Figures
Abstract
To assess the effectiveness and safety of linezolid in comparison with glycopeptides (vancomycin and teicoplanin) for the treatment of Staphylococcus aureus infections, we conducted a meta-analysis of relevant randomized controlled trials. A thorough search of Pubmed and other databases was performed. Thirteen trials on 3863 clinically assessed patients were included. Linezolid was slightly more effective than glycopeptides in the intent-to-treat population (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01–1.10), was more effective in clinically assessed patients (OR 95% CI: 1.38, 1.17–1.64) and in all microbiologically assessed patients (OR 95% CI: 1.38, 1.15–1.65). Linezolid was associated with better treatment in skin and soft-tissue infections (SSTIs) patients (OR 95% CI: 1.61, 1.22–2.12), but not in bacteraemia (OR 95% CI: 1.24, 0.78–1.97) or pneumonia (OR 95% CI: 1.25, 0.97–1.60) patients. No difference of mortality between linezolid and glycopeptides was seen in the pooled trials (OR 95% CI: 0.98, 0.83–1.15). While linezolid was associated with more haematological (OR 95% CI: 2.23, 1.07–4.65) and gastrointestinal events (OR 95% CI: 2.34, 1.53–3.59), a significantly fewer events of skin adverse effects (OR 95% CI: 0.27, 0.16–0.46) and nephrotoxicity (OR 95% CI: 0.45, 0.28–0.72) were recorded in linezolid. Based on the analysis of the pooled data of randomized control trials, linezolid should be a better choice for treatment of patients with S. aureus infections, especially in SSTIs patients than glycopeptides. However, when physicians choose to use linezolid, risk of haematological and gastrointestinal events should be taken into account according to the characteristics of the specific patient populations.
Citation: Fu J, Ye X, Chen C, Chen S (2013) The Efficacy and Safety of Linezolid and Glycopeptides in the Treatment of Staphylococcus aureus Infections. PLoS ONE 8(3): e58240. https://doi.org/10.1371/journal.pone.0058240
Editor: Hendrik W. van Veen, University of Cambridge, United Kingdom
Received: October 10, 2012; Accepted: February 1, 2013; Published: March 6, 2013
Copyright: © 2013 Fu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was supported by grants from Guangdong Natural Science Foundation (No. S2011010002481). The funding organization had no role in the design and conduct of the study and the collection, analysis, and interpretation of the data.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA) represents a predominant pathogen associated with serious nosocomial and community-acquired infections, including pneumonia, bacteraemia, and complicated skin and soft tissue infections [1]–[4]. Recent data indicated that S. aureus accounts for 52% of these infections, with MRSA responsible for 24% of staphylococcal infections [5]. In some Asian countries including China, Japan and Korea, more than 60% of gram positive cocci nosocomial infections were caused by MRSA [6]–[8]. In Europe, the overall prevalence of MRSA was 40% to 45%, and in the United States, 30% to 35% [9], [10].
Increasing MRSA infections result in substantial morbidity and mortality, thus increasing the cost of treatment and the use of medical resources [11]. Although glycopeptide antibiotics (e.g., vancomycin and teicoplanin) have long been the standard treatment for serious infections caused by multidrug resistant gram-positive bacteria, there is an increase in resistance to these antibiotics due to emergence and spread of vancomycin-resistant enterococci [12]–[16]. The pitfalls of vancomycin therapy include poor tissue penetration, adverse effects, the need for intravenous access, and increasing minimum inhibitory concentrations (MICs) among staphylococci [17], [18]. With the rising incidence of gram-positive bacterial infections and the global growing trend of antibiotic resistance, new agents with different mechanisms of action are required to counteract drug resistance or cross-resistance for the treatment of gram-positive infections.
The first available oxazolidinone linezolid is an alternative to vancomycin for effective treatment of gram-positive bacterial infections. It inhibits bacterial protein synthesis by blocking formation of the 70S initiation complex [19], [20]. Linezolid has demonstrated excellent tissue penetration [21], equivalent bioavailability between the oral and intravenous formulations [22], and it lacks cross-resistance with current antibiotic therapies due to its unique mechanism of action.
Several randomized controlled trials have compared linezolid to glycopeptides (vancomycin and teicoplanin) for the treatment of gram-positive bacterial infections. Two recent meta-analyses have demonstrated the superior efficacy of linezolid in the treatment of skin and soft tissue infections [23], [24]. Another meta-analysis showed no inferiority of linezolid treated MRSA skin and soft tissue infections [25]. One meta-analysis comparing vancomycin with linezolid detected no difference between two treatments, which seemed to contradict the other meta-analysis postulating that linezolid therapy was associated with higher clinical cure in patients with gram-positive bacterial infections [24], [26].In light of this controversy, further evaluation of linezolid for its efficacy compared to glycopeptides in the treatment of infections caused by known or suspected MRSA is important. Given the fact that several randomized controlled trials have been performed, and data have become available, we performed a meta-analysis with the goal to study the effectiveness and safety of linezolid in comparison with glycopeptide antibiotics in the treatment of infections caused by known or suspected MRSA.
Methods
Data Sources
The meta-analysis was conducted following the PRISMA guidelines [27]. An extensive search of PubMed (January 1, 1995, to September 15, 2012), Current Contents, Embase, Scopus, Cochrane Central Register of Trials database was performed to identify relevant trials. Search terms included: linezolid; oxazolidinone; vancomycin; teicoplanin; glycopeptides; skin and soft tissue; pneumonia; bacteraemia; gram-positive cocci; S. aureus; MRSA; enterococcus; infections; randomized; prospective. Published abstracts from major international conferences (CHEST, American Thoracic Society, Infectious Diseases Society of North America) were also searched but not included in the meta-analysis. Two reviewers (JJ Fu and XH Ye) independently searched the literature and examined relevant trials for further assessment of data on effectiveness and toxicity. Any disagreements were resolved by consensus.
Inclusion Criteria for Trials
A study was considered eligible if it was a randomized controlled clinical trial, if it studied the role of linezolid in comparison with a glycopeptide in the treatment of infectious caused by S. aureus, and if it assessed the effectiveness, toxicity, or mortality of both therapeutic regimens. A study would be excluded if it was an experimental trial or if it focused on pharmacokinetic or pharmacodynamic variables. Additional antimicrobial agents (those with effectiveness against gram-negative rods involved in polymicrobial infections) could be used in the analysis.
Data Extraction
The following data were extracted from each study: authors, publication year, study design, study district, patients with infection type, mean age, patient population (intention to treat [ITT], clinical evaluation [CE] and microbiological evaluation [ME]), sample size, antimicrobial agents and doses used, mean treatment duration, clinical outcome, microbiological eradication, adverse events, patients withdrawn because of adverse effects and mortality. The ITT population consisted of all randomized patients who received at least one dose of study medication. The CE population included patients who fulfilled all inclusion and exclusion criteria in the individual trial, who had complete follow-up and for whom data on treatment outcomes were available. The ME population was a subset of the CE population who had microbiologically documented infections.
According to a modified Jadad score [28], a quality review of each trial was performed to include details of randomization, generation of random numbers, details of the double blinding procedure, information on withdrawals, and allocation concealment. One point was awarded for the specification of each criterion, with a maximum score of 5. Scores of 3 or more points were high-quality trials, whereas those with 2 or fewer points were low-quality trials.
Efficacy and Safety Definitions
Treatment success included clinical cure and microbiological evaluation. Clinical cure was assessed in all patients who had complete follow-up and separated in patients with SSTIs, bacteraemia and pneumonia. Microbiological assessment and documented eradication of S. aureus and MRSA were secondary outcomes. Mortality was defined as all-cause deaths during treatment and follow-up period. Haematological effects included leucopenia, thrombocytopenia, anemia and haemolysis. Gastrointestinal effects included dyspepsia, nausea, vomiting, liver disease, pancreatitis, diarrhea and loose stools. Skin effects included rash, pruritus and red man syndrome. Nephrotoxicity included acute kidney failure and renal impairment.
Statistical Analysis
Statistical analyses were done with STATA version 10.0. The data were pooled by using the Mantel-Haenszel fixed-effects model (FEM) [29] and the DerSimonian and Laird random-effects model (REM) [30]. For all analyses, results from the FEM were presented only when there was no heterogeneity between trials, otherwise results from the REM are presented. Publication bias were examined by funnel plot and further accessed by Egger’s test, with P<0.10 indicating potential bias [31].
Results
Main Characteristics of the Pooled Trials
The flow diagram for selection of trials used in the final analysis is shown in Figure 1. By reading the abstracts and using our inclusion/exclusion criteria, forty-two trials were selected for further investigation. Twenty-nine reports of trials [32]–[60] were excluded for the reasons noted in Figure 1. Finally, thirteen trials met the inclusion criteria of our study [61]–[73], yielding a total of 3,863 patients (Table 1).
Selected Randomized Controlled Trials
The main characteristics of the analyzed trials are given in Table 1. The mean quality score of the included 13 trials was 2.9 (range 2–5), 6 trials (46%) were high quality (score≥3). All enrolled patients had a presumed or documented infection caused by S. aureus. Patients with SSTIs, bacteraemia or pneumonia were analyzed further. Administration of any antibiotics effective against S. aureus in the previous 24–48 h, including the study antibiotics, was not allowed in all the trials.
Treatment Success in Clinically Evaluable (CE) Populations
The primary clinical outcomes that were included in the meta-analysis are shown in Figure 2. Data on treatment success of the regimen for ITT and CE populations was reported in eight and thirteen of the trials, respectively. Linezolid was slightly more effective than glycopeptides in the ITT population (N = 3130, OR 95%CI: 1.05, 1.01–1.10). Success of empirical treatment in clinically assessed patients was achieved in 80.2% of linezolid-treated patients and in 76.3% of glycopeptides-treated patients. Linezolid was also more effective than glycopeptides in the CE population (N = 3863, OR 95%CI: 1.38, 1.17–1.64). When data from blinded RCTs only were analyzed, treatment with linezolid was associated with better treatment success in CE populations than glycopeptides (N = 1244, OR 95%CI: 1.29, 1.02–1.64). When combined with the non-blinded trials, linezolid treatment was found to be more effective than glycopeptides (N = 2559, OR 95%CI: 1.48, 1.16–1.88). The same was true for clinically assessed adult populations (N = 3582, OR 95%CI: 1.38, 1.16–1.63).
Test of all studies for overall effect: Z = 3.65 P = 0.000; test of blinded RCTs for overall effect: Z = 2.11 P = 0.035; test of Non-blinded RCTs for overall effect: Z = 3.03 P = 0.002; test of RCTs in adults for overall effect: Z = 3.64 P = 0.000.
The pooled data in the meta-analysis for SSTIs, bacteraemia and pneumonia were summarized in Figure 3. Success of the empirical treatment was achieved in 90.5% of linezolid-treated patients and in 86.1% of glycopeptides-treated patients in 8 RCTs that reported data on SSTIs. Empirical treatment of patients with SSTIs with linezolid was associated with significantly better success than glycopeptides (N = 2097, OR 95%CI: 1.61, 1.22–2.12).
Test of SSTI for overall effect: Z = 3.37 P = 0.001; test of bacteraemia for overall effect: Z = 0.91 P = 0.364; test of pneumonia for overall effect: Z = 1.73 P = .083.
Six trials reporting outcomes for patients with bacteraemia were available with empirical treatment success occurring in 171 of 222 (77.0%) linezolid-treated patients and in 132 of 187 (70.6%) glycopeptides-treated patients. There was no significant difference in treatment success for bacteraemia between linezolid and glycopeptides (OR 95%CI: 1.24, 0.78–1.97). The effectiveness outcomes for pneumonia were available from 10 reported RCTs. Empirical treatment success occurred in 401 of 600 (66.8%) linezolid-treated patients and in 374 of 589 (63.5%) glycopeptides-treated patients. There was no difference in treatment success for pneumonia between linezolid and glycopeptides (OR 95%CI: 1.25, 0.97–1.60).
Treatment Success in Microbiologically Evaluable (ME) Populations
All thirteen RCTs included in the meta-analysis reported data on microbiologically assessed patients was shown in Figure 4. Empirical treatment of gram-positive infections with linezolid was associated with better treatment success than glycopeptides (N = 2882, OR 95%CI: 1.38, 1.15–1.65). Empirical treatment with linezolid was associated with better eradication rates for S. aureus and MRSA in comparison with glycopeptides (N = 2058, OR 95%CI: 1.54, 1.17–2.02), (N = 1401, OR 95%CI: 1.58, 1.07–2.33), respectively.
Test of all studies with microbiological assessment for overall effect: Z = 3.46 P = 0.001; test of S.aureus eradication for overall effect: Z = 4.43 P = 0.000; test of MRSA eradication for overall effect: Z = 3.78 P = 0.000.
Adverse Effects
Although the drop-out rate was high in some RCTs (Figure 5), there was no significant difference between the treatment groups in the proportion of patients who were withdrawn from RCTs due to adverse effects (N = 5129, OR 95%CI: 0.82, 0.59–1.13). Data on adverse effects possibly related to the study regimens were reported in all trials. There was no difference between the study medications of total adverse effects (N = 6802, OR 95%CI: 1.14, 0.92–1.41) and patients withdrawn from trials (N = 5127, OR 95%CI: 0.82, 0.59–1.13). Linezolid was associated with more haematological adverse effects (N = 5354, OR 95%CI: 2.23, 1.10–4.55), and gastrointestinal adverse effects (N = 6802, OR 95%CI: 2.34, 1.53–3.59), respectively (Figure 6). Meanwhile, significantly less episodes of skin adverse effects (N = 5018, OR 95%CI: 0.27, 0.16–0.46), and nephrotoxicity (N = 2706, OR 95%CI: 0.45, 0.28–0.72) were reported in linezolid-treated patients (Figures 5 and 6). The mortality risk between linezolid and glycopeptides (N = 6797, OR 95%CI: 0.98, 0.83–1.15) was not different (Figure 7).
Test of total adverse effects for overall effect: Z = 1.58 P = 0.113; test of patients withdrawn because of adverse effects for overall effect: Z = 1.41 P = 0.159; test of nephrotoxicity for overall effect: Z = 3.36 P = 0.001.
Test of haematological adverse effects for overall effect: Z = 2.56 P = 0.010; test of gastrointestinal adverse effects for overall effect: Z = 7.74 P = 0.000; test of skin system adverse effects for overall effect: Z = 6.27 P = 0.000.
Test of mortality for overall effect: Z = 0.29 P = 0.771.
Publication Bias
Visual inspection of funnel plot and statistical tests suggested no indication of publication bias for studies on CE population (Figure S1; Begg’s test P = 0.428, Egger’s test P = 0.318), patients with SSTI, bacteraemia and pneumonia (Figure S1; Begg’s test P = 1.000, Egger’s test P = 0.416), ME population (Figure S1; Begg’s test P = 0.897, Egger’s test P = 0.563), all related adverse effects (Figure S1; Begg’s test P = 0.960, Egger’s test P = 0.796), and mortality (Figure S1; Begg’s test P = 0.127, Egger’s test P = 0.136).
Discussion
This pooled meta-analysis of randomized controlled trials for suspected S. aureus infections suggested that linezolid was significantly more effective for the treatment of all patients (those with SSTIs, bacteraemia and pneumonia) with S. aureus infections than glycopeptides. The data point toward a significantly higher effectiveness of linezolid when compared with glycopeptides in both blinded and non-blinded RCTs. Empirical linezolid treatment was associated with better treatment success in microbiologically assessed patients, and both the patient populations having either S. aureus or MRSA infection.
Empirical linezolid treatment was superior to glycopeptides with respect to patients with SSTIs. However, it should be noted that the comparative effectiveness of linezolid and glycopeptides relies mainly on open-label trials [62], [63], [66], [67], [69], [70]. When excluding the non-blinded RCTs, the remaining two blinded RCTs [65], [72] showed that glycopeptides were noninferior to linezolid for patients with SSTIs (OR 95%CI: 1.76, 0.70–4.43). On the other hand, the reported good penetration of linezolid into skin, and the availability of an oral formulation were important factors shown in several studies that may partly explain the higher efficacy of linezolid for the treatment of SSTIs, despite its higher acquisition cost.
The results of this meta-analysis suggest that linezolid is as effective as glycopeptides for the treatment of patients with bacteraemia and pneumonia due to S. aureus infections. When it comes to the treatment of patients with bacteraemia infections, several issues must be addressed. Firstly, the available evidence for the effectiveness of comparator antibiotics for the treatment of bacteraemia patients is limited. Secondly, the absolute number of some reported bacteraemia infection cases was small, which would lead to some heterogeneity between RCTs when compared with the treatment outcomes. It is noteworthy that a recently pooled meta-analysis also concluded that vancomycin was noninferior to linezolid for the treatment of S. aureus bacteraemia [24], which was contradictory to the other meta-analysis stating that linezolid therapy was associated with higher clinical cure in patients with gram-positive bacteraemia infections [23]. Some limitations of the latter meta-analysis should be known. Trials of the evaluation of bacteraemia infections included in this study were published in 2002–2004, only 5 trials were pooled, one of them focusing on the effectiveness of linezolid in comparison with β-lactam for the treatment of bacteraemia patients [23]. When this study was excluded, linezolid was not less effective than glycopeptide antibiotics in this patient population (OR 95%CI: 1.15, 0.98–1.35).
No difference in treatment of pneumonia infections was noticed in the analysis of all pooled trials, although an updated trial published recently showed that linezolid was more effective than vancomycin for the treatment of MRSA nosocomial pneumonia [61]. Similar to our results, all of the prior meta-analyses [23], [24], [26], [75], [76] demonstrated that linezolid was clinically as effective as glycopeptides for the treatment of pneumonia. These findings can be explained by various assumptions. Although one report [59] hypothesized that superior drug concentrations of linezolid in the lung would be a potential mechanism which benefits for treatment of MRSA pneumonia infection, some confounding factors such as protein binding, decreased alveolar macrophage concentrations through cell lysis and antibiotic diffusibility [60] could alter drug concentration and potentially lead to confusing results. Secondly, it is not known if subtherapeutic pulmonary drug concentration was higher in patients with pneumonia in linezolid arm compared with glycopeptides arm because of the lack of reporting of the pooled trials in our study. Thirdly, the MIC of vancomycin was not regularly monitored in the pooled trials. It is noted that high MICs are a known risk factor for vancomycin failure in MRSA bacteraemia and pneumonia [79], [80]. A better choice of linezolid would likely be taken when vancomycin MICs are >1 µg/ml as supported by consensus guidelines [81]. Besides, a large number of included patients in the pooled trials also received additional antibiotics for the treatment of gram-negative bacterial infections, which may have contributed to the increased effectiveness of studied antibiotics in some cases.
The currently available data indicates that teicoplanin is not inferior to linezolid with regard to treatment efficacy for pneumonia. However, no consistence results compared linezolid with teicoplanin in treatment of S. aureus bacteraemia is found. The lack of published data regarding the effectiveness of linezolid compared with teicoplanin for treatment of S. aureus infection is remarkable and maybe the explanation of the contradict results, although there is some evidence suggest that linezolid has a greater probability of attaining its requisite pharmacodynamic target than teicoplanin against S. aureus infection [82]. Because of the limited number of cases within each comparative group, caution should be taken in interpreting results. Further larger randomized controlled trials are required to confirm the efficacy and safety of linezolid and teicoplanin in the treatment of S. aureus infection.
No difference in mortality was noticed in the pooled trials. Of note, 7 out of 13 studies were unblinded [62]–[64], [66], [67], [70], [72]. No significant evidence of publication bias for studies on mortality was observed in both blinded and open-label pooled trials. The results were inconsistent with the latest published meta-analysis [26] which considered a higher potential for bias would occur in the open-label trials.
Linezolid was associated with similar rates of adverse events with comparator regimens. The risk of haematological and gastrointestinal effects was approximately doubled with linezolid in comparison with studied medications. On the other hand, glycopeptides were associated with more episodes of skin adverse effects and nephrotoxicity than linezolid, although the event rates for nephrotoxicity and skin adverse effects were lower than those for haematological and gastrointestinal effects. Nephrotoxicity was mainly seen with vancomycin, which was consistent with recent studies [24], [26].
The present meta-analysis has some limitations. There are some missing data from original reports which the authors could not receive from the investigators performing the trials, and thus may have introduced bias to the reported outcomes of effectiveness. Seven open-label trials meeting the criteria of randomization were included in the pooled data, the lower methodological quality may have introduced bias to the reported outcomes, although no publication bias of clinical, microbiological and survival outcomes were seen in this study. Furthermore, vancomycin serum concentrations that were not routinely monitored in several trials might have contributed to lower treatment success of the regimen, thus influencing the outcomes in favor of linezolid. Finally, a large proportion of trials did not provide the data of patients with proven S. aureus infections, which may have influenced the treatment outcomes.
This meta-analysis shows that linezolid is associated with better clinical and microbiological outcomes than glycopeptides for the treatment of S. aureus infections. Moreover, the data shows that linezolid is more effective than glycopeptides for the treatment of SSTIs. Our data did not detect superiority of linezolid over glycopeptides for the treatment of bacteraemia or pneumonia in terms of clinical cure. Linezolid was associated with more haematological and gastrointestinal events. Compared to linezolid, glycopeptides showed a significant increase in the risk of skin adverse effects and nephrotoxicity. Vancomycin has been assumed to be the first choice of treatment for patients with S. aureus infections, especially with long term MRSA infections. It is inspiring that an alternative, which is more effective, or at least equally effective in some cases, is available for patients with S. aureus infections. However, the higher risk of haematological and gastrointestinal events should be taken into account and may limit the use of linezolid according to the characteristics of the individual patient.
Supporting Information
Figure S1.
Begg’s funnel plot with 95% confidence limits to detect publication bias. Each point represents a separate study for the indicated association.
https://doi.org/10.1371/journal.pone.0058240.s001
(DOC)
Table S1.
PRISMA checklist of this meta-analysis.
https://doi.org/10.1371/journal.pone.0058240.s002
(DOC)
Author Contributions
Contributed to the revising of the paper: SDC CC. Conceived and designed the experiments: SDC CC XHY JJF. Performed the experiments: JJF XHY. Analyzed the data: JJF XHY. Contributed reagents/materials/analysis tools: JJF XHY. Wrote the paper: JJF.
References
- 1. Herold BC, Immergluck LC, Maranan MC, Lauderdale DS, Gaskin RE, et al. (1998) Community- acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 279: 593–598.
- 2. Vardakas KZ, Matthaiou DK, Falagas ME (2009) Incidence, characteristics and outcomes of patients with severe community acquired-MRSA pneumonia. Eur Respir J 34: 1148–1158.
- 3. Klein E, Smith DL, Laxminarayan R (2007) Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States,1999–2005. Emerg Infect Dis 13: 1840–1846.
- 4. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, et al. (2003) Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 36: 53–59.
- 5. Moet GJ, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR (2007) Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998–2004). Diagn Microbiol Infect Dis 57: 7–13.
- 6. Kim HB, Park WB, Lee KD, Choi YJ, Park SW, et al. (2003) Nationwide surveillance for Staphylococcus aureus with reduced susceptibility to vancomycin in Korea. J Clin Microbiol 41: 2279–2281.
- 7. Bell JM, Turnidge JD, SENTRY APAC (2002) High prevalence of oxacillin-resistant Staphylococcus aureus isolates from hospitalized patients in Asia-Pacific and South Africa: results from SENTRY antimicrobial surveillance program, 1998–1999. Antimicrob Agents Chemother 46: 879–881.
- 8. Wang F, Zhu DM, Hu FP, Zhang YY (2001) Surveillance of bacterial resistance among isolates in Shanghai in 1999. J Infect Chemother 7: 117–120.
- 9.
European Antimicrobial Resistance Surveillance System (2002) EARSS annual report 2001. Available: http://ecdc.europa.eu/en/activities/surveillance/EARS-Net/Documents/2001_EARSS_Annual_Report.pdf. Accessed 2013 January 12.
- 10. Jones ME, Karlowsky JA, Draghi DC, Thornsberry C, Sahm DF, et al. (2003) Epidemiology and antibiotic susceptibility of bacteria causing skin and soft tissue infections in the USA and Europe: a guide to appropriate antimicrobial therapy. Int J Antimicrob Agents 22 406–419.
- 11. Lodise TP Jr, McKinnon PS (2007) Burden of methicillin-resistant Staphylococcus aureus: focus on clinical and economic outcomes. Pharmacotherapy 27: 1001–1012.
- 12. Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, et al. (2005) Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 41: 1373–1406.
- 13. American Thoracic Society; Infectious Diseases Society of America (2005) Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171: 388–416.
- 14. Warren DK, Nitin A, Hill C, Fraser VJ, Kollef MH (2004) Occurrence of co-colonization or co-infection with vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus in a medical intensive care unit. Infect Control Hosp Epidemiol 25: 99–104.
- 15. Centers for Disease Control and Prevention (CDC) (2002) Staphylococcus aureus resistant to vancomycin–United States, 2002. MMWR Morb Mortal Wkly Rep 51: 565–567.
- 16. Appelbaum PC (2006) MRSA–the tip of the iceberg. Clin Microbiol Infect 12 Suppl 23–10.
- 17. Stevens DL (2006) The role of vancomycin in the treatment paradigm. Clin Infect Dis 42 Suppl 1S51–57.
- 18. Khare M, Kready D (2003) Antimicrobial therapy of methicillin resistant Staphylococcus aureus infection. Expert Opin Pharmacother 4: 165–177.
- 19. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL (1998) The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother 42: 3251–3255.
- 20. Zurenko GE, Gibson JK, Shinabarger DL, Aristoff PA, Ford CW, et al. (2001) Oxazolidinones: a new class of antibacterials. Curr Opin Pharmacol 1: 470–476.
- 21. Gee T, Ellis R, Marshall G, Andrews J, Ashby J, et al. (2001) Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother 45: 1843–1846.
- 22. French G (2001) Linezolid. Int J Clin Pract 55: 59–63.
- 23. Falagas ME, Siempos II, Vardakas KZ (2008) Linezolid versus glycopeptide or beta-lactam for treatment of Gram-positive bacterial infections: meta-analysis of randomised controlled trials. Lancet Infect Dis 8: 53–66.
- 24. Beibei L, Yun C, Mengli C, Nan B, Xuhong Y, et al. (2010) Linezolid versus vancomycin for the treatment of gram-positive bacterial infections: meta-analysis of randomised controlled trials. Int J Antimicrob Agents 35: 3–12.
- 25. Dodds TJ, Hawke CI (2009) Linezolid versus vancomycin for MRSA skin and soft tissue infections (systematic review and meta-analysis). ANZ J Surg 79: 629–635.
- 26. Vardakas KZ, Mavros MN, Roussos N, Falagas ME (2012) Meta-analysis of randomized controlled trials of vancomycin for the treatment of patients with gram-positive infections: focus on the study design. Mayo Clin Proc 87: 349–363.
- 27. Moher D, Liberati A, Tetzlaff J (2009) Altman DG; PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339: b2535.
- 28. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, et al. (1998) Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 352: 609–613.
- 29. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719–748.
- 30. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188.
- 31. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.
- 32. Sofroniadou S, Revela I, Smirloglou D, Makriniotou I, Zerbala S, et al. (2012) Linezolid versus vancomycin antibiotic lock solution for the prevention of nontunneled catheter-related blood stream infections in hemodialysis patients: a prospective randomized study. Semin Dial 25: 344–350.
- 33. Slatter JG, Stalker DJ, Feenstra KL, Welshman IR, Bruss JB, et al. (2001) Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [(14)C]linezolid to healthy human subjects. Drug Metab Dispos 29: 1136–1145.
- 34. Sisson TL, Jungbluth GL, Hopkins NK (1999) A pharmacokinetic evaluation of concomitant administration of linezolid and aztreonam. J Clin Pharmacol 39: 1277–1282.
- 35. Beringer P, Nguyen M, Hoem N, Louie S, Gill M, et al. (2005) Absolute bioavailability and pharmacokinetics of linezolid in hospitalized patients given enteral feedings. Antimicrob Agents Chemother 49: 3676–3681.
- 36. Whitehouse T, Cepeda JA, Shulman R, Aarons L, Nalda-Molina R, et al. (2005) Pharmacokinetic studies of linezolid and teicoplanin in the critically ill. J Antimicrob Chemother 55: 333–340.
- 37. Stalker DJ, Jungbluth GL, Hopkins NK, Batts DH (2003) Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. J Antimicrob Chemother 51: 1239–1246.
- 38. Burkhardt O, Borner K, von der Höh N, Köppe P, Pletz MW, et al. (2002) Single- and multiple-dose pharmacokinetics of linezolid and co-amoxiclav in healthy human volunteers. J Antimicrob Chemother 50: 707–712.
- 39. Welshman IR, Sisson TA, Jungbluth GL, Stalker DJ, Hopkins NK (2001) Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Dispos 22: 91–97.
- 40. Hendershot PE, Antal EJ, Welshman IR, Batts DH, Hopkins NK (2001) Linezolid: pharmacokinetic and pharmacodynamic evaluation of coadministration with pseudoephedrine HCl, phenylpropanolamine HCl, and dextromethorpan HBr. J Clin Pharmacol 41: 563–572.
- 41. Li Z, Willke RJ, Pinto LA, Rittenhouse BE, Rybak MJ, et al. (2001) 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 21: 263–274.
- 42. Li JZ, Willke RJ, Rittenhouse BE, Glick HA (2002) Approaches to analysis of length of hospital stay related to antibiotic therapy in a randomized clinical trial: linezolid versus vancomycin for treatment of known or suspected methicillin-resistant Staphylococcus species infections. Pharmacotherapy 22: 45S–54S.
- 43. Willke RJ, Glick HA, Li JZ, Rittenhouse BE (2002) Effects of linezolid on hospital length of stay compared with vancomycin in treatment of methicillin-resistant Staphylococcus infections. An application of multivariate survival analysis. Int J Technol Assess Health Care 18: 540–554.
- 44. Li JZ, Willke RJ, Rittenhouse BE, Rybak MJ (2003) Effect of linezolid versus vancomycin on length of hospital stay in patients with complicated skin and soft tissue infections caused by known or suspected methicillin-resistant staphylococci: results from a randomized clinical trial. Surg Infect (Larchmt) 4: 57–70.
- 45. Itani KM, Weigelt J, Li JZ, Duttagupta S (2005) Linezolid reduces length of stay and duration of intravenous treatment compared with vancomycin for complicated skin and soft tissue infections due to suspected or proven methicillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents 26: 442–448.
- 46. McKinnon PS, Sorensen SV, Liu LZ, Itani KM (2006) Impact of linezolid on economic outcomes and determinants of cost in a clinical trial evaluating patients with MRSA complicated skin and soft-tissue infections. Ann Pharmacother 40: 1017–1023.
- 47. Patanwala AE, Erstad BL, Nix DE (2007) Cost-effectiveness of linezolid and vancomycin in the treatment of surgical site infections. Curr Med Res Opin 23: 185–193.
- 48.
Deville JG, Adler S, Azimi PH, Jantausch BA, Morfin MR, et al.. (2003) Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates. Pediatr Infect Dis J 22 (9 Suppl): S158–163.
- 49.
Jantausch BA, Deville J, Adler S, Morfin MR, Lopez P, et al.. (2003) Linezolid for the treatment of children with bacteremia or nosocomial pneumonia caused by resistant gram-positive bacterial pathogens. Pediatr Infect Dis J 22 (9 Suppl): S164–171.
- 50. Weigelt J, Kaafarani HM, Itani KM, Swanson RN (2004) Linezolid eradicates MRSA better than vancomycin from surgical-site infections. Am J Surg 188: 760–766.
- 51.
Yogev R, Patterson LE, Kaplan SL, Adler S, Morfin MR, et al.. (2003) Linezolid for the treatment of complicated skin and skin structure infections in children. Pediatr Infect Dis J 22 (9 Suppl): S172–177.
- 52. Lipsky BA, Itani KM, Weigelt JA, Joseph W, Paap CM, et al. (2011) The role of diabetes mellitus in the treatment of skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus: results from three randomized controlled trials. Int J Infect Dis 15: e140–146.
- 53. Duane TM, Weigelt JA, Puzniak LA, Huang DB (2012) Linezolid and Vancomycin in Treatment of Lower-Extremity Complicated Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus in Patients with and without Vascular Disease. Surg Infect (Larchmt) 13: 147–153.
- 54.
Grudinina SA, Zubkov MM, Krotova LA, Kurdiukova IuP, Kutsenko MA, et al.. (2002) Comparison of linezolid and vancomycin in nosocomial pneumonia: results of the multicenter double-blind study. Antibiot Khimioter 47: 12–7 [Article in Russian].
- 55. Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, et al. (2006) Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis 42: 597–607.
- 56. Sharpe JN, Shively EH, Polk HC (2005) Clinical and economic outcomes of oral linezolid versus intravenous vancomycin in the treatment of MRSA-complicated, lower-extremity skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus. Am J Surg 189: 425–428.
- 57. Florescu I, Beuran M, Dimov R, Razbadauskas A, Bochan M, et al. (2008) Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin -resistant enterococci: a Phase 3, multicentre, double-blind, randomized study. J Antimicrob Chemother 62 Suppl 1i17–28.
- 58. Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, et al. (2012) Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of Phase III and IV randomized clinical trial data. J Antimicrob Chemother 67: 494–502.
- 59. Mendes RE, Deshpande LM, Smyth DS, Shopsin B, Farrell DJ, et al. (2012) Characterization of methicillin-resistant Staphylococcus aureus strains recovered from a phase IV clinical trial for linezolid versus vancomycin for the treatment of nosocomial pneumonia. J Clin Microbiol 50: 3694–3702.
- 60. Alaniz C, Pogue JM (2012) Vancomycin versus linezolid in the treatment of methicillin-resistant Staphylococcus aureus nosocomial pneumonia: implications of the ZEPHyR Trial. Ann Pharmacother 46: 1432–1435.
- 61. Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, et al. (2012) Linezolid in Methicillin- Resistant Staphylococcus aureus Nosocomial Pneumonia: A Randomized, Controlled Study. Clin Infect Dis 54: 621–629.
- 62. Itani KM, Dryden MS, Bhattacharyya H, Kunkel MJ, Baruch AM, et al. (2010) Efficacy and safety of linezolid versus vancomycin for the treatment of complicated skin and soft-tissue infections proven to be caused by methicillin-resistant Staphylococcus aureus.. Am J Surg 199: 804–816.
- 63. Wilcox MH, Tack KJ, Bouza E, Herr DL, Ruf BR, et al. (2009) Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study. Clin Infect Dis 48: 203–212.
- 64. Wunderink RG, Mendelson MH, Somero MS, Fabian TC, May AK, et al. (2008) Early microbiological response to linezolid vs vancomycin in ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus. Chest 134: 1200–1207.
- 65. Lin DF, Zhang YY, Wu JF, Wang F, Zheng JC, et al. (2008) Linezolid for the treatment of infections caused by Gram-positive pathogens in China. Int J Antimicrob Agents 32: 241–249.
- 66. Kohno S, Yamaguchi K, Aikawa N, Sumiyama Y, Odagiri S, et al. (2007) Linezolid versus vancomycin for the treatment of infections caused by methicillin-resistant Staphylococcus aureus in Japan. J Antimicrob Chemother 60: 1361–1369.
- 67. Weigelt J, Itani K, Stevens D, Lau W, Dryden M, et al. (2005) Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 49: 2260–2266.
- 68. Cepeda JA, Whitehouse T, Cooper B, Hails J, Jones K, et al. (2004) Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study. J Antimicrob Chemother 53: 345–355.
- 69. Wilcox M, Nathwani D, Dryden M (2004) Linezolid compared with teicoplanin for the treatment of suspected or proven Gram-positive infections. J Antimicrob Chemother 53: 335–344.
- 70. Kaplan SL, Deville JG, Yogev R, Morfin MR, Wu E, et al. (2003) Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children. Pediatr Infect Dis J 22: 677–686.
- 71. Wunderink RG, Cammarata SK, Oliphant TH (2003) Kollef MH; Linezolid Nosocomial Pneumonia Study Group (2003) Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther 25: 980–992.
- 72. Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, et al. (2002) Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 34: 1481–1490.
- 73. Rubinstein E, Cammarata S, Oliphant T (2001) Wunderink R; Linezolid Nosocomial Pneumonia Study Group (2001) Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 32: 402–412.
- 74. San Pedro GS, Cammarata SK, Oliphant TH (2002) Todisco T; Linezolid Community-Acquired Pneumonia Study Group (2002) Linezolid versus ceftriaxone/cefpodoxime in patients hospitalized for the treatment of Streptococcus pneumoniae pneumonia. Scand J Infect Dis 34: 720–728.
- 75. Walkey AJ, O’Donnell MR, Wiener RS (2011) Linezolid vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a meta-analysis of randomized controlled trials. Chest 139: 1148–1155.
- 76. Kalil AC, Murthy MH, Hermsen ED, Neto FK, Sun J, et al. (2010) Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis. Crit Care Med 38: 1802–1808.
- 77. Wunderink RG, Rello J, Cammarata SK, Croos-Dabrera RV, Kollef MH (2003) Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 124: 1789–1797.
- 78. Kiem S, Schentag JJ (2008) Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother 52: 24–36.
- 79. Haque NZ, Zuniga LC, Peyrani P, Reyes K, Lamerato L, et al. (2010) Relationship of vancomycin minimum inhibitory concentration to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia. Chest 138: 1356–1362.
- 80. Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, et al. (2008) Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother 52: 3315–3320.
- 81. Rybak M, Lomaestro B, Rotschafer JC, Moellering R, Craig W, et al. (2009) Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 66: 82–98.
- 82. Kuti JL, Kiffer CR, Mendes CM, Nicolau DP (2008) Pharmacodynamic comparison of linezolid, teicoplanin and vancomycin against clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci collected from hospitals in Brazil. Clin Microbiol Infect 14: 116–123.