The Impact of Vancomycin Resistance on Adverse Outcomes of Enterococci Bacteremia: A Meta- analysis of well-controlled studies

The Impact of Vancomycin Resistance on Adverse Outcomes of Enterococci Bacteremia: A Meta- analysis of well-controlled studies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report The Impact of Vancomycin Resistance on Adverse Outcomes of Enterococci Bacteremia: A Meta- analysis of well-controlled studies Ahmed Azzam, Heba Khaled This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4372419/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Previous meta-analyses have demonstrated that vancomycin-resistant Enterococcus (VRE) bacteremia is associated with increased mortality compared to vancomycin-sensitive Enterococcus (VSE) bacteremia. However, these studies relied on unadjusted data, which could potentially lead to an overestimation of the mortality risk. Therefore, we performed this systematic review with meta-analysis to investigate the impact of vancomycin resistance on adverse outcomes in enterococci blood stream infection (BSI) based on studies that were conducted after 2000 (when effective VRE therapies became available) and adjusted for age, underlying medical conditions, and time to appropriate antibiotics. Results Out of 2559 articles reviewed, four eligible articles were included in this study. Overall, vancomycin resistance was not significantly associated with increased mortality in Enterococci BSI (pooled adjusted hazard ratio for 30-day mortality, 0.927 (95% CI, 0.51 to 1.686), P = 0.8, I2% = 13.7, number of studies = 3). The remaining study reported that vancomycin resistance was not associated with in-hospital mortality (adjusted odds ratio 1.21 (95% CI, 0.53 to 2.79), P = 0.653). These findings suggest that vancomycin resistance is not a significant independent predictor of mortality in Enterococci BSI when adjusted for age, underlying medical conditions, and time to appropriate antibiotics. vancomycin-resistant Enterococci vancomycin-sensitive Enterococci in-hospital mortality Meta-analysis Figures Figure 1 Figure 2 Background Enterococci are a leading cause of nosocomial infections [ 1 , 2 ]. In the late 1980s, enterococci developed a resistance to vancomycin (vancomycin-resistant enterococci) that was first appeared in the United Kingdom and Europe. Since the late 1990s, FDA has approved several antibiotic medications to treat VRE bacteremia. Quinupristin-dalfopristin, approved in 1999, was one of the earliest authorized treatments. Linezolid gained approval in 2000. Daptomycin followed in 2003 with authorization to treat complicated VRE infections of the skin and soft tissues. Vancomycin-resistant enterococci (VRE) are associated with high in-hospital mortality and healthcare costs [ 3 , 4 ]. However, the outcomes associated with VRE bacteremia compared with VSE bacteremia remain controversial, especially after the emergence of effective VRE therapies. To our knowledge, three meta-analyses demonstrated a significantly higher mortality rate for VRE bloodstream infection (BSI) compared with VSE BSI[ 5 – 7 ]. Among these, two meta-analyses included studies conducted prior to the approval of the initial effective therapy for vancomycin-resistant enterococci (VRE)[ 6 , 7 ]. Consequently, the heightened mortality risk observed in these studies likely stemmed from the fact that patients with VRE bacteremia were more prone to receiving ineffective treatment. The most recent meta-analysis, which included studies conducted from January 2000 to 2014 and presumably employed effective treatment(s) for VRE, depended on crude, unadjusted data that did not account for potential confounding factors such as comorbid conditions, age and time to appropriate antibiotics [ 8 ]. This omission may result in an overestimation of the associations of interest. It is crucial to explore the impact of vancomycin resistance on enterococci BSI after the emergence of effective VRE therapy. To give a precise estimate of the association of vancomycin resistance with mortality, we performed this meta-analysis based on studies that were conducted after 2000 (when t effective VRE therapies became available) and reported the adjusted data. Methods Search strategy A systematic literature search was performed using MEDLINE, Web of Science, Google Scholar, and Scopus databases to identify relevant studies published from 2000 to April 2024. The search strategy included the keywords ("vancomycin resistant Enterococc* or VRE), and ("vancomycin sensitive Enterococc* or VSE"), and (“bloodstream infection or bacteremia") and (“in-hospital mortality” or mortality or death, “length of hospitalization” or LOS or “hospitalization stay “, or “recurrent bloodstream infection”). We adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines while conducting and reporting this review. Eligibility criteria Inclusion Criteria: Studies will be included if met all of the following: (1) The study utilized a comparative design to evaluate outcomes between patients with VRE bacteremia and VSE bacteremia. (2) in-hospital mortality, length of hospitalization, or recurrent BSI were reported as outcomes. (3) Potential confounding factors, particularly age, underlying medical conditions, and time to appropriate antibiotics, were adjusted for through statistical methods such as matching, or multivariate analysis. Exclusion Criteria: Publications dated prior to 2000 were not eligible for inclusion. Studies before this period were excluded, given that the first effective therapy for VRE bacteremia was not approved until 2000. Two independent reviewers selected eligible articles based on the aforementioned inclusion and exclusion criteria. Data extraction The following data points were extracted from each included study: Last name of the first author, year of publication, study design, outcome(s) reported, Sample size of VRE and VSE patient groups, method(s) used for adjusting for potential confounders, and adjusted odds ratio/risk ratio/hazard ratio. The data extraction was conducted by two independent reviewers. Quality assessment The quality of the included studies was assessed using the Newcastle-Ottawa Scale for cohort studies [ 9 ]. Data synthesis Eligible articles that reported the same effect size of outcome within the same point time were pooled under the random-effects model to obtain a summary estimate along with its 95% confidence intervals. I-squared was used to measure the heterogeneity between the studies. All statistical analyses were performed using Comprehensive Meta-Analysis version 3.0 (Biostat, Englewood, NJ, USA). Results Study selection Characteristics of the included studies Out of 2559 articles reviewed, four eligible articles were included in this study (Fig. 1 )[ 10 – 13 ]. The characteristics of the included studies are presented in Table 1 . All were retrospective, focusing on in-hospital mortality as an outcome, and had a high quality score, as depicted in Table 1 . Among these four studies, three reported the adjusted hazard ratio, which was utilized in the quantitative synthesis, while the remaining study reported adjusted odds ratios. In-hospital mortality risk for patients with VRE relative to VSE bloodstream infections The quantitative synthesis included three studies reported the adjusted hazard ratio for 30-day in-hospital mortality[ 11 – 13 ]. The pooled adjusted hazard ratio for 30 day in-hospital mortality was 0.927 (95% CI, 0.51 to 1.686, P = 0.8, I2% =13.7 number of studies = 3) as depicted in Fig. 2 . The remaining study reported that the adjusted odds ratio for in-hospital mortality was 1.21 (95% CI, 0.53 to 2.79, P = 0.653) [ 10 ]. Table 1 Characteristics of the included studies Author, publication year[citation] Study design Sample size VRE/VSE Adjusted factors* Outcome adjusted estimate, 95% CI NOS score (out of 9) Cho, 2013[ 13 ] Retrospective cohort 24/67 Age, sex, Charlson’s comorbidity, index Illness severity score, and days to appropriate antibiotic 30-day in-hospital mortality aHR = 0.75 (0.24–2.36) 9 Dubler, 2022[ 12 ] Retrospective cohort 39/138 age, sex, Illness severity score and days to appropriate antibiotic 30-day in-hospital mortality aHR = 1.8 (0.64–5.03) 8 Yang, 2022[ 11 ] Retrospective cohort 55/136 Age, sex, Charlson’s comorbidity index and days to appropriate antibiotic. 30-day in-hospital mortality aHR = 0.679 (0.308–1.498) 9 Cheah, 2013[ 10 ] Retrospective cohort 116/116 Age, sex, Charlson’s comorbidity index A and days to appropriate antibiotic in-hospital mortality aOR = 1.21(0.53–2.79) 9 Note:* These factors are either similar in baseline characteristics, non-significant in the univariate analysis, or adjusted by multivariate analysis, aHR: adjusted hazard ratio, aOR: adjusted odds ratio, NOS: Newcastle-Ottawa Scale for cohort studies. Discussion Previous meta-analyses have demonstrated that vancomycin resistance is associated with increased mortality in patients with enterococcal BSI [ 5 – 7 ]. However, these studies are limited by either including research from before effective VRE treatments were available or using unadjusted data, potentially leading to an overestimation of the association. In the study, we instead depended on studies that were published after 2000 (when the first effective VRE therapy became available) and reported the adjusted data. Our findings revealed that there was no significant difference in in-hospital mortality risk between VRE and VSE BSI after adjustment for the confounders. To our knowledge, three meta-analyses addressed the impact of vancomycin resistance on enterococci bloodstream infection (BSI) mortality[ 5 – 7 ]. Among these, two meta-analyses encompassed studies conducted prior to the approval of the initial effective therapy for vancomycin-resistant enterococci (VRE)[ 6 , 7 ]. Therefore, the increased mortality risk observed in these studies is likely attributable to the higher proportion of patients with VRE bacteremia receiving ineffective treatment. A more recent meta-analysis comprised studies conducted after January 2000, which presumably employed effective treatment(s) for VRE [ 5 ]. However, this study relied on crude, unadjusted data that did not account for potential confounding factors such as comorbid conditions, the patient's underlying health status, and the time to appropriate antibiotics. This omission may result in an overestimation of the mortality risk of VRE compared to VSE. The high risk of mortality associated with VRE bacteremia compared to VSE bacteremia may be related to factors other than vancomycin resistance. For instance, there is an anticipated delay in receiving effective antibiotics in patients with VRE bacteremia compared to VSE. A previous study found that delayed antibiotic therapy, defined as treatment initiation 48.1 hours or more after enterococci BSI onset, was associated with a 3.16 times higher risk of 30-day mortality according to their multivariate analysis (risk ratio 3.16, 95% CI 1.96–5.09) [ 14 ]. In addition, this study identified vancomycin resistance as the sole independent factor predictive of experiencing delayed therapy, after accounting for potential confounding variables in their statistical models [ 14 ]. Yang et al . [ 11 ] revealed that there is no significant difference in mortality between VSE and VRE when appropriate antibiotic use is administered in less than 3 days, with an adjusted HR of 0.679 (0.308–1.498). However, patients with VRE who received appropriate antibiotics after more than 3 days had a higher risk of mortality compared to VSE patients who got appropriate antibiotics within 3 days, with an adjusted HR of 2.045 (1.089–3.84). So, it is crucial to adjust for the appropriate antibiotics for a precise estimation of mortality risk. Strengths and Limitations One strength of this study is the utilization of adjusted data, which helps in accounting for confounding factors and enhancing the accuracy of the results. However, it is important to acknowledge the limitations of the study, including a small number of the included studies and the inherent limitations associated with observational study designs. Conclusion These findings suggest that the high risk of mortality associated with VRE bacteremia compared to VSE bacteremia may be related to factors other than vancomycin resistance. Abbreviations BSI Bloodstream Infection VRE Vancomycin-Resistant Enterococci VSE Vancomycin-Susceptible Enterococci HR Hazard Ratio OR Odds ratio RR Risk ratio CI Confidence Interval NOS Newcastle-Ottawa Scale Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and material All data generated and analyzed throughout this study were included in this article. Conflict of interest All the authors have no conflicts of interest to disclose. Competing interests The authors declare no competing interests. Funding None Authors' contributions The study was conceptualized by A.A. H.K conducted the retrieval and screening of studies, which were then cross-checked by A.A. Data collection was carried out by A.A. with subsequent verification by H.K. A.A. performed the data analysis, which was double-checked by H.K. All authors contributed to the data interpretation, discussion, and research conclusions. The manuscript was primarily drafted by A.A. with input and feedback from all H.K. The final version of the manuscript was reviewed and approved by all authors. Acknowledgments None References European Centre for Disease Prevention and Control. Healthcare-associated infections acquired in intensive care units - Annual Epidemiological Report 2016 [2014 data]. Annual Epidemiological Report on Communicable Diseases in Europe. 2016;:1–4. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: Analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39:309–17. Chiang HY, Perencevich EN, Nair R, Nelson RE, Samore M, Khader K, et al. Incidence and outcomes associated with infections caused by Vancomycin-Resistant Enterococci in the United States: Systematic literature review and meta-analysis. Infect Control Hosp Epidemiol. 2017;38:203–15. CDC. 2019 Antibiotic Resistance Threats Report | CDC. Center for Disease Control. 2021;:1–113. Prematunge C, MacDougall C, Johnstone J, Adomako K, Lam F, Robertson J, et al. VRE and VSE Bacteremia Outcomes in the Era of Effective VRE Therapy: A Systematic Review and Meta-analysis. Infect Control Hosp Epidemiol. 2016;37:26–35. DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: A meta-analysis. Clin Infect Dis. 2005;41:327–33. Salgado CD, Farr BM. Outcomes Associated With Vancomycin-Resistant Enterococci: A Meta-Analysis. Infect Control Hosp Epidemiol. 2003;24:690–8. Prematunge C, MacDougall C, Johnstone J, Adomako K, Lam F, Robertson J, et al. VRE and VSE bacteremia outcomes in the era of effective VRE therapy: A systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2016;37:26–35. Ottawa Hospital Research Institute. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 4 May 2024. Cheah ALY, Spelman T, Liew D, Peel T, Howden BP, Spelman D, et al. Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization. Clin Microbiol Infect. 2013;19:E181–9. Yang MC, Wu YK, Lan CC, Yang MC, Chiu SK, Peng MY, et al. Antibiotic Stewardship Related to Delayed Diagnosis and Poor Prognosis of Critically Ill Patients with Vancomycin-Resistant Enterococcal Bacteremia: A Retrospective Cohort Study. Infect Drug Resist. 2022;15:723–34. Dubler S, Lenz M, Zimmermann S, Richter DC, Weiss KH, Mehrabi A, et al. Does vancomycin resistance increase mortality in Enterococcus faecium bacteraemia after orthotopic liver transplantation? A retrospective study. Antimicrob Resist Infect Control. 2020;9:1–10. Cho SY, Lee DG, Choi SM, Kwon JC, Kim SH, Choi JK, et al. Impact of vancomycin resistance on mortality in neutropenic patients with enterococcal bloodstream infection: A retrospective study. BMC Infect Dis. 2013;13:1–8. Zasowski EJ, Claeys KC, Lagnf AM, Davis SL, Rybak MJ. Time Is of the Essence: The Impact of Delayed Antibiotic Therapy on Patient Outcomes in Hospital-Onset Enterococcal Bloodstream Infections. Clin Infect Dis. 2016;62:1242–50. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4372419","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":315566896,"identity":"45d80451-2586-4fd6-9f6a-9dd1884a7905","order_by":0,"name":"Ahmed Azzam","email":"data:image/png;base64,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","orcid":"","institution":"Helwan University","correspondingAuthor":true,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Azzam","suffix":""},{"id":315566897,"identity":"37d2e128-a7cf-44b5-b321-6b3ad37ab86f","order_by":1,"name":"Heba Khaled","email":"","orcid":"","institution":"Cairo University","correspondingAuthor":false,"prefix":"","firstName":"Heba","middleName":"","lastName":"Khaled","suffix":""}],"badges":[],"createdAt":"2024-05-05 16:09:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4372419/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4372419/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58544973,"identity":"68a12775-d1cc-4e8c-93d2-2c410e19837f","added_by":"auto","created_at":"2024-06-18 05:27:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":24678,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart depicting the selection of eligible articles\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4372419/v1/775b8519b7905b595cea9a86.png"},{"id":58545451,"identity":"49b702bf-54eb-4b05-a272-e4422f784a89","added_by":"auto","created_at":"2024-06-18 05:35:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":18988,"visible":true,"origin":"","legend":"\u003cp\u003eAdjusted pooled hazard ratio for 30-day in-hospital mortality risk in VRE compared to VSE bacteremia\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4372419/v1/2ee288438e9a847247748374.png"},{"id":58545476,"identity":"03497d10-c112-4861-9cf1-85c7e3935136","added_by":"auto","created_at":"2024-06-18 05:35:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":436705,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4372419/v1/8356f235-c4e8-4129-ab3a-908b9fd79c0a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Impact of Vancomycin Resistance on Adverse Outcomes of Enterococci Bacteremia: A Meta- analysis of well-controlled studies","fulltext":[{"header":"Background","content":"\u003cp\u003eEnterococci are a leading cause of nosocomial infections [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In the late 1980s, enterococci developed a resistance to vancomycin (vancomycin-resistant enterococci) that was first appeared in the United Kingdom and Europe. Since the late 1990s, FDA has approved several antibiotic medications to treat VRE bacteremia. Quinupristin-dalfopristin, approved in 1999, was one of the earliest authorized treatments. Linezolid gained approval in 2000. Daptomycin followed in 2003 with authorization to treat complicated VRE infections of the skin and soft tissues.\u003c/p\u003e \u003cp\u003eVancomycin-resistant enterococci (VRE) are associated with high in-hospital mortality and healthcare costs [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, the outcomes associated with VRE bacteremia compared with VSE bacteremia remain controversial, especially after the emergence of effective VRE therapies. To our knowledge, three meta-analyses demonstrated a significantly higher mortality rate for VRE bloodstream infection (BSI) compared with VSE BSI[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Among these, two meta-analyses included studies conducted prior to the approval of the initial effective therapy for vancomycin-resistant enterococci (VRE)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, the heightened mortality risk observed in these studies likely stemmed from the fact that patients with VRE bacteremia were more prone to receiving ineffective treatment. The most recent meta-analysis, which included studies conducted from January 2000 to 2014 and presumably employed effective treatment(s) for VRE, depended on crude, unadjusted data that did not account for potential confounding factors such as comorbid conditions, age and time to appropriate antibiotics [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This omission may result in an overestimation of the associations of interest.\u003c/p\u003e \u003cp\u003eIt is crucial to explore the impact of vancomycin resistance on enterococci BSI after the emergence of effective VRE therapy. To give a precise estimate of the association of vancomycin resistance with mortality, we performed this meta-analysis based on studies that were conducted after 2000 (when t effective VRE therapies became available) and reported the adjusted data.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eA systematic literature search was performed using MEDLINE, Web of Science, Google Scholar, and Scopus databases to identify relevant studies published from 2000 to April 2024. The search strategy included the keywords (\"vancomycin resistant Enterococc* or VRE), and (\"vancomycin sensitive Enterococc* or VSE\"), and (\u0026ldquo;bloodstream infection or bacteremia\") and (\u0026ldquo;in-hospital mortality\u0026rdquo; or mortality or death, \u0026ldquo;length of hospitalization\u0026rdquo; or LOS or \u0026ldquo;hospitalization stay \u0026ldquo;, or \u0026ldquo;recurrent bloodstream infection\u0026rdquo;). We adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines while conducting and reporting this review.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eInclusion Criteria:\u003c/h2\u003e \u003cp\u003eStudies will be included if met all of the following:\u003c/p\u003e \u003cp\u003e(1) The study utilized a comparative design to evaluate outcomes between patients with VRE bacteremia and VSE bacteremia. (2) in-hospital mortality, length of hospitalization, or recurrent BSI were reported as outcomes. (3) Potential confounding factors, particularly age, underlying medical conditions, and time to appropriate antibiotics, were adjusted for through statistical methods such as matching, or multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eExclusion Criteria:\u003c/h2\u003e \u003cp\u003ePublications dated prior to 2000 were not eligible for inclusion. Studies before this period were excluded, given that the first effective therapy for VRE bacteremia was not approved until 2000.\u003c/p\u003e \u003cp\u003eTwo independent reviewers selected eligible articles based on the aforementioned inclusion and exclusion criteria.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eData extraction\u003c/h2\u003e \u003cp\u003eThe following data points were extracted from each included study:\u003c/p\u003e \u003cp\u003eLast name of the first author, year of publication, study design, outcome(s) reported, Sample size of VRE and VSE patient groups, method(s) used for adjusting for potential confounders, and adjusted odds ratio/risk ratio/hazard ratio. The data extraction was conducted by two independent reviewers.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eQuality assessment\u003c/h2\u003e \u003cp\u003eThe quality of the included studies was assessed using the Newcastle-Ottawa Scale for cohort studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eData synthesis\u003c/h2\u003e \u003cp\u003eEligible articles that reported the same effect size of outcome within the same point time were pooled under the random-effects model to obtain a summary estimate along with its 95% confidence intervals. I-squared was used to measure the heterogeneity between the studies. All statistical analyses were performed using Comprehensive Meta-Analysis version 3.0 (Biostat, Englewood, NJ, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection Characteristics of the included studies\u003c/h2\u003e \u003cp\u003eOut of 2559 articles reviewed, four eligible articles were included in this study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)[\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The characteristics of the included studies are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. All were retrospective, focusing on in-hospital mortality as an outcome, and had a high quality score, as depicted in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among these four studies, three reported the adjusted hazard ratio, which was utilized in the quantitative synthesis, while the remaining study reported adjusted odds ratios.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eIn-hospital mortality risk for patients with VRE relative to VSE bloodstream infections\u003c/h2\u003e \u003cp\u003eThe quantitative synthesis included three studies reported the adjusted hazard ratio for 30-day in-hospital mortality[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The pooled adjusted hazard ratio for 30 day in-hospital mortality was 0.927 (95% CI, 0.51 to 1.686, P\u0026thinsp;=\u0026thinsp;0.8, I2% =13.7 number of studies\u0026thinsp;=\u0026thinsp;3) as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The remaining study reported that the adjusted odds ratio for in-hospital mortality was 1.21 (95% CI, 0.53 to 2.79, P\u0026thinsp;=\u0026thinsp;0.653) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor, publication year[citation]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003cp\u003eVRE/VSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted factors*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eadjusted estimate, 95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNOS score\u003c/p\u003e \u003cp\u003e(out of 9)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCho, 2013[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003cp\u003ecohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24/67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge, sex, Charlson\u0026rsquo;s \u003c/p\u003e \u003cp\u003ecomorbidity, index Illness \u003c/p\u003e \u003cp\u003eseverity score, and days to \u003c/p\u003e \u003cp\u003eappropriate antibiotic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30-day in-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eaHR\u0026thinsp;=\u0026thinsp;0.75 (0.24\u0026ndash;2.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDubler, 2022[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003cp\u003ecohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39/138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eage, sex, Illness severity score and days to appropriate antibiotic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30-day in-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eaHR\u0026thinsp;=\u0026thinsp;1.8 (0.64\u0026ndash;5.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYang, 2022[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003cp\u003ecohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55/136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge, sex, Charlson\u0026rsquo;s comorbidity index and days to appropriate antibiotic.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30-day in-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eaHR\u0026thinsp;=\u0026thinsp;0.679 (0.308\u0026ndash;1.498)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCheah, 2013[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003cp\u003ecohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116/116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge, sex, Charlson\u0026rsquo;s comorbidity index A and days to appropriate antibiotic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ein-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eaOR\u0026thinsp;=\u0026thinsp;1.21(0.53\u0026ndash;2.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eNote:* These factors are either similar in baseline characteristics, non-significant in the univariate analysis, or adjusted by multivariate analysis, aHR: adjusted hazard ratio, aOR: adjusted odds ratio, NOS: Newcastle-Ottawa Scale for cohort studies.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrevious meta-analyses have demonstrated that vancomycin resistance is associated with increased mortality in patients with enterococcal BSI [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, these studies are limited by either including research from before effective VRE treatments were available or using unadjusted data, potentially leading to an overestimation of the association. In the study, we instead depended on studies that were published after 2000 (when the first effective VRE therapy became available) and reported the adjusted data. Our findings revealed that there was no significant difference in in-hospital mortality risk between VRE and VSE BSI after adjustment for the confounders.\u003c/p\u003e \u003cp\u003eTo our knowledge, three meta-analyses addressed the impact of vancomycin resistance on enterococci bloodstream infection (BSI) mortality[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Among these, two meta-analyses encompassed studies conducted prior to the approval of the initial effective therapy for vancomycin-resistant enterococci (VRE)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Therefore, the increased mortality risk observed in these studies is likely attributable to the higher proportion of patients with VRE bacteremia receiving ineffective treatment. A more recent meta-analysis comprised studies conducted after January 2000, which presumably employed effective treatment(s) for VRE [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, this study relied on crude, unadjusted data that did not account for potential confounding factors such as comorbid conditions, the patient's underlying health status, and the time to appropriate antibiotics. This omission may result in an overestimation of the mortality risk of VRE compared to VSE.\u003c/p\u003e \u003cp\u003eThe high risk of mortality associated with VRE bacteremia compared to VSE bacteremia may be related to factors other than vancomycin resistance. For instance, there is an anticipated delay in receiving effective antibiotics in patients with VRE bacteremia compared to VSE. A previous study found that delayed antibiotic therapy, defined as treatment initiation 48.1 hours or more after enterococci BSI onset, was associated with a 3.16 times higher risk of 30-day mortality according to their multivariate analysis (risk ratio 3.16, 95% CI 1.96\u0026ndash;5.09) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In addition, this study identified vancomycin resistance as the sole independent factor predictive of experiencing delayed therapy, after accounting for potential confounding variables in their statistical models [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Yang \u003cem\u003eet al\u003c/em\u003e. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] revealed that there is no significant difference in mortality between VSE and VRE when appropriate antibiotic use is administered in less than 3 days, with an adjusted HR of 0.679 (0.308\u0026ndash;1.498). However, patients with VRE who received appropriate antibiotics after more than 3 days had a higher risk of mortality compared to VSE patients who got appropriate antibiotics within 3 days, with an adjusted HR of 2.045 (1.089\u0026ndash;3.84). So, it is crucial to adjust for the appropriate antibiotics for a precise estimation of mortality risk.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and Limitations\u003c/h2\u003e \u003cp\u003eOne strength of this study is the utilization of adjusted data, which helps in accounting for confounding factors and enhancing the accuracy of the results. However, it is important to acknowledge the limitations of the study, including a small number of the included studies and the inherent limitations associated with observational study designs.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThese findings suggest that the high risk of mortality associated with VRE bacteremia compared to VSE bacteremia may be related to factors other than vancomycin resistance.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBSI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBloodstream Infection\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVRE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVancomycin-Resistant Enterococci\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVSE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVancomycin-Susceptible Enterococci\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHazard Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOdds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRisk ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence Interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNewcastle-Ottawa Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable\u003cbr\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eAll data generated and analyzed throughout this study were included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eAll the authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u003cbr\u003e\u003cstrong\u003eFunding\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe study was conceptualized by A.A. H.K conducted the retrieval and screening of studies, which were then cross-checked by A.A. Data collection was carried out by A.A. with subsequent verification by H.K. A.A. performed the data analysis, which was double-checked by H.K. All authors contributed to the data interpretation, discussion, and research conclusions. The manuscript was primarily drafted by A.A. with input and feedback from all H.K. The final version of the manuscript was reviewed and approved by all authors.\u003cbr\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;None\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eEuropean Centre for Disease Prevention and Control. Healthcare-associated infections acquired in intensive care units - Annual Epidemiological Report 2016 [2014 data]. Annual Epidemiological Report on Communicable Diseases in Europe. 2016;:1\u0026ndash;4.\u003c/li\u003e\n \u003cli\u003eWisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: Analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39:309\u0026ndash;17.\u003c/li\u003e\n \u003cli\u003eChiang HY, Perencevich EN, Nair R, Nelson RE, Samore M, Khader K, et al. Incidence and outcomes associated with infections caused by Vancomycin-Resistant Enterococci in the United States: Systematic literature review and meta-analysis. Infect Control Hosp Epidemiol. 2017;38:203\u0026ndash;15.\u003c/li\u003e\n \u003cli\u003eCDC. 2019 Antibiotic Resistance Threats Report | CDC. Center for Disease Control. 2021;:1\u0026ndash;113.\u003c/li\u003e\n \u003cli\u003ePrematunge C, MacDougall C, Johnstone J, Adomako K, Lam F, Robertson J, et al. VRE and VSE Bacteremia Outcomes in the Era of Effective VRE Therapy: A Systematic Review and Meta-analysis. Infect Control Hosp Epidemiol. 2016;37:26\u0026ndash;35.\u003c/li\u003e\n \u003cli\u003eDiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: A meta-analysis. Clin Infect Dis. 2005;41:327\u0026ndash;33.\u003c/li\u003e\n \u003cli\u003eSalgado CD, Farr BM. Outcomes Associated With Vancomycin-Resistant Enterococci: A Meta-Analysis. Infect Control Hosp Epidemiol. 2003;24:690\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003ePrematunge C, MacDougall C, Johnstone J, Adomako K, Lam F, Robertson J, et al. VRE and VSE bacteremia outcomes in the era of effective VRE therapy: A systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2016;37:26\u0026ndash;35.\u003c/li\u003e\n \u003cli\u003eOttawa Hospital Research Institute. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 4 May 2024.\u003c/li\u003e\n \u003cli\u003eCheah ALY, Spelman T, Liew D, Peel T, Howden BP, Spelman D, et al. Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization. Clin Microbiol Infect. 2013;19:E181\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eYang MC, Wu YK, Lan CC, Yang MC, Chiu SK, Peng MY, et al. Antibiotic Stewardship Related to Delayed Diagnosis and Poor Prognosis of Critically Ill Patients with Vancomycin-Resistant Enterococcal Bacteremia: A Retrospective Cohort Study. Infect Drug Resist. 2022;15:723\u0026ndash;34.\u003c/li\u003e\n \u003cli\u003eDubler S, Lenz M, Zimmermann S, Richter DC, Weiss KH, Mehrabi A, et al. Does vancomycin resistance increase mortality in Enterococcus faecium bacteraemia after orthotopic liver transplantation? A retrospective study. Antimicrob Resist Infect Control. 2020;9:1\u0026ndash;10.\u003c/li\u003e\n \u003cli\u003eCho SY, Lee DG, Choi SM, Kwon JC, Kim SH, Choi JK, et al. Impact of vancomycin resistance on mortality in neutropenic patients with enterococcal bloodstream infection: A retrospective study. BMC Infect Dis. 2013;13:1\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eZasowski EJ, Claeys KC, Lagnf AM, Davis SL, Rybak MJ. Time Is of the Essence: The Impact of Delayed Antibiotic Therapy on Patient Outcomes in Hospital-Onset Enterococcal Bloodstream Infections. Clin Infect Dis. 2016;62:1242\u0026ndash;50.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"vancomycin-resistant Enterococci, vancomycin-sensitive Enterococci, in-hospital mortality, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-4372419/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4372419/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrevious meta-analyses have demonstrated that vancomycin-resistant Enterococcus (VRE) bacteremia is associated with increased mortality compared to vancomycin-sensitive Enterococcus (VSE) bacteremia. However, these studies relied on unadjusted data, which could potentially lead to an overestimation of the mortality risk. Therefore, we performed this systematic review with meta-analysis to investigate the impact of vancomycin resistance on adverse outcomes in enterococci blood stream infection (BSI) based on studies that were conducted after 2000 (when effective VRE therapies became available) and adjusted for age, underlying medical conditions, and time to appropriate antibiotics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003cbr\u003e\n \u003c/strong\u003eOut of 2559 articles reviewed, four eligible articles were included in this study. Overall, vancomycin resistance was not significantly associated with increased mortality in Enterococci BSI (pooled adjusted hazard ratio for 30-day mortality, 0.927 (95% CI, 0.51 to 1.686), P = 0.8, I2% = 13.7, number of studies = 3). The remaining study reported that vancomycin resistance was not associated with in-hospital mortality (adjusted odds ratio 1.21 (95% CI, 0.53 to 2.79), P = 0.653). These findings suggest that vancomycin resistance is not a significant independent predictor of mortality in Enterococci BSI when adjusted for age, underlying medical conditions, and time to appropriate antibiotics.\u003c/p\u003e","manuscriptTitle":"The Impact of Vancomycin Resistance on Adverse Outcomes of Enterococci Bacteremia: A Meta- analysis of well-controlled studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-18 05:27:12","doi":"10.21203/rs.3.rs-4372419/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a019c193-2b79-4faa-b347-e374845b85bc","owner":[],"postedDate":"June 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-18T05:27:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-18 05:27:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4372419","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4372419","identity":"rs-4372419","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}