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Treatment of Hospital-Acquired Pneumonia with Linezolid or

Vancomycin: A Systematic Review and Meta-Analysis

Journal: BMJ Open

Manuscript ID: bmjopen-2013-003912

Article Type: Research

Date Submitted by the Author: 29-Aug-2013

Complete List of Authors: Kalil, Andre; University of Nebraska, Klompas, Michael; Harvard University, Haynatzki, Gleb; University of Nebraska, Rupp, Mark; University of Nebraska,

<b>Primary Subject Heading</b>:

Infectious diseases

Secondary Subject Heading: Infectious diseases

Keywords: Infectious diseases & infestations < DERMATOLOGY, Thoracic medicine <

INTERNAL MEDICINE, INTENSIVE & CRITICAL CARE

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Treatment of Hospital-Acquired Pneumonia with Linezolid or Vancomycin:

A Systematic Review and Meta-Analysis

Andre C. Kalil, M.D., M.P.H.1*, Michael Klompas, M.D., M.P.H.2, Gleb Haynatzki, Ph.D.3,

Mark E. Rupp, M.D.1

1University of Nebraska Medical Center, Omaha, NE, 2Infection Control Department,

Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 3Department of

Biostatistics, University of Nebraska, Omaha, NE

*Corresponding Author:

Andre Kalil, M.D., M.P.H.

Associate Professor of Medicine

University of Nebraska Medical Center

Nebraska Medical Center

Omaha, NE 68198

Email: [email protected]

Key words : Hospital-acquired pneumonia, nosocomial, linezolid, vancomycin

Text Word Count: 2459

Abstract Word Count: 273

Running Head: Treatment of hospital-acquired pneumonia

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ABSTRACT

Objective: Hospital-acquired pneumonia remains the most lethal and expensive

nosocomial infection worldwide. Optimal therapy remains controversial. We aimed to

compare mortality and clinical response outcomes in patients treated with either

linezolid or vancomycin.

Design: Systematic review and meta-analysis.

Data Sources: PUBMED, EMBASE, Cochrane Library, American College of

Physicians Journal Club, Evidence-based Medicine BMJ, and abstracts from infectious

diseases and critical care meetings were searched through April 2013.

Eligibility Criteria for Selecting Studies: All randomized clinical trials comparing

linezolid to vancomycin for hospital-acquired pneumonia.

Data Extraction: PRISMA guidelines were followed. One author extracted the data and

two authors re-checked and verified all data.

Results: Nine randomized trials with a total of 4,026 patients were included. The

adjusted absolute mortality risk difference (RD) between linezolid and vancomycin was

0.01% (95% CI -2.1%, 2.1%; p=0.992; I2=13.5%; crude mortality: linezolid [13.7%];

vancomycin [14.9%]). The adjusted absolute clinical response difference was 0.4%

(95% CI -1.5%, 2.4%; p=0.656; I2=0%; crude response: linezolid [60.2%]; vancomycin

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[57.2%]). The risk of both microbiological (RD=5.6%, 95% CI -2.2%, 13.3%; p=0.159;

I2=0%) and methicillin-resistant Staphylococcus aureus (RD=6.4%, 95% CI -4.1%,

16.9%; p=0.230; I2=0%) eradication were not different between linezolid and

vancomycin. Gastrointestinal side effects were more frequent with linezolid (RD= 0.8%

(95% CI 0%, 1.5%; p=0.05), but no differences were found with renal failure,

thrombocytopenia, and drug discontinuation due to adverse events. Our sample size

provided 99.9% statistical power to detect differences between drugs regarding clinical

response and mortality.

Conclusions: Linezolid and vancomycin have similar efficacy and safety profiles. The

high statistical power and the near zero efficacy difference between both antibiotics

demonstrates that no drug is superior for the treatment of hospital-acquired pneumonia.

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Article focus:

• To compare mortality, clinical response, and safety outcomes in patients with

hospital-acquired pneumonia treated with either linezolid or vancomycin.

Key messages:

• Linezolid and vancomycin have similar efficacy and safety profiles.

• No drug is superior for the treatment of hospital-acquired pneumonia.

Strengths and limitations of this study:

• Randomized controlled trials set selective inclusion criteria that can limit their

generalizability to unselected populations.

• Some of the trials were open-label studies leading to potential ascertainment bias

for clinical endpoints.

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INTRODUCTION

Hospital-acquired pneumonia (HAP) remains among the most frequent type of

infection acquired in intensive care unit settings 1, 2 and is associated with substantial

mortality, ranging from 15-57% 3. Gram-positive organisms, mainly Staphylococcus

aureus, cause approximately one-third of these pneumonias 3, 4.

The optimal antibiotic therapy for the treatment of HAP caused by Gram-positive

organisms is controversial 5-7. Two systematic reviews and meta-analyses have been

performed comparing linezolid to glycopeptides for the treatment of hospital-acquired

pneumonia 8, 9. The conclusions of both meta-analyses were similar and consistent:

clinical cure and survival were equivalent for linezolid, vancomycin, and teicoplanin.

However, new randomized trials have been published since these meta-analyses, the

most recent of which concluded that linezolid is superior to vancomycin 10. This has

reawakened controversy regarding the optimal therapy for Gram-positive HAP.

There are important public health reasons to resolve the controversy regarding

the optimal treatment for Gram-positive HAP. A perceived difference in clinical efficacy

is likely to drive increased usage of one agent versus the other with consequent risk of

unintended consequences. In the case of linezolid, these include increased risk of

outbreaks of linezolid resistant organisms, higher total drug costs, and adverse drug

events such as serotonin syndrome in patients with interacting medications and

cytopenias in patients treated with prolonged courses 11. In the case of vancomycin,

these include increased risk of clinical failure if the drug is underdosed, increased risk of

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nephrotoxicity if the drug is overdosed, and central venous catheter complications such

as bloodstream infections and thromboembolic disease 12.

In light of the renewed controversy and public health significance regarding optimal

treatment for Gram-positive HAP, we present the largest systematic review and meta-

analysis on the efficacy and safety of linezolid versus vancomycin incorporating these

important new studies. Our study has long-term implications for two reasons:: 1) the

cumulative number of patients and events now available for analysis (4,026) allow close

to 100% statistical power to detect a difference in mortality outcome between these two

treatments, i.e., it is unlikely that any future trial would add clinically meaningful

information; and 2) the manufacturer (Pfizer) does not plan to perform any more

randomized trials with either drug 13.

MATERIAL AND METHODS

Literature Search:

A systematic literature search was independently performed through April 2013 in

Medline/PubMed, EMBASE, and Cochrane Library by a professional librarian (Dr.

Cynthia Schmidt) and by one of the authors (AK). Any disagreement was resolved by

consensus. We also searched abstracts published in the same time period from the

following meetings: Society of Critical Care Medicine, Infectious Diseases Society of

America, the Interscience Conference on Antimicrobial Agents and Chemotherapy,

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Chest, and American Thoracic Society. Relevant Internet sites such as the Food and

Drug Administration reports and trial results repositories (www.clinicalstudyresults.org

and www.clinicaltrialresults.org) were also searched. The keywords used were:

linezolid; oxazolidinone; vancomycin; glycopeptide; Staphylococcus; Gram-positive;

infections; randomized; prospective; lungs; respiratory; hospital-acquired, ventilator-

associated, and nosocomial pneumonia. No language restrictions were used. This study

was exempted from Institutional Review Board approval.

Study Selection:

Randomized clinical trials that compared linezolid to vancomycin for the treatment of

hospital-acquired pneumonias were included in our analysis. Trials that did not use

vancomycin as the comparator were excluded. Also excluded were articles not

containing original research (e.g., reviews, editorials, case reports).

Data Extraction:

The following variables were abstracted and collected in a standardized form: authors;

publication year; study design; gender; mean age; sample size; site of infection;

microorganism species and susceptibility; clinical response; microbiological eradication;

mortality; and adverse events. For studies that included multiple sites of infection, we

extracted data only from the patient population with hospital-acquired pneumonia. Any

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disagreement was resolved by further review of the study and consensus among

authors.

Efficacy and Safety Outcome Definitions:

Primary Efficacy Outcomes: 1) Mortality was defined as all-cause 28-day mortality

reported by each study. 2) Clinical response was defined at the test of cure evaluation

(TOC) or at the follow up visit (FUV) for the clinically evaluable population. If TOC data

were not available, then clinical response at last study follow up was used. Secondary

Efficacy Outcomes: 1) Microbiological eradication was defined as documented

eradication of all Gram-positive organisms at TOC for the microbiologically evaluable

population. If TOC data were not available, then microbiological eradication at last

study follow up was used. 2) Methicillin-resistant Staphylococcus aureus (MRSA)

eradication was defined as documented eradication of MRSA within the

microbiologically evaluable population. 3) Safety: Gastrointestinal events included

nausea, vomiting, diarrhea, hepatitis, and pancreatitis; Renal failure and

thrombocytopenia were defined as reported by the authors of each paper. Study drug

discontinuation was defined as the permanent discontinuation of either linezolid or

vancomycin due to an adverse event.

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Statistical Analysis:

All results were reported with the random-effects model. The Q statistic method was

used to assess statistical heterogeneity and the I-squared (I2) statistic was used to

evaluate the inconsistency between trials 14 15. All absolute risk difference estimates

were pooled by using the DerSimonian and Laird methodology 16. We choose the risk

difference over the risk ratio in order to better describe the direct clinical effects of our

findings. The quality of each trial was evaluated by Jadad criteria. PRISMA guidelines 17

for reporting meta-analysis were followed. All analyses were adjusted for the study

design to account for potential ascertainment bias. The software used was

Comprehensive Meta-Analysis version 2.0 (Biostat, Englewood, New Jersey). Egger

regression and Begg and Mazumdar methods18 were used to evaluate publication bias.

Statistical power calculations were performed based on the comparison of two

independent proportions by Chi-square testing using the software Power and Precision

version 4.0 (Englewood, New Jersey). The two-group test of proportions was used to

test the null hypothesis that the proportion of cases meeting the primary outcome was

identical in the two groups. Hierarchy was not accounted for because the tau-square

was zero, which indicated that the power based on either fixed- or random-effects

modeling produced exactly the same results 15.

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RESULTS

A total of nine trials met the inclusion criteria 10, 19-26 (Figure 1) with a total sample size of

4,026 patients. Study characteristics are presented in Table 1, and quality of evidence is

presented in Appendix.

EFFICACY ANALYSES:

Mortality:

The absolute risk difference (RD) between linezolid and vancomycin for 28-day all-

cause mortality based on the intention-to-treat population (N=4,026) was 0.0001 (95%

CI -0.021, 0.021; p=0.992; I2=13.5%) (Figure 2).

Clinical Response:

The absolute risk difference (RD) between linezolid and vancomycin for clinical

response based on the intention-to-treat population (N=4,026) was 0.004 (95% CI

-0.015, 0.024; p=0.656; I2=0%) (Figure 3a). The risk difference (RD) between linezolid

and vancomycin for clinical response based on the clinically evaluable and per-protocol

population (N=1,161) was 0.037 (95% CI -0.019, 0.092; p=0.192; I2=0%) (Figure 3b).

The clinical response on the per-protocol population with MRSA infection only (N=507)

showed an RD= 0.077 (95%CI -0.008, 0.162; p=0.076).

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Microbiological Eradication:

The absolute risk difference (RD) between linezolid and vancomycin for microbiological

eradication based on the microbiologically evaluable and per-protocol population

(N=600) was 0.056 (95% CI -0.022, 0.133; p=0.159; I2=0%) (Figure 4a).

Methicillin-resistant Staphylococcus aureus (MRSA) Eradication:

The absolute risk difference (RD) between linezolid and vancomycin for MRSA

eradication based on the microbiologically evaluable and per-protocol population

(N=416) was 0.064 (95% CI -0.041, 0.169; p=0.230; I2=0%) (Figure 4b).

SAFETY ANALYSES:

Gastrointestinal Events:

The absolute risk difference (RD) between linezolid and vancomycin for gastrointestinal

events based on the intention-to-treat population (N=3,421) was 0.008 (95% CI -0.000,

0.015; p=0.050; I2=78%) (Figure 5a).

Thrombocytopenia:

The absolute risk difference (RD) between linezolid and vancomycin for

thrombocytopenia based on the intention-to-treat population (N=3,421) was 0.008 (95%

CI -0.003, 0.020; p=0.161; I2=74%) (Figure 5b).

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Renal Failure:

The absolute risk difference (RD) between linezolid and vancomycin for renal failure

based on the intention-to-treat population (N=3,421) was -0.007 (95% CI -0.018, 0.005;

p=0.249; I2=48%) (Figure 6a).

Drug Discontinuation due to Adverse Events:

The absolute risk difference (RD) between linezolid and vancomycin for drug

discontinuation based on the intention-to-treat population (N=3,421) was -0.005 (95% CI

-0.016, 0.007; p=0.424; I2=0%) (Figure 6b).

SENSITIVITY ANALYSES:

The trial by Jaksic et al 24 was the only study that included patients with leukemia, active

chemotherapy treatment, and several other nephrotoxic antibiotics such as

amphotericin and aminoclycosides; since these factors can cause major gastrointestinal

events, (e.g. graft vs. host disease, mucositis, C. difficile colitis), thrombocytopenia

(e.g. disease- or drug-induced bone marrow suppression), and renal failure (e.g.

chemotherapy- or antibiotic-induced), this study was not included in the prospectively

planned side-effects analyses. However, its inclusion to these analyses did not change

any of the original results. The trial by Kaplan et al 22 was the only one that included

pediatric population only; the removal of this study from all analyses did not alter our

results (data not shown); similarly the removal of the oldest trial by Rubinstein et al also

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did not change the results. The trial by Wunderink et al 10 was the only one that did not

provide 28-day mortality (only 60-day mortality) - its removal from the mortality analysis

did not change the original findings (RD = 0.006 (95% CI -0.019, 0.031); p=0.649;

I2=21%). An analysis based on the type of Gram-negative coverage produced similar

results. The analyses based on the quality of studies by Jadad scores showed the

following: 28-day Mortality: Jadad ≤ 3: RD = 0.019 (95% CI -0.008, 0.046); p=0.18;

I2=0%; Jadad > 3: RD = -0.024 (95% CI -0.051, 0.004); p=0.10; I2=0%. Clinical

response: Jadad ≤ 3: was 0.019 (95% CI -0.054, 0.093); p=0.612; I2=0%; Jadad > 3: RD

= 0.04 (95% CI -0.058, 0.138); p=0.426; I2=30%.

POWER CALCULATIONS:

Mortality: Based on a prospectively planned expected mortality rate at least 5% lower

(95%CI -7%,-3%) with linezolid, and a control mortality rate of 15%, the sample size of

our intention-to-treat meta-analysis (N=2,000 in each arm) has 99.9% power to detect a

mortality difference of 5% with a significance level (alpha) of 0.05 (two-tailed).

Clinical Response: Based on a prospectively planned expected clinical response rate at

least 10% higher (95%CI 4%,16%) with linezolid, and a control clinical response of

57%, the sample size of our intention-to-treat meta-analysis (N=2,000 in each arm) has

99.9% power to detect a clinical response difference of 10% with a significance level

(alpha) of 0.05 (two-tailed).

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PUBLICATION BIAS ANALYSES:

Mortality outcome: No publication bias was detected by Egger regression (intercept =

-0.038; standard error = 1.236; P = 0.976), or by Begg and Mazumdar rank correlation

(Kendall’s tau < 0.0001; P = 1.000).

Clinical response outcome: No publication bias was detected by Egger regression

(intercept = -0.790; standard error = 0.762; P = 0.334), or by Begg and Mazumdar rank

correlation (Kendall’s tau -0.027; P = 0.917).

DISCUSSION

Our primary outcome analysis demonstrates that linezolid and vancomycin are

similar with respect to mortality reduction and clinical response. Our findings are robust

and clinically meaningful based on the high statistical power to detect outcome

differences between these two drugs - 100% power for both mortality and clinical

response, and the near zero heterogeneity for all efficacy analyses.

Importantly, all analyses included only randomized trials and accounted for the

differences in study design, which make the potential for selection and ascertainment

biases less likely. In addition, the clinical response analyses showed no differences

between both drugs in both the intention-to-treat and the per-protocol patient

populations. Moreover, the clinical response in the per-protocol patients with MRSA

pneumonia likewise did not show differences between drugs. Our secondary efficacy

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outcomes were also in agreement with our primary outcomes; both microbiological

eradication and MRSA eradication were not different between vancomycin and linezolid.

Even though microbiological outcomes are not necessarily as meaningful as survival

and clinical response, the absence of significant microbiological outcomes lends further

support to the results of our primary clinical and survival analysis.

Our efficacy findings are also in agreement with two previous meta-analyses 8, 9

that evaluated these antibiotics to treat HAP, and two other meta-analyses 27, 28 that

evaluated these drugs and other antibiotics in patients with multiple sites of infection,

including pneumonias. Consistency between the current meta-analysis and prior

analyses despite being performed by different research groups using different statistical

methods adds further credence to our findings.

Our conclusions are contrary to those of Wunderink and colleagues whose

recent clinical trial concluded that linezolid has superior clinical efficacy compared to

vancomycin 10. Closer examination of this trial, however, helps to reconcile their results

with our meta-analysis. Of the 1184 subjects randomized into the Wunderink et al.

study, only 339 (28%) were included in the clinical efficacy analysis. Excluding 72% of

all randomized patients undermined the balancing of potential confounders conferred by

randomization. Not surprisingly, there were notable differences between the linezolid

and vancomycin groups: patients treated with vancomycin had higher rates of

mechanical ventilation, bacteremia, diabetes, renal failure, and heart failure; and the

levels of vancomycin were sub-optimal in half of the patients enrolled in the trial biasing

against clinical success with vancomycin. The authors claimed linezolid superiority

based on their per-protocol analysis but there was no significant difference in clinical

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response or mortality in the intention-to-treat analysis. Of note, the CONSORT 29 and

ICH guidelines 30 recommend intention-to-treat analyses for all clinical trials.

Nonetheless, our meta-analysis shows that even if one combines only the per-protocol

patients from all available trials comparing linezolid versus vancomycin (figure 3b), the

pooled results including data from 1,161 per-protocol patients still do not show an

advantage with linezolid. Last, it was stated in the report by Wunderink et al 10 that

Pfizer had the power to override the clinical outcomes as determined by the

investigators, but no details regarding the reasons or extent of overriding were provided.

We found few differences in the drugs’ side effect profiles. The most significant

difference was found with respect to gastrointestinal events, which were more frequent

with linezolid, while thrombocytopenia was numerically, but not significantly higher

despite linezolid’s well-known predilection to cause bone marrow suppression.

Differences in definitions of thrombocytopenia used in the studies may have led to the

high-observed heterogeneity and may have precluded the detection of this side effect

with linezolid. The lack of difference could, however, also be explained on clinical

grounds: usual treatment courses for pneumonia may be too short to realize the time-

dependent risk of thrombocytopenia and vancomycin itself can also cause

thrombocytopenia. Renal failure may be associated with vancomycin, but it was not

significantly more frequent in patients treated with vancomycin compared to linezolid in

our meta-analysis. Definitions of renal failure did vary amongst studies, and may

explain the high heterogeneity for this analysis, but the very small difference in renal

failure rates (0.7%) among 3,421 patients makes a significant difference unlikely. The

lack of difference may also reflect the more “healthy-patient” inclusion biases of

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randomized controlled trials. Finally, the comparable rates of study drug discontinuation

due to adverse events further affirms a minimal difference in the safety profiles between

vancomycin and linezolid.

Limitations of our study follow from limitations in the source trials. Randomized

controlled trials set selective inclusion criteria that can limit their generalizability to

unselected populations. None of the studies specifically focused on MRSA with higher

vancomycin minimum-inhibitory concentrations nor did any of the studies utilize

continuous vancomycin infusion. Some of the trials were open-label studies leading to

potential ascertainment bias for clinical endpoints. The results of our analyses

remained consistent, however, when stratified by the presence or absence of blinding.

The traditional limitation of a lack of power to detect mortality differences from individual

trials on hospital-acquired pneumonia is no longer a concern as our meta-analysis

included approximately 4,000 patients and allowed close to 100% power to detect a

mortality or clinical response difference, thereby conferring a high degree of confidence

that there are no advantages for either drug. The heterogeneity was substantial for both

gastrointestinal events and thrombocytopenia, however, the lack of differences and low

heterogeneity seen within the study drug discontinuation due to adverse events analysis

supports our overall findings of a similar safety profile between drugs.

In conclusion, similar efficacy and safety profiles show that both vancomycin and

linezolid are equivalent in patients with hospital-acquired pneumonia.

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Acknowledgements: The authors thank Ms Ashley Calhoon for providing administrative

support and Dr. Cynthia Schmidt for the library support.

Institutional Review Board: Exempted.

Authors’ Contributions:

Conception and design: Andre Kalil; Collection of data: Andre Kalil and Mark Rupp;

Statistical Analysis: Andre Kalil and Gleb Haynatski. Analysis and interpretation of the

data: Andre Kalil, Michael Klompas, Gleb Haynatski, and Mark Rupp; Drafting of the

article and critical revision for important intellectual content: Andre Kalil, Michael

Klompas, Gleb Haynatski, and Mark Rupp; Final approval of the version to be

published: Andre Kalil, Michael Klompas, Gleb Haynatski, and Mark Rupp. Andre Kalil is

the guarantor of the paper and takes responsibility for the integrity of the work as a

whole, from inception to published article.

Competing Interest Declaration:

All authors have completed the Unified Competing Interest form at

www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author)

and declare that (1) Andre Kalil has no conflicts of interest to disclose. Michael Klompas

has no conflicts of interest to disclose. Gleb Haynatski has no conflicts of interest to

disclose. Mark Rupp: Research grants from 3M and Molnlycke in the form of contracts

to the University of Nebraska Medical Center, and advisory board/consultant/honoraria

from 3M, Bard, Molnlycke, Artise; (2) Mark Rupp has relationships with 3M, Bard,

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Molnlycke, Artise that might have an interest in the submitted work in the previous 3

years; (3) their spouses, partners, or children have no financial relationships that may

be relevant to the submitted work; and (4) Andre Kalil, Michael Klompas and Gleb

Haynatski have no non-financial interests that may be relevant to the submitted work.

Funding: No funding was received in support of this study.

Exclusive Licence:

The Corresponding Author has the right to grant on behalf of all authors and does grant

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REFERENCES:

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13. Pfizer Report. New phase 4 study shows higher rates of clinical and microbiological

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hospitalized patients with nosocomial pneumonia: A randomized, double-blind,

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treatment of methicillin-resistant staphylococcus aureus infections. Clin Infect Dis 2002;

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of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia.

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compared with vancomycin in a randomized, double-blind study of febrile neutropenic

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25. Kohno S, Yamaguchi K, Aikawa N, et al. Linezolid versus vancomycin for the

treatment of infections caused by methicillin-resistant staphylococcus aureus in japan. J

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26. Wunderink RG, Mendelson MH, Somero MS, et al. Early microbiologic response to

linezolid versus vancomycin in ventilator-associated pneumonia (VAP) due to

methicillin-resistant staphylococcus aureus (MRSA). Chest 2008; PMID: 18719064;

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27. Falagas ME, Siempos II, Vardakas KZ. Linezolid versus glycopeptide or beta-lactam

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10.1016/S1473-3099(07)70312-2.

28. Beibei L, Yun C, Mengli C, et al. Linezolid versus vancomycin for the treatment of

gram-positive bacterial infections: Meta-analysis of randomised controlled trials. Int J

Antimicrob Agents 2010; 35:3-12; PMID: 19900794; DOI:

10.1016/j.ijantimicag.2009.09.013; 10.1016/j.ijantimicag.2009.09.013.

29. Piaggio G, Elbourne DR, Altman DG, et al. Reporting of noninferiority and

equivalence randomized trials: An extension of the CONSORT statement. JAMA 2006;

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Table and Figure Legends:

Table 1: Randomized Trial Characteristics

Figure 1: PRISMA Flow of Randomized Controlled Trials

Figure 2: All-cause Mortality

Figure 3a: Clinical Response – Intention-to-Treat Population

Figure 3b: Clinical Response – Per-Protocol Population

Figure 4a: Microbiological Eradication – Per-Protocol Population

Figure 4b: MRSA Eradication – Per-Protocol Population

Figure 5a: Gastrointestinal Events

Figure 5b: Thrombocytopenia

Figure 6a: Renal Failure

Figure 6b: Study Drug Discontinuation due to Adverse Events

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Table 1: Randomized trials characteristics

Study, Year

Total

sample

size

Mean Age (Linezolid/

Vancomcyin) Type of infection

Intubation

(%) at

baseline (Linezolid/

Vancomycin)

Mean days

of therapy (Linezolid/

Vancomycin)

Linezolid

arm (Gram-

negative

coverage)

Vancomycin

arm (Gram-negative

coverage)

Primary

outcome

Jadad

score

Rubinstein E

(2001) 20

402 63/61 Hospital-acquired

pneumonias

57.1/57.5 9.6/8.9 Linezolid +

Aztreonam

Vancomycin

+ Aztreonam

CR and

ME at TOC 4

Stevens DL

(2002) 21

460 64/60

MRSA infections,

including hospital-

acquired pneumonias

NR/NR 12.6/11.3 Linezolid +

Aztreonam

or

Gentamicin

Vancomycin

+ Aztreonam

or

Gentamicin

CR and

ME at TOC 3

Kaplan SL

(2003) 22

316 2.2/2.9

Gram-positive

infections, including

hospital-acquired

pneumonias


Aztreonam

or

Gentamicin

Vancomycin

+ Aztreonam

or

Gentamicin

CR and

ME at TOC 3

Wunderink R

(2003) 23

623 63/62 Hospital-acquired

pneumonias


Aztreonam

Vancomycin

+ Aztreonam

CR and

ME at TOC 3

Jaksic B

(2006) 24

421 48/47

Neutropenic fever,

including hospital-

acquired pneumonias


Gram-

negative

coverage

Vancomycin

+ Gram-

negative

coverage

CR and

ME at TOC 4

Kohno S

(2007) 25

151 68/67

MRSA infections,

including hospital-

acquired pneumonias


Aztreonam

or

Gentamicin

Vancomycin

+ Aztreonam

or

Gentamicin

CR and

ME at TOC 3

Wunderink R

(2008) 26

50 56/55 MRSA hospital-

acquired pneumonias

100/100 10.8/11.5 Linezolid +

Gram-

negative

coverage

Vancomycin

+ Gram-

negative

coverage

CR and

ME at FUV 3

Lin D

(2008) 19

144 56.3/59.6

Gram-positive

infections, including

hospital-acquired

pneumonias

5.6/11.3 12.2/10.7

Linezolid +

Aztreonam

Vancomycin

+ Aztreonam

CR at FUV

and EOT 3

Wunderink R

(2012) 10

1225 60.7/61.6 MRSA hospital-

acquired pneumonias

60.5/66.5 10/10 Linezolid +

Gram-

negative

coverage

Vancomycin

+ Gram-

negative

coverage

CR at FUV 4

TRE = Treatment; CON = Control; MRSA = Methicillin Resistant Staphylococcus aureus; CR = Clinical response;

ME = Microbiological eradication; TOC = Test of cure visit; FUV: Follow-up visit; EOT: end of therapy; NR = not reported

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1

Figure 1: PRISMA Flow of Randomized Controlled Trials

Relevant articles identified and screened for

retrieval (n=102)

Excluded:

- Case reports/series studies: 12

- Non-randomized cohort studies: 8

- Reviews, editorials, correspondences: 48

- Cost-effectiveness studies: 10

Randomized trials retrieved for more detailed

evaluation (n=24)

Excluded:

- Trials with other glycopeptides as

comparators: 2

- Trials with community-acquired

pneumonias: 4

- Trials evaluating safety only: 3

- Trials evaluating cost-effectiveness: 6

Randomized controlled trials included in the

meta-analysis (n=9)

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Group byStudy Design

Study name Statistics for each study Mortality / Total Risk difference and 95% CI

Risk Lower Upper difference limit limit p-Value Linezolid Vancomycin

Randomized Double-blind Rubinstein E 2001 -0.077 -0.157 0.004 0.063 36 / 203 49 / 193

Randomized Double-blind Wunderink R 2003 -0.003 -0.066 0.060 0.935 64 / 321 61 / 302

Randomized Double-blind Jaksic B 2006 -0.020 -0.060 0.019 0.310 17 / 304 23 / 301

Randomized Double-blind Lin D 2008 0.042 -0.029 0.113 0.243 5 / 71 2 / 71


Randomized Double-blind -0.013 -0.040 0.014 0.342 216 / 1496 235 / 1454

Randomized Open-label Stevens D 2002 0.033 -0.035 0.101 0.337 44 / 240 33 / 220

Randomized Open-label Kaplan S 2003 0.031 -0.015 0.077 0.189 13 / 215 3 / 101

Randomized Open-label Kohno S 2007 0.003 -0.114 0.119 0.963 14 / 100 7 / 51

Randomized Open-label Wunderink R 2008 -0.028 -0.108 0.053 0.498 4 / 75 6 / 74

Randomized Open-label 0.019 -0.014 0.052 0.253 75 / 630 49 / 446

Overall -0.000 -0.021 0.021 0.992 291 / 2126 284 / 1900

-0.50 -0.25 0.00 0.25 0.50

Favors Linezolid Favors Vancomycin

Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: Mortality*

*Intention-to-Treat Population. Z=0.010; P=0.992; Heterogeneity: Q=9.251; P=0.322; I2=13.5%

Figure 2. All-cause Mortality

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Study name Statistics for each study Mortality / Total Risk difference and 95% CI


Randomized Double-blind Rubinstein E 2001 0.029 -0.064 0.121 0.548 71 / 203 62 / 193


Randomized Double-blind Jaksic B 2006 0.019 -0.016 0.055 0.288 19 / 304 13 / 301


Randomized Double-blind Wunderink R 2012 0.021 -0.019 0.062 0.306 95 / 597 81 / 587

Randomized Double-blind 0.017 -0.007 0.041 0.159 318 / 1496 285 / 1454

Randomized Open-label Stevens D 2002 -0.014 -0.056 0.029 0.529 12 / 240 14 / 220

Randomized Open-label Kaplan S 2003 -0.057 -0.121 0.007 0.081 9 / 215 10 / 101

Randomized Open-label Kohno S 2007 -0.008 -0.115 0.100 0.889 11 / 100 6 / 51

Randomized Open-label Wunderink R 2008 0.052 -0.062 0.165 0.372 13 / 75 9 / 74

Randomized Open-label -0.019 -0.051 0.013 0.252 45 / 630 39 / 446

Overall 0.004 -0.015 0.024 0.656 363 / 2126 324 / 1900

-0.50 -0.25 0.00 0.25 0.50

Favors Vancomycin Favors Linezolid

Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: Clinical Response*

*Intention-to-Treat Population. Z=0.445; P=0.656; Heterogeneity: Q=6.747; P=0.564; I2=0%

Figure 3a. Clinical Response – Intention-to-Treat Population

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Study name Statistics for each study Clinical Response / Total Risk difference and 95% CI




Randomized Double-blind Jaksic B 2006 -0.041 -0.272 0.191 0.731 19 / 23 13 / 15


Randomized Double-blind Wunderink R 2012 0.110 0.005 0.216 0.041 95 / 165 81 / 174



Randomized Open-label Kaplan S 2003 -0.100 -0.337 0.137 0.409 9 / 10 10 / 10

Randomized Open-label Kohno S 2007 -0.015 -0.212 0.182 0.881 11 / 51 6 / 26



Overall 0.037 -0.019 0.092 0.192 365 / 596 325 / 565

-0.75 -0.38 0.00 0.38 0.75


Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: Clinical Response*

*Clinical Evaluable/Per Protocol Population. Z=1.303; P=0.192; Heterogeneity: Q=6.458; P=0.596; I2=0%

Figure 3b. Clinical Response – Per-Protocol Population

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Figure 4a. Microbiological Eradication – Per-Protocol Population


Study name Statistics for each study Micro Eradication / Total Risk difference and 95% CI











Overall 0.056 -0.022 0.133 0.159 170 / 318 139 / 282

-0.75 -0.38 0.00 0.38 0.75


Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: Microbiological Eradication*

*Microbiological Evaluable/Per-Protocol Population. Z=1.408; P=0.159; Heterogeneity: Q=3.404; P=0.757; I2=0%

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Study name Statistics for each study MRSA Eradication / Total Risk difference and 95% CI











Overall 0.064 -0.041 0.169 0.230 111 / 227 82 / 189

-0.75 -0.38 0.00 0.38 0.75


Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: MRSA* Eradication

*Methicillin-Resistant Staphylococcus aureus Microbiological Ev aluable/Per-Protocol Population. Z=1.199; P=0.230; Heterogeneity: Q=4.146; P=0.657; I2=0%

Figure 4b. MRSA Eradication – Per-Protocol Population

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Study name Statistics for each study GI Events / Total Risk difference and 95% CI







Randomized Open-label Stevens D 2002 0.144 0.073 0.215 0.000 64 / 240 27 / 220


Randomized Open-label Kohno S 2007 0.190 0.102 0.279 0.000 21 / 100 1 / 51



Overall 0.008 -0.000 0.015 0.050 137 / 1822 57 / 1599

-0.25 -0.13 0.00 0.13 0.25


Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: Gastrointestinal Events*


Figure 5a. Gastrointestinal Events

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Study name Statistics for each study Thrombocytopenia / Total Risk difference and 95% CI




Randomized Double-blind Lin 2008 0.028 -0.018 0.075 0.234 2 / 71 0 / 71

Randomized Double-blind Wunderink 2012 0.032 -0.008 0.072 0.122 97 / 597 77 / 587


Randomized Open-label Stevens D 2002 0.069 0.026 0.112 0.002 23 / 240 6 / 220


Randomized Open-label Kohnos S 2007 0.170 0.085 0.256 0.000 19 / 100 1 / 51

Randomized Open-label Wunderink 2008 0.013 -0.023 0.050 0.471 1 / 75 0 / 74

Randomized Open-label 0.053 0.008 0.099 0.021 47 / 630 7 / 446

Overall 0.008 -0.003 0.020 0.161 158 / 1822 94 / 1599

-0.25 -0.13 0.00 0.13 0.25


Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: Thrombocytopenia*


Figure 5b. Thrombocytopenia

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Study name Statistics for each study Renal Failure / Total Risk difference and 95% CI





Randomized Double-blind Wunderink R 2012 -0.036 -0.062 -0.010 0.006 22 / 597 43 / 587




Randomized Open-label Kohno S 2007 -0.088 -0.172 -0.004 0.040 1 / 100 5 / 51



Overall -0.007 -0.018 0.005 0.249 30 / 1822 54 / 1599

-0.25 -0.13 0.00 0.13 0.25


Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: Renal Failure*

*Intention-to-Treat Population. Z=-1.152; P=0.249; Heterogeneity: Q=13.525; P=0.06; I2=48%

Figure 6a. Renal Failure

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Study name Statistics for each study Discontinuation / Total Risk difference and 95% CI




Randomized Double-blind Lin D 2008 -0.056 -0.147 0.035 0.225 4 / 71 8 / 71








Overall -0.005 -0.016 0.007 0.424 105 / 1822 84 / 1599

-0.25 -0.13 0.00 0.13 0.25


Hospital-Acquired Pneumonia: Linezolid vs. Vancomycin: Discontinuation due to Adverse Events*

*Intention-to-Treat Population. Z=-0.800; P=0.424; Heterogeneity: Q=4.499; P=0.721; I2=0%

Figure 6b. Study Drug Discontinuation due to Adverse Events

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Study Random Sequence Generation

Allocation Concealment

Blinding of Participants and Personnel

Blinding of Outcome Assessment

Incomplete Outcome Data

Selective Reporting

Other Bias

Rubinstein 2001

+ ? + ? + + Industry funded

Stevens 2002

+ - - - + + Industry funded

Kaplan 2003


Wunderink 2003

+ - + - + + Industry funded

Jaksic 2006 + ? + ? + + Industry funded

Kohno 2007


Wunderink 2008


Lin 2008 + - + - + + Industry funded

Wunderink 2012

+ ? + - - - Industry funded

Key: (+) Low Risk Bias; (-) High Risk Bias; (?) Unclear Risk of Bias

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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist

Section/topic # Checklist item Reported on page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

2-3

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 4

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

5

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

na

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

7

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

5-5

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

5-6

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

6

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

5-6

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

6

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

7-8

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 7-8

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I

2) for each meta-analysis.

7-8

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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist

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Section/topic # Checklist item Reported on page #

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

7-8

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

7-8

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Figure 1

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

24-25

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 11

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

24

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 8-12

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 11

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 11

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

13-16

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

15-16

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 16

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

17

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma-statement.org.

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