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Intervention Review

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Linezolid versus vancomycin for skin and soft tissue infections

  1. Jirong Yue1,
  2. Bi Rong Dong1,*,
  3. Ming Yang1,
  4. Xiaomei Chen2,
  5. Taixiang Wu3,
  6. Guan J Liu4

Editorial Group: Cochrane Wounds Group

Published Online: 12 JUL 2013

Assessed as up-to-date: 9 MAY 2013

DOI: 10.1002/14651858.CD008056.pub2


How to Cite

Yue J, Dong BR, Yang M, Chen X, Wu T, Liu GJ. Linezolid versus vancomycin for skin and soft tissue infections. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD008056. DOI: 10.1002/14651858.CD008056.pub2.

Author Information

  1. 1

    West China Hospital, Sichuan University, Department of Geriatrics, Chengdu, Sichuan, China

  2. 2

    West China Hospital, Sichuan University, Department of Dermatology & Venereology, Chengdu, Sichuan, China

  3. 3

    West China Hospital, Sichuan University, Chinese Clinical Trial Registry, Chinese Ethics Committee of Registering Clinical Trials, Chengdu, Sichuan, China

  4. 4

    West China Hospital, Sichuan University, Chinese Cochrane Centre, Chinese Evidence-Based Medicine Centre, Chengdu, Sichuan, China

*Bi Rong Dong, Department of Geriatrics, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. birongdong@163.com.

Publication History

  1. Publication Status: New
  2. Published Online: 12 JUL 2013

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This is not the most recent version of the article. View current version (07 JAN 2016)

 
Characteristics of included studies [ordered by study ID]
Itani 2010

MethodsOpen-label, multicentred, randomised study.


ParticipantsLocation: 102 centres in the USA, Eastern and Western Europe, Latin America, South Africa, Malaysia, and Singapore.
Time frame: October 2004-July 2007.
Inclusion criteria: patients ≥18 years, with MRSA-infected cSSTIs.
Patient numbers: 1052 randomised. 640 were confirmed as MRSA positive, 322 in linezolid group, and 318 in vancomycin group.
Average age: Linezolid group: 49.7 years, Vancomycin group: 49.4 years.
Male:female ratio: Linezolid group: 305:232, Vancomycin group: 315:200.


InterventionsLinezolid group (n = 537): 600 mg IV linezolid every 12 h; could be switched to oral at any time at investigator's discretion.
Vancomycin group (n = 515): IV 15 mg/kg vancomycin every 12 h with dose adjustment as necessary, based on trough levels and creatinine clearance.
Treatment duration: 7–14 days for both groups.


OutcomesClinical outcomes: the number of cures.
Microbiological outcomes: measured by pathogen eradication rate.
Safety: treatment-related adverse events.
Mortality: number of deaths in each group; investigator considered cause of death to be unrelated to the study drug.
Length of hospital stay.
Duration of intravenous therapy.


NotesAztreonam (or other antibiotic known to be inactive against Gram-positive organisms/MRSA) and metronidazole were permitted to treat suspected Gram-negative pathogens and anaerobic pathogens, respectively.

Quote: "This study was funded by Pfizer, Inc; editorial support was provided by Elizabeth Melby Wells and Jean Turner of PAREXEL, Stamford, CT, and was funded by Pfizer, Inc; Kamal Itani has been a consultant and speaker for Pfizer; Matthew Dryden has been a member of advisory boards and has been a speaker for Pfizer, Wyeth, Bayer, and Jansen Cilag; Helen Bhattacharyya, Mark Kunkel, and Alice Baruch are employees of Pfizer; John Weigelt is a consultant to Pfizer, Ortho McNeil, and Schering-Plough."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised".
Comment: the method of sequence generation was not reported in the trial.

Allocation concealment (selection bias)High riskQuote: "This prospective, randomised, open-label, comparator-controlled, multicenter study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - participants
High riskQuote: "This prospective, randomised, open-label, comparator-controlled, multicenter study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - care givers
High riskQuote: "This prospective, randomised, open-label, comparator-controlled, multicenter study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
High riskQuote: "This prospective, randomised, open-label, comparator-controlled, multicenter study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
High riskDropouts: Linezolid group: 93/322 (28.9%); Vancomycin group: 108/318 (33.9%).
Comment: the reasons for dropping-out were not reported, and the rate of dropout was high. We think this level of losses would have affected the outcome.

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
High risk1052 randomised, 640 included in analysis.
Comment: ITT was not undertaken.

Selective reporting (reporting bias)Low riskQuote: "study was conducted between October 2004 and July 2007 (Clinical Trials gov: no. NCT00087490)".
Comment: the study protocol was available and all of the study's pre-specified (primary and secondary) outcomes that were of interest in the review were reported in the pre-specified way.

Other biasLow riskNo other biases identified.

Jaksic 2006

MethodsRandomised, multicentred, multinational, double-blind study.


ParticipantsLocation: 58 sites in Australia, Austria, Belgium, Croatia, France, Germany, Greece, Italy, Poland, Russia, Slovenia, South Africa, Spain, and Switzerland.
Time frame: November 2000-May 2002.
Inclusion criteria: patients ≥ 13 years, hospitalised febrile adults with cancer and proven, or suspected, Gram-positive bacterial infection.
Patient numbers: 605 randomised, 47 had SSTIs.
Average age: Linezolid group: 47.2 years, Vancomycin group : 48.1 years (for all study participants).
Male:female ratio: Linezolid group: 129:125, Vancomycin group: 161:140 (for all study participants).


InterventionsLinezolid group (n = 304, 27 SSTIs): linezolid: 600 mg IV every 12 h.
Vancomycin group (n = 301, 20 SSTIs): vancomycin: 1 g IV every 12 h.
Treatment duration: median length of therapy 10 days for both groups.
Follow-up duration: 10–28 days for both groups.


OutcomesClinical outcomes: clinical success was defined as cure (defervescence (abatement of fever) and resolution of signs and symptoms of infection), or improvement (defervescence and improvement of signs and symptoms of infection). Defervescence was defined as maximum oral temperature of ≤ 37.5 oC or axillary temperature of ≤ 36.7 oC on 3 consecutive days. Failure was defined as persistence, or progression, of clinical signs and symptoms of infection, or development of new findings. An indeterminate outcome was defined as an inability to make an assessment.
Microbiological outcomes: assessed as success (documented eradication, presumed eradication, or colonisation), failure (documented persistence, presumed persistence, or superinfection), indeterminate, or missing.
Safety: drug-related adverse events.
Mortality: mortality rates at 16 days after completion of therapy.


NotesSSTIs as a subgroup of Gram-positive bacterial infection.

Quote: "B.J., G.M., and J.P.-O. received research grants from Pfizer. C.S.H., L.B.L, and K.J.T. are employed by Pfizer."
Comment: the study was supported by a grant from Pfizer.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Eligible patients were randomly assigned in a 1:1 ratio".
Comment: the method of sequence generation was not reported in the trial.

Allocation concealment (selection bias)Unclear riskComment: did not report whether allocation was concealed.

Blinding (performance bias and detection bias)
All outcomes - participants
Low riskQuote: "To maintain blinding, a research pharmacist prepared study medications; an unblinded co investigator monitored vancomycin or serum creatinine levels in accordance with local practice".
Comment: participants were blinded.

Blinding (performance bias and detection bias)
All outcomes - care givers
Low riskQuote: "To maintain blinding, a research pharmacist prepared study medications; an unblinded co investigator monitored vancomycin or serum creatinine levels in accordance with local practice".
Comment: the care-giver was blinded.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
Unclear riskQuote: "an unblinded co investigator monitored vancomycin or serum creatinine levels in accordance with local practice".

Comment: knowledge of the intervention was unlikely to cause bias of vancomycin or serum creatinine levels, but the trial report did not state whether the assessor of signs and symptoms of infection was blinded.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
Unclear riskComment: dropouts reported for all study participants, but not clear for SSTIs.

dropouts: Linezolid group: 53/304 (17.4%); Vancomycin group: 64/301 (21.2%).

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
High risk605 randomised, 488 included in analysis for all study participants.

47 randomised, 38 included in analysis for SSTIs.
Comment: ITT was not undertaken.

Selective reporting (reporting bias)Unclear riskComment: the study protocol is not available and the trial authors did not report whether the published reports included all expected outcomes.

Other biasLow riskNo other biases identified.

Kohno 2007

MethodsOpen-label, comparator-controlled, multicentred study, 2:1 ratio randomised.


ParticipantsLocation: 84 sites in Japan.
Time frame: October 2001-January 2004.
Inclusion criteria: patients > 20 years, with confirmed, or suspected, MRSA-related pneumonia, cSSTI or sepsis.
Patient numbers: 151 randomised, 48 had MSRA SSTIs.
Average age: Linezolid group: 68.4 years, Vancomycin group: 67.5 years (for all study participants).
Male:female ratio: Linezolid group: 70:30, Vancomycin group: 36:15 (for all study participants).


InterventionsLinezolid group (n = 100, 31 SSTIs): linezolid 600 mg IV every 12 h, could be switched to oral after a minimum of 3 days.
Vancomycin group (n = 51, 17 SSTIs): vancomycin 1 g IV every 12 h.
Treatment duration: 7–28 days for both groups.


OutcomesClinical outcomes: the success rate was defined as the number of cures and improvements divided by the number of cures, improvements and failures. "Cured" defined as resolution of the clinical signs and symptoms of infection when compared with baseline; "improved" defined as improvement in 2 or more, but not all, clinical signs and symptoms of infection when compared with baseline; "failed" defined as persistence or progression of baseline clinical signs and symptoms of infection; and "indeterminate" defined as unable to assess.
Microbiological outcomes: microbiological eradication rates.
Safety: treatment-related adverse events.


NotesPatients could receive aztreonam or gentamicin (or other aminoglycosides with no activity against the isolated MRSA) for Gram-negative coverage.

Quote: "This study was sponsored by Pfizer Inc. Editorial support was provided by Philip Matthews at PAREXEL and was funded by Pfizer Inc."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised".
Comment: the method of sequence generation in the trial was not reported.

Allocation concealment (selection bias)High riskQuote: "This was a open-label, comparator-controlled, multicentre study".

Comment: the trial had an open-label design, and, therefore was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - participants
High riskQuote: "This was a open-label, comparator-controlled, multicentre study".

Comment: the trial had an open-label design, and, therefore was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - care givers
High riskQuote: "This was a open-label, comparator-controlled, multicentre study".

Comment: the trial had an open-label design, and, therefore was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
High riskQuote: "This was a open-label, comparator-controlled, multicentre study".

Comment: the trial had an open-label design, and, therefore was judged to be at high risk of bias.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
High riskOnly reported the number of dropouts, but not the reasons. These figures were not clear for SSTIs.

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
High risk151 randomised, 92 were included in analysis for all study participants.

48 randomised, 28 were included in analysis for SSTIs.
Comment: ITT was not undertaken.

Selective reporting (reporting bias)Unclear riskComment: the study protocol is not available and the trial authors did not state whether the published reports included all expected outcomes.

Other biasLow riskNo other biases identified.

Lin 2008

MethodsRandomised, double-blind, multicentred study.


ParticipantsLocation: 7 sites in China.
Time frame: April 2001-March 2005.
Inclusion criteria: hospitalised patients aged 18–75 years with known, or suspected, infection due to Gram-positive bacteria, including pneumonia and cSSTI.
Patient numbers: 142 randomised, 62 had cSSTI.
Average age: Linezolid group: 56.3 years, Vancomycin group: 59.6 years (for all study participants).
Male:female ratio: Linezolid group: 46:25, Vancomycin group: 42:29 (for all study participants).


InterventionsLinezolid group ( n = 71, 33 SSTIs): linezolid 600 mg IV every 12 h.
Vancomycin group (n = 71, 29 SSTIs): vancomycin 1 g IV every 12 h if aged ≤ 60 years, or 0.75 g if aged > 60 years.
Treatment duration: 7–21 days for both groups.


OutcomesClinical outcomes: "cured" defined as complete resolution of 4 areas identified at baseline as abnormal: (i) signs; (ii) symptoms; (iii) haematology and chemistry; and (iv) microbiology; "marked improvement" defined as resolution of 3/4 areas; "improved" defined as resolution of at least 2 areas; "failed"defined as persistence or progression of baseline.
Microbiological outcomes: measured by pathogen eradication rate.
Safety: drug-related adverse events.


NotesConcomitant use of aztreonam was permitted in patients with documented mixed Gram-positive and Gram-negative organisms.

Quote: "This study was sponsored by Pfizer Inc. Editorial support was provided by Jean Turner and Elizabeth Melby Wells of PAREXEL (Stamford, CT) and was funded by Pfizer Inc."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised".
Comment: the method of sequence generation in the trial was not reported.

Allocation concealment (selection bias)Unclear riskComment: no report of whether allocation was concealed.

Blinding (performance bias and detection bias)
All outcomes - participants
Unclear riskQuote: "This Phase 3, randomised, double-blind, comparator controlled, multicentre study".

Comment: reported to be double-blind, but no specific details provided about who was blinded.

Blinding (performance bias and detection bias)
All outcomes - care givers
Unclear riskQuote: "This Phase 3, randomised, double-blind, comparator controlled, multicentre study"
Comment: reported to be double-blind, but no specific details provided about who was blinded.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
Unclear riskQuote: "This Phase 3, randomised, double-blind, comparator controlled, multicentre study"
Comment: reported to be double-blind, but no specific details provided about who was blinded.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
Low riskdropouts were adequately addressed.

dropouts(for all study participants): Linezolid group: 12/71 (16.9%); Vancomycin group: 14/71 (19.7%).

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
High risk142 randomised, 121 included in analysis for all study participants.

62 randomised, 59 were included in analysis for SSTIs.
Comment: ITT was not undertaken.

Selective reporting (reporting bias)Unclear riskComment: the study protocol is not available and the trial authors did not state whether the published reports included all expected outcomes.

Other biasLow riskNo other biases identified.

Sharpe 2005

MethodsSingle-centred, open-label randomised study.


ParticipantsLocation: USA.
Unknown time frame.
Inclusion criteria: patients ≥18 years, with proven MRSA-related cSSTIs requiring surgical intervention.
Patient numbers: 60 randomised.
Average age: Linezolid group: 66 years, Vancomycin group: 76 years.
Male:female ratio: Linezolid group: 10:20, Vancomycin group: 10:20.


InterventionsLinezolid group (n = 30): linezolid 600 mg orally every 12 h.
Vancomycin group (n = 30): vancomycin 1 g IV every 12 h.
Treatment duration: the median length of therapy was 10 days for both groups.


OutcomesClinical outcomes: clinical cure defined as temperature normalization; presence of granulation or wound healing; resolution of pain; and decreased or resolved erythema, oedema, induration, and colour. Ulceration could persist, but lesions must appear noninfected to be defined as clinically cured. Clinical improvement defined as moderate resolution of 2 or more clinical symptoms. Clinical failure defined as persistence or progression of baseline signs and symptoms, development of new symptoms consistent with Gram-positive infection, or inability to complete the study because of adverse events.
Microbiological outcomes: microbiological eradication documented by culture or presumed because of an absence of clinical symptoms. Microbiological persistence documented by presence of 1 or more of the original infecting organisms on the culture test for cure. Microbiological recurrence defined as presence on final culture of an original infecting organism whose eradication had been either documented or presumed at the end of therapy.
Hospitalisation duration: median length of hospital stay.
Cost: total hospital charges per patient; the daily cost of outpatient therapy.


NotesAll patients received perioperative cefazolin while awaiting culture results. Patients could receive up to 48 h of topical or systemic antibiotics before randomisation.

Quote: "Supported by an unrestricted educational grant from Pfizer Inc." Comment: this study was supported by Pfizer, Inc.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Thirty patients were randomised".
Comment: the method of sequence generation used in the trial was not reported.

Allocation concealment (selection bias)High riskQuote: "This single-center, open-label study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - participants
High riskQuote: "This single-center, open-label study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - care givers
High riskQuote: "This single-center, open-label study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
High riskQuote: "This single-center, open-label study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
High riskComment: data concerning dropouts were not reported. The trial paper only reported the percentage cured. We calculated the number of clinical cures from this percentage.

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
Unclear riskComment: did not report whether ITT was undertaken.

Selective reporting (reporting bias)Unclear riskComment: the study protocol is not available and trial authors did not report whether the published reports included all expected outcomes.

Other biasUnclear riskComment: there was baseline imbalance as the group of patients who received linezolid were significantly younger than those who received vancomycin (66 vs 76 years), this is unlikely to be clinically significant.

Stevens 2002

MethodsOpen-label, multicentred, randomised phase III clinical trial.


ParticipantsLocation: 104 sites in North America, Europe, Latin America and Asia.
Time frame: July 1998-July 1999.
Inclusion criteria: patients ≥ 13 years, hospitalised with presumed MRSA infection.
Patient numbers: 460 randomised, 230 had SSTIs.
Average age: Linezolid group: 63.9 years, Vancomycin group: 59.8 years (for all study participants).
Male:female ratio: Linezolid group: 143:97, Vancomycin group: 131:89 (for all study participants).


InterventionsLinezolid group (n = 240, 122 SSTI): linezolid 600 mg IV twice daily, which could be changed to oral with clinical improvement.
Vancomycin group (n = 220, 108 SSTI): vancomycin 1 g IV twice daily.
Treatment duration: 7–14 days for both groups.


OutcomesClinical outcomes: used 4 possible clinical outcomes: "cure," "treatment failure," "indeterminate," or "missing." "Cure" defined as resolution of baseline clinical signs and symptoms of infection after ≥ 5 days and ≥ 10 doses of treatment. "Treatment failure" assigned if there was persistence or progression of signs and symptoms of infection after ≥ 2 days and ≥ 4 doses of treatment, or if there was no clinical assessment at end of therapy and test-of-cure. "Indeterminate" assigned if there was clinical improvement, or cure, at end of therapy but no test-of-cure assessment, or if there was cure after receipt of < 5 days or < 10 doses of study medication. "Missing" was assigned if < 2 days or < 4 doses of treatment were received.
Microbiological outcomes: 4 possible microbiological outcomes: "success," "treatment failure," "indeterminate," or "missing." "Success" defined as documented or presumed eradication of all pathogens present at baseline or colonization. "Treatment failure" defined as documented or presumed persistence of 1 pathogen present at baseline, superinfection, or reinfection. "Indeterminate" assigned if the clinical outcome at test-of-cure visit was indeterminate or missing. "Missing" assigned if there were no microbiological data from the test-of-cure visit.
Safety: drug-related adverse events.

Length of stay.


NotesSSTIs were a subset of MRSA infection. The trial also included other infection types such as bacteraemia, pneumonia, and urinary-tract infections.
Gram-negative coverage was allowed.

Quote: "D.L.S. has received funding from Pharmacia, Pfizer Pharmaceuticals, and Wyeth-Ayerst for investigator-initiated research proposals".
Comment: DLS was the lead author of the study report.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Hospitalized patients were randomised".
Comment: the method of sequence generation used in the trial was not reported.

Allocation concealment (selection bias)High riskQuote: "This randomised open-label trial".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - participants
High riskQuote: "This randomised open-label trial".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - care givers
High riskQuote: "This randomised open-label trial".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
High riskQuote: "This randomised open-label trial".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
Unclear riskQuote: "Overall, 78 (32.5%) of 240 patients in the linezolid group and 69 (31.4%) of 220 in the vancomycin group discontinued treatment. The most common reasons for discontinuation of study medication were as follows: no methicillin-resistant pathogen detected at baseline (13.3% of patients [32/240] in the linezolid group vs 17.3% of patients [38/220] in the vancomycin group) . . ."
Comment: dropouts reported for all MRSA infections, but not clear for SSTIs.

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
High risk460 randomised, 361 included in analysis for all study participants.

230 randomised, 186 included in analysis for SSTIs.
Comment: ITT was not undertaken.

Selective reporting (reporting bias)Unclear riskComment: the study protocol is not available and trial authors did not report whether the published reports included all expected outcomes

Other biasUnclear riskQuote: "patients who received linezolid were significantly older than those who received vancomycin (63.9 vs 59.8 yrs p = 0.0157)".

Comment: baseline imbalance reported, this is unlikely to be clinically significant, therefore, judged to be at unclear risk of bias.

Weigelt 2005

MethodsRandomised, open-label, multicentred study.


ParticipantsLocation: Asia Pacific, South America, North America, Europe and New Zealand.
Timeframe: October 2002-March 2003.
Inclusion criteria: suspected or proven MRSA complicated SSTIs requiring hospitalisation.
Patient numbers: 1200 randomised; 20 of these were randomised but never received treatment (8 never received linezolid and 12 never received vancomycin).
Average age: 52 years in both groups.
Male:female ratio: Linezolid group: 375:217, Vancomycin group: 363:225.


InterventionsLinezolid group (n = 592): linezolid 600 mg every 12 h, IV or oral.
Vancomycin group (n = 588): vancomycin 1 g IV every 12 h.
Treatment duration: 4–21 days for both groups.


OutcomesClinical outcomes: patients counted as (i) "cured" if complete resolution of all pre-therapy clinical signs and symptoms of infection (e.g. body temperature and white blood cell count) was achieved; (ii) "improved" if, at the end of treatment, 2 or more (but not all) of the pre-therapy clinical signs and symptoms of CSSTI were resolved; (iii) "failed" if they exhibited persistence or progression of baseline clinical signs and symptoms of infection, development of new clinical findings consistent with active infection, or an inability to complete the study because of adverse events; and (iv) "indeterminate" if extenuating circumstances precluded classification to one of the above-described categories, usually because of missed appointments.
Microbiological outcomes: were categorised as: (i) "success" if had documented or presumed eradication of the pathogen present at baseline; (ii) "failure" if had documented or presumed persistence of pathogen present at baseline; (iii) "indeterminate" if pathogen data were indeterminate; or (iv) "missing" if the pathogen data were missing.

Mortality: the number of death in each group. Cause of death was judged by the investigator to be unrelated to the study drug.

Duration of treatment.
Safety: drug-related adverse events.

Length of stay.

Cost.


NotesIf MSSA was found, patients were switched to an appropriate antibiotic. Concomitant use of aztreonam or other antibiotics for Gram-negative organisms was permitted.

Quote: "J. Weigelt, D. Stevens, K. Itani, W. Lau, and M. Dryden have conducted research on behalf of Pfizer and have been on the Pfizer speakers' bureau. C. Knirsch is an employee of Pfizer, Inc."
Comment: this study was supported by Pfizer, Inc.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised".
Comment: the method of sequence generation used in the trial was not reported.

Allocation concealment (selection bias)High riskQuote: "This was a randomised, open-label".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - participants
High riskQuote: "This was a randomised, open-label".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - care givers
High riskQuote: "This was a randomised, open-label".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
High riskQuote: "This was a randomised, open-label".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
Low riskdropouts were adequately addressed.
dropouts: Linezolid group: 46/592 (7.8%); Vancomycin group: 66/588 (11.2%).

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
High risk1200 randomised, 930 included in analysis.
Comment: ITT was not undertaken.

Selective reporting (reporting bias)Unclear riskComment: the study protocol is not available and trial authors did not state whether the published reports included all expected outcomes.

Other biasLow riskNo other biases identified.

Wilcox 2009

MethodsOpen-label, multicentred, randomised study.


ParticipantsLocation: 100 centres in Europe, USA, Latin America and Asia.
Time frame: May 2002-May 2005.
Inclusion criteria: patients ≥ 13 years, with a central venous, pulmonary artery, or arterial catheter in place for 13 days and suspected catheter-related infection.
Patient numbers: 726 randomised, 315 had cSSTI.
Average age: Linezolid group: 53.7 years, Vancomycin group: 53.8 years; (for all study participants).
Male:female ratio: Linezolid group: 202:161, Vancomycin group: 210:153 (for all study participants).


InterventionsLinezolid group (n = 363, 164 SSTIs): linezolid 600 mg IV every 12 h; could be switched to oral.
Vancomycin group (n = 363, 151 SSTIs): vancomycin 1 g IV every 12 h.
Duration: 7–28 days for both groups.


OutcomesClinical outcomes: assessed as "success" (cure with resolution of signs and symptoms or, at end of treatment only, improvement
with moderate resolution of signs and symptoms and no additional antibiotic treatment); or "failure" (persistence or progression of clinical signs and symptoms or new clinical findings of infection).

Microbiological outcomes: assessed as "success" (documented or presumed eradication based on clinical outcome) or "failure"
(documented or presumed persistence based on clinical failure and either missing microbiologic outcome or use of non-study antibiotic because of lack of efficacy).
Safety: all adverse events.

All cause mortality: 1-2 weeks after treatment.


NotesFor methicillin-susceptible pathogens, vancomycin could be switched to oxacillin 2 g IV, or dicloxacillin 500 mg orally, each given every 6 h. Concomitant therapy allowed on the basis of susceptibility and local practice.

Quote: "M.H.W. has received honoraria for consultancy work, financial support to attend meetings, and research funding from Astra-Zeneca, Bayer, Cerexa, Genzyme, Nabriva, Pfizer, Targanta, Vicuron"
Comment: M.H.W was the lead author of the study report.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly assigned".
Comment: the method of sequence generation used in the trial was not reported.

Allocation concealment (selection bias)High riskQuote: "This was a open-label, multicenter comparative study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - participants
High riskQuote: "This was a open-label, multicenter comparative study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - care givers
High riskQuote: "This was a open-label, multicenter comparative study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
High riskQuote: "This was a open-label, multicenter comparative study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
High riskdropouts (for all study participants):
Linezolid group: 177/363 (48.8%); Vancomycin group: 179/363 (49.3%).
Comments: reasons for dropouts were reported, but the levels were very high. In addition, the dropout rate was not clear for SSTIs, therefore, this was judged to be at high risk of bias.

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
High risk726 randomised, 422 included in analysis for all study participants.

315 randomised, 296 included in analysis for SSTIs.
Comment: ITT was not undertaken.

Selective reporting (reporting bias)Unclear riskComment: the study protocol is not available and trial authors did not stated whether the published reports included all expected outcomes.

Other biasLow riskNo other biases identified.

Yogev 2003

MethodsOpen label, randomised, multicentred study, randomised in a 2:1 ratio.


ParticipantsLocation: 59 sites throughout USA, Mexico and South America.
Time frame: February 2001-December 2001.
Inclusion criteria: hospitalised patients ≤ 12 years, with pneumonia, SSTIs, catheter-related bacteraemia, or bacteraemia of unknown source because of resistant Gram-positive pathogen. This paper only addressed the cSSTIs outcome.
Patient numbers: 120 randomised.
Average age: Linezolid group: 3.48 years, Vancomycin group: 3.03 years.
Male:female ratio: Linezolid group: 46:34, Vancomycin group: 23:17.


InterventionsLinezolid group (n = 80): linezolid 10 mg/kg IV every 8 h; could be switched to oral after at least 3 days.
Vancomycin group (n = 40): vancomycin 10–15 mg/kg IV every 6–24 h; duration: 10–28 days.
Treatment duration: 7–14 days for both groups.


OutcomesClinical outcomes: resolution of the signs associated with the cSSI, including lesion size, tenderness, erythema, swelling, induration, fluctuance, heat/localized warmth or discharge (purulent or nonpurulent).
Microbiological outcomes: individual pathogen eradication rates.
Safety: drug-related adverse events.
All cause mortality: the number of death in each group.


NotesSSTIs as a subset of study Kaplan 2003.
Vancomycin patients could be switched to an alternative antibiotic if non-MRSA pathogen isolated. Gram-negative coverage was allowed.

Quote: "From the Children's Memorial Hospital, Chicago . . . and Pharmacia Corp.".

Comment: the study was funded by Pharmacia Corporation.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised in a 2:1 ratio".
Comment: the method of sequence generation used in the trial was not reported.

Allocation concealment (selection bias)High riskQuote: "The methods for this open-label, randomised, multicenter study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - participants
High riskQuote: "The methods for this open-label, randomised, multicenter study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - care givers
High riskQuote: "The methods for this open-label, randomised, multicenter study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Blinding (performance bias and detection bias)
All outcomes - outcome assessors
High riskQuote: "The methods for this open-label, randomised, multicenter study".

Comment: the trial had an open-label design, and, therefore, was judged to be at high risk of bias.

Incomplete outcome data (attrition bias)
All outcomes drop outs reported
High riskComment: data relating to dropouts were not reported.

Incomplete outcome data (attrition bias)
All outcomes ITT analysis reported
High risk120 randomised, 108 included in analysis for all study participants.
Comment: ITT was not undertaken.

Selective reporting (reporting bias)Unclear riskComment: the study protocol is not available and trial authors did not state whether the published reports included all expected outcomes.

Other biasLow riskNo other biases identified.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bounthavong 2009Cost-effectiveness analysis, not an RCT.

Hau 2002Cost-effectiveness analysis, not an RCT.

Joseph 2007Not an RCT.

Kalil 2006A comment, not an RCT.

Lipsky 2011A review; pooled data from three prospective clinical trials.

McKinnon 2007Health economics analysis, not an RCT.

Patanwala 2007Cost-effectiveness analysis, not an RCT.

Schurmann 2009Cost-effectiveness analysis, not an RCT.

 
Comparison 1. Clinical cure

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All participants93114Risk Ratio (M-H, Fixed, 95% CI)1.09 [1.03, 1.16]

 2 Adults' subgroup (≥ 18 years)52402Risk Ratio (M-H, Random, 95% CI)1.16 [1.02, 1.32]

 3 MRSA subgroup62659Risk Ratio (M-H, Fixed, 95% CI)1.09 [1.03, 1.17]

 
Comparison 2. Microbiological cure

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All participants92014Risk Ratio (M-H, Random, 95% CI)1.08 [1.01, 1.16]

 2 Adults' subgroup (≥ 18 years)51458Risk Ratio (M-H, Random, 95% CI)1.17 [1.02, 1.34]

 3 MRSA subgroup61289Risk Ratio (IV, Random, 95% CI)1.17 [1.04, 1.32]

 
Comparison 3. Mortality

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality during follow-up32352Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.75, 2.80]

 
Comparison 4. Adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia21300Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.33, 1.62]

 2 Diarrhoea32352Risk Ratio (IV, Random, 95% CI)1.78 [0.81, 3.88]

 3 Red man syndrome21172Risk Ratio (M-H, Fixed, 95% CI)0.04 [0.01, 0.29]

 4 Pruritus32352Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.17, 0.75]

 5 Rash32352Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.12, 0.58]

 6 Thrombocytopenia21300Risk Ratio (IV, Fixed, 95% CI)13.06 [1.72, 99.22]

 7 Headache22232Risk Ratio (IV, Fixed, 95% CI)1.23 [0.59, 2.61]

 8 Nausea22232Risk Ratio (M-H, Fixed, 95% CI)2.45 [1.52, 3.94]

 9 Vomiting22232Risk Ratio (M-H, Fixed, 95% CI)2.20 [0.96, 5.04]

 
Comparison 5. Duration of treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of treatment (day)11180Mean Difference (IV, Fixed, 95% CI)0.90 [0.32, 1.48]