Efficacy and safety of linezolid versus teicoplanin for the treatment of MRSA infections: a meta-analysis

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of serious infections. Linezolid and teicoplanin are widely used in the treatment of infections caused by MRSA. However, the efficacy and safety of linezolid compared with teicoplanin remains controversial. The purpose of this study was to systematically review the efficacy and safety of linezolid versus teicoplanin for the treatment of MRSA infections. Methodology: A meta-analysis was performed on the published studies. Pooled relative risk (RR) and 95% confidence interval (95% CI) were calculated to determine whether there were significant differences between the linezolid group and the teicoplanin group on the efficacy and safety. Results: Seventeen studies were included, involving 2,040 patients. The results showed that linezolid was associated with better clinical cure rate (RR = 1.14, 95% CI = 1.08-1.21, p < 0.00001) and microbiological eradication rate (RR = 1.28, 95% CI = 1.18-1.39, p < 0.00001) compared with teicoplanin. There were no statistically significant differences between the two groups in the treatment of MRSA infections regarding the adverse events (RR = 1.15, 95% CI = 0.97-1.35, p = 0.10) and the mortality (RR = 0.85, 95% CI = 0.61-1.18, p = 0.33). Conclusions: The results suggest that linezolid may be a better choice for the treatment of patients with MRSA infections. However, our recommendation is that the decision about treating MRSA infections with linezolid or with teicoplanin should depend on local availability, patient population, dosage regimens, costs and safety, rather than presumed differences in efficacy.


Introduction
Methicillin-resistant Staphylococcus aureus (MRSA) represents a predominant pathogen associated with serious infections, including pneumonia, bacteremia and skin and soft tissue infection. The mortality rate in patients with MRSA pneumonia ranged from 33% to 55% [1]. Therefore, the treatment options against MRSA infections have become an urgent priority. The glycopeptide antibiotic teicoplanin is the first or second line drug in the treatment of MRSA infections [2]. The level of plasma concentrations (Cmin) of teicoplanin are widely considered as the predominant factor for the positive clinical outcome [3]. However, pharmacokinetic disposition of teicoplanin in patients with MRSA infections is scarce and shows extensive individual variation, while the appropriate dosage regimens for teicoplanin remain controversial [4,5,6,7]. Furthermore, adverse effect, such as renal toxicity, limits its use in patients with renal dysfunction [8]. Linezolid has also been widely used in the treatment of MRSA infections in recent years [9,10]. It inhibits bacterial protein synthesis by preventing formation of the 70S initiation complex [11], resulting in good efficacy in treating MRSA infections. However, several studies reported that critically ill patients receiving the standard dosing regimen of linezolid still show treatment failure even though the isolated pathogens are sensitive to linezolid [12,13]. Other potential problems of treatment with linezolid include its bacteriostatic rather than bactericidal action and the high incidence of adverse events [11].
Several studies compared the efficacy and safety of linezolid and teicoplanin in the past ten years. However, the results are diverse, and unique conclusion has not been made. For example, a meta-analysis of nine randomized controlled trials (RCTs) did not demonstrate the clinical superiority of linezolid versus glycopeptide antibiotics for the treatment of nosocomial pneumonia [14]. Another meta-analysis of eight RCTs reported similar results [15]. Though, only RCTs published until 2011 were included in that metaanalysis. Recently, a meta-analysis of seven studies reported superior clinical effective rate and microbiological eradication rate of linezolid comparing to teicoplanin [16]. The results were consistent with the findings of other meta-analysis [17,18]. However, only patients with pneumonia were included in these metaanalysis.
In light of this controversy, it is necessary to review the efficacy and safety of linezolid versus teicoplanin in patients with MRSA infections. Therefore, we conducted the meta-analysis to highlight the present evidence for both, the efficacy and safety, of linezolid versus teicoplanin for the treatment of MRSA infections, and thus provide valuable information for clinicians in the clinical practice.

Literature search
The literature search was performed on the PubMed, Cochrane Central Register of Controlled Trials, ScienceDirect, China National Knowledge Infrastructure (CNKI), Chinese Biological Medicine Database (CBM), VIP Database for Chinese Technical Periodicals (VIP) and Wan Fang Digital Periodicals Database (WFDP) from their inception up to May 2017. The following subject headings were employed: "linezolid", "teicoplanin or targocid", "MRSA" or "Methicillin-resistant Staphylococcus aureus".

Study selection
The following inclusion criteria were applied: (1) study designed RCTs, including quasi-RCT; (2) study population consisting of patients with MRSA infections and (3) intervention therapies consisting of linezolid and teicoplanin; (4) outcome variables: the primary outcomes provided should include at least one of the following: total clinical cure, microbiological eradication, major drug adverse events and the mortality. Studies were excluded if: (1) they were not written in English or Chinese; (2) the control group did not use teicoplanin; (3) clinical success was not assessed as an end point; (4) the data were either not complete or not available; (5) the focus was pharmacokinetic or pharmacodynamics variables.

Data collection and quality assessment
The following data were extracted from each study: name of first author, publication year, gender, median age, total number of treatment and control group, dosage regimens, a type of infection, treatment duration. In order to maintain uniformity and reduce potential bias, two investigators independently assessed the quality and extracted the data according to the inclusion and exclusion criteria. They examined and recorded the trial characteristics and outcomes, using the Jadad-scale [19] to review the reliability of studies and discussed with each other if there were any disagreement. One point was awarded for each procedure, 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.

Statistical analysis
Meta-analysis was performed according to the Quality of reporting of meta-analyses guidelines and the Cochrane handbook 5.0.1 for Systematic reviews of interventions [20]. The Mantel-Haenszel (MH) RR, 95% CI and p-value were used to assess efficacy and safety endpoints. Heterogeneity was examined by Chisquare test. Chi-square statistics with a p-value < 0.1 was considered to be significant across trials. Treatment effects across trials were combined using a random effects model (I 2 > 50%) and a fixed effects model (I 2 < 50%). The publication bias was assessed using funnel plots with visual inspection of asymmetry and Begg's or Egger's tests, with a p < 0.05 indicating potential bias (STATA version 11.0). Forest plots for the relevant comparisons were performed using Review Manager version 5.2 software.
In these seventeen studies, all studies design included a baseline assessment and no significant differences were found between the baseline data.

Clinical cure and microbiological eradication
Comparisons of clinical cure and microbiological eradication between linezolid and teicoplanin are  Figure 2 and Figure 3, respectively. Heterogeneity was considered absent at the sensitivity analyses. A fixed effects model was performed on outcome measurements. The results showed that clinical cure between linezolid and teicoplanin for the treatment of MRSA infections were statistically significant differences (n = 14 studies, 1678 patients; RR = 1.14, 95% CI = 1.08-1.21，p < 0.00001, I 2 = 38%). The results were similar for microbiological eradication (n = 14 studies, 1,100 patients; RR = 1.28, 95% CI = 1.18-1.39, p < 0.00001, I 2 = 37%).

Adverse events and mortality
There were no statistically significant differences in the total adverse events (Figure 4)

Publication bias analysis
Begg's funnel plot and Egger's test were performed to assess the publication bias of the seventeen studies. The results of Begg's funnel plot are shown in Figure 6. No publication bias was detected in this meta-analysis with either Begg's test (p > 0.05) or Egger's test (p > 0.05).

Sensitivity analyses
The trial by Cepeda et al was the only study adopted double-blind [22]. Its removal from all analyses did not change our results for the meta-analysis. For clinical cure, there was no change on our results (RR = 1.15， 95% CI = 1.09-1.22, p < 0.00001). The results were similar for microbiological eradication (RR = 1.28, 95% CI = 1.18-1.39, p < 0.00001). For adverse events and mortality, the data were not used for sensitivity analysis due to lower heterogeneity.

Informed consent
Informed consent was obtained from all individual participants included in the study.

Discussion
In the present meta-analysis, we collected and analyzed the clinical data from seventeen studies. The results showed that linezolid was associated with better clinical cure and microbiological eradication compared  with teicoplanin. It is possible that efficacy differences between linezolid and teicoplanin might be related to excellent tissue penetration and 100% oral bioavailability of linezolid [38,39]. On the other hand, the reported good penetration of linezolid into skin was an important factor shown in several studies that may partly explain the higher efficacy of skin and soft tissue infection (SSTI). Meanwhile, the availability of an oral formulation can improve the patient's quality of life [40]. In the present meta-analysis, several studies focused on elderly patients with nosocomial pneumonia and reported linezolid was associated with better efficacy compared with teicoplanin in elderly patients [27,29,[32][33][34]. We believe that higher clinical cure rate may contribute to better outcomes in elderly patients with nosocomial pneumonia because the immune system and organ function are often affected by aging and underlying diseases [41]. In contrast, teicoplanin have significant drawbacks which compromise their clinical usefulness for the treatment of serious MRSA infections. For example, clinical efficacy is relatively slow following initiation of therapy [42], and continued administration invariably results in the need for monitoring of serum levels and prolonged hospital stay. Consequently, some clinicians recommend that loading doses of teicoplanin should be used for critically ill patients. Data on whether or not loading doses of teicoplanin were used are not available for patients in this study. In brief, we recommend that linezolid may be a better choice for the treatment of skin and soft tissue infections and nosocomial pneumonia. Notably, our findings argue against widespread routine use of linezolid for MRSA infection based on the presumption of superior efficacy. Targeted use of linezolid may be of greater importance given the outbreak of linezolidresistant Staphylococcus aureus [43].
There were no statistically significant differences in the total adverse events. Falagas et al. demonstrated that the increased thrombocytopenia was associated with linezolid [44]. Similar results were found in our study. Besides, adverse events such as diarrhea, nausea, headache and fever were associated with linezolid. Given these potential adverse events, the safety of linezolid should be monitored during treatment. Clinicians should be aware of the symptoms and sign of toxicity so that linezolid can be immediately discontinued if these occur. In contrast, the most common adverse event of teicoplanin is renal toxicity, which may limit its use in patients with renal dysfunction [8]. Therefore, linezolid may be safer than teicoplanin for treating patients with renal dysfunction caused by MRSA. Clinicians should pay careful attention to the safety of antibiotics for treating specific patient population with MRSA infections. In addition, no difference in mortality was noticed in the pooled trials. This could be attributed to the patients with more serious infections were enrolled in the linezolid group.
Previous economic studies have demonstrated that linezolid was more cost-effective than teicoplanin in treating MRSA infections [45,46]. This may be due to linezolid's higher efficacy and fewer days of hospital stay, leading to a reduction in the total duration of hospital stay, treatment and costs.
The funnel plot is asymmetric, which reveal a potential publication bias may be caused by a language bias, inflated estimates by a flawed methodological design in small and low quality studies. Therefore, publication bias was assessed using Begg's and Egger's test. The results showed that no publication biases were detected, and the included studies could be thought no affect the outcomes assessment.
There are several limitations that should be considered in the present meta-analysis: (1) some studies were not double-blind and the lack of blinding could affect the outcomes assessment; (2) only English and Chinese studies were included in this analysis, which may cause language bias and finally (3) the most important limitation was publication bias. In the present analysis, although the assessment of publication bias was not significant, the possibility of publication bias may exist in any research, because the negative studies and studies with small sample sizes may be less likely to be published.

Conclusion
In conclusion, based on currently available data from seventeen studies, the findings suggest that linezolid has superior clinical efficacy and similar safety for the treatment of MRSA infections compared to teicoplanin. It may provide valuable information for clinicians to decide and optimize dosage regimens of linezolid and teicoplanin for treating MRSA infections in clinical practice. The conclusions still need to be further validated by more well-designed RCTs with large samples.