg/ml. Slightly higher MICs
were obtained for Staphylococcus haemolyticus
(MIC90, 8 µg/ml). The MIC90s of cefotaxime,
cefepime, meropenem, and ciprofloxacin against MRS were not
in the range of susceptibility. For the MRSA strain S. aureus Mu50, which has decreased susceptibility to vancomycin (so-called vancomycin-intermediate S. aureus [VISA]
strain) and was isolated after therapeutic failure with vancomycin
(8), the MIC of Ro 63-9141 (2 µg/ml) was not higher than
those for vancomycin-susceptible MRSA strains. For a
-lactamase-producing strain of S. aureus showing
borderline oxacillin resistance with the same characteristics as those
described by McDougal and Thornsberry in 1996 (e.g., lowering of
oxacillin MICs into the susceptible range in the presence of
-lactamase inhibitors) (13), the Ro 63-9141 MIC was 1 µg/ml. Addition of 2% sodium chloride to MHA had little influence on
the MIC of Ro 63-9141; it increased by at most one dilution step for
some strains. Penicillin-susceptible strains of S. pneumoniae were highly susceptible to the new compound (MIC90, 0.03 µg/ml). The MIC90 of Ro 63-9141 for penicillin-resistant pneumococci was twofold lower than those of
cefotaxime and cefepime and equal to that of meropenem. In contrast
to the reference cephalosporins, which were inactive, Ro 63-9141 was
equivalent to ampicillin in activity against ampicillin-susceptible
isolates of Enterococcus faecalis and Enterococcus
faecium. Ro 63-9141 did not inhibit ampicillin-resistant
enterococci. In E. faecium these isolates are generally also
resistant to vancomycin.
Since the formation of extended-spectrum -lactamases
(ESBLs) has a major influence on the susceptibility of
Enterobacteriaceae to -lactam antibiotics, MICs for
ESBL-producing and ESBL-nonproducing isolates were determined
separately for E. coli and K. pneumoniae. Likewise, isolates of P. aeruginosa were categorized
according to susceptibility or resistance to ceftazidime before
testing. Ro 63-9141 showed high and consistent activity against
ESBL-negative isolates of E. coli and K. pneumoniae as well as against Proteus mirabilis, Morganella
morganii, Providencia spp., Vibrionaceae, Haemophilus
influenzae, Neisseria gonorrhoeae, and Moraxella
catarrhalis. Comparable activities were obtained with the
reference -lactams. About 15% of the ESBL-positive E. coli and K. pneumoniae isolates were resistant to Ro
63-9141 (MIC50, 4 µg/ml; MIC90, >32
µg/ml). Cefepime and particularly meropenem were more potent against
these strains. Ro 63-9141 was slightly more active than cefepime
against Enterobacter aerogenes, of which 2 of the 10 strains studied were ESBL producers, but it was intermediate
to cefepime and cefotaxime against Enterobacter
cloacae and Citrobacter freundii. A concentration of 8 µg of Ro 63-9141 per ml was needed to prevent growth in 100% of
these strains. Ro 63-9141 did not inhibit most isolates of Proteus vulgaris, in contrast to the comparator drugs. Ro
63-9141 was similar to ceftazidime and cefepime in activity against
ceftazidime-susceptible P. aeruginosa (MIC90s,
16, 8, and 16 µg/ml, respectively), whereas cefotaxime was virtually
inactive. No compound inhibited ceftazidime-resistant P. aeruginosa at low concentration, and cross-resistance between ceftazidime, cefepime, and Ro 63-9141 was noticed for most, but not
all, strains. The activities of the tested cephalosporins, including Ro
63-9141, against B. fragilis varied widely, but for most
isolates high MICs were exhibited.
Bactericidal activity. Ro 63-9141 exhibited time-dependent bactericidal activity against MSSA, MRSA, E. coli, and other species. Killing rates were dependent on the inoculum and growth phase, as with other cell wall-active agents. For the surviving cells after 24 h of exposure to Ro 63-9141, MICs were not higher than those for the isolates before exposure.
The rapid bactericidal activity of Ro 63-9141 against both MSSA and MRSA contrasted with the activity of vancomycin, which produced a modest drop in the viable cell count (Fig. 3).
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Inhibition of PBPs. A number of PBPs have been cloned and purified after expression of the genes in E. coli in soluble form. These proteins were used to test Ro-63-9141 and reference compounds for inhibition (17).
Fifty percent inhibitory concentrations (IC50s), determined with a fluorescein-labeled penicillin, showed that Ro 63-9141 had a high affinity (IC50 = 0.87 µM) for S. epidermidis PBP 2', in contrast to all other-lactams
measured (Table 2). The affinity for PBP
1b from C. freundii, a gram-negative organism, was
comparable to that of ceftriaxone (IC50 of 0.16 versus 0.19 µM). It was also shown that Ro 63-9141 acylates PBP 2' more rapidly
than other -lactam antibiotics do and forms a more stable
acyl-enzyme complex through a unique mode of interaction with the
protein. These effects lead to 100% inhibition of PBP 2' and hence to
potent antibacterial activity.
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-Lactamase stability.
Like many third-generation
cephalosporins (e.g., ceftriaxone), Ro 63-9141 is a poor substrate for
class C -lactamases and is hydrolyzed at very low rates compared to
those of cephalothin or penicillin G (Table
3). This appears to be due to substrate inhibition induced by the 7-hydroxyiminoacetamido side chain (2, 17). Ro 63-9141 is also a poor substrate for class A enzymes, particularly penicillinases (e.g., S. aureus PC1). It is
more readily hydrolyzed by the class A cephalosporinase from
Proteus vulgaris 1028 and by ESBLs (TEM derivatives), but it
is still relatively stable compared to good substrates.
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Resistance development in MRSA.
Serial passage on increasing
concentrations of Ro 63-9141 was performed with three MRSA strains and
one MSSA strain. In no case was there an increase in the MIC of more
than one dilution step after six to eight passages, and the MICs
remained below 4 µg/ml. In a more demanding approach, development of
resistance to Ro 63-9141 was studied with a high inoculum of an MRSA
strain (S. aureus 745) in parallel with that to imipenem,
ciprofloxacin, and linezolid, a compound that is reported to show a
very low incidence of resistance development (9). The size
of the inoculum was increased to 2 × 108 CFU per
plate. Resistance to imipenem, ciprofloxacin, and even linezolid emerged rapidly, resulting in final MICs of 32 µg/ml or higher, whereas an increase in MIC of only a factor of 2 was observed for Ro 63-9141 and was not sustained after reisolation (Fig.
5).
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Experimental septicemia in mice.
Ro 63-9141 was studied
against septicemias caused by pathogens that differed in their
susceptibilities to this compound. Cefepime, ceftriaxone, and
meropenem, were used as comparators. Ro 63-9141 was highly effective
upon s.c. administration (ED50s, <3 mg/kg) to animals with
infections with strains for which MICs were 2 µg/ml (Table
4). This includes isolates
of MSSA, MRSA, Streptococcus pyogenes, Streptococcus pneumoniae,
E. coli, K. pneumoniae, C. freundii, Serratia marcescens, and
Proteus mirabilis. In particular, Ro 63-9141 showed activity
against three penicillin-resistant strains of Streptococcus
pneumoniae, including a strain (Streptococcus pneumoniae 23 F-CTR) that showed reduced susceptibility to
third-generation cephalosporins in vitro (MIC of ceftriaxone, 4 µg/ml; MIC of cefotaxime, 8 µg/ml versus that of Ro 63-9141 1 µg/ml) as well as in vivo (ED50 of
ceftriaxone, 8.8 mg/kg; ED50 of cefotaxime, >12 mg/kg versus that of Ro 63-9141, 1.0 mg/kg). Against the MRSA strain S. aureus I-6, Ro 63-9141 (ED50, 2.4 mg/kg)
was more effective than vancomycin (ED50, 6.7 mg/kg), in
spite of demonstrating the same in vitro activity. Meropenem and
cefepime were inactive at the highest dose tested (25 mg/kg). For a
strain of P. aeruginosa for which the MIC was 8 µg/ml
(P. aeruginosa BA) and one of Enterobacter cloacae for which the MIC was 4 µg/ml
(Enterobacter cloacae MRW) ED50s of
Ro 63-9141 were 4.0 and 3.8 mg/kg, respectively. The strain
Proteus vulgaris 1028 with in vitro resistance to
Ro 63-9141 was also resistant in vivo
(ED50, >12 mg/kg). The activity of Ro 63-9141 after
oral dosing was only marginal, as was found in MSSA septicemia
(data not shown).
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Experimental s.c. abscesses in mice.
Ro 63-9141 was
tested against two MRSA strains in this model in comparison with
linezolid and vancomycin. Ro 63-9141 (10 mg/kg i.p.) was more
bactericidal than vancomycin (10 mg/kg i.p.) and linezolid (20 mg/kg
i.p.) against the vancomycin-susceptible strain S. aureus
I-6 (Table 5). The median
viable count in the Ro 63-9141 group was 5.12 log units lower than in
the untreated control group, compared to 3.42 log units lower in the
vancomycin group and 0.80 log unit lower in the linezolid group. The
same dose of Ro 63-9141 was also very effective against the VISA strain
Mu50, as the pathogen was completely eliminated from most animals.
Vancomycin (40 mg/kg i.p.) and linezolid (20 mg/kg i.p.) reduced the
viable count only by a very minor extent, compared to the number of
viable cells in the untreated control.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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High affinity for PBP 2' is crucial for the antibacterial
activity of -lactams against MRS. Unfortunately, none of the
available -lactam antibiotics sufficiently fulfils this requirement.
This fact increasingly limits the therapeutic potential against
staphylococcal infections of these otherwise very useful drugs.
However, the intensive search for new antistaphylococcal drugs has
shown recently (1, 7, 11, 12, 14) that it is possible to
achieve strong inhibition of PBP 2' with selected -lactam
structures. Ro 63-9141 is a member of the class of
pyrrolidinone-3-ylidenemethyl cephems, which show high
potency against PBP 2' of S. aureus but higher
IC50s against normal, sensitive PBPs than other -lactam antibiotics, e.g., methicillin and imipenem. This appears to be a
common property of the pyrrolidinone-3-ylidenemethyl cephems, as it has
been observed before for other members of this structural class
(7). Ro 63-9141 shares features of cephalosporins with 7-aminothiazolylhydroxyimino side chains in that it is remarkably stable to hydrolysis by the S. aureus PC 1 enzyme.
Inhibition of PBP 2' together with stability against the action of
-lactamase translates into bactericidal activity against MRS cells.
Similar to those of other penicillins or cephalosporins, the
bactericidal activity of Ro 63-9141 was time dependent. Ro 63-9141 inhibited all 77 tested clinical isolates of MRSA which stem from
different parts of the world at a concentration of 4 µg/ml or
below. These isolates also include strains highly resistant to
imipenem and strains showing homogenous or heterogenous
resistance to methicillin (21). Sodium chloride added
at 2% hardly influenced the MICs of Ro 63-9141. Decreased
susceptibility to vancomycin does not seem to affect the activity of Ro
63-9141 against MRSA, as the MIC of 2 µg/ml against the VISA strain
S. aureus Mu50 is identical to that observed for many
vancomycin-susceptible MRSA strains. It is vital for an antimicrobial
agent that its antibacterial properties are not overcome easily by the
rapid emergence of resistant strains. In our experiments, development
of resistance to Ro 63-9141 could not be demonstrated during
multipassage exposure to the compound, even when high inocula were used.
In contrast, resistant mutants could easily be selected for the reference compounds, including linezolid. This result differs from previously published findings (9), and it must be left open whether this is due to the experimental conditions used or a property of the particular strain used.
In keeping with the in vitro activities, Ro 63-9141 showed therapeutic efficacy in septicemia models of the mouse against both MSSA and MRSA after parenteral administration. The in vivo bactericidal properties of Ro 63-9141 could be demonstrated in a mouse abscess model. In this model the bactericidal effect is quantified by determination of the viable cell count after exposure to a test compound. Administration of 10 mg of Ro 63-9141 per kg i.p. reduced the viable count of a vancomycin-susceptible MRSA strain to a greater extent than the same dose of vancomycin, a slowly bactericidal drug in vitro. The cell count of a VISA strain fell below the limit of detection in this model upon administration of Ro 63-9141. The bactericidal properties of Ro 63-9141 (administered as the prodrug Ro 65-5788) against MRSA became obvious also in an endocarditis rat model, where it was more effective than vancomycin and amoxicillin-clavulanic acid (J. M. Entenza, P. Hohl, I. Heinze-Krauss, J. Vouillamoz, M. P. Glauser, and P. Moreillon, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-014, 1998).
Our findings suggest that Ro 63-9141 may have potential against infections caused by pneumococci. Its in vitro activity against both penicillin-susceptible and penicillin-resistant pneumococci was confirmed in vivo by its high therapeutic efficacy in mice. In particular, Ro 63-9141 is still active against a strain (Streptococcus pneumoniae 23 F-CTR) that had reduced in vitro and in vivo susceptibility to ceftriaxone (MIC of ceftriaxone, 4 µg/ml).
Ro 63-9141 was comparable to ampicillin in potency against
penicillin-susceptible enterococci, which are not inhibited by available cephalosporins. However, Ro 63-9141 lacked affinity to PBP 5, which is overexpressed and mutated in penicillin-resistant enterococci,
and thus lacked activity against such organisms. Ro 63-9141 also showed
strong inhibition of essential PBPs in gram-negative organisms. The
major targets in E. coli appear to be PBP 1b and PBP 2 and
not PBP 3, the target for ceftriaxone and other third-generation
cephalosporins. High affinity for PBP 2 was observed already with
earlier pyrrolidinone-3-ylidenemethyl cephems (7) and
again appears to be a general, novel property of this class of
cephalosporins. PBP affinities to and stability with different classes
of -lactamases determine the antibacterial spectrum of Ro 63-9141 against gram-negative pathogens. Relatively high-level stability
towards broad-spectrum class A -lactamases allowed high
antibacterial activity similar to those of cefotaxime and ceftriaxone
to be obtained against Enterobacteriaceae
producing such enzymes. On the other hand, the new cephalosporin was
more labile than cefepime to some ESBLs, and as a
consequence, its inhibitory activity against ESBL-producing isolates
was weaker and inconsistent. Stability with class C chromosomal
-lactamases appears to be the determining factor for the
activity of Ro 63-9141 against cefotaxime-resistant isolates of
Enterobacter cloacae and C. freundii, which
was, however, less pronounced than that of cefepime. The
lack of activity against Proteus vulgaris relies on the
efficient enzymatic hydrolysis of Ro 63-9141.
Unlike earlier pyrrolidinone-3-ylidenemethyl cephems, Ro 63-9141 showed substantial activity against strains of P. aeruginosa, at least those susceptible to ceftazidime. The mere presence of the 7-aminothiadiazolylhydroxyimino side chain cannot explain this activity because most cephalosporins bearing this substituent do not inhibit P. aeruginosa. This finding suggests that the positively charged 3' substituent significantly contributes to Pseudomonas activity.
Susceptibility against many anaerobic isolates, including gram-positive cocci and a few strains of Clostridium difficile, has been demonstrated (K. E. Bowker, M. Wootton, H. A. Holt, and A. P. MacGowan, Abstr. 38th Intersci. Conf. Antimcrob. Agents Chemother., abstr. F-20, 1998), but members of the B. fragilis group were mostly resistant to the new compound. As it was the case for gram-positive pathogens, the studied gram-negative organisms responded to the therapy with Ro 63-9141 in animal models in line with their in vitro susceptibilities.
Ro 63-9141 is not sufficiently soluble in water to be used for parenteral administration in humans. Thus, a soluble prodrug, Ro 65-5788, has been prepared for development. Following parenteral dosing, Ro 65-5788 is rapidly cleaved in the blood to yield Ro 63-9141. The level of protein binding of Ro 63-9141 is relatively low, i.e., 38% for human plasma (personal communication of A. Schmitt-Hoffmann), which is characteristic for cephems with a basic 3' side chain. A low level of protein binding, meaning a high fraction of freely available, active drug, is a favorable prerequisite for in vivo efficacy.
In conclusion, Ro 63-9141 is a new -lactam antibiotic that combines
activity against MRS with broad-spectrum activity against gram-negative
bacteria and other gram-positive bacteria. The bases of its
antimicrobial properties are inhibition of essential PBPs, including
PBP 2' of MRS, and stability against the hydrolytic actions of
-lactamases. In vivo experiments confirmed the potential utility of
Ro 63-9141 against infections caused by susceptible pathogens. A
water-soluble prodrug, Ro 65-5788, was selected for developmental studies.
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ACKNOWLEDGMENTS |
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We thank Pia Aubry, Nicole Bingler, Pia Celesti, Gunther Gass, Margaret Kania, Barbara Mensch, Heinz Meyer, Véronique Schirmer, Heidi Schlunegger, Marie-Thérèse Traendlin, and Cäcilia Wolfgang for expert technical assistance.
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FOOTNOTES |
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* Corresponding author. Mailing address: F. Hoffmann-La Roche Ltd., Biological Technologies, Bldg. 70.8, CH-4070 Basel, Switzerland. Phone: 0041-61-688 4182. Fax: 0041-61-688 2729. E-mail: rudolf.then{at}roche.com.
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REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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| 1. |
Chambers, H. F.
1995.
In vitro and in vivo antistaphylococcal activities of L-695,256, a carbapenem with high affinity for penicillin-binding protein PBP 2a.
Antimicrob. Agents Chemother.
39:462-466 |
| 2. |
Charnas, R. L., and R. L. Then.
1988.
Mechanism of inhibition of chromosomal -lactamases by third-generation cephalosporins.
Rev. Infect. Dis.
10:752-760[Medline].
|
| 3. |
Emori, T. G., and R. P. Gaynes.
1993.
An overview of nosocomial infections, including the role of the microbiology laboratory.
Clin. Microbiol. Rev.
6:428-442 |
| 4. | Finney, D. J. 1978. Statistical method in biological assay, 3rd ed. Charles Griffin & Co., Ltd., London, United Kingdom. |
| 5. | Fluit, A. C., M. E. Jones, F.-J. Schmitz, J. Acar, R. Gupta, J. Verhoef, and the SENTRY Participants Group. 2000. Antimicrobial susceptibility and frequency of occurrence of clinical blood isolates in Europe from SENTRY Antimicrobial Surveillance Program, 1997 and 1998. Clin. Infect. Dis. 30:454-460[CrossRef][Medline]. |
| 6. | Hecker, S. J., I. S. Cho, T. Glinka, Z. J. Zhang, M. E. Price, V. J. Lee, B. G. Christensen, A. Boggs, S. Chamberland, F. Malouin, T. R. Parr, T. Annamalaj, J. Blais, E. L. Bond, L. Case, C. Chan, J. Crase, R. Frith, D. Griffith, L. Harford, N. Liu, M. Ludwikow, K. Mathias, D. Rea, and R. Williams. 1998. Discovery of MC-02,331, a new cephalosporin exhibiting potent activity against methicillin-resistant Staphylococcus aureus. J. Antibiot. 51:722-734[Medline]. |
| 7. | Heinze-Krauss, L., P. Angehrn, P. Guerry, P. Hebeisen, C. Hubschwerlen, I. Kompis, M. G. P. Page, H. G. F. Richter, V. Runtz, H. Stalder, U. Weiss, and C.-C. Wei. 1996. Synthesis and structure-activity relationship of (lactamylvinyl)cephalosporins exhibiting activity against staphylococci, pneumococci, and enterococci. J. Med. Chem. 39:1864-1871[CrossRef][Medline]. |
| 8. |
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 |
| 9. | Kaatz, G. W., and S. M. Seo. 1996. In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob. Agents Chemother. 40:799-801[Abstract]. |
| 10. | Kresken, M., D. Hafner, W. Witte, and R. R. Reinert. 1999. Resistenzentwicklung bei Staphylokokken and anderen grampositiven Erregern gegenüber Chemotherapeutika im mitteleuropäischen Raum. Chemother. J. 8:136-145. |
| 11. | Lee, V. J., and S. J. Hecker. 1999. Antibiotic resistance versus small molecules, the chemical evolution. Med. Res. Rev. 19:521-542[CrossRef][Medline]. |
| 12. |
Matsumoto, M.,
H. Tamaoka,
H. Ishikawa, and M. Kikuchi.
1998.
In vitro and in vivo antibacterial activities of OPC-20001 1, a novel broad-spectrum 2-oxaisocephem antibiotic.
Antimicrob. Agents Chemother.
42:2943-2949 |
| 13. |
McDougal, C. K., and C. Thornsberry.
1996.
The role of -lactamase in staphylococcal resistance to penicillinase-resistant penicillins and cephalosporins.
J. Clin. Microbiol.
23:832-839.
|
| 14. |
Nagano, R.,
K. Shibata,
Y. Adachi,
H. Imamura,
T. Hashizume, and H. Morishima.
2000.
In vitro activities of novel trans-3,5-disubstituted pyrrolidinylthio-1-methyl-carbapenems with potent activities against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.
Antimicrob. Agents Chemother.
44:489-495 |
| 15. | National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7-A4 National Committee for Clinical Laboratory Standards, Wayne, Pa. |
| 16. | National Committee for Clinical Laboratory Standards. 1997. Methods for antimicrobial susceptibility testing of anaerobic bacteria, 4th ed. Approved standard M11-A4 National Committee for Clinical Laboratory Standards, Wayne, Pa. |
| 17. | Page, M. G. P. 1993. The kinetics of non-stoichiometric bursts of beta-lactam hydrolysis catalysed by class C beta-lactamases. Biochem. J. 295:295-304. |
| 18. |
Reacher, M. H.,
A. Shah,
D. M. Livermore,
M. C. J. Wale,
C. Graham,
A. P. Johnson,
H. Heine,
M. A. Monnickendam,
K. F. Barker,
D. James, and R. C. George.
2000.
Bacteremia and antibiotic resistance of its pathogens reported in England and Wales between 1990 and 1998: trend analysis.
Br. Med. J.
320:213-216 |
| 19. | Singh, N., D. L. Paterson, F. Y. Chang, T. Gayowski, C. Squier, M. M. Wagener, and I. R. Marino. 2000. Methicillin-resistant Staphylococcus aureus: the other emerging resistant gram-positive coccus among liver transplant recipients. Clin. Infect. Dis. 30:322-327[CrossRef][Medline]. |
| 20. | Sumita, Y., H. Nouda, K. Kanazawa, and M. Fukasawa. 1995. Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 39:910-916[Abstract]. |
| 21. |
Tomasz, A.,
S. Nachman, and H. Leaf.
1991.
Stable classes of phenotypic expression in methicillin-resistant clinical isolates of staphylococci.
Antimicrob. Agents Chemother.
35:124-129 |
Antimicrobial Agents and Chemotherapy, March 2001, p. 825-836, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.825-836.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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