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Antimicrobial Agents and Chemotherapy, May 2001, p. 1422-1430, Vol. 45, No. 5
Microcide Pharmaceuticals Inc, Mountain View,
California 94043
Received 20 October 2000/Returned for modification 29 December
2000/Accepted 13 February 2001
RWJ-54428 (MC-02,479) is a new cephalosporin with a high level of
activity against gram-positive bacteria. In a broth microdilution susceptibility test against methicillin-resistant Staphylococcus aureus (MRSA), RWJ-54428 was as active as vancomycin, with an MIC
at which 90% of isolates are inhibited (MIC90) of 2 µg/ml. For coagulase-negative staphylococci, RWJ-54428 was 32 times
more active than imipenem, with an MIC90 of 2 µg/ml.
RWJ-54428 was active against S. aureus, Staphylococcus
epidermidis, and Staphylococcus haemolyticus isolates
with reduced susceptibility to glycopeptides (RWJ-54428 MIC range,
Multidrug-resistant gram-positive
bacteria have become an increasing problem for the management of
serious infections (13). Methicillin-resistant
Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS) represent a challenge in
hospitals and are now also established in the community
(3). Staphylococci producing a Penicillin resistance can now be found in 25% of clinical isolates of
Streptococcus pneumoniae and viridans group streptococci worldwide (9). In addition to resistance to penicillin,
many of these strains are also resistant to macrolides. Resistance to
penicillins and cephalosporins in streptococci is mediated by
target-site mutations in penicillin-binding proteins. In S. pneumoniae, mosaic genes encoding altered penicillin-binding
proteins mediate resistance to penicillin and related antibiotics
(6, 21). Nonpneumococcal streptococci have also become
increasingly prevalent and are often the cause of fatal bacteremia in
immunocompromised patients. As many as 9% of clinical isolates of
viridans group streptococci in the United States are resistant to
penicillin G. More importantly, viridans group streptococci that are
not susceptible to penicillin G are often also resistant to ceftriaxone or erythromycin, or to both antibiotics (19).
Enterococci represent a particular clinical challenge because of their
high level of intrinsic resistance to antibiotics (12, 17). They are tolerant to most cell wall-active agents and are not readily killed by Several years ago, we initiated a program to design new cephalosporins
with optimal activity against multidrug-resistant gram-positive bacteria (F. Malouin, C. Chan, S. Bond, S. Chamberland, and V. J. Lee, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr.
F-177, 1997). The details concerning the discovery of the RWJ-54428
(MC-02,479; Fig. 1) and its
structure-activity relationship and potency against a limited number of
organisms have been described elsewhere (7). This report
describes in detail the in vitro activity of this agent against
staphylococci, streptococci, and enterococci, as well as against
Haemophilus influenzae, Moraxella catarrhalis, and other
gram-negative bacteria.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1422-1430.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
In Vitro Activities of RWJ-54428 (MC-02,479)
against Multiresistant Gram-Positive Bacteria
and
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
0.0625 to 1 µg/ml). RWJ-54428 was eight times more potent than
methicillin and cefotaxime against methicillin-susceptible S. aureus (MIC90, 0.5 µg/ml). For
ampicillin-susceptible Enterococcus faecalis (including
vancomycin-resistant and high-level aminoglycoside-resistant strains),
RWJ-54428 had an MIC90 of 0.125 µg/ml. RWJ-54428 was also
active against Enterococcus faecium, including vancomycin-, gentamicin-, and ciprofloxacin-resistant strains. The potency against
enterococci correlated with ampicillin susceptibility; RWJ-54428 MICs
ranged between 0.0625 and 1 µg/ml for ampicillin-susceptible strains and 0.125 and 8 µg/ml for ampicillin-resistant strains. RWJ-54428 was more active than penicillin G and cefotaxime against penicillin-resistant, -intermediate, and -susceptible strains of
Streptococcus pneumoniae (MIC90s, 0.25, 0.125, and 0.0625 µg/ml, respectively). RWJ-54428 was only marginally
active against most gram-negative bacteria; however, significant
activity was observed against Haemophilus influenzae and
Moraxella catarrhalis (MIC90s, 0.25 and 0.5 µg/ml, respectively). This survey of the susceptibilities of more
than 1,000 multidrug-resistant gram-positive isolates to RWJ-54428
indicates that this new cephalosporin has the potential to be useful in
the treatment of infections due to gram-positive bacteria, including
strains resistant to currently available antimicrobials.
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactamase capable of
hydrolyzing penicillins were isolated soon after the introduction of
these antibiotics (10). To overcome this resistance
problem, semisynthetic penicillins resistant to staphylococcal
-lactamases, such as methicillin, were introduced, but it did not
take long for the strains with resistance to these agents to surface
(1; M. P. Jevons, Letter, Br. Med. J. i:124-125, 1961; G. N. Rolinson, Letter, Br. Med.
J. i:125-126, 1961). The genetic determinant of methicillin resistance has been identified as mec DNA, which is a 30- to
50-kb region of foreign DNA found only in methicillin-resistant
staphylococci, possibly acquired by transposition from
Staphylococcus sciuri (22). This DNA region
contains the mecA gene, which encodes penicillin-binding
protein 2a, which has a low affinity for -lactam antibiotics
(3). The wide distribution of methicillin resistance has
led to a marked increase in the use of vancomycin; however, the
existence of MRSA and MRCoNS strains with reduced susceptibility to
vancomycin in several regions of the world is now of great concern
(14, 20). Such multidrug-resistant strains may become a
significant threat to public health, and new agents active against MRSA
and MRCoNS are needed.
-lactam antibiotics and vancomycin. Some enterococci have also acquired genes that confer a high level of
resistance to most antibacterial agents (15). In a recent survey of isolates from the United States, vancomycin resistance occurred in 3.5% of Enterococcus faecalis isolates and 53%
of Enterococcus faecium isolates. High-level resistance to
gentamicin was encountered in 33 and 43% of E. faecalis and
E. faecium isolates, respectively (18).
View larger version (9K):
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FIG. 1.
Chemical structure of RWJ-54428 (MC-02,479).
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MATERIALS AND METHODS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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Bacterial strains.
A total of 671 clinical isolates of
staphylococci, 164 clinical isolates of streptococci, and 212 clinical
isolates of enterococci obtained from various geographical locations
within the United States and abroad were used in the studies described
here. These representative clinical isolates were collected at various
hospitals between 1993 and 1998. Thirty-one clinical isolates of
H. influenzae were included in this study. These isolates
were collected during the late 1980s in the United States and Canada
and included serotype a, b, c, d, e, and f isolates and nonserotypeable
isolates. Seventeen clinical isolates of M. catarrhalis,
collected during the 1980s in the United States and Canada, were
included in the study. Nine of these isolates were -lactamase
positive. A total of 111 clinical isolates of gram-negative bacteria,
including multidrug-resistant strains of the families
Enterobacteriaceae, Pseudomonadaceae, and
Neisseriaceae and other nonaffiliated gram-negative
bacteria, were studied.
Antibiotics.
RWJ-54428 was supplied as the
monomethanesulfonate. A stock solution of 2 mg of active RWJ-54428 per
ml was prepared in a 1:1 solution of dimethyl sulfoxide-sterile water.
Commercially available antibiotics were obtained from various sources:
amoxicillin, ampicillin, cefotaxime, ceftriaxone, erythromycin,
gentamicin, methicillin, penicillin G, and vancomycin were obtained
from Sigma Chemical Co. The other antibiotics were purchased or
obtained from their respective manufacturers: azithromycin, Pfizer;
cefepime, Bristol Myers-Squibb Co.; ceftazidime, Glaxo Pharmaceuticals; ciprofloxacin, Bayer; imipenem-cilastatin (Primaxin), Merck & Co.;
levofloxacin, Daiichi Pharmaceuticals; and teicoplanin, Advantis. Amoxicillin (Sigma) was also used in combination with clavulanate (SmithKline Beecham) at a 2:1 ratio. The potency of each antibiotic powder was considered for preparation of stock solutions. All antibiotics except imipenem and erythromycin were prepared at a
concentration of 10 mg/ml in sterile water. Imipenem was prepared at a
concentration of 5 mg/ml in sterile water. Erythromycin was prepared at
a concentration of 5 mg/ml in ethanol. Stock solutions of all
antibiotics except clavulanic acid were aliquoted and kept frozen at
80°C; clavulanic acid was prepared daily. Each aliquot was rapidly
thawed and used only once. Antibiotics were prepared at a concentration
equivalent to twofold the highest desired final concentration.
Antibiotics were then diluted directly in 96-well microtiter plates by
serial twofold dilution with a multichannel pipette.
Antibiotic susceptibility testing. Susceptibility tests were performed by a broth microdilution assay according to NCCLS reference methods (16), with the following specifications: testing of beta-lactams against all methicillin-susceptible S. aureus (MSSA) strains, and MRSA strains, and coagulase-negative staphylococci tested was performed in cation-adjusted Mueller-Hinton broth supplemented with 2% NaCl. The incubation period was 24 h at 35°C. The supplemental NaCl was excluded when non-beta-lactam drugs were tested. The MICs of the drugs tested for E. faecium and E. faecalis were determined in cation-adjusted Mueller-Hinton broth incubated at 35°C for 24 h. The MICs of the drugs for all streptococci were determined in cation-adjusted Mueller-Hinton broth supplemented with 2.5% lysed horse blood (Remel). All incubation periods were 24 h at 35°C. The MICs of the drugs tested for H. influenzae were determined in Haemophilus Test Medium (Remel) supplemented with 2% Fildes enrichment (Remel). All incubations were for 24 h at 35°C. For all other gram-negative bacteria, MICs were determined in cation-adjusted Mueller-Hinton broth following incubation at 35°C for 20 h. The microtiter plates were read with a microtiter plate reader (Molecular Devices) at 650 nm as well as by visual observation with a reading mirror.
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RESULTS |
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Introduction
Materials and Methods
Results
Discussion
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MSSA (n = 167).
On the basis of the MICs at
which 50% of isolates are inhibited (MIC50s), and the
MIC90s, RWJ-54428 was eightfold more active than
methicillin and cefotaxime and was as potent as imipenem against MSSA
isolates (Table
1). The
new cephalosporin was also twofold more active than vancomycin and
teicoplanin against the MSSA isolates tested. The results were similar
for 18 ciprofloxacin-resistant MSSA isolates, indicating that
resistance to quinolones was not associated with decreased
susceptibility to RWJ-54428 (data not shown).
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MRSA (n = 259). RWJ-54428 was also found to be very active against a large group of MRSA isolates (Table 1). Among all MRSA strains surveyed, the highest MIC of RWJ-54428 observed was 4 µg/ml (for one strain), and the MIC50 and MIC90 were 1 and 2 µg/ml, respectively. RWJ-54428 was 32-fold more active than imipenem and >256-fold more active than methicillin and cefotaxime against these MRSA isolates. Results were similar for a subset of 160 ciprofloxacin-resistant MRSA isolates, indicating, as expected, that resistance to this agent was not associated with decreased susceptibility to RWJ-54428 (data not shown). The results of a survey of the susceptibilities of genotypically characterized clinical isolates of MRSA is shown in Table 1. RWJ-54428 was highly active against this sample of genetically diverse MRSA strains from North America, Europe, and Japan, with an MIC50 and an MIC90 of 1 and 2 µg/ml, respectively. The potency of RWJ-54428 was similar to those of vancomycin and teicoplanin. All strains were inhibited by 2 µg of RWJ-54428 per ml, whereas the strains were inhibited by 4 and 32 µg of vancomycin and teicoplanin per ml, respectively. All isolates were susceptible to RWJ-54428, despite high levels of resistance to other beta-lactam antibiotics (methicillin, cefotaxime, and imipenem), ciprofloxacin, and erythromycin.
MRCoNS (n = 89). The susceptibility of MRCoNS to the drugs tested is shown in Table 1. RWJ-54428 was the most active agent against MRCoNS. In addition to resistance to conventional beta-lactam antibiotics, most of these isolates were highly resistant to ciprofloxacin and erythromycin.
Staphylococci with reduced susceptibility to glycopeptide
antibiotics.
A group of five staphylococci, including two S. aureus strains, two Staphylococcus epidermidis strains,
and one Staphylococcus haemolyticus strain, with reduced
susceptibility to glycopeptide antibiotics was tested (Table
2). For these isolates, the vancomycin MIC was 8 µg/ml and teicoplanin MICs ranged from 4 to 32 µg/ml. These isolates were readily inhibited by RWJ-54428, with MICs ranging
from 0.0625 to 1 µg/ml.
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S. pneumoniae.
RWJ-54428 was highly active against
S. pneumoniae, including penicillin-resistant pneumococci
(PRSP). For 34 PRSP isolates, the MIC90 of RWJ-54428 was
0.25 µg/ml, with the highest MIC being 0.5 µg/ml. On the basis of
the MIC90s, RWJ-54428 was 16-fold more potent than
penicillin G and 8-fold more active than ceftriaxone or cefotaxime
against these clinical isolates of PRSP. RWJ-54428 outperformed
erythromycin. The potency of RWJ-54428 was equivalent to that of
vancomycin against penicillin-intermediate pneumococci and PRSP (Table
3).
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Group A and group B streptococci.
Clinical isolates of group A
streptococci (n = 13) were all susceptible to
penicillin G, with MICs ranging from 0.0625 to 0.125 µg/ml (Table
3). For this same group of isolates, the RWJ-54428 MIC ranged from
0.0625 to 0.5 µg/ml. A total of 10 isolates of group B streptococci
were found to be equally highly susceptible to penicillin and to
RWJ-54428, with both drugs having MICs of 0.0625 µg/ml for all
isolates. The 10 isolates of group B streptococci were also susceptible
to cefotaxime and erythromycin (Table 3).
Viridans group streptococci.
Penicillin-susceptible viridans
group streptococci were susceptible to RWJ-54428, with an
MIC50 and an MIC90 of 0.0625 µg/ml (Table
3). RWJ-54428 was more than eightfold more active than ceftriaxone. The
unique potency of RWJ-54428 against this group was best seen with
penicillin-intermediate and penicillin-resistant isolates of viridans
group streptococci. RWJ-54428 was 8- to 32-fold more active than
penicillin G, ceftriaxone, or cefotaxime against penicillin-intermediate and penicillin-resistant clinical isolates of
viridans group streptococci (Table 3).
Enterococci.
RWJ-54428 was found to be very active against 78 isolates of vancomycin-susceptible E. faecalis, with an
MIC50 and an MIC90 of 0.125 and 0.25 µg/ml,
respectively. On the basis of the MIC90s, RWJ-54428 was
8-fold more active than vancomycin and 32-fold more active than
ampicillin against vancomycin-susceptible E. faecalis (Table
4). A single vancomycin-intermediate
E. faecalis strain (vancomycin MIC, 8 µg/ml) was
identified among the clinical isolates that we have studied. This
isolate was susceptible to ampicillin and gentamicin, and the RWJ-54428
MIC for the isolate was 0.25 µg/ml. RWJ-54428 was also very potent
against 11 isolates of vancomycin-resistant E. faecalis,
with an MIC90 of 0.125 µg/ml (Table 4). Data for the
E. faecalis strains were also analyzed according to their susceptibilities to ampicillin, regardless of their level of resistance to vancomycin. RWJ-54428 MIC50 and MIC90 were
both 0.125 µg/ml for a population of 82 ampicillin-susceptible
E. faecalis isolates (Table 4). For eight isolates of
ampicillin-resistant E. faecalis, the range of RWJ-54428
MICs was 0.125 to 4 µg/ml. RWJ-54428 was the most active antibiotic
studied against E. faecium (Table 4). Most E. faecium isolates (100 of 122 [82%]) were resistant to ampicillin, with MICs ranging from 16 to >128 µg/ml. Seventy-two percent of the ampicillin-resistant isolates were also resistant to
vancomycin. For these isolates, the MICs of RWJ-54428 ranged between 1 and 8 µg/ml (MIC90, 8 µg/ml) (Table 4). RWJ-54428 was found to be potent against 22 isolates of ampicillin-susceptible E. faecium, with an MIC50 and an
MIC90 of 0.5 and 1 µg/ml, respectively (Table 4). Two of
these isolates were resistant to vancomycin (MIC, >64 µg/ml), with
ampicillin MICs of 0.5 and 2 µg/ml, respectively, and RWJ-54428 MICs
of 0.125 and 0.5 µg/ml, respectively. These results indicate that
RWJ-54428 is active against these ampicillin-susceptible, vancomycin-resistant E. faecium isolates.
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H. influenzae.
RWJ-54428 was found to be very
potent against H. influenzae, with MICs ranging from
0.0625 to 2 µg/ml and an MIC50 and an MIC90
of 0.125 and 0.25 µg/ml, respectively. On the basis of the MIC90s, RWJ-54428 was 4-fold more active than ampicillin
and 32-fold more active than erythromycin. The activity of RWJ-54428
was similar to those of cefotaxime and imipenem (Table
5). The MICs of RWJ-54428 and ampicillin
were 0.125 and 4 µg/ml, respectively, for the only -lactamase-producing isolate of H. influenzae tested. For
isolates with reduced ampicillin susceptibility (MIC range, 0.5 to 4 µg/ml) due to known alterations in penicillin-binding proteins,
RWJ-54428 MICs ranged from 0.25 to 2 µg/ml.
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M. catarrhalis.
RWJ-54428 was also found to be
very active against M. catarrhalis, with an
MIC50 and an MIC90 of 0.0625 and 0.5 µg/ml,
respectively. RWJ-54428 was fourfold more active than ampicillin. The
activity of RWJ-54428 was similar to that of cefotaxime (Table 5).
Other gram-negative bacteria. In a panel containing multidrug-resistant isolates, RWJ-54428 had limited activity against Escherichia coli, Klebsiella spp., Serratia spp., Providencia spp., Proteus spp., Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter spp. (Table 5). RWJ-54428 MIC ranges for other species were as follows: Citrobacter spp. (n = 9), 2 to >128 µg/ml; Enterobacter spp. (n = 9), 4 to >128 µg/ml; Burkholderia cepacia (n = 7), 16 to >128 µg/ml; Alcaligenes faecalis (n = 1), 2 µg/ml; Alcaligenes xylosoxidans (n = 2), >128 µg/ml; Flavobacterium meningosepticum (n = 1), 32 µg/ml; and Flavobacterium spp. (n = 1), 32 µg/ml.
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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RWJ-54428 is a new parental cephalosporin (7) with potent in vitro activity against multidrug-resistant gram-positive bacteria. The spectrum of activity includes MRSA, MRCoNS, and staphylococci with reduced susceptibility to glycopeptide antibiotics; penicillin-susceptible and -resistant pneumococci; group A streptococci; group B streptococci; penicillin-susceptible and -resistant viridans group streptococci; and vancomycin-susceptible and -resistant enterococci.
The unique and potent activity of RWJ-54428 against multidrug-resistant staphylococci was first reported in 1997 (Malouin et al., 37th ICAAC). In the present study, the susceptibilities of 671 clinical isolates of Staphylococcus spp. were examined. These data further establish that RWJ-54428 has potent antistaphylococcal activity in vitro. RWJ-54428 is consistently active against genotypically characterized clinical isolates of MRSA and large populations of clinical isolates of staphylococci from several geographical locations in the United States, Canada, and Europe (Table 1). Overall, RWJ-54428 is 500-fold more active than methicillin against MRSA and MRCoNS. RWJ-54428 is at least eightfold more potent than vancomycin against glycopeptide-intermediate staphylococci. RWJ-54428 is also more active than ciprofloxacin against MSSA, MRSA, MRCoNS, and glycopeptide-intermediate staphylococci.
RWJ-54428 was highly active against S. pneumoniae, including penicillin- and ceftriaxone-resistant strains (Table 3). RWJ-54428 was 8- to 16-fold more potent than penicillin G, ceftriaxone, or cefotaxime against penicillin-intermediate pneumococci and penicillin-resistant pneumococci. There was no correlation between the MICs of ceftriaxone and those of RWJ-54428 for the 34 penicillin-resistant pneumococca strains studied (data not shown). RWJ-54428 was also more potent than ceftriaxone and cefotaxime against penicillin-susceptible, -intermediate, and -resistant viridans group streptococci. The potency of RWJ-54428 was equivalent to that of penicillin against penicillin-susceptible viridans group streptococci; however, RWJ-54428 was significantly more active than penicillin G and the other beta-lactam antibiotics tested against viridans group streptococci with reduced susceptibilities to those agents.
RWJ-54428 possesses significant in vitro antibacterial activity against a variety of enterococci and is among the most active agents against drug-resistant isolates. RWJ-54428 was 8-fold more active than vancomycin and 32-fold more active than ampicillin against vancomycin-susceptible E. faecalis. Vancomycin-resistant E. faecalis remained susceptible to RWJ-54428 (which was 1,000-fold more active than vancomycin against these isolates). The activity of RWJ-54428 paralleled that of ampicillin against ampicillin-susceptible, vancomycin-intermediate, and vancomycin-resistant enterococci. Against ampicillin-resistant, vancomycin-resistant E. faecium, RWJ-54428 was 16-fold more active than ampicillin, and RWJ-54428 was the most active antibiotic against these multidrug-resistant isolates tested in the present study.
S. pneumoniae, H. influenzae, and M. catarrhalis
are the most common causes of acute exacerbation of chronic bronchitis
(2, 4, 8, 11). This survey of the susceptibilities of
H. influenzae and M. cattarhalis to RWJ-54428
indicated that these organisms are more susceptible to this new
cephalosporin than to ampicillin. -Lactamase-mediated ampicillin
resistance in H. influenzae and M. cattarrhalis
was associated with a lower level of susceptibility to RWJ-54428;
however, RWJ-54428 remained significantly more active than ampicillin
against these isolates.
In addition to in vitro potency, pharmacologic data are important in assessments of the clinical usefulness of a new agent. The level of serum protein binding for RWJ-54428 in preclinical studies with animal species and humans ranges between 48 and 84% (L. Harford K. Huie, D. Clark, D. Griffith, K. Jackson, M. Price, L. Case, K. Mathias, S. Chamberland, M. Mohler, D. Desai-Kriefer, S. Aresta, A. Takacs, and M. N. Dudley, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-18, 1998). Studies with six animals species show that RWJ-54428 has pharmacokinetic properties comparable to those of other cephalosporin antibiotics used in humans (Harford et al., 37th ICAAC).
In summary, this survey of the susceptibilities of multidrug-resistant gram-positive bacteria to RWJ-54428 indicates that this agent has the potential to be a useful agent against gram-positive bacteria and remains actively pursued as a candidate for clinical development. Phase I clinical trials have been initiated.
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ACKNOWLEDGMENTS |
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We thank Fred Tenover, Nosocomial Pathogens Laboratory Branch, the Centers for Disease Control and Prevention, for the staphylococcal isolates with reduced susceptibility to glycopeptide antibiotics and Barry Kreiswirth for the sample of genetically diverse MRSA and MSSA strains with distinct staphylococcal protein A genotypes and coagulase A genotypes. We thank the medicinal chemists that made this program possible: Scott J. Hecker, Tomasz W. Glinka, Aesop Cho, Zhijia J. Zhang, Mary Price, and Ving J. Lee.
The work described herein was conducted as part of a research collaboration with the R. W. Johnson Pharmaceutical Institute.
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FOOTNOTES |
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* Corresponding author. Mailing address: Microcide Pharmaceuticals, Inc., 850 Maude Ave., Mountain View, CA 94043. Phone: (650) 428-3519. Fax: (650) 428-3550. E-mail: johanneb{at}microcide.com.
Present address: Université de Sherbrooke, Sherbrooke,
Québec, Canada J1K 2R1.
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REFERENCES |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, May 2001, p. 1422-1430, Vol. 45, No. 5
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1422-1430.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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