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Antimicrobial Agents and Chemotherapy, August 1999, p. 2059-2062, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro Activities of Linezolid against Important
Gram-Positive Bacterial Pathogens Including Vancomycin-Resistant
Enterococci
Gary A.
Noskin,1,2,3,*
Farida
Siddiqui,2
Valentina
Stosor,1,2,4
Donna
Hacek,4 and
Lance R.
Peterson1,2,4
Division of Infectious Diseases, Department
of Medicine,1 and Clinical Microbiology
Division, Department of Pathology,2
Northwestern University Medical School, and Departments of
Infection Control3 and Prevention and Clinical
Microbiology,4 Northwestern Memorial
Hospital, Chicago, Illinois
Received 21 December 1998/Returned for modification 29 April
1999/Accepted 18 May 1999
 |
ABSTRACT |
The emergence of resistance in gram-positive bacteria has
necessitated a search for new antimicrobial agents. Linezolid is an
oxazolidinone, a new class of antibacterial agents with enhanced activity against pathogens. We compared the activity of linezolid to
those of other antimicrobial agents against 3,945 clinical isolates.
Linezolid demonstrated potent activity against all isolates tested. For
all vancomycin-susceptible enterococci, staphylococci, and
streptococci, the activity of linezolid was comparable to that of
vancomycin. Against oxacillin-resistant staphylococci and
vancomycin-resistant enterococci, linezolid was the most active agent
tested. In summary, linezolid appears to be a promising new
antimicrobial agent for the treatment of gram-positive infections.
| |
TEXT |
In recent years, there has been a
dramatic increase in the number of infections caused by gram-positive
bacteria (13). This is compounded by the emergence of
resistance in enterococci, staphylococci, and pneumococci. For many
patients infected with these resistant organisms, there may not be
effective antimicrobial therapy.
Linezolid is a member of a new class of antibacterial agents called
oxazolidinones, which are chemically unrelated to currently available
agents. This agent selectively binds to the 50S ribosomal subunit,
thereby resulting in selective inhibition of bacterial protein
synthesis (7). These compounds inhibit the formation of the
initiation complex constructed with 30S ribosomes, mRNA, initiation
factors IF2 and IF3, and fMet-tRNA (3, 4, 7, 14). In
addition, linezolid is bioavailable both orally and parenterally, is
highly active against gram-positive organisms, and is difficult to
select for resistance in vitro (6, 15). In this study, we
investigated the in vitro activity of linezolid against fresh clinical
isolates of streptococci, enterococci, and staphylococci.
(This study was presented in part at the 36th Annual Meeting of the
Infectious Diseases Society of America, Denver, Colo., 12 to 15 November 1998.)
All clinical isolates of gram-positive cocci submitted to the clinical
microbiology laboratory at Northwestern Memorial Hospital (Chicago,
Ill.) for bacterial susceptibility testing from 1 April 1997 to 4 March
1998 were tested against linezolid.
The following antimicrobial agents were obtained from their
manufacturers for use in this investigation: linezolid
(Pharmacia & Upjohn, Kalamazoo, Mich.), vancomycin (Eli Lilly
& Co., Indianapolis, Ind.), teicoplanin (Marion Merrell
Dow, Cincinnati, Ohio), ampicillin-sulbactam (Pfizer Inc., New
York, N.Y.), piperacillin and piperacillin-tazobactam (Wyeth-Ayerst, Philadelphia, Pa.), levofloxacin (Ortho-McNeil Pharmaceuticals, Raritan, N.J.), imipenem (Merck Inc., Wilmington, Del.), and trovafloxacin (Pfizer, Inc.). Ampicillin, chloramphenicol, clindamycin, erythromycin, oxacillin, and penicillin were obtained from
the Sigma Chemical Co. (St. Louis, Mo.). Agar dilution testing was
performed according to the guidelines established by the National Committee for Clinical Laboratory Standards (8). Using a
Steers replicator, an organism density of 104 CFU/spot
was inoculated onto Mueller-Hinton plates (Difco) with various
concentrations of antimicrobial agents. For Streptococcus pneumoniae, susceptibility testing was performed by using in-house prepared microtiter panels. Isolates were grown in tryptic soy broth
(Difco) to reach log-phase growth and were then diluted in sterile
tryptic soy broth to achieve a final inoculum density in the microtiter
wells of approximately 5 × 105 CFU/ml. The microtiter
trays contain an enrichment medium consisting of Mueller-Hinton broth
supplemented with 3 to 5% lysed horse blood.
Linezolid was tested at concentrations of 0.5, 1, 2, 4, 8, and 16 µg/ml, and teicoplanin was tested at a concentration of 10 µg/ml.
The other antimicrobial agents were tested at concentrations determined
by National Committee for Clinical Laboratory Standards guidelines.
Plates were incubated at 35°C for 18 to 24 h and examined for
visible growth. The MIC was defined as the lowest dilution at which
growth of 
1 colony occurred or at which only a faint haze caused by
the inoculum occurred. Along with the clinical isolates, the reference
quality control strains Staphylococcus aureus ATCC 29213 and
Enterococcus faecalis ATCC 29212 were tested on a daily basis.
The MICs of linezolid and the comparison antimicrobial agents for 3,945 bacterial clinical isolates of streptococci, enterococci, and
staphylococci are summarized in Table
1.
Linezolid demonstrated in vitro activity against all isolates tested.
The activity of linezolid was comparable to that of vancomycin for all
vancomycin-susceptible bacterial groups. Among enterococci, linezolid
had an activity similar to those of vancomycin and the 
-lactam
agents (ampicillin, imipenem, and piperacillin) against E. faecalis. For Enterococcus faecium, linezolid was the
most active agent tested, although two-thirds of these isolates were
vancomycin resistant. Against Enterococcus avium and
Enterococcus durans, the activities of linezolid and
vancomycin were comparable (data not shown). In addition,
vancomycin-resistant enterococci (VRE) of either the VanA or VanB
phenotype were inhibited by linezolid at a MIC of 2 to 4 µg/ml. Both
vancomycin and linezolid demonstrated activity against staphylococci.
Against oxacillin-susceptible S. aureus, there were many
agents with in vitro activity, including the new fluoroquinolones
levofloxacin and trovafloxacin as well as clindamycin and the
antistaphylococcal -lactams. For oxacillin-resistant S. aureus, the potency of linezolid was comparable to that of vancomycin. Against the coagulase-negative staphylococci (both oxacillin susceptible and oxacillin resistant), the activity of linezolid was within one twofold dilution of vancomycin for all of the
species tested.
Against streptococci, there were many active agents and the activity of
linezolid was comparable or superior to that of vancomycin. There
was no difference in activity between linezolid and vancomycin against pneumococci, including penicillin-resistant strains. We did not test linezolid against gram-negative bacteria or
anaerobes, although the oxazolidones are known to possess
activity against anaerobes (15).
Emerging antimicrobial resistance is a significant problem among
both nosocomially and community-acquired gram-positive bacteria. While VRE have become endemic at many medical centers (1,
5), the recent identification of glycopeptide-insensitive
S. aureus represents a formidable therapeutic challenge. As
resistance among gram-positive bacteria continues to spread,
therapeutic options have become increasingly limited. Thus, the
oxazolidinones represent a novel class of investigational antibacterial
agents for the treatment of these multidrug-resistant infections.
The primary antimicrobial activity of linezolid is against
gram-positive bacteria. This investigation describes the largest in
vitro experience to date with linezolid and confirms that this antibacterial has excellent activity against all of the organisms tested, including staphylococci, streptococci, and enterococci. These
tests were performed on fresh clinical isolates concurrently with other
testing performed in the clinical microbiology laboratory. Against
oxacillin-resistant strains of both S. aureus and
Staphylococcus epidermidis, the activity of linezolid was
comparable to that of vancomycin. This novel antimicrobial agent also
demonstrated excellent activity against enterococci, including both
vancomycin-susceptible and vancomycin-resistant isolates of E. faecalis and E. faecium. For E. faecalis,
the activity of linezolid was similar to that of other agents tested;
however, linezolid was the most active of all agents tested against
E. faecium. There was no difference in activity for VRE.
Significant in vitro activity was also observed for streptococci,
including penicillin-resistant pneumococci. Our results confirm those
previously reported by others (2, 11, 15); however, they
represent a significant increase in the number of isolates tested.
Based on data from pharmacokinetic studies (6), the
preliminary susceptibility breakpoint for linezolid is 8 µg/ml. If
this remains as the breakpoint, all of the gram-positive organisms that
we tested were fully susceptible.
Previous reports have indicated that linezolid is bacteriostatic
against VRE. This is consistent with the results reported from phase I
trials with linezolid (12). While we did not perform time-kill kinetics analyses with staphylococci and streptococci, other
investigators have demonstrated bacteriostatic activity against
S. aureus and S. epidermidis (10, 11)
and bactericidal activity against pneumococci (15). Despite
the reported lack of in vitro bactericidal activity, we successfully
treated a neutropenic patient who developed persistent VRE bacteremia
with the combination of linezolid and gentamicin (9). This
would suggest that the current in vitro testing method may not be able
to fully assess the clinical activity of linezolid.
In summary, linezolid was the most active antimicrobial agent tested
against oxacillin-resistant S. aureus, oxacillin-resistant S. epidermidis, and VRE (both E. faecalis and
E. faecium). Based on our in vitro results, linezolid
appears to be a promising new antimicrobial agent for the treatment of
gram-positive infections.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Northwestern
University Medical School, Division of Infectious Diseases, 251 E. Huron St., Feinberg 16-704, Chicago, IL 60611. Phone: (312) 926-2729. Fax: (312) 926-7845. E-mail: gnoskin{at}nwu.edu.
| |
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Antimicrobial Agents and Chemotherapy, August 1999, p. 2059-2062, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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