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Antimicrobial Agents and Chemotherapy, December 2000, p. 3408-3413, Vol. 44, No. 12
Infectious Diseases Section, Veterans
Administration Medical Center, Boise, Idaho1;
University of Washington School of Medicine,
Seattle, Washington2; Saint
Michael's Medical Center, Newark, New
Jersey3; and Pharmacia & Upjohn, Kalamazoo, Michigan4
Received 14 February 2000/Returned for modification 12 July
2000/Accepted 6 September 2000
This randomized, double-blind, multicenter trial compared the
efficacy and safety of linezolid, an oxazolidinone, with those of
oxacillin-dicloxacillin in patients with complicated skin and soft
tissue infections. A total of 826 hospitalized adult patients were
randomized to receive linezolid (600 mg intravenously [i.v.]) every
12 h or oxacillin (2 g i.v.) every 6 h; following sufficient clinical improvement, patients were switched to the respective oral
agents (linezolid [600 mg orally] every 12 h or dicloxacillin [500 mg orally] every 6 hours). Primary efficacy variables were clinical cure rates in both the intent-to-treat (ITT) population and
clinically evaluable (CE) patients and microbiological success rate in
microbiologically evaluable (ME) patients. Safety and tolerability were
evaluated in the ITT population. Demographics and baseline
characteristics were similar across treatment groups in the 819 ITT
patients. In the ITT population, the clinical cure rates were 69.8 and
64.9% in the linezolid and oxacillin-dicloxacillin groups,
respectively (P = 0.141; 95% confidence interval
Skin and soft tissue infections are
frequently encountered in clinical practice, and gram-positive bacteria
are a leading cause (18). These infections are classified as
complicated when surgical intervention is required and/or the
infectious process is suspected or confirmed to involve deeper tissue
(e.g., subcutaneous tissues, fascia, and/or skeletal muscle)
(18). Complications of improperly treated skin and soft
tissue infections may include endocarditis, osteomyelitis, brain
abscess or meningitis, lung abscess, or pneumonia. Skin and soft tissue
infections include superficial infections such as erysipelas,
cellulitis, simple abscesses, furuncles, wound infections, and deeper
infections such as necrotizing fasciitis, myositis, and gas gangrene.
Streptococcus pyogenes, Staphylococcus aureus,
Streptococcus agalactiae, and group C and G streptococci are
the most commonly involved pathogens (27, 28). Intravenous
antibiotics are often used in patients with complicated infections, and
most patients are hospitalized for management of their infection. In
addition, some patients acquire such infections while hospitalized for
surgical procedures or trauma (18).
The usual treatment for most gram-positive skin and soft tissue
infections is a penicillinase-resistant penicillin or a cephalosporin (15). However, the worldwide emergence of pathogens with
decreased susceptibility to available therapies has created a need for
new antimicrobial agents (3, 4, 11, 12, 20, 21, 29, 30).
Linezolid (PNU-100766) is the first of the oxazolidinones, a new class
of antimicrobial agents that inhibit bacterial protein synthesis by
blocking formation of the initiation complex (26, 31).
Linezolid has demonstrated in vitro and in vivo antibacterial activity
against staphylococci, streptococci, and enterococci, including
resistant strains such as methicillin-resistant S. aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, and
vancomycin-resistant enterococci (6, 8, 9, 10, 14, 17, 19, 23,
31).
In early, phase II clinical trials, linezolid was safe and
effective in the treatment of gram-positive skin and soft tissue infections and pneumonia (S.-K. Cammarata, B. Hafkin, W. M. Todd, and D. H. Batts, Am. J. Respir. Crit. Care Med.
159(Suppl.):844, part 2, abstr., 1999; S.-K.
Cammarata, B. Hafkin, D. M. Demke, S. M. Eckert, and D. H. Batts, Clin. Microbiol. Infect. 5(Suppl. 3):133,
abstr., 1999). This randomized trial compared the efficacy and safety
of linezolid with oxacillin-dicloxacillin in the treatment of adults
with complicated skin and soft tissue infections.
Study design.
This prospective, randomized, double-blind,
double-dummy, multicenter, multinational study was conducted from
November 1998 to June 1999 at 133 sites. Study objectives included
assessment of the comparative clinical and microbiological efficacy,
safety, and tolerability of linezolid versus oxacillin-dicloxacillin in the treatment of adults with complicated skin and soft tissue infections. The study consisted of (i) a baseline or screening visit,
(ii) an end-of-treatment visit, and (iii) a follow-up visit 15 to 21 days after the final dose of study medication. A test-of-cure (TOC)
evaluation was conducted at the follow-up visit. Patients underwent
daily clinical assessments while hospitalized (one intravenous [i.v.]
dose minimum) and every 6 days after discharge. The protocol, informed
consent, and all other forms of patient information related to the
study were reviewed and approved by each investigator's institutional
review board and/or independent ethics committee. All patients provided
written informed consent prior to enrollment.
Patient selection.
Hospitalized patients who were at least
18 years of age with a suspected gram-positive complicated skin and
soft tissue infection were eligible for participation. Infections
included those that involved deep soft tissue (e.g., major abscess,
infected ulcer, major burn, or deep and extensive cellulitis) with at
least two of the following symptoms: drainage and/or discharge,
erythema, fluctuance, heat and/or localized warmth, pain and/or
tenderness to palpation, or swelling and/or induration. At least one of
the following conditions must have been present: fever (defined as body
temperature of >38°C [orally]), elevated total peripheral white
blood cell (WBC) count (>10,000/mm3), or >15% immature
neutrophils (bands) irrespective of total peripheral WBC count. In
addition, patients must have been able to take i.v. and oral (p.o.)
medications, have an accessible infection site for Gram staining and
culture, and have been willing to return for end-of-treatment and
follow-up visits.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Randomized Comparison of Linezolid (PNU-100766)
versus Oxacillin-Dicloxacillin for Treatment of Complicated Skin
and Soft Tissue Infections
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
1.58 to 11.25). In 298 CE linezolid-treated patients, the clinical cure rate was 88.6%, compared with a cure rate of 85.8% in 302 CE
patients who received oxacillin-dicloxacillin. In 143 ME
linezolid-treated patients, the microbiological success rate was
88.1%, compared with a success rate of 86.1% in 151 ME
patients who received oxacillin-dicloxacillin. Both agents were well
tolerated; most adverse events were of mild-to-moderate intensity. No
serious drug-related adverse events were reported in the linezolid
group. These data support the use of linezolid for the treatment of
adults with complicated skin and soft tissue infections.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Treatment. Patients were randomized in a 1:1 ratio to receive either linezolid (supplied by Pharmacia & Upjohn, Kalamazoo, Mich.) (600 mg i.v.) every 12 h or oxacillin (Marsam Pharmaceuticals, Inc., Cherry Hill, N.J.) (2 g i.v.) every 6 h for 10 to 21 days. Linezolid and placebo were alternated every 6 h to maintain the study blind. Patients in both treatment groups who required empiric gram-negative coverage were allowed to receive i.v. aztreonam (1 to 2 g) three or four times daily as appropriate. When a patient demonstrated clinical improvement, the patient could be switched to oral study medication at the investigator's discretion. Patients initially randomized to i.v. linezolid were switched to linezolid tablets (600 mg p.o.) every 12 h (study medication and placebo were alternated every 6 h to maintain the study blind), while those initially randomized to oxacillin were switched to dicloxacillin (Apothecon, Princeton, N.J.) (500 mg capsules p.o.) every 6 h. In each treatment group, placebo dummies were identical to the active antibiotic for the respective group.
Clinical assessments. Clinical evaluations including a medical history and physical examination, with vital signs, clinical observations (i.e., chills, drainage and/or discharge, swelling and/or induration, tenderness and/or pain to palpation, heat and/or localized warmth, and fluctuance), clinical laboratory assays (i.e., hematology, clinical chemistries, urinalysis), and electrocardiogram, were performed at baseline, during inpatient and/or outpatient treatment, at the end of treatment, and at follow-up. These assessments also were performed as patients were switched from i.v. to p.o. therapy. The follow-up evaluation scheduled for 15 to 21 days following treatment was considered the TOC evaluation. TOC assessments were based upon improvement and/or resolution of clinical signs and symptoms of the skin and soft tissue infection.
Microbiological assessments.
Prior to the first infusion of
either study drug, deep culture specimens of the area contiguous to the
primary infected area were obtained for Gram's stain, culture, and
susceptibility testing. All isolated pathogens were submitted to a
central laboratory for identification. Complete identification of each
bacterial isolate was performed, and each organism was classified as a
pathogen or a nonpathogen. Susceptibility testing was performed in
accordance with National Committee for Clinical Laboratory Standards
guidelines. Sponsor-defined breakpoints were used for linezolid
susceptibility testing (
4 µg/ml, sensitive; >4 µg/ml,
resistant). Patients whose cultures grew gram-positive or gram-negative
pathogens that were not susceptible to study medications were
discontinued from the study unless they demonstrated clinical
improvement and did not require concomitant antimicrobial therapy
(other than aztreonam).
Efficacy variables. Primary efficacy variables were clinical outcome and microbiological outcome based on resolution or improvement of clinical signs and symptoms of infection at the end of treatment compared with those at baseline. Objective and subjective clinical observations recorded throughout the course of the study included anatomical site of infection, extent of infection, degree of involvement, infected-site description, and body temperature. Criteria for assessing clinical outcome were as follows: cure was defined as resolution of baseline clinical signs and symptoms of infection or improvement such that no further antimicrobial treatment was necessary after at least 5 days and 10 doses of study medication; failure was defined as a need for nonstudy antibiotic due to lack of efficacy after at least 2 days and 8 doses of study medication or absence of clinical assessments at the end of treatment and follow-up; indeterminate response was defined as clinically improved or cured at the end of treatment and no assessment at TOC; and missing was defined as those patients receiving less than 2 days of therapy or fewer than 8 doses. Criteria for assessing microbiological outcome were as follows: success was defined as documented eradication (absence of original pathogen[s] from culture at TOC) or presumed eradication (clinical cure at TOC with no microbiological data); failure was defined as documented persistence (presence of original pathogen [one or more] from culture at TOC) or presumed persistence, superinfection, or reinfection (clinical failures at TOC with no microbiological data or those who received nonstudy antibiotic therapy); indeterminate was defined as those patients classified as indeterminate in clinical assessment; and missing was defined as the absence of clinical determination and no microbiological data at TOC.
Other variables evaluated included body temperature, WBC counts, clinical signs and symptoms of infection (chills, erythema, drainage and/or discharge, swelling and/or induration, tenderness and/or pain to palpation, heat and/or localized warmth, and fluctuance), and selected organism or pathogen eradication rates.Safety variables. The safety of linezolid and oxacillin-dicloxacillin therapy was monitored throughout the study by physical examination, vital signs, laboratory evaluations, and assessment of adverse events. All patients who received at least one dose of study medication were included in the safety analysis. Physical examination was conducted at baseline and follow-up visits, and vital signs were assessed at all visits. The following laboratory evaluations were conducted: hematology, chemistry, urinalysis, pregnancy test (for females of childbearing potential), site culture and Gram staining, blood culture, and bacterial isolate susceptibility testing. Adverse events were reported from the time of first dose of study drug to the final study visit and were monitored until they resolved or until the patient's participation in the study ended.
Population for analysis. Three patient populations were evaluated in this study: the intent-to-treat (ITT) population, the clinically evaluable patients, and the microbiologically evaluable patients. The ITT population included all patients who received at least one dose of double-blind study drug. Clinically evaluable patients included patients from the ITT population who (i) had not received concomitant antibiotic therapy (other than aztreonam) during the study, (ii) had received at least 7 days and 24 doses of study medication (unless the patient discontinued the study for any reason other than lack of efficacy), (iii) had taken at least 80% of prescribed study medications throughout the study and did not miss two or more consecutive doses through day 7 of treatment, and (iv) had a postbaseline assessment during the follow-up period (15 to 21 days posttreatment). Microbiologically evaluable patients included clinically evaluable patients who had a confirmed pathogen from the infection site or blood culture at baseline that was not resistant to study medications.
Statistical methods.
Analyses were performed to compare the
efficacy and safety of linezolid with oxacillin-dicloxacillin. All data
listings, summaries, and statistical analyses were generated using the
Statistical Analysis System (version 6; SAS Institute Inc., Cary,
N.C.). All statistical tests were two-sided, and P values of
0.05 were considered statistically significant. Analyses of efficacy
variables were performed for the ITT, clinically evaluable, and
microbiologically evaluable patient populations. Assuming each
treatment group would yield a 90% success rate, 142 evaluable patients
per treatment group were required to determine, with 80% power,
equivalence between the groups to within 10%. Assuming an evaluability
rate of 45%, this translated to a requirement of 316 enrolled patients per treatment group. All 95% confidence intervals (95% CI) were based
on the normal approximation to the binomial distribution and were
considered consistent with equivalence if the following conditions were
met: there were at least 142 patients per treatment group, the CI
included 0, and the lower limit of the CI exceeded 10%. Due to the
expected small numbers of evaluable patients in each center, terms for
investigator effect and treatment group-by-investigator interaction
were not included in the models for statistical analysis.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Patient demographics.
Of the 826 patients enrolled in 133 centers, 403 and 423 were randomized to the linezolid and
oxacillin-dicloxacillin treatment groups, respectively. The ITT
population consisted of 819 patients who received at least one dose of
study drug (400 received linezolid and 419 received
oxacillin-dicloxacillin). The study evaluation groups and reasons for
nonevaluability are shown in Table 1. Six
hundred patients (298 receiving linezolid and 302 receiving oxacillin-dicloxacillin) made up the clinically evaluable subgroup. The
microbiologically evaluable patients included 143 linezolid and 151 oxacillin-dicloxacillin patients. The most common reason for clinical
nonevaluability was lack of a baseline assessment. Lack of a baseline
pathogen was the most frequent reason for microbiological nonevaluability. Demographics and baseline characteristics of the ITT
population (Table 2) and clinically
evaluable patients were similar in both treatment groups. The most
common complicated skin and soft tissue diagnoses at baseline were
cellulitis, skin abscess, and erysipelas. The majority of patients in
the study had relatively serious infections, with 319 of 397 (80.4%)
of the linezolid-treated patients and 322 of 417 (77.2%) of the
oxacillin-dicloxacillin-treated patients having deep involvement of the
skin at the primary site of infection. Clinically relevant pathogens
isolated at baseline included: S. aureus in 140 linezolid
patients and 143 oxacillin-dicloxacillin patients; S. pyogenes in 41 linezolid patients and 46 oxacillin-dicloxacillin patients; and S. agalactiae in 10 linezolid patients and 12 oxacillin-dicloxacillin patients.
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Treatment.
The total durations of treatment (i.v. and p.o.)
were similar in both treatment groups; the mean duration of treatment
was 13.4 ± 5.4 days in the linezolid group and 13.4 ± 6.0 days in the oxacillin-dicloxacillin group. (Unless otherwise noted,
values are means ± standard deviations.) Among the clinically
evaluable patients, the total durations of treatment (i.v. and p.o.)
also were similar, with a mean duration of 14.3 ± 4.6 days in the
linezolid group and 14.1 ± 4.6 days in the
oxacillin-dicloxacillin group. Most ITT patients in both treatment
groups received 5 days of i.v. therapy, with a mean duration of
4.7 ± 3.3 days for linezolid-treated patients and 4.7 ± 3.1 days for oxacillin-dicloxacillin-treated patients. Similar results were
observed in clinically evaluable patients.
Discontinuations. Overall, the percentages of patients who completed treatment and follow-up were similar between treatment groups (336 of 403 [84%] in the linezolid group and 327 of 423 [78%] in the oxacillin-dicloxacillin group). In the ITT population, more patients in the oxacillin-dicloxacillin group (70 of 419 [16.7%]) than in the linezolid group (43 of 400 [10.8%]) discontinued participation during treatment. The most frequent reason for discontinuation, regardless of treatment group, was lack of efficacy (9 of 400 [2.3%] patients in the linezolid group and 15 of 419 [3.6%] patients in the oxacillin-dicloxacillin group). Similarly, the percentage of patient discontinuations during follow-up was slightly higher in the oxacillin-dicloxacillin group (73 of 419 [17.4%] patients) than in the linezolid group (54 of 400 [13.5%] patients), with loss to follow-up representing the most common reason for discontinuation (27 of 400 [6.8%] patients in the linezolid group and 32 of 419 [7.6%] patients in the oxacillin-dicloxacillin group).
Efficacy.
In the ITT population, the clinical cure rates at
the TOC visit were comparable in the two treatment groups, with 279 of
400 (69.8%) linezolid-treated patients and 272 of 419 (64.9%)
oxacillin-dicloxocillin-treated patients achieving a clinical cure
(P = 0.141; 95% CI, 1.58 to 11.25 [point estimate,
4.9]). In clinically evaluable patients, clinical cure rates at the
TOC visit also were comparable in linezolid and oxacillin-dicloxacillin
groups (264 of 298 [88.6%] patients versus 259 of 302 [85.8%]
patients, respectively) (P = 0.300; 95% CI, 2.5 to
8.2 [point estimate, 2.8]) (Table 3).
Subgroup analysis of clinical outcome by gender, age, and race
demonstrated similar results between treatment groups, except for males
in the ITT population, for whom cure rates were 85.3% (174 of 204 patients) and 76.7% (171 of 223 patients) in the linezolid and oxacillin-dicloxacillin groups, respectively (P = 0.024; 95% CI, 1.2 to 16.5 [point estimate, 8.6]). In addition, no
statistically significant differences in clinical cure rate were
observed between treatment groups when analyzed by diagnosis.
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5.6 to
9.7 [point estimate, 2.0]). Subgroup analysis of microbiological outcome by gender, age, and race demonstrated comparable results between treatment groups. Eradication rates of selected baseline pathogens (S. aureus, S. pyogenes, and S. agalactiae) at the TOC visit are summarized for the
microbiologically evaluable patients in Table
4. Eradication rates generally were
similar between treatment groups for these pathogens. For S. aureus, the eradication rate in the linezolid group was 91.4% (85 of 93 patients) compared with 84.5% (87 of 103 patients) in the
oxacillin-dicloxacillin group (P = 0.139; 95% CI,
2.1 to 16.0 [point estimate, 6.9]).
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Safety.
Safety assessments were performed on the ITT
population. The frequencies of adverse events reported, regardless of
causality, were comparable between treatment groups. A total of 47.3%
(189 of 400) of the patients in the linezolid group and 41.3% (173 of
419) of the patients in the oxacillin-dicloxacillin treatment group
experienced at least one adverse event. Frequencies of reported adverse
events reported in 
2% of patients in either treatment group are
presented in Table 5. The most frequently
reported adverse events in the linezolid group were nausea (23 of 400 patients [5.8%]), headache (22 of 400 patients [5.5%]), and
vomiting (13 of 400 patients [3.3%]), while those most frequently
reported in the oxacillin-dicloxacillin group were nausea (24 of 419 patients [5.7%]), headache (16 of 419 patients [3.8%]), and
constipation (13 of 419 patients [3.1%]).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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This well-designed randomized trial compared the efficacy and safety of linezolid, a new oxazolidinone, with those of oxacillin-dicloxacillin, a therapy of choice in many parts of the world, for patients with complicated skin and soft tissue infections. Both treatment groups were similar with respect to their demographics, baseline infections, and evaluability of the patients. Results of this study indicated that linezolid is as effective as oxacillin-dicloxacillin in the treatment of these infections. Clinical cure rates and microbiological success rates for linezolid-treated patients were high (88.6 and 88.1%, respectively) and compared favorably with those observed in oxacillin-dicloxacillin-treated patients (85.8 and 86.1%, respectively). Linezolid also was as effective as oxacillin-dicloxacillin in eradicating S. aureus, S. pyogenes, and S. agalactiae. Most patients in both treatment groups were able to switch from i.v. to p.o. therapy (based on clinical improvement) within 5 days of therapy initiation, and 80% of patients completed both the treatment and follow-up phases of the study.
Gram-positive bacteria are important pathogens among patients with skin and soft tissue infections. Historically, oxacillin has been a drug of choice for many gram-positive skin and soft tissue infections (27). However, the emergence of multidrug-resistant gram-positive species, particularly MRSA, is an increasing concern; in recent surveys in the United States and Europe, methicillin resistance has been observed in 22 to 25% of S. aureus isolates from patients with skin and soft tissue infections (5, 13). Although patients with MRSA were excluded from this study, the increasing prevalence of resistant gram-positive pathogens suggests that many patients will require treatment with an antimicrobial that has activity against these resistant strains.
Linezolid may substantially impact the approach to treatment of skin and soft tissue infections caused by many gram-positive species because it has a unique mechanism of action, possesses significant activity against gram-positive pathogens (including MRSA), and has excellent clinical efficacy as demonstrated in this and other studies (6, 22). Thus, it is a promising empiric treatment for either community-acquired or nosocomial skin and soft tissue infections. Linezolid's efficacy in treating skin and soft tissue infections may be due, in part, to the high concentrations achieved in the skin (K. M. Donaldson, P. Blood., T. J. Parker, P. T. Daly-Yates, and J. D. Harry, unpublished data) and its ability to inhibit bacterial virulence factor and toxin production in S. aureus and S. pyogenes at concentrations well below the MICs (C. G. Gemmell and C. W. Ford, Abstr. 39th Intersci Conf. Antimicrob. Agents Chemother., abstr. 1537, 1994). It has been suggested that antimicrobials that have both antibacterial properties as well as the ability to inhibit the synthesis of bacterial toxins may provide greater efficacy and improved outcomes in these gram-positive bacterial toxin-mediated diseases (1, 24, 25).
Unlike other antibiotics, the oral formulation of linezolid is 100% bioequivalent to the intravenous formulation, ensuring that patients receive adequate serum and tissue concentrations of drug upon switch to oral therapy. This will allow physicians to switch to the oral formulation earlier in hospitalized patients and may result in earlier discharge (16). Further studies evaluating the use of oral linezolid alone in the treatment of complicated skin and soft tissue infections are needed.
In the present study, linezolid proved to be safe and well tolerated regardless of the site of infection. The majority of adverse events reported were mild or moderate in intensity. No serious drug-related adverse events were reported in the linezolid group. In addition, there was no evidence of a drug interaction between linezolid and MAO inhibitors or any other concomitant medications. Hypertension was reported in 3.0% of patients receiving linezolid; however, a direct causal relationship could not be determined. In addition, although linezolid may cause mild MAO inhibition (2, 7), the hypertension observed in this trial did not appear to be related to this property of the drug.
Complicated skin and soft tissue infections are a significant cause of morbidity and mortality in hospitalized patients. The emergence of resistant pathogens has created the need for newer, more effective antimicrobial therapies, which can be given parenterally or p.o. In conclusion, linezolid is well tolerated and as effective as oxacillin-dicloxacillin for complicated skin and soft tissue infections, with the added advantages of convenient twice-daily dosing administered either i.v. or p.o.
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ACKNOWLEDGMENTS |
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This study was supported by Pharmacia Corporation.
We thank the participating investigators in the Linezolid Skin and Soft Tissue Infections Study Group and the investigator site staff for their efforts in providing care to the patients.
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FOOTNOTES |
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* Corresponding author. Mailing address: Infectious Diseases Section, Bldg. 45, VA Medical Center, 500 W. Fort St., Boise, ID 83702. Phone: (208) 422-1599. Fax: (208) 422-1364. E-mail: dlsteven{at}primenet.com.
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REFERENCES |
|---|
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Introduction
Materials and Methods
Results
Discussion
References
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| 1. |
Bisno, A. L., and D. L. Stevens.
1996.
Current concepts: streptococcal infections of skin and soft tissues.
N. Engl. J. Med.
334:240-245 |
| 2. | Brickner, S. J. 1996. Oxazolidinone antibacterial agents. Curr. Pharm. Des. 2:175-194. |
| 3. |
Centers for Disease Control and Prevention.
1997.
Staphylococcus aureus with reduced susceptibility to vancomycin United States, 1997.
Morb. Mortal. Wkly. Rep.
46:765-766[Medline].
|
| 4. |
Centers for Disease Control and Prevention.
1997.
Update: Staphylococcus aureus with reduced susceptibility to vancomycinUnited States, 1997.
Morb. Mortal. Wkly. Rep.
46:813-815[Medline].
|
| 5. |
Colsky, A. S.,
R. S. Kirsner, and F. A. Kerdel.
1998.
Analysis of antibiotic susceptibilities of skin wound flora in hospitalized dermatology patients. The crisis of antibiotic resistance has come to the surface.
Arch. Dermatol.
134:1006-1009 |
| 6. |
Daly, J. S.,
G. M. Eliopoulos,
S. Willey, and R. C. Moellering, Jr.
1988.
Mechanism of action and in vitro and in vivo activities of S-6123, a new oxazolidinone compound.
Antimicrob. Agents Chemother.
32:1341-1346 |
| 7. | Dostert, P. L., M. Strolin Benedetti, and K. F. Tipton. 1989. Interactions of monoamine oxidase with substrates and inhibitors. Med. Res. Rev. 9:45-89[CrossRef][Medline]. |
| 8. | Dresser, L. D., and M. J. Rybak. 1998. The pharmacologic and bacteriologic properties of oxazolidinones, a new class of synthetic antimicrobials. Pharmacotherapy 18:456-462[Medline]. |
| 9. | Eliopoulos, G. M., C. B. Wennersten, H. S. Gold, and R. C. Moellering, Jr. 1996. In vitro activities of new oxazolidinone antimicrobial agents against enterococci. Antimicrob. Agents Chemother. 40:1745-1747[Abstract]. |
| 10. | Ford, C. W., J. C. Hamel, D. M. Wilson, J. K. Moerman, D. Stapert, R. J. Yancey, Jr., D. K. Hutchinson, M. R. Barbachyn, and S. J. Brickner. 1996. In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections. Antimicrob. Agents Chemother. 40:1508-1513[Abstract]. |
| 11. | Hiramatsu, K. 1998. The emergence of Staphylococcus aureus with reduced susceptibility to vancomycin in Japan. Am. J. Med. 104:7S-10S[CrossRef][Medline]. |
| 12. | Hiramatsu, K., N. Aritaka, H. Hanaki, S. Kawasaki, Y. Hosoda, S. Hori, Y. Fukuchi, and I. Kobayashi. 1997. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogenously resistant to vancomycin. Lancet 350:1670-1673[CrossRef][Medline]. |
| 13. | Jones, M. E., F. J. Schmitz, A. C. Fluit, J. Acar, R. Gupta, J. Verhoef, and the SENTRY Participants Group. 1999. Frequency of occurrence and antimicrobial susceptibility of bacterial pathogens associated with skin and soft tissue infections during 1997 from an international surveillance programme. Eur. J. Clin. Microbiol. Infect. Dis. 18:403-408[CrossRef][Medline]. |
| 14. | Jorgensen, J. H., M. L. McElmeel, and C. W. Trippy. 1997. In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766, two novel fluorinated oxazolidinones. Antimicrob. Agents Chemother. 47:465-467. |
| 15. | Lewis, R. T. 1998. Soft tissue infections. World J. Surg. 22:146-151[CrossRef][Medline]. |
| 16. | Li, Z., L. Pinto, H. A. Glick, R. J. Willke, B. E. Rittenhouse, and B. Hafkin. 2000. Comparing hospital length of stay (LOS) between linezolid and vancomycin in the treatment of methicillin-resistant Staphylococci species (MRSS) infections: a randomized, multi-center clinical trial. Proceedings of the Annual Meeting of the American College of Clinical Pharmacy, Monterey, Calif. |
| 17. | Mercier, R. C., S. R. Penzak, and M. J. Rybak. 1997. In vitro activities of investigational quinolone, glycylcycline, glycopeptide, streptogramin, and oxazolidinone tested alone and in combinations against vancomycin-resistant Enterococcus faecium. Antimicrob. Agents Chemother. 41:2573-2575[Abstract]. |
| 18. |
Nichols, R. L.
1999.
Optimal treatment of complicated skin and skin structure infections.
J. Antimicrob. Chemother.
44:19-23 |
| 19. |
Noskin, G. A.,
F. Siddiqui,
V. Stosor,
D. Hacek, and L. R. Peterson.
1999.
In vitro activities of linezolid against important gram-positive bacterial pathogens including vancomycin-resistant enterococci.
Antimicrob. Agents Chemother.
43:2059-2062 |
| 20. | Panlilio, A. L., D. H. Culver, R. P. Gaynes, S. Banerjee, T. S. Henderson, J. S. Tolson, and W. J. Martone. 1992. Methicillin-resistant Staphylococcus aureus in U.S. hospitals, 1975-1991. Infect. Control Hosp. Epidemiol. 13:582-586[Medline]. |
| 21. | Ploy, M. C., C. Grelaud, C. Martin, L. de Lumley, and F. Denis. 1998. First clinical isolate of vancomycin-intermediate Staphylococcus aureus in a French hospital. Lancet 351:1212[Medline]. |
| 22. | Rubinstein, E., and R. G. Wunderink for the Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-10076) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin. Infect. Dis., in press. |
| 23. |
Rybak, M. J.,
D. M. Cappelletty,
T. Moldovan,
J. R. Aeschlimann, and G. W. Kaatz.
1998.
Comparative in vitro activity 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.
Antimicrob. Agents Chemother.
42:721-724 |
| 24. | Stevens, D. L, A. E. Bryant, and S. P. Hackett. 1995. Antibiotic effects on bacterial viability, toxin production, and host response. Clin. Infect. Dis. 20:S154-S157. |
| 25. |
Stevens, D. L.,
K. A. Maier, and J. E. Mitten.
1987.
Effect of antibiotics on toxin production and viability of Clostridium perfringens.
Antimicrob. Agents Chemother.
31:213-218 |
| 26. |
Swaney, S. M.,
H. Aoki,
M. C. Ganoza, and D. L. Shinabarger.
1998.
The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria.
Antimicrob. Agents Chemother.
42:3251-3255 |
| 27. |
Swartz, M. N.
1990.
Cellulitis and superficial infections, p. 796-807.
In
G. Mandell, R. Douglas, and J. Bennett (ed.), Principles and practice of infectious diseases1990. Churchill Livingstone Inc., New York, N.Y.
|
| 28. |
Swartz, M. N.
1990.
Subcutaneous tissue infections and abscesses, p. 808-818.
In
G. Mandell, R. Douglas, and J. Bennett (ed.), Principles and practice of infectious diseases1990. Churchill Livingstone Inc., New York, N.Y.
|
| 29. | Voss, A., D. Milatovic, C. Wallrauch-Schwarz, V. T. Rosdahl, and I. Braveny. 1994. Methicillin-resistant Staphylococcus aureus in Europe. Eur. J. Clin. Microbiol. Infect. Dis. 13:50-55[CrossRef][Medline]. |
| 30. | Wong, S. S. Y., P. L. Ho, P. C. Y. Woo, and K. Y. Yuen. 1999. Bacteremia caused by staphylococci with inducible vancomycin heteroresistance. Clin. Infect. Dis. 29:760-767[Medline]. |
| 31. | Zurenko, G. E., B. H. Yagi, R. D. Schaadt, J. W. Allison, J. O. Kilburn, S. E. Glickman, D. K. Hutchinson, M. R. Barbachyn, and S. J. Brickner. 1996. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob. Agents Chemother. 40:839-845[Abstract]. |
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