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Linezolid versus Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections

  1. L. Stevens Dennis1,2,
  2. Herr Daniel3,
  3. Lampiris Harry4,5,
  4. Lee Hunt John6,
  5. H. Batts Donald7,
  6. Hafkin Barry7, and
  7. Linezolid MRSA Study Group
  1. 1Infectious Diseases Section, Veterans Administration Medical Center, Boise, Idaho
  2. 2Department of Medicine, University of Washington School of Medicine, Seattle
  3. 3Surgical Critical Care Department, Washington Hospital Center, Washington, D.C.
  4. 4Infectious Disease Section, Department of Medicine, Veterans Administration Medical Center, San Francisco
  5. 5University of California, San Francisco, San Francisco
  6. 6Division of Infectious Diseases, Southwestern Medical Center, University of Texas, Dallas
  7. 7Pharmacia Corporation, Peapack, New Jersey
  1. Reprints or correspondence: Dr. Dennis L. Stevens, Infectious Diseases Section, Building 45, VA Medical Center, 500 West Fort St., Boise, ID 83702 (dlsteven{at}mindspring.com).
 
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Abstract

Linezolid, the first available member of a new antibiotic class, the oxazolidinones, is broadly active against gram-positive bacteria, including drug-resistant strains. In this randomized, open-label trial, hospitalized adults with known or suspected methicillin-resistant Staphylococcus aureus (MRSA) infections were treated with linezolid (600 mg twice daily; n = 240) or vancomycin (1 g twice daily; n = 220) for 7–28 days. S. aureus was isolated from 53% of patients; 93% of these isolates were MRSA. Skin and soft-tissue infection was the most common diagnosis, followed by pneumonia and urinary tract infection. At the test-of-cure visit (15–21 days after the end of therapy), among evaluable patients with MRSA, there was no statistical difference between the 2 treatment groups with respect to clinical cure rates (73.2% of patients in the linezolid group and 73.1% in the vancomycin group) or microbiological success rates (58.9% in the linezolid group and 63.2% in the vancomycin group). Both regimens were well tolerated, with similar rates of adverse events.

Gram-positive bacteria have emerged as important causes of hospital-acquired and community-acquired infections [1–11]. Recent data from the National Nosocomial Infection Surveillance System indicate that Staphylococcus aureus is the most common cause of nosocomial pneumonia and the second most common cause of bloodstream infections in the United States [12]. This trend is complicated by the increasing prevalence (from 2% in 1974 to as high as 64% in recent surveys) of methicillin-resistant S. aureus (MRSA) among nosocomial isolates [1, 13,14,15–16].

Some investigations suggest that MRSA infections are associated with prolonged hospitalizations, increased mortality, and increased costs, compared with infections due to methicillin-susceptible S. aureus; however, such comparisons may be confounded by an increased incidence of comorbid conditions among patients with MRSA infection [17,18–19, 20]. Unfortunately, therapeutic options for patients with MRSA infections are limited. The primary option is intravenous vancomycin therapy, because other antimicrobials, including the fluoroquinolones and third-generation cephalosporins, are ineffective against MRSA [13, 21]. The recent emergence of S. aureus with intermediate resistance to glycopeptides and heteroresistant MRSA [20, 22,23,24–25] suggests that full glycopeptide resistance may soon develop and limit the usefulness of vancomycin [26, 27], which underscores the need for new antibiotics.

Linezolid, the first available oxazolidinone antibiotic, has broad in vitro activity against antibiotic-susceptible and antibiotic-resistant gram-positive bacteria [28,29,30,31,32,33,34–35], including activity against MRSA and against S. aureus with intermediate resistance to glycopeptides [2, 3, 28, 36]. Linezolid uniquely inhibits bacterial protein synthesis by preventing formation of the 70S initiation complex [29, 35,36,37,38–39]. Plasma concentrations of intravenous and oral linezolid are equivalent [40], with average concentrations exceeding the MICs for susceptible pathogens throughout the 12-h dosing interval [41, 42]. Clinical trials demonstrate that linezolid is well tolerated and that it is as effective as standard therapies [43, 44]. We report the results of the largest randomized, comparator-controlled, open-label clinical trial to date comparing the safety and efficacy of linezolid with that of vancomycin in treating patients with presumed MRSA infections.

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Methods

Study design. This randomized, open-label trial evaluated patients with presumed MRSA infections and was conducted at 104 sites in North America, Europe, Latin America, and Asia from July 1998 to July 1999. General and infection-specific inclusion and exclusion criteria are listed in table 1. Study sites obtained approval from local independent ethics committees or institutional review boards, and each patient provided written informed consent.

Table 1
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Table 1

Summary of general and infection-specific inclusion and exclusion criteria for patients in a study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections.

Hospitalized patients were randomized to receive either linezolid (600 mg iv twice daily) or vancomycin (1 g iv twice daily) for at least 7 days. When they had shown clinical improvement, linezolid-treated patients could have their treatment changed to oral linezolid (600 mg twice daily) at the discretion of the investigator. Concomitant administration of aztreonam or gentamicin was allowed. Use of topical antiseptics and topical steroids (not in direct contact with the skin and soft-tissue infection [SSTI] site) was permitted. The recommended infection-specific durations of treatment were as follows: for SSTI or urinary tract infection, 7–14 days; for pneumonia, 10–14 days; and for bacteremia of unknown source, 14–28 days. Medical histories were obtained, and physical examinations, routine hematologic and serum chemical assays, electrocardiography, and chest radiography (for patients with pneumonia) were performed for each patient at baseline (at study entry) and periodically during the study. Baseline comorbid conditions (as judged by the investigator) were reported.

Each patient was assessed at the end of therapy (EOT) and during an indication-specific test-of-cure (TOC) visit. The evaluation of clinical response was made on the basis of the resolution of clinical signs and symptoms, including fever, leukocytosis, reduction in the size of the lesion (for SSTI), and radiographically observed abnormalities (for pneumonia). Specimens of blood, sputum, and urine were obtained at baseline for Gram's staining, culture, and susceptibility testing, as appropriate. For skin lesions, performance of fine-needle aspiration or closed biopsy was required; for purulent lesions, swabs were obtained for culture. If bacteremia was suspected, ⩾2 blood samples for culture were obtained from separate sites before the initiation of therapy, and 2 additional samples were obtained within 48–72 h. Culture was also done at the time of the switch from intravenous to oral therapy (in the linezolid group), at EOT, and at the TOC visit. Susceptibility testing was done in a central laboratory according to National Committee for Clinical Laboratory Standards guidelines [45].

Populations for analysis. Study populations were defined as follows. The intent-to-treat (ITT) population included all randomized patients who received ⩾1 dose of study medication. The microbiological intent-to-treat (MITT) population included all ITT patients who had a culture-confirmed infection with a staphylococcal pathogen at baseline. The MRSA-ITT population was the subset of MITT patients with culture and susceptibility testing results that confirmed infection with an MRSA isolate at baseline. The evaluable MRSA population was the subset of MRSA-ITT patients who met enrollment criteria, received adequate study medication (⩾7 days and 13 doses), had received no prohibited antibiotics before or during study therapy, and returned for a follow-up assessment (unless clinical or microbiological outcome at EOT was "treatment failure").

Efficacy variables. Efficacy was assessed according to the clinical outcome at the TOC visit. There were 4 possible clinical outcomes: "cure," "treatment failure," "indeterminate," or "missing." "Cure" was defined as resolution of the baseline clinical signs and symptoms of infection after ⩾5 days and ⩾10 doses of treatment. The outcome "treatment failure" was assigned if there was persistence or progression of signs and symptoms of infection after ⩾2 days and ⩾4 doses of treatment or if there was no clinical assessment at EOT and TOC. "Indeterminate" was assigned if there was clinical improvement or cure at EOT and no assessment at TOC or if there was cure after receipt of <5 days or <10 doses of study medication. The outcome "missing" was assigned if <2 days or <4 doses of treatment were received.

There were 4 possible microbiological outcomes: "success," "treatment failure," "indeterminate," or "missing." "Success" was defined as documented or presumed eradication of all pathogens present at baseline or colonization. "Treatment failure" was defined as documented or presumed persistence of ⩾1 pathogen present at baseline, superinfection, or reinfection. "Indeterminate" was assigned if the clinical outcome at the TOC visit was indeterminate or missing. The outcome "missing" was assigned if there was no microbiological data from the TOC visit. Specific pathogen eradication rates were determined.

Safety variables. All patients who received ⩾1 dose of study medication were included in the safety analyses. Evaluations included periodic assessment of adverse events; performance of laboratory tests (including hematologic and serum chemical analyses), urinalysis, and physical examination; measurement of vital signs; and monitoring of concomitant nonstudy medications.

Statistical analyses. Assuming a 90% treatment success rate, 142 evaluable patients were required per treatment group for an equivalence determination within 10%, with a 2-sided test level of 5% and a desired statistical power of 80%. Ninety-five percent confidence intervals were calculated for differences between treatment groups in the rates of clinical cure, microbiological success, and pathogen eradication. Categorical variables were compared by the χ2 test. All statistical tests were 2-sided; P ≥.05 was considered statistically significant. Analyses were done with SAS, version 6.0 (SAS Institute). Stepwise logistic regression analysis was used to evaluate differences between treatment groups in the rate of clinical outcomes for the ITT population and for subsets of ITT patients with pneumonia or SSTI at the follow-up visit. Odds ratios and the level of significance were also calculated.

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Results

Study population. Table 2 shows the distribution of patients in each study population. Sixty-five percent of the ITT population had culture-confirmed infection with a staphylococcal organism at baseline. S. aureus was identified in 80% of the MITT population, and 93% of these isolates were methicillin resistant. Demographic characteristics (for the ITT population) were similar at baseline for the 2 treatment groups with respect to weight, sex, race, region, and diagnosis (table 3). The treatment groups were similar with respect to medical history, physical examination findings, clinical signs and symptoms, vital signs, and clinical laboratory values. The size of skin lesions of patients with SSTI, the degree of lobar involvement in patients with pneumonia, and the number of bacteremic patients were similar between the 2 groups. The mean age was higher in the linezolid group than in the vancomycin group. Among ITT patients, 154 (64.2%) of 240 patients in the linezolid group and 134 (60.9%) of 220 in the vancomycin group had ⩾1 comorbid condition; 34 (14.2%) of 240 and 21 (9.5%) of 220, respectively, had ⩾3 comorbid conditions. The most common diagnoses were SSTI and pneumonia, and proportions of diagnoses were similar for the 2 treatment groups (table 4).

Table 2
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Table 2

Populations for analysis in a study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections.

Table 3
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Table 3

Summary of baseline demographic and clinical characteristics of the intent-to-treat population in a study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus infections.

Table 4
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Table 4

Clinical diagnosis at baseline (ITT and MRSA-ITT populations) in a study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections.

The duration of treatment (in the ITT population) was similar between the 2 treatment groups: 188 (78.3%) of 240 patients in the linezolid group and 166 (75.5%) of 220 in the vancomycin group received study medication for ⩾7 days. The mean duration of treatment (±SD) was 12.6 ± 7.1 days in the linezolid group and 11.3 ± 6.7 days in the vancomycin group. Sixty-one percent of patients in the linezolid group received oral linezolid. Overall, 78 (32.5%) of 240 patients in the linezolid group and 69 (31.4%) of 220 in the vancomycin group discontinued treatment. The most common reasons for discontinuation of study medication were as follows: no methicillin-resistant pathogen detected at baseline (13.3% of patients [32 of 240] in the linezolid group vs. 17.3% of patients [38 of 220] in the vancomycin group), death (6.7% [16 of 240] vs. 5.9% [13 of 220]), adverse events (3.8% [9 of 240] vs. 3.2% [7 of 220]), lack of treatment efficacy (2.9% [7 of 240] vs. 1.4% [3 of 220]), noncompliance (0.8% [2 of 240] vs. 0.9% [2 of 220]), personal request (0.8% [2 of 240] in the linezolid group), and unspecified (4.2% [10 of 240] vs 2.7% [6 of 220]).

Efficacy data. There were no statistically significant differences between the treatment groups in the rates of clinical cure or microbiological success; this was true for all 4 patient populations (table 5). In the evaluable MRSA population, the clinical outcome for 73.2% of patients in the linezolid group and 73.1% of patients in the vancomycin group was "cure"; the microbiological outcome for 58.9% and 63.2% of patients, respectively, was "success" at the time of the TOC visit. Resistance to linezolid or vancomycin was not detected at baseline or after the end of treatment in any patient. Concomitant aminoglycoside use in patients with suspected gram-negative pathogens was rare; for these patients, the clinical and microbiological outcomes were similar between treatment groups. Pathogen eradication rates for all staphylococcal species (regardless of resistance status) were 52.3% (68 of 130 isolates) in the linezolid group and 51.2% (64 of 125 isolates) in the vancomycin group. MRSA eradication rates in evaluable MRSA isolates were 60.7% (34 of 56 isolates) and 63.2% (36 of 57 isolates), respectively. At baseline, few patients were infected with isolates of other methicillin-susceptible or methicillin-resistant staphylococcal species (i.e., Staphylococcus epidermidis and Staphylococcus haemolyticus).

Table 5
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Table 5

Clinical and microbiological outcomes at the test-of-cure visit in a study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections.

Efficacy results were not different among patients with the same baseline diagnosis between the 2 treatment groups (table 6). Despite the small number of patients, similar efficacy was observed among patients with bacteremia (cure rates ranged from 51.5% to 60% in the linezolid group and from 46.9% to 70% in the vancomycin group) (table 6). Among 6 bacteremic patients who had failure of linezolid therapy, 1 died before EOT, secondary to an unrelated aspiration pneumonia; 2 had sepsis (1 due to Klebsiella species and 1 due to Candida species); and 1 had persistent infection that resulted from an infected dialysis catheter that was not removed. Of the remaining 2 patients, 1 had myeloma and blood cultures that were persistently positive for S. aureus, and 1 had persistently negative blood culture results and died of "uncontrolled sepsis." Two of the 3 bacteremic patients who had failure of vancomycin therapy died of sepsis or multiple-system organ failure before EOT; the other died of respiratory failure and severe thrombocytopenia after treatment. Development of drug-resistant strains as the reason for clinical failure was not detected in either group.

Table 6
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Table 6

Clinical cure rates by site of infection in a study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections.

Logistic regression analysis revealed that, at baseline, there were no differences between the linezolid and vancomycin groups with respect to the conditions assessed but did reveal that there were differences between patients with and patients without specific baseline comorbidities. ITT patients with cardiac, hepatic, or respiratory conditions were at a significantly increased risk of treatment failure, regardless of treatment group.

Safety data. Adverse events were generally mild to moderate in severity and of limited duration, and they usually did not result in discontinuation of study medication; however, a higher percentage of linezolid-treated patients experienced gastrointestinal effects (table 7). Fewer than 5% of patients in each group discontinued study medication because of an adverse event (4.2% of patients [10 of 240] in the linezolid group vs. 4.5% of patients [10 of 220] in the vancomycin group; P = .842). A higher proportion of patients in the linezolid group than patients in the vancomycin group had ⩾1 drug-related adverse event (as judged by the investigator). This difference was due to a higher frequency of gastrointestinal events (diarrhea and nausea) and special senses events (i.e., changes in taste perception). The incidence of pseudomembranous colitis due to Clostridium difficile was 0.4% (1 of 240 patients) in the linezolid group and 1.4% (3 of 220) in the vancomycin group, despite a higher frequency of drug-related diarrhea in the linezolid group. The rate of occurrence of serious adverse events (26.7% of patients [64 of 240] in the linezolid group vs. 25.5% [56 of 220] in the vancomycin group; P = .767) and death was not significantly different between the treatment groups (16.7% [40 of 240] vs. 13.6% [30 of 220]; P = .4). A poststudy effort to collect missing hospital discharge data identified an additional 7 deaths (mortality rates, 18.3% [44 of 240 patients] in the linezolid group vs. 15.0% [33 of 220] in the vancomycin group; P = .4) [20]. None of these deaths were considered to be related to receipt of study medication.

Table 7
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Table 7

Summary showing the most frequent adverse events, by category, in a study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus infections.

Changes in the results of serum chemical and hematologic assays were similar between the 2 treatment groups. Mean serum chemistry values remained within normal ranges. Mean WBC and neutrophil counts decreased in both groups during the study, a finding consistent with resolution of infection. Mean hemoglobin levels increased: the mean increases from baseline were 0.24 g/dL in the linezolid group and 0.95 g/dL in the vancomycin group (P = .008). For platelet counts, the mean decrease from baseline was greater for the vancomycin group (3.5 × 103 cells/mm3 decrease in the linezolid group vs. 25.5 × 103 cells/mm3 in the vancomycin group), but the difference was not statistically significant (P = .230). The 2 treatment groups had similar percentages of patients who had, at any time during the study, ⩾1 substantially abnormal serum chemical or hematolgogic assay result (defined as twice the upper limit of the normal range or, if the baseline value was abnormal, twice the baseline value for serum chemical values and <75% of the lower limit of the normal range or, if the baseline value was abnormal, <75% of the baseline value for hematologic values), except with respect to platelet counts. Substantially low platelet counts were noted in 23 (10.0%) of 230 patients in the linezolid group and in 6 (2.9%) of 210 patients in the vancomycin group (P = .003). Most of these linezolid-treated patients had decreased platelet counts at baseline or underlying risk factors associated with thrombocytopenia; none had a drug-related bleeding event. Drug-related thrombocytopenia was reported in only 4 of these patients, each of whom was receiving concomitant heparin, warfarin, or aspirin therapy. The thrombocytopenia resolved in 2 patients, 1 patient was lost to follow-up, and 1 died of underlying comorbidities after life-support measures were withdrawn.

No clinically significant differences were noted between groups with respect to urinalysis results, vital sign measurements, or findings of physical examination. Drug interactions between study medications and other concomitant medications were not evident. The incidence of possibly monoamine oxidase inhibitor–related adverse events was similar between treatment groups, and the occurrence of these events did not require the discontinuation of study medication.

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Discussion

This study is the largest reported comparator-controlled study to date of patients with presumed MRSA infections. More than 200 enrolled patients had culture-proven MRSA infections, and ã100 patients met clinical and microbiological evaluability criteria. The 2 treatment groups were similar with respect to baseline clinical characteristics across the study populations. However, as expected, cure rates were lower among patients with multiple comorbid conditions, because of underlying illnesses, a finding that is consistent with the results of other studies [46,47–48]. Most patients received ⩾7 days of treatment, and 60% of patients completed treatment and follow-up visits.

Linezolid therapy was clinically and microbiologically as effective as standard vancomycin therapy for patients hospitalized with methicillin-resistant staphylococcal infections, including SSTI and nosocomial pneumonia due to MRSA. This effect was consistent across all efficacy assessments. Approximately one-half of the MRSA-ITT patients had a clinical diagnosis of SSTI at baseline, with similar clinical cure and microbiological success rates for linezolid and vancomycin treatments. The consistent outcome results and the use of objective end points (e.g., pathogen eradication) provided a solid basis for comparing efficacy, despite the open-label design of the trial. Regarding aminoglycoside use, in vitro and in vivo models suggest no evidence of synergy between linezolid and aminoglycosides. Although vancomycin and aminoglycosides potentially have synergistic activity against MRSA, few patients received concurrent aminoglycosides for more than 3–4 days in either treatment group, and outcomes were similar for such patients in both groups. Linezolid-resistant MRSA were not detected in this trial, nor have they been detected in any other clinical trial, but infection with these organisms has been reported in a patient receiving oral therapy for peritonitis who had an infected catheter that was not removed [49]. This avascular nidus of infection likely contributed to the development of resistance.

Safety assessment results were similar in the linezolid and vancomycin groups. Most adverse events were mild to moderate and of limited duration. The most common adverse events among linezolid-treated patients were gastrointestinal. The use of oral therapy may account for these differences, because these adverse events are known to be associated with oral antibiotic therapy; alternatively, because of the open-label design, investigators may have been more likely to report adverse events in linezolid-treated patients than in vancomycin-treated patients. No significant differences were noted between treatment groups with respect to serious adverse events, discontinuations due to adverse events, or increased numbers of adverse events because of thrombocytopenia. More than 50% of enrolled patients received a concomitant monoamine oxidase inhibitor–interacting drug, but no clinically relevant or significant monoamine oxidase inhibitor–related events were noted, nor were differences in the results of clinical laboratory assessments noted between treatment groups.

From both the clinical and economic perspectives, gram-positive bacteria have become increasingly important nosocomial pathogens worldwide [17,18–19, 50,51,52,53,54–55]. Widespread use of broad-spectrum antimicrobial agents and the limited potency of some agents has exerted heavy selective pressure in hospital environments; thus, reemergence of resistant gram-positive pathogens, particularly MRSA, is of increasing concern.

Until recently, there were few therapeutic options for the treatment of MRSA infections [13]. Intravenous vancomycin remains the standard therapy, but concerns about S. aureus strains with reduced sensitivity to vancomycin and about emerging prevalence of these organisms in the community [6–11] may limit the usefulness of vancomycin in the future. Agents such as teicoplanin and quinupristin-dalfopristin are available in some countries but only in parenteral formulations, which may necessitate prolonged hospitalizations or costly and inconvenient home health care arrangements. Linezolid, in contrast to other anti-MRSA agents, is 100% bioavailable after oral administration [40, 41]. In this study, ∼61% of patients received oral linezolid, and most switched to oral therapy within 5 days after the initiation of therapy. The availability of an effective, convenient oral formulation shortens the length of hospital stay [20]. As reported elsewhere [20], in the evaluable population, the median length of stay for the linezolid group was 2 days shorter than it was for the vancomycin group (14 vs. 16 days; P = .08), and, among patients with SSTI (ITT population), it was 5 days shorter for the linezolid group (9 vs. 14 days, respectively; P = .052). Also, more linezolid-treated than vancomycin-treated patients were discharged during the first 7 days of hospitalization (ITT population: 30% vs. 19%, respectively; P = .005) . These results suggest that use of oral linezolid for treatment of presumed MRSA infection may yield potentially significant economic benefits.

In conclusion, empirical intravenous-to-oral linezolid therapy was safe, well tolerated, and as effective as vancomycin in the treatment of nosocomial infections due to MRSA. Linezolid is a suitable alternative to vancomycin for the treatment of MRSA infections and may relieve pressure on vancomycin use.

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Acknowledgments

We wish to honor and acknowledge Robert J. Schaser, who was the statistician responsible for much of the analysis of this study and who died on 1 January 2001. We thank the participating investigators in the Linezolid MRSA Study Group and the investigator site staff for their efforts in providing care to the patients.

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Footnotes

  • Financial support: Pharmacia Corporation. D.L.S. has received funding from Pharmacia, Pfizer Pharmaceuticals, and Wyeth-Ayerst for investigator-initiated research proposals.

  • Received August 13, 2001.
  • Revision received January 15, 2002.
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References

  1. 1.↵
    1. Fluckiger U,
    2. Widmer AF
    . Epidemiology of methicillin-resistant Staphylococcus aureus. Chemotherapy 1999;45:121-34.
    CrossRefMedlineWeb of Science
  2. 2.↵
    1. Jones RN,
    2. Pfaller MA,
    3. Erwin ME,
    4. et al
    . Program and abstracts of the 37th annual meeting of the Infectious Diseases Society of America (Philadelphia). Alexandria, VA: Infectious Diseases Society of America; 1999. Antimicrobial activity of linezolid (formerly U-100766) tested against 3,808 strains of gram-positive organisms having resistance to various drugs [abstract 108]; p. 58.
  3. 3.↵
    1. Jones RN,
    2. Pfaller MA,
    3. Erwin ME
    . Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco). Washington, DC: American Society for Microbiology; 1999. Antimicrobial activity of linezolid (U-100766) tested against 7,599 recent clinical isolates from over 50 medical center laboratories [abstract 97]; p. 264.
  4. 4.
    1. From the Centers for Disease Control and Prevention
    . Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus—Minnesota and North Dakota, 1997–1999. JAMA 1999;282:1123-5.
    FREE Full Text
  5. 5.
    1. O'Brien FG,
    2. Pearman JW,
    3. Gracey M,
    4. et al
    . Community strain of methicillin-resistant Staphylococcus aureus involved in a hospital outbreak. J Clin Microbiol 1999;37:2858-62.
    Abstract/FREE Full Text
  6. 6.↵
    1. Herold BC,
    2. Immergluck LC,
    3. Maranan MC,
    4. et al
    . Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 1998;279:593-8.
    Abstract/FREE Full Text
  7. 7.
    1. Moreno F,
    2. Crisp C,
    3. Jorgensen JH,
    4. et al
    . Methicillin-resistant Staphylococcus aureus as a community organism. Clin Infect Dis 1995;21:1308-12.
    Abstract/FREE Full Text
  8. 8.
    1. Layton MC,
    2. Hierholzer WJ,
    3. Patterson JE
    . The evolving epidemiology of methicillin-resistant Staphylococcus aureus at a university hospital. Infect Control Hosp Epidemiol 1995;16:12-7.
    MedlineWeb of Science
  9. 9.
    1. Embil J,
    2. Ramotar K,
    3. Romance L
    . Methicillin-resistant Staphylococcus aureus in tertiary care institutions on the Canadian prairies. Infect Control Hosp Epidemiol 1994;15:646-51.
    MedlineWeb of Science
  10. 10.
    1. Rathore MH,
    2. Kline MW
    . Community-acquired methicillin-resistant Staphylococcus aureus infections in children. Pediatr Infect Dis J 1989;8:645-7.
    MedlineWeb of Science
  11. 11.↵
    1. Frank AL,
    2. Marcinak JF,
    3. Mangat PD,
    4. et al
    . Community-acquired and clindamycin-susceptible methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J 1999;18:993-1000.
    CrossRefMedlineWeb of Science
  12. 12.↵
    National Nosocomial Infections Surveillance (NNIS) System report, data summary from October 1986 through April 1998. Atlanta: Hospital Infections Program, National Center for Infectious Diseases, Centers for Disease Control and Prevention; 1998.
  13. 13.↵
    1. Maranan MC,
    2. Moreira B,
    3. Boyle-Vavra S,
    4. et al
    . Antimicrobial resistance in staphylococci: epidemiology, molecular mechanisms, and clinical relevance. Infect Dis Clin North Am 1997;11:813-49.
    CrossRefMedlineWeb of Science
  14. 14.↵
    1. Jones RN,
    2. Kerhberg EN,
    3. Erwin ME,
    4. et al
    . Prevalence of important pathogens and antimicrobial activity of parenteral drugs at numerous medical centers in the United States. I. Study on the threat of emerging resistances: real or perceived? Diagn Microbiol Infect Dis 1994;19:203-15.
    Medline
  15. 15.↵
    1. Panlilio AL,
    2. Culver DH,
    3. Gaynes RP,
    4. et al
    . Methicillin-resistant Staphylococcus aureus in US hospitals, 1975–1991. Infect Control Hosp Epidemiol 1992;13:582-6.
    MedlineWeb of Science
  16. 16.↵
    1. Voss A,
    2. Milatovic D,
    3. Wallrauch-Schwarz C,
    4. et al
    . Methicillin-resistant Staphylococcus aureus in Europe. Eur J Clin Microbiol Infect Dis 1994;13:50-5.
    CrossRefMedlineWeb of Science
  17. 17.↵
    1. Abramson MA,
    2. Sexton DJ
    . Nosocomial methicillin-resistant and methicillin-susceptible Staphylococcus aureus primary bacteremia: at what costs. Infect Control Hosp Epidemiol 1999;20:408-11.
    CrossRefMedlineWeb of Science
  18. 18.↵
    1. Carbon C
    . Costs of treating infections caused by methicillin-resistant staphylococci and vancomycin-resistant enterococci. J Antimicrob Chemother 1999;44:31-6.
    Abstract
  19. 19.↵
    1. Rubin RJ,
    2. Harrington CA,
    3. Poon A,
    4. et al
    . The economic impact of Staphylococcus aureus infection in New York City hospitals. Emerg Infect Dis 1999;5:9-17.
    MedlineWeb of Science
  20. 20.↵
    1. Li J,
    2. Willke R,
    3. Pinto L,
    4. et al
    . Comparison of length of hospital stay for patients with known or suspected methicillin-resistant Staphylococcus species infections treated with linezolid or vancomycin: a randomized, multicenter trial. Pharmacotherapy 2001;21:263-74.
    CrossRefMedline
  21. 21.↵
    1. Fridkin SK,
    2. Edwards JR,
    3. Pichette SC,
    4. et al
    . Determinants of vancomycin use in adult intensive care units in 41 United States hospitals. Clin Infect Dis 1999;28:1119-25.
    Abstract/FREE Full Text
  22. 22.↵
    1. Hiramatsu K,
    2. Aritaka N,
    3. Hanaki H,
    4. et al
    . Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 1997;350:1670-3.
    CrossRefMedlineWeb of Science
  23. 23.↵
    1. Ariza J,
    2. Pujol M,
    3. Peña C,
    4. et al
    . Vancomycin in surgical infections to methicillin-resistant Staphylococcus aureus with heterogenous resistance to vancomycin. Lancet 1999;353:1587-8.
    CrossRefMedlineWeb of Science
  24. 24.↵
    1. Sieradzki K,
    2. Villari P,
    3. Tomasz A
    . Low-level teicoplanin resistance and heteroresistance to vancomycin [letter]. Ann Intern Med 1998;128:245.
    FREE Full Text
  25. 25.↵
    1. Sieradzki K,
    2. Roberts RB,
    3. Haber SW,
    4. et al
    . The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999;340:517-23.
    CrossRefMedlineWeb of Science
  26. 26.↵
    1. Wong SSY,
    2. Ho PL,
    3. Woo PCY,
    4. et al
    . Bacteremia caused by staphylococci with inducible vancomycin heteroresistance. Clin Infect Dis 1999;29:760-7.
    Abstract/FREE Full Text
  27. 27.↵
    1. Centers for Disease Control and Prevention
    . Update: Staphylococcus aureus with reduced susceptibility to vancomycin—United States, 1997. MMWR Morb Mortal Wkly Rep 1997;46:813-5.
    Medline
  28. 28.↵
    1. Brickner SJ,
    2. Hutchinson DK,
    3. Barbachyn MR,
    4. et al
    . Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections. J Med Chem 1996;39:673-9.
    CrossRefMedlineWeb of Science
  29. 29.↵
    1. Dresser LD,
    2. Rybak MJ
    . The pharmacologic and bacteriologic properties of oxazolidinones, a new class of synthetic antimicrobials. Pharmacotherapy 1998;18:456-62.
    MedlineWeb of Science
  30. 30.↵
    1. Eliopoulos GM,
    2. Wennersten CB,
    3. Gold HS,
    4. et al
    . In vitro activities of new oxazolidinone antimicrobial agents against enterococci. Antimicrob Agents Chemother 1996;40:1745-7.
    Abstract/FREE Full Text
  31. 31.↵
    1. Ford CW,
    2. Hamel JC,
    3. Wilson DM,
    4. et al
    . In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections. Antimicrob Agents Chemother 1996;40:1508-13.
    Abstract/FREE Full Text
  32. 32.↵
    1. Jorgensen JH,
    2. McElmeel ML,
    3. Trippy CW
    . In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766 against Staphylococcus aureus and coagulase-negative Staphylococcus species. Antimicrob Agents Chemother 1997;41:465-7.
    Abstract/FREE Full Text
  33. 33.↵
    1. Mercier RC,
    2. Penzak SR,
    3. Rybak MJ
    . In vitro activities of investigational quinolone, glycylcycline, glycopeptide, streptogramin, and oxazolidinone tested alone and in combinations against vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother 1997;41:2573-5.
    Abstract/FREE Full Text
  34. 34.↵
    1. Rybak MJ,
    2. Cappelletty DM,
    3. Moldovan T,
    4. et al
    . Comparative in vitro activity and postantibiotic effect of 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 1998;42:721-4.
    Abstract/FREE Full Text
  35. 35.↵
    1. Zurenko GE,
    2. Yagi BH,
    3. Schaadt RD,
    4. et al
    . In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob Agents Chemother 1996;40:839-45.
    Abstract/FREE Full Text
  36. 36.↵
    1. Tenover FC,
    2. Lancaster MV,
    3. Hill BC,
    4. et al
    . Characterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides. J Clin Microbiol 1998;36:1020-7.
    Abstract/FREE Full Text
  37. 37.↵
    1. Matassova NB,
    2. Rodnina MV,
    3. Endermann R,
    4. et al
    . Ribosomal RNA is the target for oxazolidinones, a novel class of translational inhibitors. RNA 1999;5:939-46.
    Abstract
  38. 38.↵
    1. Shinabarger DL,
    2. Marotti KR,
    3. Murray RW,
    4. et al
    . Mechanism of action of oxazolidinones: effect of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother 1997;41:2132-6.
    Abstract/FREE Full Text
  39. 39.↵
    1. Swaney SM,
    2. Aoki H,
    3. Ganoza MC,
    4. et al
    . The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother 1998;42:3251-5.
    Abstract/FREE Full Text
  40. 40.↵
    1. Welshman IR,
    2. Sisson TA,
    3. Jungbluth GL,
    4. Stalker DJ,
    5. Hopkins NK
    . Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Dispos 2001;22:91-7.
    CrossRefMedlineWeb of Science
  41. 41.↵
    1. Stalker DJ,
    2. Wajszczuk CP,
    3. Batts DH,
    4. et al
    . Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (Toronto). Washington, DC: American Society for Microbiology; 1997. Linezolid safety, tolerance, and pharmacokinetics following oral dosing twice daily for 14.5 days [abstract A-115]; p. 23.
  42. 42.↵
    1. Stalker DJ,
    2. Wajszczuk CP,
    3. Batts DH
    . Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (Toronto). Washington, DC: American Society for Microbiology; 1997. Linezolid safety, tolerance, and pharmacokinetics after intravenous dosing twice daily for 7.5 days [abstract A-116]; p. 23-4.
  43. 43.↵
    1. Stevens DL,
    2. Smith LG,
    3. Bruss JB,
    4. et al
    . Randomized comparison of linezolid (PNU-100766) versus oxacillin/dicloxacillin for treatment of complicated skin and soft-tissue infections. Antimicrob Agents Chemother 2000;44:3408-13.
    Abstract/FREE Full Text
  44. 44.↵
    1. Rubinstein E,
    2. Cammarata SK,
    3. Oliphant TH,
    4. Wunderkink RG
    . Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001;32:402-12.
    Abstract/FREE Full Text
  45. 45.↵
    1. National Committee for Clinical Laboratory Standards (NCCLS)
    . 10th Informational Supplement. Wayne, PA: NCCLS; 2000. NCCLS document M100-S10.
  46. 46.↵
    1. Kollef MH,
    2. Sherman G,
    3. Ward S,
    4. et al
    . Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999;115:462-74.
    Abstract/FREE Full Text
  47. 47.↵
    1. Cook DJ,
    2. Kollef MH
    . Risk factors for ICU-acquired pneumonia. JAMA 1998;279:1605-6.
    FREE Full Text
  48. 48.↵
    1. Greenaway CA,
    2. Embil J,
    3. Orr PH,
    4. et al
    . Nosocomial pneumonia on general medical and surgical wards in a tertiary-care hospital. Infect Control Hosp Epidemiol 1997;18:749-56.
    MedlineWeb of Science
  49. 49.↵
    1. Tsiodras S,
    2. Gold HS,
    3. Sakoulas G,
    4. et al
    . Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001;358:207-8.
    CrossRefMedlineWeb of Science
  50. 50.↵
    1. File TM Jr.
    Overview of resistance in the 1990s. Chest 1999;115(Suppl 3):S3-8.
    CrossRefMedlineWeb of Science
  51. 51.↵
    1. Holmberg SD,
    2. Solomon SL,
    3. Blake PA
    . Health and economic impacts of antimicrobial resistance. Rev Infect Dis 1987;9:1065-78.
    MedlineWeb of Science
  52. 52.↵
    1. Romero-Vivas J,
    2. Rubio M,
    3. Fernandez C,
    4. et al
    . Mortality associated with nosocomial bacteremia due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis 1995;21:1417-23.
    Abstract/FREE Full Text
  53. 53.↵
    1. Shlaes DM,
    2. Gerding DM,
    3. John JF,
    4. et al
    . Society for Healthcare Epidemiology of America and Infectious Diseases Society of America joint committee on the prevention of antimicrobial resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis 1997;25:584-99.
    Abstract/FREE Full Text
  54. 54.↵
    1. Bonten MJM,
    2. Weinstein RA
    . Bird's-eye view of nosocomial infections in medical ICU: blue bugs, fungi, and device days. Crit Care Med 1999;27:853-4.
    CrossRefMedlineWeb of Science
  55. 55.↵
    1. Richards MJ,
    2. Edwards JR,
    3. Culver DH,
    4. et al
    . Nosocomial infections in medical intensive care units in the United States. Crit Care Med 1999;27:887-92.
    CrossRefMedlineWeb of Science
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  1. Clin Infect Dis. (2002) 34 (11): 1481-1490. doi: 10.1086/340353
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