Service Line: Rapid Response Service Version: 1.0 Publication Date: October 25, 2017 Report Length: 60 Pages

Transcription

1 CADTH RAPID RESPONSE REPORT: PEER REVIEW WITH CRITICAL APPRAISAL Linezolid for the Treatment of Infections: A Review of the Clinical and Cost- Effectiveness Service Line: Rapid Response Service Version: 1.0 Publication Date: October 25, 2017 Report Length: 60 Pages

2 Authors: Ismat Kanga, Veronica Poitras, Caitlyn Ford Cite As: Linezolid f or the treatment of inf ections: A rev iew of the clinical and cost-ef fectiveness. Ottawa: CADTH; 2017 Sep. (CADTH rapid response report: peer-rev iewed summary with critical appraisal). Acknowledgments: ISSN: (online) Disclaimer: The inf ormation in this document is intended to help Canadian health care decision-makers, health care prof essionals, health sy stems leaders, and policy -makers make well-inf ormed decisions and thereby improv e the quality of health care serv ices. While patients and others may access this document, the document is made av ailable f or inf ormational purposes only and no representations or warranties are made with respect to its f itness f or any particular purpose. The inf ormation in this document should not be used as a substitute f or prof essional medical adv ice or as a substitute f or the application of clinical judgment in respect of the care of a particular patient or other prof essional judgment in any decision-making process. The Canadian Agency f or Drugs and Technologies in Health (CADTH) does not endorse any inf ormation, drugs, therapies, treatments, products, processes, or serv ices. While care has been taken to ensure that the inf ormation prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was f irst published by CADTH, CADTH does not make any guarantees to that ef f ect. CADTH does not guarantee and is not responsible f or the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The v iews and opinions of third parties published in this document do not necessarily state or ref lect those of CADTH. CADTH is not responsible f or any errors, omissions, injury, loss, or damage arising f rom or relating to the use (or misuse) of any inf ormation, statements, or conclusions contained in or implied by the contents of this document or any of the source materials. This document may contain links to third-party websites. CADTH does not hav e control ov er the content of such sites. Use of third-party sites is gov erned by the third-party website owners own terms and conditions set out f or such sites. CADTH does not make any guarantee with respect to any inf ormation contained on such third-party sites and CADTH is not responsible f or any injury, loss, or damage suf f ered as a result of using such third-party sites. CADTH has no responsibility f or the collection, use, and disclosure of personal inf ormation by third-party sites. Subject to the af orementioned limitations, the v iews expressed herein are those of CADTH and do not necessarily represent the v iews of Canada s f ederal, prov incial, or territorial gov ernments or any third party supplier of inf ormation. This document is prepared and intended f or use in the context of the Canadian health care sy stem. The use of this docum ent outside of Canada is done so at the user s own risk. This disclaimer and any questions or matters of any nature arising f rom or relating to the content or use (or misuse) of this document will be gov erned by and interpreted in accordance with the laws of the Prov ince of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusiv e jurisdiction of the courts of the Prov ince of Ontario, Canada. The copy right and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document f or non-commercial purposes only, prov ided it is not modif ied when reproduced and appropriate credit is giv en to CADTH and its licensors. About CADTH: CADTH is an independent, not-f or-prof it organization responsible f or prov iding Canada s health care decision-makers with objectiv e ev idence to help make inf ormed decisions about the optimal use of drugs, medical dev ices, diagnostics, and procedures in our health care sy stem. PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 2

3 Reviewers This document was externally reviewed by content experts and the following individuals granted permission to be cited. Caroline Quach, MD MSc FRCPC Associate Professor Department of Microbiology, Infectious Diseases & Immunology, Université de Montréal Montreal, Quebec, Canada PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 3

4 Context and Policy Issues Antibiotic resistance or the decreasing susceptibility of bacteria to traditional antibiotics is a significant concern, 1 resulting in substantial socioeconomic burden from increased hospitalizations, hospital length of stay, health care costs, and loss of productivity. 2 Methicillin-resistant Staphylococcus aureus (MRSA) bacteria contain a gene that makes them resistant to methicillin, and other beta-lactam antibiotics including flucloxacillin, certain cephalosporins, and carbapenems. 3 MRSA can exist as part of the body s normal flora, particularly in the nasal passages. 3 However, in individuals with prolonged hospital stays, underlying disease or after antibiotic use, MRSA can cause skin and soft tissue infections, pneumonia, bacteremia, and endocarditis. 3 In Canada, the rate of all MRSA infections was 2.12 per 1,000 patient admissions in Though rates have declined since 2008, MRSA infections remain a concern in certain populations including Indigenous peoples, and in homeless, and intravenous drug user populations. 2 Enterococcus faecium most frequently causes vancomycin-resistant enterococci (VRE) infections. 4 VRE infections are predominantly healthcare-associated infections, resulting in bloodstream, surgical wound, urinary tract, and intra-abdominal infections. 2,4 In 2014, 54 Canadian hospitals reported a total of 294 cases of VRE infections equating to 0.45 cases per 10,000 patient days. 2 Of the 294 reported cases, 29% resulted in bloodstream infections. 2 Vancomycin, linezolid, and daptomycin are common antibiotics for the treatment of MRSA infections, 5 while linezolid and daptomycin are considered front-line therapies for the treatment of VRE infections. 6 Vancomycin and linezolid exhibit bacteriostatic activity, by inhibiting proper cell wall synthesis in Gram-positive bacteria and by disrupting protein synthesis in the ribosomes by attaching to the 50S ribosomal unit respectively. 1 In contrast, daptomycin exhibits potent bactericidal activity by causing membrane depolarization resulting in cessation of DNA, RNA and protein synthesis. 7 Vancomycin and daptomycin are administered intravenously, 1,8 however patients treated with linezolid can be switched from intravenous to oral linezolid to potentially reduce costs, prevent catheter-related infections and reduce hospital length of stay. 1,9 Given the availability of several antibiotics with different mechanisms of action and modes of administration, determining their comparative clinical and cost-effectiveness is warranted to inform clinical practice. The purpose of this report is to examine the comparative clinical effectiveness of linezolid, vancomycin and daptomycin for MRSA infections, the comparative clinical effectiveness of linezolid and daptomycin for the treatment of VRE infections, and the cost-effectiveness of linezolid and daptomycin for MRSA and VRE infections. Additionally, the clinical effectiveness and cost-effectiveness of oral versus intravenous linezolid will be examined. PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 4

5 Research Question 1. What is the comparative clinical effectiveness of linezolid to vancomycin or daptomycin in the treatment of bacteremia, bone and joint infections, skin and soft tissue infections, and pneumonia caused by methicillin-resistant staphylococcus aureus (MRSA)? 2. What is the comparative clinical effectiveness of linezolid to daptomycin in the treatment of bacteremia, bone and joint infection, infective endocarditis, intraabdominal infections, and skin and soft tissue infections caused by vancomycinresistant enterococci (VRE)? 3. What is the cost-effectiveness of using intravenous or oral linezolid com pared to daptomycin for the treatment of methicillin-resistant staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE)? 4. What is the comparative clinical effectiveness of oral versus intravenous linezolid for the treatment of infections? 5. What is the cost-effectiveness of oral versus intravenous linezolid for the treatment of infections? Key Findings The evidence suggests that for MRSA bacteremia, the clinical outcomes of linezolid in comparison to daptomycin or vancomycin are comparable. For skin and soft tissue infections caused by MRSA, the evidence favoured treatment with linezolid, possibly due to suboptimal dosing of vancomycin. Conflicting results were reported in the publications on MRSA pneumonia; while some favoured treatment with linezolid others reported no statistically significant differences between linezolid- and vancomycin-treated groups. The evidence suggests that for VRE bacteremia, there is no difference in clinical outcomes between patients treated with linezolid and high-dose daptomycin. One retrospective study found no differences in outcomes between patients who were switched from intravenous to oral linezolid in comparison to those receiving intravenous linezolid. In general, due to variation in study findings and lack of high quality comparative trials, the effectiveness of linezolid over vancomycin or daptomycin for the treatment of MRSA infections and daptomycin for VRE infections remains uncertain. No relevant evidence was identified regarding the clinical effectiveness of oral or intravenous linezolid for the treatment of bone and joint infections due to MRSA. No evidence was identified assessing the clinical effectiveness of oral or intravenous linezolid for the treatment of bone and joint infections, skin and soft tissue infections, infective endocarditis, and intra-abdominal infections due to VRE infections. Furthermore, no evidence was identified regarding the cost-effectiveness of using intravenous or oral linezolid compared to daptomycin for the treatment of MRSA or VRE infections or the costeffectiveness of oral versus intravenous linezolid for the treatment of infections. Methods Literature Search Methods A limited literature search was conducted on key resources including PubMed, Ovid Medline, Ovid Embase, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 5

6 agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, and economic studies. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2012 and August 21, Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Table 1: Selection Criteria Population Intervention Comparator Outcomes Study Designs Patients in acute care with infections Q1-3: Linezolid Q4-5: Oral linezolid Q1: Vancomycin or daptomycin Q2-3: Daptomycin Q4-5: Intravenous linezolid Clinical effectiveness (benefit/harm), VRE resistance, cost Health Technology Assessments, Systematic Reviews and Meta-Analyses, Randomized Controlled Trials, and Non-Randomized Studies Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, or they were duplicate publications. Due to the large volume of articles identified for full-text retrieval, articles published prior to 2014 were excluded. Critical Appraisal of Individual Studies The included systematic reviews were critically appraised using the AMSTAR 10 tool, clinical studies were critically appraised using the Downs and Black checklist. 11 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described. Summary of Evidence Quantity of Research Available A total of 891 citations were identified in the literature search. Following screening of titles and abstracts, 844 citations were excluded and 47 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, 25 PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 6

7 publications were excluded for various reasons, while 22 publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Additional references of potential interest are provided in Appendix 7. Summary of Study Characteristics The body of evidence included eight systematic reviews (SRs) 1,3,5,12-16 with or without metaanalyses (MAs) and fourteen clinical studies 6,9,17-28 addressing the effectiveness of linezolid for the treatment of MRSA and VRE infections and clinical effectiveness of oral versus intravenous linezolid. Additional details regarding the characteristics of included SRs and clinical studies are presented below and in Appendix 2. Study Design Eight relevant systematic reviews were identified. 1,3,5,12-16 A meta-analysis was performed in six of the SRs. Three SRs included randomized controlled trials (RCTs), 1,5,13 three SRs included retrospective cohort studies 14-16, one was a review of SRs, 3 and one only included MAs 12. The date of publication for individual studies included in the SRs ranged from to There was a substantial overlap in the included studies in the SRs on MRSA skin and soft tissue infections (SSTIs) and VRE bacteremia, which is summarized in Appendix 5 Fourteen primary clinical studies were included. 6,9,17-28 Three were RCTs, 17,19,20 ten were retrospective cohort studies, 6,9,18,21,22,24-28 and one was labeled by the authors of the study as a randomized case-control study. 23 Ten primary clinical studies were included comparing the effectiveness of linezolid to vancomycin or daptomycin for MRSA infections, three evaluated the effectiveness of linezolid compared to daptomycin for VRE infections, 6,27,28 and one evaluated the clinical outcomes in patients changing from intravenous to oral linezolid. 9 Country of Origin The SRs were led by authors based in China, 1,13,14 Greece, 12,15 United Kingdom, 3,5 and Taiwan. 16 The clinical studies were led by authors in Germany, 22 India, 23 Japan, 9,18 Taiwan, 28 and United States. 6,17,19-21,24-27 Patient Population Systematic Reviews Five SRs included patients with MRSA infections. 1,3,5,12,13 Of the five SRs, one included patients with all types of MRSA infections, but demographic characteristics of patients were not adequately described. 3 Three SRs were assessed MRSA SSTIs. 1,5,12 Of these three, one SR included patients of all ages, 1 one SR included only adult patients, 5 and one SR did PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 7

8 not provide demographic characteristics of the included patients. 12 The fifth SR assessed nosocomial pneumonia in patients of all ages. 13 Three SRs assessed VRE infections, specifically VRE bacteremia One SR included patients 18 years and older, 15 while the ages for patients included in the other two SRs were not reported. 14,16 Clinical Studies Eleven clinical studies included patients with MRSA infections. 9,17-26 One included patients with SSTIs and pneumonia and the median age of included patients was greater than 18 years of age. 23 Two clinical studies included adult patients with SSTIs, 20,22 and one clinical study included adult patients with bacteremia. 24 Six clinical studies included adult patients with MRSA pneumonia ,21,25,26 Of these six studies, one study specifically included patients above 65 years of age. 18 Three clinical studies included adult patients with vancomycin-resistant Enterococcus faecium (VREF) bacteremia. 6,16,27 Interventions and Comparators Systematic Reviews Five SRs were included comparing the effectiveness of linezolid to vancomycin for MRSA infections. 1,3,5,12,13 When reported, the dosage of linezolid ranged from 10mg/kg to 600mg every 8 to 12 hours. 1,3,13 The route of administration was either intravenous or oral in three SRs 1,3,13 and not reported in two SRs. 5,12 The dosage of vancomycin when reported ranged from 10mg to 1g every 6 to 24 hours or 1g to 15mg/kg every 12 hours. 1,3,13 Three SRs compared the effectiveness of linezolid to daptomycin for VRE infections The dose of linezolid when reported was 1200mg per day or 600mg twice per day, but the route of administration of linezolid was not reported in any of the SRs The daptomycin dose when reported ranged from 3.7 to 10.4mg/kg/day 15,16 or 6 to 11.5mg/kg/day. 14 Clinical Studies Nine clinical studies compared the effectiveness of linezolid to vancomycin for MRSA infections ,25,26 The dosage of linezolid was 600mg twice a day in five clinical studies, 17-20, g per day in one study, 21 and was not reported in three clinical studies. 22,25,26 Linezolid was administered intravenously in four studies, 17,19,20,22 orally or intravenously in three studies 21,23,25 and the route of administration was not reported in two studies. 18,26 The reported vancomycin dosages were 15mg/kg every twelve hours 17,19,20 or ranged from 1 to 3 g per day. 18,21-23 Two studies did not report the dose of vancomycin. 25,26 Only one clinical study included a comparison of linezolid to vancomycin and daptomycin for MRSA infections. 24 The linezolid dose was 600mg every 12 hours; the daptomycin dose was 6.7±1.8 mg/kg per day, and vancomycin dose was 13.4 ± 4mg/kg per dose. 24 The route of administration of linezolid was not reported. 24 Three clinical studies compared linezolid with daptomycin for VRE infections. 6,27,28 The linezolid dose was 600mg twice a day in two clinical studies 6,27 and not reported in the third. 28 Linezolid was administered either intravenously or orally in one study 6 and the route of administration was not reported in two studies. 27,28 The dose of daptomycin varied across the three studies. 6,27,28 The median dose was 6.15mg/kg in the first clinical study, 27 the mean dose was 7.9mg/kg in the second study, 6 and the dose ranged from 6 to 9mg/kg in the third study. 28 PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 8

9 One clinical study compared the clinical effectiveness of changing from intravenous to oral linezolid to patients receiving intravenous linezolid. 9 The linezolid doses for both intervention groups was not reported. 9 Outcomes Additional details regarding the interpretation of clinical and microbiological outcomes are provided in Appendix 6. The outcomes considered in the SRs related to the clinical effectiveness of linezolid were the following: improvement in clinical outcomes (e.g., clinical cure rate, clinical treatment success), 1,3,12-16 microbiological cure rate, 1,3,12-16 bacterial clearance rate, 3 mortality, 3,12,14-16 treatment success at test-of-cure visit, 5 relapse rate, 14 discontinuation due to adverse events (AEs), 12 AEs, and recurrence of VRE bacteremia. 15,16 The outcomes considered in the clinical studies were the following: improvement in clinical outcomes (e.g., clinical success, clinical cure rate), 17,19,22,23,25,26 20,24 improvement in microbiological outcomes (e.g., microbiological success, microbiological cure rate, microbiological efficacy), 17,19 23,24 20 adverse events, 17,19,21,23,26-28 mortality, 6,9,18,21,24,26-28 Sequential Organ Failure Assessment (SOFA) scores, 18 length of stay, 21,22,24,26,27 mechanical ventilation days, 21,26 duration of treatment, 6,9,21,22 probability of discharge, 21 probability of mortality 21, number of surgical procedures, 22 recurrence rate, 6,24 re-infection rate, 24 treatment failure, 24 time to 30-day mortality, 25 hospital discharge, 25 intensive care unit (ICU) discharge, 25 MRSA re-infection, 25 MRSA re-admission, 25 rate of therapy change, 25 persistent vancomycin-resistant Enterococcus faecium bloodstream infection (VREF-BSI), 27 duration of VREF-BSI, 6,27 reduction in C-reactive protein level, 9 reduction in platelet count, 9 and re-administration of an anti-mrsa agent. 9 Summary of Critical Appraisal Additional details regarding the strengths and limitations of included SRs and clinical studies are provided in Appendix 3. Systematic Reviews Two SRs referenced a protocol, objective or inclusion criteria prior to the conduct of the review. 1,3 A comprehensive literature search was conducted in all eight included systematic reviews. 1,3,5,12-16 However, an appropriate search of the grey literature was only conducted in four SRs. 1,5,13,16 It was unclear whether study selection was done in duplicate in four SRs 3,5,12,15 and data extraction in five SRs. 3,5,12,13,15 No consensus procedure was described to resolve discrepancies during data extraction in one SR. 1 All included SRs provided a list of included studies, but only one SR provided references for excluded studies. 1 Key characteristics of the included studies were adequately provided in six SRs. 1,5,12,13,15,16 Scientific quality was appropriately assessed and considered when formulating conclusions in only two SRs. 1,3 Meta-analyses were conducted in six SRs. 1,5,13-16 Publication bias was adequately addressed in three SRs with the use of statistical and graphical aids One SR partially addressed publication bias by only using a statistical test, 13 and one SR reported that assessment of publication bias was not performed due to the small number of included studies. 1 Conflict of interest for the included studies was provided in only one SR. 1 All the included studies in the SR were either funded by a pharmaceutical company or had an author who had received funding from a pharmaceutical company. 1 One SR was funded by PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 9

10 a pharmaceutical company, 5 and at least one author in four SRs 3,5,12,15 had previously received fees from pharmaceutical companies. Clinical Studies The study objectives, patient inclusion and exclusion criteria, intervention, comparators, outcomes and main findings were described in all included clinical studies. 6,9,17-28 Two studies failed to provide adequate information regarding the characteristics of included patients. 9,23 All patients were recruited over the same period and were representative of the population from which they were recruited. Additionally, in all the included studies, the staff, places, and facilities were representative of the treatment of majority of patients. 6,9,17-28 With respect to confounding variables, the distribution of principal confounders was similar between groups in four clinical studies. 18,20,21,28 Confounders were statistically different but were adequately adjusted for in four clinical studies. 6,25-27 Despite propensity-score weighting, two important confounders remained unbalanced in one clinical study. 22 Two clinical studies failed to adequately report key confounding variables 9,23 and it is unclear if adjustment for confounding occurred during the analyses in three studies. 17,19,24 Valid and reliable outcomes and appropriate statistical tests were used in all clinical studies. 6,9,17-28 One included clinical study performed a post hoc analysis, however this analysis was clearly reported. 20 Compliance with the study intervention was not specifically measured and power calculations were not performed in any of the included clinical studies. 6,9,17-28 Probability values (i.e. p-values) were not adequately reported in four studies 17,19,20,25 and statistical estimates of variability were not adequately reported in five studies. 20,21,23,24,26 Adverse events associated with the interventions were not considered in three clinical studies 22,24,25 The retrospective nature of seven studies resulted in no patient loss to follow-up. 6,9,18,21,22,26-28 There was no randomization, concealment of treatment allocation, attempt to blind study participants to the intervention received or blinding of outcome assessors in ten clinical studies due to their retrospective study design. 6,9,18,21,22,24-28 Concealment of treatment allocation was unclear and patients loss to follow-up were not reported in two RCTs. 17,19 One RCT had appropriate randomization, concealment of treatment allocation, blinding of participants and outcome assessors. 20 The prospective case-control study, as defined by the study authors, randomized participants into different intervention groups, but there was no attempt to conceal treatment allocation or blind participants or outcome assessors and loss to follow-up was not reported. 23 Summary of Findings Rapid Response reports are organized so that the evidence for each research question is presented separately. Additional details regarding the main findings of included SRs and clinical studies are provided in Appendix 4: Table A5 and A6 respectively. 1. What is the comparative clinical effectiveness of linezolid to vancomycin or daptomycin in the treatment of bacteremia, bone and joint infections, skin and soft tissue infections, and pneumonia caused by methicillin-resistant staphylococcus aureus (MRSA)? Bacteremia PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 10

11 One review of SRs 3 and one retrospective cohort study 24 provided evidence on the clinical effectiveness of linezolid compared to vancomycin and daptomycin for MRSA bacteremia. The review by Rae et al. 3 included two SRs on MRSA bacteremia. When reported, the linezolid dosage ranged from 10mg/kg to 600mg every 8 to 12 hours and vancomycin ranged from 10mg to 1g every 6 to 24 hours. One SR reported no statistically significant differences in clinical cure rates and the other reported no difference in mortality between the two groups. The retrospective cohort study by Usery et al. 24 evaluated the effectiveness of daptomycin, linezolid and vancomycin for MRSA bacteremia. The mean dose of linezolid administered was 600mg twice a day and the mean doses of vancomycin and daptomycin were 12.6 ± 4 mg/kg and 6.7 ± 1.8 mg/kg per dose. Therapeutic drug monitoring was performed in 16 patients receiving vancomycin, and 42.6% of all levels drawn were below 15 mcg/ml. The study found no statistically significant differences between groups receiving daptomycin, linezolid, and vancomycin with respect to clinical cure rate, microbiological cure rate, recurrence, re-infection, treatment failure, and total length of stay. The linezolid group had a longer intensive care unit length of stay, but this failed to reach statistical significance. 24 The linezolid group had a higher rate of mortality in comparison to the daptomycin and vancomycin groups. 24 Skin and Soft Tissue Infections Three SRs, 1,5,12 one RCT, 20 one retrospective cohort study, 22 and one randomized casecontrol study provided evidence on the clinical effectiveness of linezolid compared to vancomycin for SSTIs. The first SR, by Yue et al. 1 included a subgroup analysis on infections due to MRSA. The linezolid dosage in the included studies was 600mg every 12 hours and the vancomycin dosage was 1000mg or 15mg/kg every 12 hours. Only one included RCT adjusted vancomycin dosage based on trough levels. Treatment with linezolid was more effective than vancomycin with regards to clinical cure rate (relative risk [RR] 1.09; 95 % confidence interval [CI], 1.03 to 1.17; heterogeneity, I 2 = 0%) and microbiological cure rate (RR 1.17; 95% CI, 1.04 to 1.32; I 2 = 46%). 1 The second SR, by Thom et al. 5 included network meta-analysis on the comparative efficacy of antibiotics for acute bacterial skin and skin structure infections (ABSSSIs). The dosage and duration of treatment was not reported for either group. A sub-group analysis was conducted to assess treatment success at the Test-of-Cure visit (TOC: between seven and 14 days after the end of the treatment) on confirmed MRSA populations. 5 There was no statistically significant difference in TOC response between patients treated with vancomycin and linezolid. 5 The third SR, by Tsoulas and Nathwani 12 included four MAs that assessed the comparative effectiveness of linezolid and vancomycin for SSTIs. The dosages and duration of treatment for either group was not reported. Three of the four MAs reported statistically significant differences in clinical cure rates and microbiological cure rates favouring treatment with linezolid. One of the MAs included data on adverse events and reported no differences in the risk of adverse events between groups. The RCT by Kingsley et al. 20 evaluated the outcomes in patients with ABSSSIs with linezolid or vancomycin. 20 The linezolid dose administered was 600mg twice a day and vancomycin was administered at 15mg/kg twice a day. Vancomycin dosages were adjusted to reach a trough concentration of 15 to 20 mcg/ml. Subgroup analyses for patients with PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 11

12 MRSA infections revealed no statistically significant differences in linezolid-treated and vancomycin-treated groups with regards to clinical cure rate and microbiological efficacy. 20 The retrospective cohort study by Eckmann et al. 22 investigated the comparative efficacy of linezolid and vancomycin for SSTIs in patients with peripheral vascular disease (PVD) and/or diabetes. The linezolid dosage was not reported. Vancomycin dosage ranged from 1.92g to 2.88g per day, however it is unclear if dosage was adjusted based on trough levels. In patients with PVD and/or diabetes, treatment with linezolid resulted in shorter hospital length of stay, total length of treatment, and intravenous length of treatment. 22 Though the number of patients requiring surgery in the linezolid group was significantly higher, the number of surgeries per patient was not significantly different between groups. 22 In patients with PVD, with or without diabetes; the linezolid group had a significantly shorter length of stay. 22 Similarly, in patients with PVD and a lower extremity MRSA complicated SSTIs, with or without diabetes; the linezolid group had a significantly shorter length of stay. 22 The study by Jindal et al., 23 which the authors label as a randomized case-control study, included a subgroup analysis on patients with complicated SSTIs. The dose of linezolid was 600mg every 12 hours and vancomycin dose was 1g every 12 hours. It is unclear whether vancomycin dosage was adjusted based on trough levels. The study found no statistically significant differences in success rate or microbiological eradication rates between patients treated with linezolid and vancomycin. 23 Pneumonia Two SRs, 3,13 two RCTs, 17,19 four retrospective cohort studies, 18,21,25,26 and one randomized case-control study provided evidence on the clinical effectiveness of linezolid compared to vancomycin for the treatment of MRSA pneumonia. The first SR, by Rae et al. 3 included two reviews comparing linezolid to vancomycin for MRSA nosocomial pneumonia. When reported, the linezolid dosage ranged from 10mg/kg to 600mg every 8 to 12 hours and vancomycin ranged from 10mg to 1g every 6 to 24 hours. The SR reported conflicting results, as one SR reported statistically significant differences favouring linezolid in clinical cure and bacterial clearance rates and the second SR reported no statistically significant difference between groups in clinical success at TOC visit in patients with nosocomial or ventilator-associated pneumonia. The second SR, by Wang et al. 13 included a culture-proven MRSA sub-group analysis which investigated the comparative efficacy of linezolid and vancomycin in patients with MRSA nosocomial pneumonia. 13 The linezolid dosage administered was 600mg every 12 hours and vancomycin dosage was 1g or 15mg/kg every 12 hours. Trough levels of vancomycin was not monitored in all trials included in the SR. The SR found no statistically significant differences in clinical cure or MRSA eradication rates between the two groups. 13 The first RCT, by Liu et al. 17 evaluated the efficacy and safety of linezolid and vancomycin in patients with MRSA pneumonia, stratified by renal function. 17 Linezolid dosage was 600mg every 12 hours and vancomycin dosage was 15mg/kg every 12 hours. Vancomycin dose was adjusted based on trough levels, however the concentrations were not reported. In patients with normal renal function, clinical success at end-of-treatment and microbiological success at end-of-treatment and end-of-study were significantly higher in the linezolid-treated group in comparison to vancomycin. 17 Occurrence of acute kidney injury was also lower in the linezolid-treated group. 17 In patients with mild to moderate and severe renal impairment, there was no significant difference in clinical success or PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 12

13 occurrence of acute kidney injury in patients treated with linezolid compared to vancomycin. The second RCT, by Equils et al., 19 determined whether diabetes affected outcomes in patients with MRSA nosocomial pneumonia. 19 Linezolid dosage was 600mg every 12 hours and vancomycin dosage was 15mg/kg every 12 hours. Vancomycin dose was adjusted based on trough levels, however the concentrations were not reported. For patients with diabetes, clinical and microbiological success rates were significantly higher in patients receiving linezolid compared to vancomycin at the end-of-treatment and end-of-study visits. 19 For patients without diabetes, clinical success at end-of-treatment and end-of-study were not statistically significant between linezolid- and vancomycin-treated groups, however, microbiological success at end-of-treatment was significantly higher in the linezolid treated group. 19 The rates of adverse events were not different between the two drug treatment groups in patients with or without diabetes. 19 The first retrospective cohort study, by Takada et al., 18 determined the effectiveness of linezolid and vancomycin in a cohort of elderly patients with MRSA pneumonia. 18 The linezolid dosage was 600mg every 12 hours. The vancomycin dosage was 1 to 2 g per day and adjusted to reach a trough concentration between 15 and 20 mcg/ml. 30-day mortality rate was significantly higher in the vancomycin (41%) group than the linezolid (0%) group (P = 0.02). 18 The total SOFA scores were significantly lower in the linezolid group, representing a decreased risk of mortality (P < 0.01). 18 SOFA renal scores were significantly lower in the linezolid group (P = 0.01). SOFA respiratory, coagulation, hepatic, cardiovascular and central nervous system scores were not significantly different between the two groups. 18 The second retrospective cohort study, by Tong et al., 21 compared linezolid and vancomycin for the treatment of MRSA pneumonia. The linezolid dose was 1.2g per day. Vancomycin dose was 3 g per day and adjusted to reach a trough concentration of 15 to 20 mcg/ml. No statistically significant differences were noted between groups with respect to hospital and ICU length of stay (LOS), mechanical ventilation, adverse events, readmission, time to death (if occurred) or duration of treatment. 21 A significantly higher mortality rate was noted in the vancomycin group (P =0.046). 21 Univariate and multivariate subdistribution hazard ratios revealed the linezolid-treated group had a significantly higher likelihood of being discharged, resulting in a shorter hospital LOS. 21 The authors attributed the shorter LOS to a switch from intravenous to oral linezolid. 21 The odds of mortality was higher in the vancomycin-treated group than the linezolid-treated group (multivariate odds ratio [OR] 1.52; 95% CI, 1.02 to 2.28). 21 The third retrospective cohort study, by Caffrey et al., 25 analyzed National Veterans admitted with MRSA pneumonia. The dosage and duration of treatment was not reported for either treatment group. For the primary outcome, time to 30-day mortality, no statistically significant differences were found between groups receiving linezolid and vancomycin. 25 Additionally, no statistically significant differences were found for therapy change, hospital discharge, discharge from intensive care, intubation, 30-day readmission, and 30-day MRSA reinfection. 25 The linezolid-treated group demonstrated a significantly lower rate of therapy change in comparison to the vancomycin-treated group (adjusted hazard ratio [ahr] 0.68; 95% CI, 0.48 to 0.96). 25 Patients treated with linezolid also demonstrated a higher clinical success rate ( ahr 0.68; 95% CI, 0.48 to 0.96). 25 A subgroup analysis was conducted on patients with microbiology-confirmed MRSA (validated sub-group) and patients meeting the clinical criteria for infection (clinical sub-group). 25 Linezolid-treated patients in the validated sub-group (ahr 1.46; 95% CI, 1.13 to 1.87) and PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 13

14 clinical subgroup (ahr 1.25; 95% CI 1.03 to 1.52) also exhibited higher rates of clinical success. 25 The last retrospective cohort study, by Peyrani et al. 26 evaluated the efficacy of linezolid versus vancomycin in patients with ventilator-associated pneumonia (VAP) due to MRSA. The dosages of linezolid and vancomycin were not reported, however, vancomycin trough levels were monitored. Overall trough levels were 21 ± 11 mcg/ml. After adjusting for confounding, the linezolid-treatment group had significantly higher rate of clinical success in comparison to the vancomycin-treated group. 26 Patients in the linezolid-treated group were more likely to reach clinical success by day 14 than the vancomycin-treated group (RR 1.24; 95% CI, 1.06 to 1.32). 26 The adjusted number needed to treat with linezolid to attain an additional case of clinical success was six. 26 There were no statistically significant differences in unadjusted secondary outcomes between the two groups with respect to mortality, adverse events (e.g., thrombocytopenia, anemia and nephrotoxicity), and resource utilization (e.g., days on mechanical ventilation, ICU LOS, and hospital LOS). 26 The study by Jindal et al. 23 included a subgroup analysis on patients with MRSA pneumonia. The dosages for linezolid and vancomycin were not reported. The study found no statistically significant differences in success rates or microbiological eradication rates between the two groups. 23 Bone and Joint Infections No relevant evidence regarding the clinical effectiveness of oral or intravenous linezolid for the treatment of bone and joint infections due to MRSA was identified; therefore, no summary can be provided. 2. What is the comparative clinical effectiveness of linezolid to daptomycin in the treatment of bacteremia, bone and joint infection, infective endocarditis, intraabdominal infections, and skin and soft tissue infections caused by vancomycin-resistant enterococci (VRE)? Bacteremia Three SRs with MAs and three retrospective cohort studies 6,27,28 were identified that provided evidence for the clinical effectiveness of linezolid compared to daptomycin for the treatment of bacteremia caused by VRE. In the first SR, by Zhao et al., 14 the daptomycin dosage ranged from 6 to 11.5mg/kg/day and when reported, the linezolid dosage was 1200mg per day. The SR found no statistically significant differences in daptomycin-treated patients and linezolid-treated patients with respect to crude overall mortality, clinical cure rate, microbiological cure rate and relapse rate of VRE bloodstream infection (VRE-BSI). 14 Additionally, there were no differences between groups with respect to incidence of thrombocytopenia and rate of creatine phosphokinase (CPK) elevation. 14 This SR was distinct from the other two 15,16 in that low-quality conference abstracts were excluded, and only studies that included daptomycin doses of 6 mg/kg/day were included. 14 In the second SR, by Balli et al., 15 the dosages of daptomycin and linezolid when reported were 3.7 to 10.4mg/kg/day and 600mg twice a day. The study found that patients in the daptomycin-treated group had significantly higher 30-day all-cause mortality, infectionrelated mortality and overall mortality when compared to linezolid-treated patients. 15 After adjusting for confounders, in-hospital mortality was no longer significant between the two groups, but 30-day all-cause mortality was still significantly greater in patients who received PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 14

15 daptomycin versus linezolid. 15 No significant differences were demonstrated in clinical cure rates, microbiological cure rates and recurrence of VRE bacteremia. 15 Additionally, there were no differences in the occurrence of adverse events between the two groups. 15 In the third SR, by Chuang et al., 16 the dosages of daptomycin and linezolid when reported were 3.7 to 10.4 mg/kg/day and 600mg twice a day. The SR found that daptomycin was associated with significantly higher mortality in comparison to linezolid and this remained significant after adjusting for confounding factors. The VRE-relapse rate was higher in the daptomycin group. 16 No significant differences were found between groups for short-term and long-term mortality, clinical cure rates, microbiological cure rates and adverse events. 16 In the first retrospective cohort study, by Britt et al., 27 patients were administered 600mg of linezolid twice a day and median dose of daptomycin was 6.15mg/kg. \The linezolid-treated group demonstrated higher 30-day mortality, infection-related mortality, persistent VREF- BSI, hospital mortality, median duration of VREF-BSI and median duration of hospital length of stay compared to the daptomycin-treated group. 27 Sub-group analyses on patients with infective endocarditis revealed 30-day and 60-day mortality was significantly higher in the linezolid-treated group. 27 In patients without endocarditis, there was no significant difference between treatment groups. 27 Adverse events were not significantly different between treatment groups. 27 In the second retrospective cohort study, by Suleyman et al., 6 the daptomycin dose ranged from 6 to 10mg/kg and 600mg of linezolid was administered every 12 hours. The study found no statistically significant difference in 90-day all-cause mortality between the linezolid-treated and daptomycin-treated groups after adjusting for confounding (receipt of chemotherapy, neutropenia and renal replacement therapy). 6 Additionally, length of stay, recurrence within 30-days and antibiotic duration were not significantly different between groups. 6 In the third retrospective cohort study, by Chuang et al., 28 the dosages and duration of treatment was not reported for either intervention group. The study found that 14-day allcause mortality and infection-related mortality were significantly higher in the daptomycintreated group in comparison to the linezolid-treated group. 28 No significant differences were reported with respect to 28-day all-cause mortality, elevated CPK levels and thrombocytopaenia. 28 Higher daptomycin dose ( 9 mg/kg) and linezolid independently predicted lower mortality in comparison to a lower daptomycin dos e (6 to 9 mg/kg). 28 However, there were no significant differences in 14-day all-cause mortality between patients treated with a higher daptomycin dose and linezolid. 28 The propensity score matched subgroup analysis also reported that mortality was significantly lower in patients treated with linezolid compared to lower dose daptomycin, but not higher dose daptomycin. 28 Bone and Joint Infections, Skin and Soft Tissue Infections, Infective Endocarditis, and Intraabdominal Infections No relevant evidence regarding the clinical effectiveness of oral or intravenous linezolid for the treatment of bone and joint infections, skin and soft tissue infections, infective endocarditis, and intra-abdominal infections due to VRE infections was identified. 3. What is the cost-effectiveness of using intravenous or oral linezolid compared to daptomycin for the treatment of methicillin-resistant staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE)? PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 15

16 No relevant evidence regarding the cost-effectiveness of using intravenous or oral linezolid compared to daptomycin for the treatment of MRSA or VRE infections was identified. 4. What is the clinical effectiveness of oral versus intravenous linezolid for the treatment of infections? One small retrospective cohort study was identified that provided evidence on the clinical effectiveness of switching from intravenous linezolid to oral linezolid in patients with MRSA infections. 9 Dosage and duration of treatment were not reported for either intervention group. There were no statistically significant differences in patients who switched to oral linezolid therapy in comparison to those who continued to receive intravenous linezolid with respect to duration of treatment, reduction in C-reactive protein, platelet count, readministration of an anti-mrsa within 90 days of hospital discharge, and death within 28 days after discharge What is the cost-effectiveness of oral versus intravenous linezolid for the treatment of infections? No relevant evidence regarding the cost-effectiveness of oral versus intravenous linezolid for the treatment of infections was identified. Limitations All the studies included in the body of evidence had substantial methodological limitations. The preponderance of evidence was retrospective in nature. Three SRs included only retrospective cohort studies, and ten primary clinical studies were retrospective cohort studies. 6,9,18,21,22,24,25,27,28 Due to the retrospective nature of the study design, there is a possibility that the patient population may not be representative of the intended target population and the effect of all influencing variables may not have been adequately adjusted for during the analyses.. 18 The reasons for the decisions to prescribe linezolid, vancomycin or daptomycin, alter doses and switch from one antibiotic to another are unknown as they are at the discretion of attending physician. In addition to introducing selection bias, 18 it limits the repeatability and reproducibility of the study. The serum levels of vancomycin levels need to be monitored to ensure adequate concentrations are being administered. 13 Serum trough concentrations of 15 to 20 mcg/ml are recommended for serious infections. 24 Suboptimal concentrations of vancomycin would reduce its success rate and favour treatment with linezolid. 13 Several trials included in the SRs by Wang et al. 13 and Yue et al., 1 did not monitor serum vancomycin concentrations. It is unclear whether monitoring of serum concentrations occurred in the trials included in three SRs 3,5,12 and three clinical studies. 22,23,25 For daptomycin, the minimum guideline recommended dose is 6mg/kg daily and doses administered below this level may result in treatment failure. 24 The daptomycin doses ranged from 3.7 to 10.4mg/kg per day in the SRs by Balli et al. 15 and Chuang et al. 16 The lower range of doses included in the SRs may favour treatment with linezolid. Additionally, the dose of daptomycin was not reported in the cohort study by Chuang et al. 28 The inadequate reporting of treatment doses, failure to monitor vancomycin dosing and potential suboptimal dosing makes it challenging to determine the clinical effectiveness across treatment groups. In one RCT, 20 the MRSA subgroup analysis contained a small sample size; therefore, it was underpowered to detect a difference in clinical and microbiological cure rates between the intervention groups. In the prospective randomized case-control study 23 there was no concealment of treatment allocation or blinding of patients and investigators. Liu et al. 17 PEER REVIEW WITH CRITICAL APPRAISAL Linezolid f or the Treatment of Inf ections: A Rev iew of the Clinical and Cost-Ef fectiveness 16