TITLE: Daptomycin for Vancomycin-Resistant Enterococcal Infection: A Review of the Clinical Effectiveness, Cost-Effectiveness and Guidelines

Transcription

1 TITLE: Daptomycin for Vancomycin-Resistant Enterococcal Infection: A Review of the Clinical Effectiveness, Cost-Effectiveness and Guidelines DATE: 14 January 2016 CONTEXT AND POLICY ISSUES Enterococci are bacteria found in normal human flora. 1 These bacteria can cause a variety of infections, such as bacteremia, skin and soft tissue infections, and intraabdominal infections. These infections are usually treated with antibiotics, although enterococci can develop resistance to antibiotics, thus limiting treatment options. One such strain of bacteria is vancomycin-resistant enterococci (VRE). In Canada, a total of 1,241 cases of hospital-based VRE infections were reported to the Public Health Agency of Canada (PHAC) between 1999 and 2011, with rates of infections increasing since According to PHAC, over half of infected patients were female (56%) or aged 65 years or older (56%). The vast majority (99%) of infections were attributed to the Enterococcus faecium species, while the remaining cases were due to Enterococcus faecalis. Moreover, the majority (77%) of patients with VRE infections had been hospitalized within the last 12 months. VRE infections can mostly be treated with antibiotics other than vancomycin, and laboratory tests can be performed to identify optimal treatment regimens. Daptomycin is one antibiotic with known in vitro activity against VRE. 3 Daptomycin and vancomycin have different bactericidal mechanisms of action; specifically, daptomycin works by binding or inserting into the outer membrane, 4 while vancomycin inhibits cell wall synthesis. 5 Other possible options for treating VRE include linezolid, tigecycline, oritavancin, televancin, and a combination of quinupristin and dalfopristin. This Rapid Response report aims to review the comparative clinical- and costeffectiveness of daptomycin for patients with VRE infections. Evidence-based guidelines on the optimal use of daptomycin in patients with VRE infections will also be summarized. RESEARCH QUESTIONS 1. What is the comparative clinical effectiveness and safety of daptomycin versus alternative antibiotic therapies for VRE bacteremia or infection? Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts w ithin the time allow ed. Rapid responses should be considered along w ith other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that ef fect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in w hich a third party ow ns copyright. This report may be used for the purposes of rese arch or private study only. It may not be copied, posted on a w eb site, redistributed by or stored on an electronic system w ithout the prior w ritten permission of CADTH or applicable copyright ow ner. Links: This report may contain links to other information available on the w ebsites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 2. What is the cost-effectiveness of daptomycin versus alternative antibiotic therapies for VRE bacteremia or infection? 3. What are the evidence-based guidelines regarding the optimal dose of daptomycin for VRE bacteremia or infection? 4. What are the evidence-based guidelines regarding the use of daptomycin for VRE bacteremia or infection? KEY FINDINGS Evidence from one systematic review (SR) and three non-randomized studies is inconsistent regarding the comparative effectiveness and safety of daptomycin in patients with VRE infection. In particular, some studies suggest that daptomycin is similar to linezolid or β-lactams, while others favour one therapy over another. However, several important limitations exist among these studies, which threaten the validity of the evidence and limit its utility for decisionmaking. No evidence was found regarding the cost-effectiveness of daptomycin versus alternative antibiotic therapies in patients with VRE infection. Further, no evidence-based guidelines on the optimal use of daptomycin in patients with VRE infection were found. METHODS Literature Search Methods A limited literature search was conducted on key resources including PubMed, The Cochrane Library, and University of York Centre for Reviews and Dissemination databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2010 and December 1, Selection Criteria and Methods One reviewer screened the search results in two stages to identify relevant research studies. During the first stage, the reviewer used the criteria in Table 1 to screen the titles and abstracts of identified citations, and acquire the full texts of articles that were potentially eligible. The reviewer then assessed the full texts for definitive inclusion based on the same criteria. Population Intervention Comparator Outcomes Table 1: Selection Criteria Adult patients in acute care with any VRE-attributed infection Daptomycin Q1 and 2: Any alternative antibiotic therapy Q3 and 4: No comparator Effectiveness Safety Cost-effectiveness Guidelines and recommendations Daptomycin for VRE Infections 2

3 Study Designs Health technology assessments Systematic reviews (with or without meta-analyses) Randomized controlled trials Non-randomized studies (cohort, case-control) Evidence-based clinical practice guidelines Exclusion Criteria SRs were excluded if they were superseded by a more recent SR, or if all of the included studies were captured in a more recent SR. Primary studies were excluded if they were captured in an eligible SR. Additional exclusion criteria were studies of combination therapeutic agents (i.e. daptomycin plus another agent), and publication prior to Critical Appraisal of Individual Studies One reviewer assessed the quality of eligible SRs using A Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist, which includes the following 11 items: (1) a priori design of the review; (2) duplicate study selection and data extraction; (3) comprehensive literature search; (4) appropriate inclusion and exclusion criteria; (5) provision of list of included and excluded studies; (6) clear presentation of study characteristics; (7) assessment of study quality; (8) scientifically-sound interpretation of the results; (9) appropriate methods to combine data from studies; (10) assessment of publication bias; and, (11) reporting of funding sources. 6 The same reviewer evaluated the quality of eligible non-randomized studies using the Newcastle-Ottawa Scale (NOS), which includes three assessment criteria: (1) selection of the study groups; (2) comparability of the groups; and, (3) ascertainment of either the exposure or outcome of interest for case-control or cohort studies, respectively. 7 Summary scores for the included studies were not calculated; rather, the strengths and limitations of each study were described narratively. SUMMARY OF EVIDENCE Quantity of Research Available A total of 255 citations were identified in the literature search. Following screening of titles and abstracts, 39 potentially relevant reports were retrieved for full-text review. Of these, 35 publications were excluded for various reasons, and four reports were included. Appendix 1 presents the flowchart of the study selection. Appendix 2 provides additional references of potential interest that were found that did not meet the selection criteria. Summary of Study Characteristics Appendix 3 summarizes the study characteristics. Study Design Four relevant reports were identified one SR, 8 and three retrospective cohort studies Daptomycin for VRE Infections 3

4 The SR included 13 non-randomized studies nine full papers and four conference abstracts which were published between 2005 and All studies had retrospective cohort study designs. Country of Origin The SR included two studies that were conducted in Taiwan, while the rest were from the United States of America (USA). 8 All three non-randomized studies were conducted in the USA. Specifically, the study by Britt et al. was conducted using a nationwide cohort, 9 whereas the two other studies were conducted in single medical centres in single states. 10,11 Patient Population The SR included studies of patients with VRE bacteremia. 8 No details were provided about the demographic characteristics of the patients. In total, 1,188 participants were enrolled across the studies, each of which enrolled between 31 and 201 participants. All three non-randomized studies enrolled patients with blood cultures positive for VRE. Hayakawa et al. and Patel et al. specified enrolled 225 and 65 patients, respectively, with bacteremia due to vancomycin-resistant Enterococcus faecalis or Enterococcus faecium. 10,11 Britt et al. enrolled 644 patients with vancomycin-resistant Enterococcus bloodstream infections (VRE-BSI), of which over 80% were attributed to Enterococcus faecium. 9 Further, Patel et al. exclusively recruited patients who were previously diagnosed with cancer. 10 The characteristics of patients receiving daptomycin across the three studies varied. Specifically, the mean or median age of participants receiving daptomycin in the studies ranged from 54.6 years to 67 years. Moreover, 96.9% of patients receiving daptomycin in the study by Britt et al. were male, 9 whereas 58.9% and 74.2% were male in the other studies. 10,11 Interventions and Comparators The SR focused on comparing daptomycin with linezolid. 8 When reported, the mean or median dose of daptomycin used in the individual studies ranged from 5.5 mg/kg to 6.4 mg/kg. In the same studies, linezolid was consistently prescribed at a dose of 600 mg every 12 hours, when reported. The route of administration of the two treatments was unclear. All three non-randomized studies compared daptomycin with linezolid. Hayakawa et al. also included β-lactams as a comparator arm. 11 In that study, daptomycin was delivered at a median dose of 6 mg/kg either orally or intravenously, whereas there were no details about the other two treatments. In the study by Patel et al., linezolid was administered orally or intravenously at a dose of 600 mg every 12 hours, while the average dose of daptomycin was 6.1 mg/kg intravenously. 10 Britt et al. delivered daptomycin at a mean dose of 5.93 mg/kg, while, of those who received linezolid, 99.4% of patients did so at a dose of 600 mg every 12 hours. 9 Outcomes The SR compared the effects of daptomycin versus linezolid across a range of effectiveness and safety outcomes, including long-term and short-term mortality, clinical cure, microbiological Daptomycin for VRE Infections 4

5 cure, relapse, and several adverse events, including thrombocytopenia, acute kidney injury (AKI), and elevated creatinine kinase (CK) levels. 8 Across the three non-randomized studies, two common effectiveness outcomes were mortality and length of stay (LOS). Britt et al. also evaluated treatment failure (composite of 30-day allcause mortality, microbiologic failure, 60-day VRE-BSI recurrence), microbiologic failure, VRE- BSI recurrence, and duration of bacteremia. 9 Hayakawa et al. did not compare the effects of daptomycin versus linezolid on safety outcomes, 11 but the other studies did, specifically examining thrombocytopenia, and elevated CK levels. Summary of Critical Appraisal Appendix 4 summarizes the results of the critical appraisal. Overall, the extent to which the SR by Chuang et al. was conducted using high methodological rigor remains uncertain. First, although the authors reported following the recommendations of the PRISMA guidelines, they stated that no protocol was previously published or registered, which is an item in the PRISMA checklist. 8 In addition, although two reviewers independently evaluated each study and abstracted data, there was no indication that the individuals underwent piloting or calibration exercises, and the authors did not provide the level of agreement, which threatens the reproducibility of the findings. Moreover, although the SIGN50 checklist was used to assess study quality, the tool was not referenced, which leaves uncertain the version used, and the results of the quality assessment were not provided. The authors did not provide the individual assessments of study quality, nor did they evaluate the quality of the body of evidence (e.g. using the Grading of Recommendations Assessment, Development and Evaluation approach) which limits the ability to evaluate the internal validity of the included studies, and ultimately judge the underlying quality of the evidence. In addition, given that the SR only identified non-randomized studies, there is a high likelihood of clinical and methodological heterogeneity between studies. Although the authors attempted to account for differences across studies by pooling adjusted odds ratios (aors) when reported, they did not list the factors that the individual studies considered in the multivariable regression models. Last, given the inherent nature of non-randomized studies, it is possible that there are residual factors (not accounted for in the analyses) that might affect the strength or direction of the magnitude of the effect seen in the studies. The three non-randomized studies all retrospective cohort studies featured few strengths and several limitations. All studies defined the outcomes of interest in a clear manner. Further, two of the studies Britt et al. and Hayakawa et al. used propensity score matching to statistically reduce the bias due to possible confounding. 9,11 However, the third study, by Patel et al., naively compared the two treatment groups (daptomycin vs. linezolid) as if they were comparable. In other words, they did not attempt to statistically match the two groups based on possible confounders or effect modifiers which leaves uncertain the validity of the results. 10 In addition, as retrospective investigations, authors of all studies had to rely on data that was not designed for research purposes, which meant that variables may have been collected suboptimally, or certain factors that may be known confounders were unavailable. None of the studies reported measures to ensure the quality of data extraction (e.g. duplicate checks) nor did the investigators conduct formal sample size or power calculations, which threaten the robustness of the findings. The manner in which factors were selected for the multivariable analyses in the studies by Britt et al. and Hayakawa et al. was also prone to spurious findings, as only those variables that were significantly associated with the outcomes of interest in Daptomycin for VRE Infections 5

6 bivariate analyses were included in the multivariable regression models, which were built using stepwise approaches. 9,11 Summary of Findings Rapid Response reports are organized so that the evidence for each research question is presented separately. Appendix 5 summarizes the individual study findings. What is the comparative clinical effectiveness and safety of daptomycin versus alternative antibiotic therapies for VRE bacteremia or infection? The SR by Chuang et al. demonstrated that, overall, linezolid treatment for VRE bacteremia was significantly associated with lower mortality when compared with daptomycin treatment. 8 The authors noted that there were no significant differences in mortality rates between studies that reported aors versus those that did not, those that reported long- versus short-term mortality, and full papers versus conference abstracts. Further, there were no statistically significant differences between daptomycin and linezolid with respect to rates of clinical and microbiological cures, although daptomycin use was associated with significantly higher relapse rates. Last, there were no statistically significant differences between daptomycin and linezolid with respect to occurrence of thrombocytopenia, AKI, and elevated CK levels. Across the three non-randomized studies, the effects of daptomycin versus linezolid were inconsistent, particularly with respect to mortality. Specifically, while Britt et al. found that treatment with daptomycin resulted in significantly lower 30-day all-cause mortality, 9 Patel et al. demonstrated that there were no differences in mortality due to persistence of bacteremia during treatment course between linezolid and daptomycin. 10 Further, Hayakawa et al. noted that there were no differences in in-hospital all-cause mortality or mortality within 3 months of discharge between daptomycin, linezolid, and β-lactams. 11 None of the studies found any statistically significant differences in hospital LOS between treatment groups. Britt et al. demonstrated that daptomycin was associated with lower microbiologic failure rates, 9 but Patel et al. did not find any difference between the two treatments with respect to microbiologic cure. 10 Britt et al. also highlighted that treatment failure (a composite of 30-day all-cause mortality, microbiologic failure, 60-day VRE-BSI recurrence) was significantly more common in patients who received linezolid versus daptomycin, and the authors acknowledged that this was driven by differences in mortality and microbiologic failure between the two groups. 9 Further, although they did not find any differences between the treatments with respect to 60-day VRE-BSI recurrence, the researchers noted that the median duration of bacteremia was significantly higher among patients treated with linezolid than with daptomycin. Lastly, none of the studies found statistically significant differences between daptomycin and linezolid with respect to occurrence of adverse events. What is the cost-effectiveness of daptomycin versus alternative antibiotic therapies for VRE bacteremia or infection? No relevant evidence was found to answer this question. What are the evidence-based guidelines regarding the optimal dose of daptomycin for VRE bacteremia or infection? No relevant evidence was found to answer this question. Daptomycin for VRE Infections 6

7 What are the evidence-based guidelines regarding the use of daptomycin for VRE bacteremia or infection? No relevant evidence was found to answer this question. Limitations Several methodological limitations exist among studies that evaluate the comparative effectiveness and safety of daptomycin in patients with VRE infections. Most importantly, existing primary studies have been observational by design, and despite adjusting for potential confounders in the analyses, the extent to which observed treatment effects are valid remains uncertain, thus limiting the utility of the results. To this end, the inconsistent evidence regarding the comparative effectiveness and safety of daptomycin may be attributed to the enrolment of heterogeneous patients across the studies. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Overall, in the face of poor quality evidence, the comparative effectiveness and safety of daptomycin in patients with VRE infections remains uncertain. There is a need for researchers to conduct large, methodologically rigorous ideally, randomized studies that provide more definitive evidence regarding the comparative effectiveness and safety of daptomycin in patients with VRE infections. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Daptomycin for VRE Infections 7

8 REFERENCES 1. Vancomycin-resistant enterococci (VRE). Fact sheet [Internet]. Ottawa: Public Health Agency of Canada; 2010 Nov 15. [cited 2015 Dec 23]. Available from: 2. Vancomycin-resistant enterococci infections in Canadian acute-care hospitals: surveillance report January 1, 1999 to December 31, 2011 [Internet]. Ottawa: Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada; [cited 2015 Dec 4]. Available from: rt_1999_to_2011-en.pdf 3. Jorgensen JH, Crawford SA, Kelly CC, Patterson JE. In vitro activity of daptomycin against vancomycin-resistant enterococci of various Van types and comparison of susceptibility testing methods. Antimicrob Agents Chemother [Internet] Dec [cited 2015 Dec 23];47(12): Available from: 4. DrugBank [Internet]. Version 4.3. Edmonton: The Metabolomics Innovation Centre; Daptomycin. Accession Number DB00080; 2014 Nov 12 [cited 2016 Jan 12]. Available from: 5. DrugBank [Internet]. Version 4.3. Edmonton: The Metabolomics Innovation Centre; Vancomycin. Accession Number DB00512; 2014 Nov 12 [cited 2016 Jan 12]. Available from: 6. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] [cited 2016 Jan 12];7:10. Available from: 7. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle- Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: The Ottawa Hospital Research Institute; Chuang YC, Wang JT, Lin HY, Chang SC. Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. BMC Infect Dis [Internet] [cited 2015 Dec 4];14:687. Available from: 9. Britt NS, Potter EM, Patel N, Steed ME. Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: A national cohort study of Veterans Affairs patients. Clin Infect Dis Sep 15;61(6): Patel K, Kabir R, Ahmad S, Allen SL. Assessing outcomes of adult oncology patients treated with linezolid versus daptomycin for bacteremia due to vancomycin-resistant Enterococcus. J Oncol Pharm Pract Oct 17. Daptomycin for VRE Infections 8

9 11. Hayakawa K, Martin ET, Gudur UM, Marchaim D, Dalle D, Alshabani K, et al. Impact of different antimicrobial therapies on clinical and fiscal outcomes of patients with bacteremia due to vancomycin-resistant enterococci. Antimicrob Agents Chemother [Internet] Jul [cited 2015 Dec 4];58(7): Available from: Daptomycin for VRE Infections 9

10 APPENDIX 1: Selection of Included Studies 255 citations identified from electronic literature search and screened 216 citations excluded 39 potentially relevant articles retrieved for full-text review 0 potentially relevant reports retrieved from other sources (grey literature, hand search) 35 reports excluded: -irrelevant question (4) -irrelevant population (4) -irrelevant or no comparator (13) -irrelevant outcomes (3) -irrelevant study design (4) -already included in at least one of the selected systematic review (4) -systematic review, but all articles included in selected systematic review (3) 4 reports included in review Daptomycin for VRE Infections 10

11 APPENDIX 2: Additional References of Potential Interest 1. McComb MN, Collins CD. Comparative cost-effectiveness of alternative empiric antimicrobial treatment options for suspected enterococcal bacteremia. Pharmacotherapy Jun;34(6): This report was excluded because although the starting population was patients with suspected enterococcal bacteremia, it was uncertain whether the strain was vancomycin-resistant. The decision tree accounted for patients who changed to a VRE-active agent after identification of enterococcus faecium, but the authors did not specifically present the results, e.g. costeffectiveness, of treatments for patients with VRE infections. 2. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis Feb 15;52(4):e56-e93. This report did not provide recommendations for patients with confirmed VRE infections; rather, it recommended modifications to initial empirical therapy for patients at risk for infection with VRE, particular if their condition is unstable or if they have positive blood culture results suspicious for resistant bacteria. It stated that early addition of linezolid or daptomycin in febrile patients with neutropenia who are at risk for VRE infections should be considered. It assigned this recommendation a strength level of B, which indicates moderate evidence, and a quality level of III, which indicates that the evidence was drawn from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. 3. King EA, McCoy D, Desai S, Nyirenda T, Bicking K. Vancomycin-resistant enterococcal bacteraemia and daptomycin: are higher doses necessary? J Antimicrob Chemother [Internet] Sep [cited 2015 Dec 4];66(9): Available from: This report did not compare daptomycin with an alternative antibiotic therapy; instead, it evaluated standard dose daptomycin ( 6 mg/kg) versus high dose (>6 mg/kg) in patients with VRE bacteremia. The study found that there was no statistically significant difference in time to microbiological cure between the two treatment groups. Daptomycin for VRE Infections 11

12 APPENDIX 3: Characteristics of Included Publications Table A1: Characteristics of Included Systematic Reviews (with or without Meta-Analyses) Types and Population Intervention Comparator(s) Clinical Outcomes of numbers of Characteristics Interest primary studies included First Author, Publication Year, Country Chuang, 2014, Taiwan 8 Type and number of studies included: 13 nonrandomized studies Total number of patients: 1188 (31 to 201 per study) Patients with VRE bacteremia Daptomycin Linezolid Effectiveness Long-term mortality (30 days, and overall inhospital) Short-term mortality (14 days, mortality at EOT, mortality within 7 days after EOT, and infection-related) Clinical cure Study locations: Taiwan, USA Microbiological cure Relapse Safety Adverse events thrombocytopenia, AKI, elevated CK AKI = acute kidney injury; CK = creatinine kinase; EOT = end of therapy; USA = United States of America; VRE = vancomycinresistant enterococci First Author, Publication Year, Country Britt, 2015, USA 9 Table A2: Characteristics of Included Non-Randomized Studies Study Design Patient Intervention Comparator(s) Clinical Outcomes Characteristics Retrospective cohort study Inclusion: Adult patients with 1 blood culture positive for VRE admitted to any Veterans Affairs Medical Centre Exclusion: Treatment with another anti- VRE agent; treatment with linezolid and daptomycin Daptomycin Linezolid Effectiveness Treatment failure, (composite of 30-day all-cause mortality, microbiologic failure, 60- day VRE-BSI recurrence) 30-day all-cause mortality Microbiologic failure 60-day VRE-BSI Daptomycin for VRE Infections 12

13 First Author, Publication Year, Country Table A2: Characteristics of Included Non-Randomized Studies Study Design Patient Intervention Comparator(s) Clinical Outcomes Characteristics combination therapy, including sequential treatment; treatment with daptomycin or linezolid for <48 hours recurrence Early (7-day) mortality Hospital LOS Duration of bacteremia Safety Hayakawa, Retrospective 2014, USA 11 cohort study Patel, 2014, USA 10 Retrospective cohort study Inclusion: Patients who had a positive blood culture for vancomycinresistant E. faecalis or E. faecium Exclusion: Patients who did not receive effective IV therapy for >24 hours; treatment with daptomycin at a dose of <6 mg/kg Inclusion: Patients >18 years admitted to the oncology service who had documented positive blood cultures with E. faecalis or E. faecium Exclusion: Treatment with daptomycin or linezolid for <48 hours; pregnant Daptomycin Linezolid, β- lactam Adverse events thrombocytopenia, elevated CK Effectiveness In-hospital mortality (allcause) Mortality within 3 months of discharge LOS after VRE bacteremia (excluding deaths) Daptomycin Linezolid Effectiveness Microbiological cure (clearance of bacteremia for 2 weeks during or after initiation of antimicrobials) Mortality (death due to persistence of bacteremia during treatment course) LOS Daptomycin for VRE Infections 13

14 First Author, Publication Year, Country Table A2: Characteristics of Included Non-Randomized Studies Study Design Patient Intervention Comparator(s) Clinical Outcomes Characteristics patients Safety Adverse events CPK (increase >200 IU/L), serum creatinine (increase 1.5), platelet count (decrease from normal range of x 10 3 to below 150 x 10 3 per microliter or a 50% decrease from the patients baseline) CPK = creatinine phosphokinase; CK = creatinine kinase; IV = intravenous; LOS = length of stay; USA = United States of America; VRE-BSI = vancomycin-resistant Enterococcus bloodstream infection Daptomycin for VRE Infections 14

15 APPENDIX 4: Critical Appraisal of Included Publications Table A1: Strengths and Limitations of Systematic Reviews (with or without Meta-Analyses) using AMSTAR Strengths Limitations Chuang, Study reported to conform to PRISMA guidelines. Two physician reviewers independently evaluated each study and abstracted data, although no statistics on level of agreement were provided. Funnel plots were generated and inspected to evaluate publication bias. Random-effects meta-analyses were performed. Univariate meta-regression analyses were conducted to examine impact of study-level covariates and reported results. Protocol not published or publicly registered. Few search terms were used and few databases were checked, although authors checked the reference list of other review articles to identify studies not captured in the electronic searches. Although the SIGN50 checklist was used to assess study quality, the tool was not referenced, which leaves uncertain the version used, and the results of the quality assessment were not provided. No information provided about whether studies were screened (titles/abstracts and full-texts) independently and in duplicate. Although statistical heterogeneity between studies was assessed, clinical and methodological heterogeneity were not. No method to assess clinical importance of results. No evaluation of certainty of body of evidence, e.g. using GRADE. Table A2: Strengths and Limitations of Non-Randomized Studies using the Newcastle-Ottawa Quality Assessment Scale Strengths Limitations Britt, Participants were recruited from 47 centres across 29 states in USA and Puerto Rico likely representative of the average veteran. Method for generating propensity scores clear, including variables considered. The large sample size provides precise estimates of results. Clear outcome definitions. Participants unlikely to be representative of the general population. No information provided regarding methods taken to ensure quality of data extraction, e.g. duplicate checks. Primary outcome was a composite, and it is unlikely whether the individual components of the outcome are equally important to patients. Variable selection for multivariable analyses was suboptimal, as only those variables that were significantly associated (p <0.2) with the outcomes of interest in bivariate analyses were included. Daptomycin for VRE Infections 15

16 Table A2: Strengths and Limitations of Non-Randomized Studies using the Newcastle-Ottawa Quality Assessment Scale Strengths Limitations A backward stepwise approach was used to build the Poisson and Cox PH regression models. Stepwise models, compared to those in which variables are entered simultaneously, are at a greater risk for spurious findings. Hayakawa, No a priori hypotheses (effect on outcome) presented for covariates in the multivariable regression models. No formal sample size/power calculations conducted. Inherent to all observational studies, residual confounding (factors not accounted for in analyses) remains possible. Method for generating propensity scores clear, including variables considered. Clear outcome definitions. All-cause mortality used instead of infection-related mortality to avoid data abstraction bias. No information provided about the representativeness of the sample to the general population. No information provided regarding methods taken to ensure quality of data extraction, e.g. duplicate checks. Variable selection for multivariable analyses was suboptimal, as only those variables that were significantly associated (p <0.1) with the outcomes of interest in bivariate analyses were included. A stepwise approach was used to multivariable regression models. Stepwise models, compared to those in which variables are entered simultaneously, are at a greater risk for spurious findings. Despite multiple comparisons, statistical significance was set at p <0.05. No a priori hypotheses (effect on outcome) presented for covariates in the multivariable regression models. No formal sample size/power calculations conducted. Inherent to all observational studies, residual confounding (factors not accounted for in analyses) remains possible. Daptomycin for VRE Infections 16

17 Table A2: Strengths and Limitations of Non-Randomized Studies using the Newcastle-Ottawa Quality Assessment Scale Strengths Limitations Patel, Clear outcome definitions. No information provided about the representativeness of the sample to the general population. No information provided regarding methods taken to ensure quality of data extraction, e.g. duplicate checks. No attempt to statistically match the treatment groups by known confounders. Naively comparing groups is inappropriate. No formal sample size/power calculations conducted. Very small sample size. Inherent to all observational studies, residual confounding (factors not accounted for in analyses) remains possible. PH = proportional hazards; USA = United States of America Daptomycin for VRE Infections 17

18 APPENDIX 5: Main Study Findings and Author s Conclusions Table A1: Summary of Findings of Systematic Reviews (with or without Meta-Analyses) Main Study Findings Author s Conclusions Chuang, Effectiveness Note: OR <1 indicates a result favouring daptomycin. Mortality Raw mortality: OR 1.43 (95% CI: 1.09, 1.86) (I 2 = 0%) (13 studies) Studies in which aors were and were not reported Although limited data is available, the current meta-analysis shows that linezolid treatment for VRE bacteremia results in lower mortality than daptomycin treatment. (p. 9) The present results surprisingly show daptomycin was not associated with significantly better microbiological cure rate than linezolid. (p. 4) o Overall effect: OR 1.47 (1.07, 2.01) (I 2 = 0%) (13 studies) o Subgroup of studies that reported aor: OR 1.59 (95% CI: 1.02, 2.52) (I 2 = 2%) (8 studies); subgroup of studies that did not report aor: OR 1.47 (95% CI: 1.07, 2.01) (I 2 = 0%) (5 studies); test for subgroup difference, p=0.60 Long-term or short-term mortality o Overall effect: OR 1.47 (1.07, 2.01) (I 2 = 0%) (13 studies) o Subgroup of studies that reported long-term mortality: OR 1.44 (95% CI: 0.99, 2.09) (I 2 = 0%) (8 studies); subgroup of studies that reported short-term mortality: OR: 1.52 (95% CI: 0.67, 3.46) (I 2 = 46%) (5 studies); test for subgroup difference, p=0.90 Long-term or short-term mortality Clinical cure o Overall effect: OR 1.47 (1.07, 2.01) (I 2 = 0%) (13 studies) o Subgroup of full papers: OR 1.46 (95% CI: 1.02, 2.09) (I 2 = 0%) (9 studies); subgroup of conference abstracts: OR: 1.41 (95% CI: 0.44, 4.47) (I 2 = 63%) (4 studies); test for subgroup difference, p=0.95 Note: OR <1 indicates a result favouring linezolid. OR: 0.85 (95% CI: 0.48, 1.49) (I 2 = 38%) (5 studies) Daptomycin for VRE Infections 18

19 Table A1: Summary of Findings of Systematic Reviews (with or without Meta-Analyses) Main Study Findings Author s Conclusions Microbiological cure Note: OR <1 indicates a result favouring linezolid. OR: 0.67 (95% CI: 0.42, 1.06) (I 2 = 0%) (8 studies) Relapse Note: OR <1 indicates a result favouring daptomycin. OR: 2.65 (95% CI: 1.03, 6.78) (I 2 = 0%) (5 studies) Safety Note: OR <1 indicates a result favouring daptomycin. Adverse events - thrombocytopenia OR 0.41 (95% CI: 0.14, 1.18) (I 2 = 0%) (3 studies) Adverse events - AKI OR 1.59 (95% CI: 0.49, 5.14) (I 2 = 0%) (2 studies) Adverse events - elevated CK OR 1.97 (95% CI: 0.37, 10.46) (I 2 = 0%) (3 studies) AKI = acute kidney injury; aor = adjusted odds ratio; CI = confidence interval; CK = creatinine kinase; OR = odds ratio Britt, Table A2: Summary of Findings of Non-Randomized Studies Main Study Findings Author s Conclusions If results from multiple analyses were reported, they were collected in the following order of priority: (1) multivariable analyses; (2) adjusted bivariate analyses, i.e. after propensity matching; (3) unadjusted bivariate analyses, i.e. before or without propensity matching. Effectiveness Note: RR >1 indicates a result favouring daptomycin. Where applicable, results are presented as linezolid vs. daptomycin. In the present analysis, daptomycin consistently performed better than linezolid in all the clinical outcomes evaluated, whereas no differences in adverse events were observed. (p. 877) Overall, daptomycin treatment for VRE- BSI appeared to result in better clinical outcomes than linezolid. (p. 877) Treatment failure Multivariable analysis (Poisson regression) RR: 1.15 (95% CI: 1.04, 1.50) 30-day all-cause mortality Daptomycin for VRE Infections 19

20 Table A2: Summary of Findings of Non-Randomized Studies Main Study Findings Author s Conclusions Multivariable analysis (Cox PH) HR: 1.36 (95% CI: 1.05, 1.76) Microbiologic failure Adjusted bivariate analysis RR: 1.81 (95% CI: 1.09, 3.03) 60-day VRE-BSI recurrence Adjusted bivariate analysis RR: 1.03 (95% CI: 0.82, 1.29) Early (7-day) mortality Adjusted bivariate analysis RR: 1.19 (95% CI: 0.82, 1.73) Hospital LOS Adjusted bivariate analysis median (Q1, Q3): 12 (7, 24) vs. 12 (6, 22) (p=0.233) Duration of bacteremia Adjusted bivariate analysis median (Q1, Q3): 4 (2, 7) vs. 3 (2, 5) (p=0.038) Safety Note: OR >1 indicates a result favouring daptomycin. Adverse events - thrombocytopenia Unadjusted bivariate analysis OR 1.30 (95% CI: 0.60, 2.87) Adverse events - elevated CK Unadjusted bivariate analysis OR 0.54 (95% CI: 0.01, 4.61) Hayakawa, If results from multiple analyses were reported, they were collected in the following order of priority: (1) multivariable analyses; (2) adjusted bivariate analyses, i.e. after propensity matching; (3) unadjusted bivariate analyses, i.e. before or without propensity matching. Effectiveness OR <1 indicates a result favouring first treatment in comparison. Differences in mortality were not significant after matching on propensity score and controlling for time to effective therapy and VRE species. (p. 3973) In conclusion, this large study revealed that daptomycin, linezolid, and β-lactams were similarly efficacious in the treatment of bacteremia due to VRE. (p. 3974) Daptomycin for VRE Infections 20

21 In-hospital mortality Table A2: Summary of Findings of Non-Randomized Studies Main Study Findings Author s Conclusions Daptomycin vs. linezolid: Multivariable analysis (logistic regression) OR 1.54 (95% CI: 0.59, 4.02) Daptomycin vs. β-lactams: Multivariable analysis (logistic regression) OR 0.47 (95% CI: 0.05, 4.9) Mortality within 3 months of discharge Daptomycin vs. linezolid vs. β-lactams: Unadjusted analysis: 16% vs. 15% vs. 4% (p=nr, but authors declare no statistical significance) Median LOS after VRE bacteremia (excluding deaths) Daptomycin vs. linezolid: Multivariable analysis (linear regression on natural log-transformed LOS) antilog(β) 0.88 (95% CI: 0.48, 1.32) Daptomycin vs. β-lactams: Multivariable analysis (linear regression on natural log-transformed LOS) antilog(β) 1.25 (95% CI: 0.64, 2.97) Patel, If results from multiple analyses were reported, they were collected in the following order of priority: (1) multivariable analyses; (2) adjusted bivariate analyses, i.e. after propensity matching; (3) unadjusted bivariate analyses, i.e. before or without propensity matching. We conclude that linezolid and daptomycin are each reasonable options to treat VRE bacteremia in oncology patients. (p. 6) Effectiveness Note: Results are presented as daptomycin vs. linezolid. Results are from unadjusted bivariate analyses, i.e. without propensity matching. Microbiological cure Unadjusted analysis: 71.0% vs. 76.5% (p=0.6141) LOS Unadjusted analysis Median (Q1, Q3) days: 42 (28, 62) vs. 30 (27, 44) (p=0.0714) Mortality Unadjusted analysis: 25.8% vs. 20.6% (p=0.6180) Daptomycin for VRE Infections 21

22 Effectiveness Table A2: Summary of Findings of Non-Randomized Studies Main Study Findings Author s Conclusions Development of thrombocytopenia, leukopenia, neutropenia and anemia from the start of therapy to end of therapy was also not significantly different between the treatment groups. (p. 4) CI = confidence interval; CK = creatinine kinase; HR = hazards ratio; LOS = length of stay; OR = odds ratio; PH = proportional hazards; Q1 = first quartile; Q3 = third quartile; RR = risk ratio; VRE = vancomycin-resistant Enterococcus; VRE-BSI = vancomycinresistant Enterococcal bloodstream infection Daptomycin for VRE Infections 22