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Antimicrobial Agents and Chemotherapy, March 1998, p. 721-724, Vol. 42, No. 3
The Anti-Infective Research Laboratory,
Received 7 July 1997/Returned for modification 21 November
1997/Accepted 22 December 1997
The activities of the oxazolidinone antibacterial agents eperezolid
(PNU-100592) and linezolid (PNU-100766) were compared with that of
vancomycin against clinical isolates of methicillin-susceptible and
-resistant Staphylococcus aureus (n = 200), coagulase-negative staphylococci (n = 100), and
vancomycin-susceptible and -resistant Enterococcus faecalis
and Enterococcus faecium (n = 50).
Eperezolid and linezolid demonstrated good in vitro inhibitory
activity, regardless of methicillin susceptibility for staphylococci
(MIC at which 90% of the isolates are inhibited [MIC90]
range, 1 to 4 µg/ml) or vancomycin susceptibility for enterococci
(MIC90 range, 1 to 4 µg/ml). In time-kill studies,
eperezolid and linezolid were bacteriostatic in action. A
postantibiotic effect of 0.8 ± 0.5 h was demonstrated for
both eperezolid and linezolid against S. aureus, S. epidermidis, E. faecalis, and E. faecium.
Eperezolid (PNU-100592 [formally
U-100592]) and linezolid (PNU-100766 [formally U-100766]) are
members of the new synthetic class of antibacterial compounds known as
the oxazolidinones. Initial screening of these compounds indicated that
they are active against a variety of gram-positive organisms, including
methicillin-resistant strains of Staphylococcus aureus and
Staphylococcus epidermidis; Enterococcus spp.,
including vancomycin-resistant strains; and Streptococcus
spp., including viridans streptococci and penicillin-resistant pneumococci. These compounds also demonstrate activity against Corynebacterium spp., Bacteroides fragilis,
Moraxella catarrhalis, Listeria monocytogenes,
and strains of Mycobacterium tuberculosis (1, 2-4, 9,
10, 12, 14, 16). Although the exact mechanism of action is
unknown, structure-activity investigations have determined that these
compounds are bacteriostatic and exert their mechanism of action by
protein synthesis inhibition (4-6). In addition,
spontaneous mutations resulting in resistance among staphylococci occur
rarely, and there appears to be no cross-resistance between these
compounds and other antibacterial agents (10, 17). Newer
agents with unique activity against multi-drug-resistant gram-positive organisms are clearly needed. We investigated the in vitro activities of the oxazolidinones eperezolid and linezolid versus that of vancomycin against various clinical strains of methicillin-susceptible and -resistant staphylococci and
vancomycin-susceptible and -resistant enterococci.
Susceptibility-grade powders for eperezolid and linezolid were supplied
by Pharmacia and Upjohn, Inc., Kalamazoo, Mich. Vancomycin susceptibility powder was purchased commercially (Sigma Chemical Co.,
St. Louis, Mo.).
Clinical isolates of Staphylococcus aureus, S. epidermidis, various other coagulase-negative staphylococci,
E. faecalis, and E. faecium were collected over a
6-month period from hospitalized patients at Detroit Receiving Hospital
and University Health Center, Detroit, Mich. Methicillin susceptibility
was determined by the oxacillin disk method (13).
MICs were determined by a microdilution method with Mueller-Hinton
broth (Difco Laboratories, Detroit, Mich.) supplemented (SMHB) with
calcium (25 mg/liter) and magnesium (12.5 mg/liter). Susceptibility
testing for each drug was performed according to the guidelines of the
National Committee for Clinical Laboratory Standards (13).
The bactericidal activities of eperezolid and linezolid were compared
to that of vancomycin by use of time-kill analyses. Four representative
clinical isolates (methicillin-resistant S. aureus R323,
methicillin-susceptible S. epidermidis R264,
vancomycin-resistant E. faecalis R581, and
vancomycin-resistant E. faecium R20) were evaluated. The
test strains were grown overnight at 35°C in SMHB and diluted to
yield a starting inoculum of 106 CFU/ml. Sufficient stock
antibiotic solution was added to achieve a desired concentration of
four times the respective MICs. Growth controls were prepared in a
similar fashion with substitution of the appropriate medium in place of
the stock antibiotic solution. All tubes were incubated at 35°C with
constant rotation for 24 h. Samples (0.1 ml) were removed at 0, 4, 8, and 24 h; diluted at least 250-fold with 0.9% sodium chloride
to reduce antibiotic carryover; and plated on tryptic soy agar (Difco).
The limit of detection for this method is 30 CFU/plate, corresponding
to 300 CFU/ml (11). At time points at which bacterial counts
were expected to be below limits of detection, 0.1-ml samples were
placed in 10 ml of cold 0.9% sodium chloride and filtered by a
0.45-µm-pore-diameter filter (Millipore, Bedford, Mass.). Filters
were placed aseptically on tryptic soy agar and incubated for 24 h. The limit of detection for this method is 10 CFU/plate,
corresponding to 100 CFU/ml (11). All time-kill-curve
experiments were performed in duplicate.
The presence of a postantibiotic effect (PAE) was determined for
eperezolid, linezolid, and vancomycin for representatives of each group
of organisms by the method described by Craig and Gudmundsson
(3). An overnight growth of S. aureus, S. epidermidis, E. faecalis, or E. faecium was
diluted into fresh SMHB to 106 CFU/ml and then incubated on
a rotor at 37°C for 3 to 4 h until the logarithmic growth phase
was achieved. At the end of this period, the inoculum size was
determined, and each tube containing the test organisms was then
exposed to eperezolid, linezolid, or vancomycin at the MIC and at four
times the MIC for 1 h at 37°C on a rotor. One test tube of each
organism was also used as a growth control and was subjected to the
same procedures as described above but was not exposed to the
antibiotic. Following incubation with the antibiotic, the cultures,
including the growth controls, were diluted 1:1,000 into 10 ml of fresh
prewarmed SMHB and reincubated at 37°C. Samples were removed in
duplicate every 1.0 h and plated onto tryptic soy agar to
determine the PAE. Each PAE experiment was performed in duplicate. The
duration of the PAE was calculated by the equation PAE = T The activities of eperezolid and linezolid compared to that of
vancomycin are shown in Table 1. For
S. aureus, vancomycin was one- to twofold more active than
eperezolid and linezolid. The oxazolidinones were equipotent to
vancomycin against all coagulase-negative staphylococci tested.
Compound eperezolid was at least one- to twofold more active than
linezolid against coagulase-negative staphylococci. In time-kill
studies, eperezolid and linezolid displayed bacteriostatic action
against all isolates tested. As expected, vancomycin displayed
bactericidal activity against S. aureus and S. epidermidis but not E. faecalis or E. faecium (Fig. 1).
The oxazolidinones represent a unique class of synthetic antimicrobials
that have activity against a wide variety of problematic pathogens,
including methicillin-resistant staphylococci and vancomycin-resistant enterococci (7, 9, 10, 12, 14, 16, 17). Other unique
features of these compounds include their novel mechanism of action,
for which they do not display cross-resistant activity with other
classes of antimicrobials, and the fact that the spontaneous rate of
mutation to resistance for these compounds is very low. This may
translate to a low incidence of resistance developing during therapy
(4-6, 10, 17). Our susceptibility data are similar to those
reported by other investigators in that the MICs of eperezolid, in
general, were 1 to 2 dilutions lower than those of linezolid against
coagulase-negative staphylococci (10). However, this
difference in susceptibility was minimal and was not noted for S. aureus or for the enterococci tested. Previous investigators have
demonstrated that eperezolid and linezolid display bacteriostatic
activity and do not display concentration-dependent killing
(9). Our time-kill-curve experiments also demonstrated bacteriostatic activity, as opposed to the bactericidal activity displayed by vancomycin for vancomycin-susceptible organisms. We
demonstrated that both oxazolidinones possess a PAE and that the PAEs
of eperezolid and linezolid were similar (Table
2). The PAE was greater at four times the
MIC (range, 0.2 to 1.4 h) than at the MIC (0.1 to 0.8 h) for
both compounds against all organisms tested. This was also true for
vancomycin against staphylococci (four times the MIC, 1.1 to 2.9; MIC,
0 to 1.9 h). The PAE for eperezolid and linezolid was considerably
lower against the E. faecalis isolate than against the
E. faecium and staphylococci isolates. This was an
interesting finding, since the MICs for E. faecalis tended
to be slightly higher than those for the E. faecium isolates
tested. This trend was also apparent upon visual inspection of the
killing curves. A similar phenomenon has been reported with the
investigational antibiotic RP 59500 (15). Currently, the
mechanism behind the apparent differences in activity of RP 59500 against E. faecium versus E. faecalis is not
known. The combination of an antibiotic's pharmacokinetic profile and its PAE is important in determining the most appropriate dosing interval. Our data indicate that the PAEs for these two oxazolidinones are relatively short. However, based upon preliminary pharmacokinetic studies which have reported a serum half-life of 6 h for the
oxazolidinones, the PAE, which has a tendency to be longer in vivo, may
allow these agents to be given at intervals of 8 to 12 h or longer
(8). Human studies to determine the appropriate dosage range
based upon pharmacokinetic-pharmacodynamic relationships such as area under the concentration-time curve-MIC and time above the MIC are
needed to assess the true potential of this novel class of antimicrobials.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Comparative In Vitro Activities and Postantibiotic
Effects of the Oxazolidinone Compounds Eperezolid (PNU-100592) and
Linezolid (PNU-100766) versus Vancomycin against Staphylococcus
aureus, Coagulase-Negative Staphylococci, Enterococcus
faecalis, and Enterococcus faecium
ABSTRACT
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C, where T is the time required for the
CFU count in the culture exposed to antibiotic to increase 1 log10 unit above the count observed immediately after
antibiotic removal and C is the time required for the CFU count in the control to increase 1 log10 unit above the
count observed immediately after the same procedure used on the test culture for the antibiotic removal.
TABLE 1.
Eperezolid (PNU-100592), linezolid (PNU-100766), and
vancomycin activities against selected pathogens
View larger version (21K):
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FIG. 1.
Time-kill experiments performed in duplicate. Results
are means ± standard deviations. (A and B) Methicillin-resistant
S. aureus (R323) and methicillin-susceptible S. epidermidis (R264), respectively. (C and D) Vancomycin
(Vanco)-resistant E. faecalis (R581) and E. faecium (R20), respectively.
TABLE 2.
PAEs for eperezolid (PNU-100592), linezolid (PNU-100766),
and vancomycin activities against selected pathogens
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ACKNOWLEDGMENTS |
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This study was supported in part by a grant from Pharmacia and Upjohn, Kalamazoo, Mich.
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FOOTNOTES |
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* Corresponding author. Mailing address: The Anti-Infective Research Laboratory, Department of Pharmacy Services (1B), Detroit Receiving Hospital/University Health Center, 4201 St. Antoine Blvd., Detroit, MI 48201. Phone: (313) 745-4554. Fax: (313) 993-2522. E-mail: mrybak{at}dmc.org.
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Antimicrobial Agents and Chemotherapy, March 1998, p. 721-724, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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