Get 20M+ Full-Text Papers For Less Than $1.50/day. Subscribe now for You or Your Team.

Learn More →

The importance of adjusting for enterococcus species when assessing the burden of vancomycin resistance: a cohort study including over 1000 cases of enterococcal bloodstream infections

The importance of adjusting for enterococcus species when assessing the burden of vancomycin... Background: Infections caused by vancomycin-resistant enterococci (VRE) are on the rise worldwide. Few studies have tried to estimate the mortality burden as well as the financial burden of those infections and found that VRE are associated with increased mortality and higher hospital costs. However, it is unclear whether these worse outcomes are attributable to vancomycin resistance only or whether the enterococcal species (Enterococcus faecium or Enterococcus faecalis) play an important role. We therefore aimed to determine the burden of enterococci infections attributable to vancomycin resistance and pathogen species (E. faecium and E. faecalis) in cases of bloodstream infection (BSI). Methods: We conducted a retrospective cohort study on patients with BSI caused by Enterococcus faecium or Enterococcus faecalis between 2008 and 2015 in three tertiary care hospitals. Data was collected on true hospital costs (in €), length of stay (LOS), basic demographic parameters, and underlying diseases including the results of the Charlson comorbidity index (CCI). We used univariate and multivariable regression analyses to compare risk factors for in-hospital mortality and length of stay (i) between vancomycin-susceptible E. faecium- (VSEm) and vancomycin-susceptible E. faecalis- (VSEf) cases and (ii) between vancomycin-susceptible E. faecium- (VSEm) and vancomycin-resistant E. faecium-cases (VREm). We calculated total hospital costs for VSEm, VSEf and VREm. Results: Overall, we identified 1160 consecutive cases of BSI caused by enterococci: 596 (51.4%) cases of E. faecium BSI and 564 (48.6%) cases of E. faecalis BSI. 103 cases of E. faecium BSI (17.3%) and 1 case of E. faecalis BSI (0.2%) were infected by vancomycin-resistant isolates. Multivariable analyses revealed (i) that in addition to different underlying diseases E. faecium was an independent risk factor for in-hospital mortality and prolonged hospital stay and (ii) that vancomycin-resistance did not further increase the risk for the described outcomes among E. faecium- isolates. However, the overall hospital costs were significantly higher in VREm-BSI cases as compared to VSEm- and VSEf-BSI cases (80,465€ vs. 51,365€ vs. 31,122€ p < 0.001). (Continued on next page) * Correspondence: tobias.kramer@charite.de Charité Universitätsmedizin Berlin, Institute of Hygiene and Environmental Medicine, Berlin, Germany National Reference Center for the Surveillance of Nosocomial Infections, Berlin, Germany Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 2 of 9 (Continued from previous page) Conclusion: Our data indicates that in-hospital mortality and infection-attributed hospital stay in enterococci BSI might rather be influenced by Enterococcus species and underlying diseases than by vancomycin resistance. Therefore, future studies should consider adjusting for Enterococcus species in addition to vancomycin resistance in order to provide a conservative estimate for the burden of VRE infections. Keywords: Bloodstream infection, Vancomycin-resistant enterococci, Enterococcus faecium Introduction Cases were identified in the Charité microbiology data- Enterococcus spp. are part of the normal gastrointestinal base as hospitalized patients with blood cultures positive flora. Among those pathogens, resistance to antimicrobial for one of these pathogens. Data on costs and hospital substances, notably to vancomycin, results in limited thera- financial accounting was provided by the Charité peutic options [1, 2]. In recent years, hospital-acquired in- Department of Financial Controlling as true hospital fections (HAI) caused by vancomycin-resistant enterococci expenses in Euros. For all patients enrolled in this study, (VRE) have emerged as a relevant burden on patients and the following demographic and clinical characteristics healthcare systems globally [3–5]. In order to reduce the were collected: age, sex, in-hospital death, length of spread of resistant strains in hospitals, infection control hospital stay (LOS), day of BSI onset and stay on an measures, e.g. contact precautions, have been proposed intensive care unit (days). Length of stay in total and [6, 7]. To assess the efficiency of VRE prevention after BSI onset were defined as length of stay until death measures, the mortality- and financial burden of VRE or discharge. The Charlson comorbidity index (CCI) was infections has to be assessed. However, the methodo- obtained on the basis of the patients’ diagnosed comor- logical approach on assessing VRE-burden remains bidities using the method of Charlson et al. and the controversial [2, 8, 9] and only few studies have addressed adaptation for the ICD-10 by Thygesen et al. [28, 29]. economic aspects [10–15]. As costs are often not available The original 17 Charlson comorbidity categories were as infection-attributable costs (costs after onset for cumulated based on the affected organ system in the fol- infection) length of stay (LOS) after onset of infection is lowing ten disease categories: heart disease, cerebrovas- being used as a surrogate parameter [2, 8, 16]. cular disease, neurologic disease, lung disease, rheumatic Although analyses should compare VRE infections disease, gastrointestinal disease, liver disease, diabetes, to VSE-infected patients when the attributable effect renal disease and cancer/immunological disease. of vancomycin resistance is addressed, [2, 8, 16]prior studies also utilized comparisons to cohorts with Definitions and statistical methods non-enterococcus infections [17, 18]or cohorts Cases were defined as patients with BSI caused by without infection [8, 12, 19–24]. Since the course of Enterococcus spp. (Enterococcus faecalis or Enterococcus enterococcal infections may also be influenced by the faecium) during the study period. Each patient was in- enterococcus subspecies itself [2, 8, 9, 25, 26], cluded in the analysis once. Onset of BSI was defined as analyses not considering the pathogen species may the date of the first blood culture positive for the re- therefore be biased as result of the different virulence spective pathogen. BSI was considered hospital-onset if of the pathogens. it occurred after the third day of hospitalization. Mortality In a large cohort of cases with bloodstream infection was assessed based on discharge alive or in-hospital death. (BSI), we therefore studied the influence of vancomycin Data on hospital costs were derived from true hospital resistance and enterococcus subspecies on in-hospital costs (hospital expenses). The costs analyzed cover direct mortality, hospital costs and length of hospital stay. costs to the hospital of treatment and diagnostics as well as indirect hospital costs of activities without patient Methods contact (e.g. administration, hospital maintenance). The Setting, study design and data collection estimated cost of individual cases was based on definite The study was conducted at three different tertiary care performances and on settlement keys (e.g. nurse working hospitals of the Charité university hospital in Berlin, time per patient). Economic data was available on total with 3011-beds in total [27]. After a confirmatory ethics hospital costs and on daily costs. A differentiation of costs vote was obtained from the Charité University Medicine before and after the infection was not available. However, ethics committee (internal processing key EA4/229/17), as length of stay directly correlates with hospital costs, we performed a cohort study that included all cases of length of stay after onset for infection can be applied as BSI caused by Enterococcus faecalis or Enterococcus fae- proxy for infection attributable additional expenditures cium between January 1, 2008 and December 31, 2015. [2, 30, 31]. We therefore assessed the multiplicative Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 3 of 9 effect on length of stay after BSI onset in a multivari- transformation and referred to as the multiplicative able linear regression. effect (ME) of investigated parameters. P-values < 0.05 Descriptive, univariate analyses were performed for the were considered significant. total cohort, stratified by enterococcus species (i.e. Multivariable, binary logistic regression was performed vancomycin susceptible E. faecium vs. vancomycin sus- for in-hospital death by stepwise forward selection. The ceptible E. faecalis) and by vancomycin susceptibility p-values for including a variable in the model was 0.05 (i.e. vancomycin susceptible enterococci vs. vancomycin and for excluding 0.06 respectively. Odds ratios (HR) resistant enterococci). Since among E. faecalis-isolates with 95% confidence intervals (95% CI) were calculated. only one isolate was resistant against vancomycin, only Parameters considered in the model were sex, age, E. faecium (VSEm vs. VREm) were analyzed in the pathogen species (E. faecium vs. E. faecalis) with the second analysis. Additionally, we compared in univariate interaction of the vancomycin resistance and all under- analysis deceased patients and patients discharged alive. lying diseases assessed as described above. The median and the interquartile range (IQR) were cal- All analyses were performed using SPSS (IBM SPSS culated for continuous parameters; number and percent- statistics, Somer, NY, USA) and SAS (SAS Institute, age were calculated for binary parameters. Univariate Cary, NC, USA). differences were tested using the Wilcoxon rank-sum test for continuous variables and the Chi-square test for Microbiological methods binary variables. If a blood stream infection was suspected, blood cultures The two linear regression analyses were performed for were drawn and incubated for up to seven days using length of stay (LOS) after onset of enterococcal BSI by standard blood culture tubes (BACTEC, Becton stepwise forward variable selection. The continuous Dickinson Heidelberg Germany). If growth was detected, parameters LOS after onset of BSI was log transformed gram staining and culturing were performed. MALDI to achieve normal distribution. Only surviving patients TOF MS and Vitek 2 automated system (Biomerieux were included. Parameters considered in the full Marcy l’etoile France) were used for identification and model were vancomycin resistance OR pathogen susceptibility testing of bacterial strains. They were species (E. faecium or E. faecalis), sex, age and all interpreted using EUCAST definitions. underlying diseases assessed as described above. From the full model, parameters with the smallest Results Chi-square statistic and p > 0.05 in the type III test We initially extracted n = 24,086 clinical isolates diag- were removed. The regression coefficients were con- nosed with Enterococcus faecium or Enterococcus faecalis verted to the measures of effect using an exponential from the microbiology database. After excluding all Fig. 1 Flowchart depicting patient recruitment based on blood culture isolates Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 4 of 9 Table 1 Univariate analysis of epidemiologic parameters, length of stay, and direct hospital costs of cases with blood stream infection caused by enterococcus spp. stratified by vancomycin resistance Parameter (A) VS-E. faecium (n = 493) (B) VS-E. faecalis (n = 563) P-Value for A) vs. B) (C) VR-E. faecium (n = 103) P-Value for C) vs. A) P-Value OR (CI 95) P-Value OR (CI 95) In-hospital mortality 39.6% (195) 24.4% (132) 0.000 2.137 (1.638-2.787) 50.5% (52) 0.041 1.558 (1.017–2.387) Male 58.6% (289) 63.1% (355) 0.141 0.830 (0.648-1.063) 66.0% (68) 0.163 1.371 (0.879–2.141) Age in years, median (IQR) 67 (54–75) 64 (53–73) 0.059 n.a. 61 (52–70) 0.107 Cardiac disease 28.2% (139) 29.0% (163) 0.786 0.964 (0.737-1.259) 26.2% (27) 0.683 0.905 (0.559-1.464) Vascular disease 22.1% (109) 22.4% (126) 0.916 0.984 (0.736-1.317) 22.3% (23) 0.961 1.013 (0.608-1.687) Pulmonary disease 20.1% (99) 23.1% (130) 0.236 0.837 (0.623-1.124) 21.4% (22) 0.769 1.081 (0.643-1.818) Rheumatic disease 3.0% (15) 3.6% (20) 0.644 0.852 (0.431-1.683) 2.9% (3) 0.944 0.956 (0.272-3.364) Gastrointestinal disease 5.5% (27) 3.7% (21) 0.174 1.495 (0.834-2.680) 5.8% (6) 0.888 1.068 (0.429-2.656) Diabetes 22.9% (113) 32.0% (180) 0.001 0,633 (0,481-0,833) 19.4% (20) 0.437 0,810 (0.476-1.379) Renal disease 59.0% (291) 52.8% (297) 0.041 1.290 (1.011-1.647) 70.9% (73) 0.025 1.689 (1.065-2.679) Liver disease 29.6% (146) 19.9% (112) 0.000 1.694 (1.276-2.249) 42.7% (44) 0.009 1.772 (1.146-2,74) Cancer/ immunological disease 48.1% (237) 36.1% (203) 0.000 1.642 (1.283-2.101) 53.4% (55) 0.325 1.238 (0.809-1.894) Neurological disease 7.3% (36) 13.0% (73) 0.003 0,529 (0,348-0,804) 8.7% (9) 0.616 1.215 (0.566-2.608) Charlson comorbidity index, median (IQR) 7 (4–9) 7 (4–9) 0.907 n.a. 7 (5–9) 0.377 n.a. Length of stay as Median (IQR) LOS total (days) 42 (23–78) 32 (16–61) 0.000 n.a. 54 (36–85) 0.010 n.a. LOS before BSI (days) 19 (9–34) 10 (2–25) 0.000 n.a. 27 (15–39) 0.003 n.a. LOS after BSI (days) 18 (8–41) 16 (8–33) 0.308 n.a. 23 (8–45) 0.183 n.a. LOS normal ward 15 (1–36) 11 (1–25) 0.010 n.a. 17 (0–44) 0.368 n.a. LOS ICU 18 (1–49) 10 (1–40) 0.016 n.a. 24 (5–57) 0.050 n.a. Hospital costs as median (IQR) Total hospital costs 51,365 (22,535-119,789) 31,122 (11,829-74,344) 0.000 n.a. 80,465 (47,887–157,447) 0.000 n.a. Daily costs 1,237 (729–1,812) 1,014 (614–1,466) 0.000 n.a. 1,484 (1,095–2,186) 0.000 n.a. Medical staff 7,600 (3169-16,468) 5,344 (1841-12,213) 0.000 n.a. 10,390 (6,364–20,983) 0.002 n.a. Nursing staff 11,499 (4,476-26,237) 7,141 (2,610-21,591) 0.000 n.a. 16,661 (8,029–32,905) 0.003 n.a. Assistant medical technicians 2,630 (1,028-5694) 1,906 (646–4,325) 0.000 n.a. 3,665 (1,397–6,795) 0.082 n.a. Pharmacy 6,924 (2,200-20,922) 2,742 (636–7,865) 0.000 n.a. 17,145 (8,087–36,779) 0.000 n.a. Expenses for implants/transplants 0 (0–412) 0 (0–170) 0.005 n.a. 20 (0–605) 0.767 n.a. Medical supply 6,858 (2,820-15,057) 3,926 (− 1,338-9,782) 0.000 n.a. 9,878 (5,104–18,957) 0.002 n.a. Medical infrastructure 1,893 (939–4,128) 1,473 (547–3,271) 0.000 n.a. 2,629 (1,611–5,219) 0.001 n.a. Non-medical infrastructure 8,975 (4,215-18,206) 6,176 (2,576-14,049) 0.000 n.a. 12,244 (6,763–20,002) 0.003 n.a. Categorical variables displayed as percentage and number; continuous variable displayed as median and interquartile range. *P-value, categorical variables tested with Chi-square test, continuous variable tested with Wilcoxon rank sum test. BSI = blood stream infection, IQR = interquartile range, OR = odds ratio, CI95 = 95% confidence interval. VRE = vancomycin-resistant enterococcus, VSE = vancomycin-susceptible enterococcus. N.a. = not applicable Bold entries represent statistically significant factors Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 5 of 9 isolates not derived from blood cultures and correcting studies demonstrate that vancomycin resistance is as- for copy strains, 1242 patients with BSI caused by E. fae- sociated with overall worsened outcome (mortality, cium or E. faecalis were included in the analysis (Fig. 1). length of stay and hospital costs). However, although Sufficient data on all relevant parameters was available former studies indicated that E. faecium isolates for 96.4% of the patients. Overall, this accounted for might be more virulent than E. faecalis isolates irre- 1160 patients, 91% with infections caused by VSE and spective of vancomycin resistance [2, 8, 9, 26], many 9% by VRE. Table 1 gives an overview of the parameters of the above mentioned studies did not adjust for en- for all patients and shows the results of the (i) univariate terococcal subspecies. As Kaye et al. showed in 2004, comparison of VSEm vs. VSEf and (ii) the comparison of this could lead to an overestimation of the outcome VSEm vs. VREm BSI cases. The highest in-hospital effects attributable to vancomycin resistance [9]. Some mortality rate was found among VREm cases (50.5%) of the authors discussed this issue in their articles, ar- followed by VSEm cases (39.6%) and VSEf cases (24.4%). guing that meta-analyses cannot improve the quality Also regarding LOS, highest numbers were found among of data published [22, 24]. VREm cases (total LOS, 54 days) followed by VSEm In our analyses, in-hospital mortality and length of (42 days) and VSEf (32 days). In all three groups, the stay after BSI onset were independently associated with Charlson comorbidity score was similar with a median underlying diseases, age and E. faecium but not with of 7. vancomycin resistance. In multivariable analyses on LOS after BSI onset Regarding mortality vancomycin resistance was among vancomycin-susceptible enterococci cases, some associated with increased in-hospital mortality in the chronic diseases and E. faecium statistically significant univariate analysis. This result is in agreement with increased LOS as compared to E. faecalis (see Table 2). recent studies including three meta-analyses [19, 22, 24]. Vancomycin-resistance was not found to additionally in- However, after adjusting for underlying diseases, age, crease LOS among E. faecium cases (see Table 2 and and species (E. faecium vs. E. faecalis), in-hospital Fig. 2). Regarding in-hospital death, patients with E. mortality was no longer associated with VRE. There are faecium-BSI had a higher chance for death as compared several possible explanations for these differences with to E. faecalis-cases when only vancomycin-susceptible other studies. cases were considered (see Table 3 and 4). Among E. fae- Systemic enterococci infections mainly occur in pa- cium cases, vancomycin-resistant was not found to be tients with severe underlying diseases and comorbidities an additional risk factor for death (Table 4). [33, 34] which also applies to our study cohort. Patients Regarding economic aspects, almost all hospital costs had a very high Charlson comorbidity score with a were significantly higher in the VREm BSI cohort median of 7. In this regard, there was no significant compared to the VSEm BSI and the VSEf cohort. difference between the cases infected with E. faecalis, E. faecium or vancomycin-resistant strains. Furthermore, Discussion infections caused by antimicrobial-resistant bacteria are During the last 15 years (since 2003), 4 meta-analyses often associated with increased morbidity and mortality on mortality- and financial burden of VRE infections [19]. These differences are explained by the delay in or [19, 22–24], and few recent studies on costs associ- even complete lack of an effective antibiotic treatment ated with VRE infections (not included in the despite the availability of effective drugs [1, 24]. meta-analyses) were published [13, 15, 32]. The Prematunge et al. adjusted for appropriate antimicrobial Table 2 Multivariable linear regression on length of stay of surviving patients after BSI onset Parameter VS-E. faecium vs. VS-E. faecalis VS-E. faecium vs. VR-E. faecium ME Sig. CI 95 (lower-upper) ME Sig. CI 95 (lower-upper) Renal Disease 1.588 0000 1.891 – 3.868 1516 0.001 1.472 – 4.201 Age (years) 0.659 0000 0.969 – 0.987 Not significant Lung Disease 1.457 0000 1.800 – 4.342 1333 0.018 1.151 – 4.409 Gastrointestinal Disease 1.323 0001 1.959 – 11.025 Not significant Liver Disease 1.270 0.003 1.256 – 3.100 1370 0.009 1.226 – 4.155 Vascular Disease 1.216 0.016 1.104 – 2.622 Not significant Enterococcus species E. faecium 1.258 0.004 1.170 – 2.324 Not applicable E. faecalis Reference = 1 BSI = bloodstream infection, CI95 = 95% confidence interval, ME multiplicative effect Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 6 of 9 Fig. 2 Kaplan Meier survival curve of patients with enterococcal blood stream infection (BSI). VSE, vancomycin-resistant enterococcus. VRE, vancomycin-susceptible enterococcus. Censored = left the hospital alive therapy but found that the differences remained [24]. we observed significantly increased mortality associated Outcome differences resulting from varying pathogen- with vancomycin-susceptible E. faecium compared to icity of enterococci species is an alternative explanation vancomycin-susceptible E. faecalis. [35, 36]. In the multivariable analysis we found only Possibly because E. faecium is the most common type of small differences for in-hospital mortality resulting VRE worldwide and most E. faecalis isolates from from vancomycin resistance, differences which are infections are vancomycin-susceptible, it might be a limi- insufficient to explain the univariate results. However, tation to most existing studies that this confounder is not Table 3 Univariate analysis on risk factors for in-hospital death Parameter Discharge alive (n = 781) In-hospital death (n = 379) *P-value OR (CI 95) Vancomycin resistance 6.7% (52) 13.7% (52) < 0.001 2.273 (1.512-3.417) E. faecium 44.7% (349) 65.2% (247) < 0.001 2.311 (1.792-2.979) E. faecalis 55.3% (432) 34.8% (132) 1 = Reference Male 61.2% (478) 62.0% (235) 0.792 1.037 (0.805-1.334) Age (years), median (IQR) 64.0 (51–73) 66.0 (56–74) 0.011 n.a. Heart disease 25.1% (196) 35.4% (134) < 0.001 1.641 (1.258-2.14) Vascular disease 19.6% (153) 27.7% (105) 0.002 1,57 (1,18-2.091) Lung disease 19.6% (153) 26.1% (99) 0.011 1.461 (1.093-1.952) Rheumatic disease 2.6% (20) 4.7% (18) 0.050 1.895 (0,99-3.626) Gastrointestinal disease 4.1% (32) 5.8% (22) 0.195 1,44 (0,825-2.515) Diabetes 26.8% (209) 27.4% (104) 0.807 1.033 (0,784-1.361) Renal disease 46.9% (366) 78.1% (296) < 0.001 4.055 (3.061-5.371) Liver disease 18.2% (142) 42.2% (160) < 0.001 3.283 (2.498-4.314) Cancer/Immunological disease 41.4% (323) 45.4% (172) 0.194 1.176 (0,918-1.506) Neurological disease 10.8% (84) 9.0% (34) 0.346 0,817 (0.537-1.241) Categorical variables displayed as percentage and number; continuous variable displayed as median and interquartile range. *P-value, categorical variables tested with Chi-square test, continuous variable tested with Wilcoxon rank sum test. BSI = blood stream infection, IQR = interquartile range, OR = odds ratio, CI95 = 95% confidence interval. VRE = vancomycin-resistant enterococcus, VSE = vancomycin-susceptible enterococcus. N.a. = not applicable Bold entries represent statistically significant factors Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 7 of 9 Table 4 Results of multivariable binary logistic regression of risk factors for in-hospital death after enterococcal bloodstream infection Parameter VS-E. faecium vs. VS-E. faecalis VS-E. faecium vs. VR-E. faecium OR P-value CI95 (lower-upper) OR P-value CI95 (lower-upper) Age 1015 0,002 1005 – 1025 1016 0,010 1004 – 1029 Vascular disease 1407 0,042 1012 – 1956 Not significant Renal disease 3120 0,000 2274 – 4280 4005 0,000 2708 – 5922 Liver disease 2909 0,000 2109 – 4011 2390 0,000 1618 – 3529 Enterococcus species VS-E. faecium 2023 0,000 1519 – 2695 Not applicable VS-E. faecalis Reference = 1 Not applicable Vancomycin-resistant Not applicable 1.283 0.300 0.801 – 2.057 Vancomycin-susceptible Not applicable Reference = 1 OR = odds ratio, CI95 = 95% confidence interval considered [10–16, 18–24, 32]. Prematunge et al. already these differences could be due to higher antibiotics costs pointed out in their 2016 meta-analysis, that it is possible or to differences in underlying conditions treated. For that many observations on VRE-associated outcome are this reason, we analyzed the length of stay before and based on differences in the infection-causing species after onset of BSI. Our data showed increased lengths of rather than on vancomycin resistance [24]. stay overall and before onset of VREm-BSI, but not after. Attempts to assess the pathogenicity of enterococci go Interestingly, all BSIs were classified as HAIs as none far back in time. In some of the previous studies, the occurred prior to day 3 after hospital admission. On pathogenic potential of commensal E. faecium was average, the BSI episodes occurred on day 16 of determined, whereas most of nowadays HAIs are caused hospitalization. Moreover, the same phenomenon was by isolates of a different E. faecium lineage [37, 38]. observed in the analysis of the infection-attributable These so-called hospital-associated strain types (formerly LOS stratified by the two clinically relevant Entero- known as clonal complex CC17) differ from commensal coccus species. Cases with vancomycin susceptible E. human and animal isolates by a distinct core and accessory faecium BSI were in-hospital longer before onset of in- genome content. Ampicillin resistance is a phenotypic fection than vancomycin susceptible E. faecalis cases. No marker of these hospital-associated strain types [39–41]. It difference in LOS was observed after onset of infection. has been shown that AMP-R E. faecium isolates causing This study has several limitations. The cases were identi- healthcare-associated infections are in fact more pathogenic fied retrospectively through a microbiological database and than commensal variants [42, 43]. In a supplementary ana- 6.6% lacked sufficient data for this analysis. We did not lysis (Additional file 1: Tables S1 and S2) we found that have data on the course or severity of infection and the 95% of our E. faecium isolates were ampicillin-resistant antibiotic treatment performed. We did not have separate (AMP-R), in contrast to only 1% of the E. faecalis isolates. data on true costs before and after the bloodstream infec- Due to the uneven distribution of ampicillin resistance tion. We did not perform molecular analyses on the entero- over the two pathogens we were not able to assess cocci isolates to assess their potential virulence traits. potential virulence differences between commensal and hospital-associated isolates. However, our results are sup- Conclusion portive to previous population-based and molecular ana- In our study, vancomycin resistance in patients with lyses of E. faecium from hospital-acquired infections. Enterococcus faecium bloodstream infection was asso- Several reports have linked VRE infections with in- ciated with increased total costs, length of stay before creased costs [13, 15, 19, 32]. In the univariate analyses, onset of infection, but not with infection-attributable our data showed similar results as almost all costs were LOS or in-hospital mortality. We observed that significantly higher in VREm-BSI patients than in vancomycin-susceptible E. faecium infections were patients with VSEm-BSI. Butler et al. reported that more strongly associated with increased LOS and pharmacy costs are the second most relevant driver of mortality than vancomycin susceptible E. faecalis increased costs, making up to 18% of the total amount infections and might indicate higher virulence of E. [21]. In our cohort, the percentage of pharmaceutical faecium as compared to E. faecalis. In order to avoid costs for patients with VREm made up 21% of the total overestimation of VRE-attributable effects, in addition hospital costs while they made up only 9% of the costs to vancomycin-resistance species should be taken into of patents with BSI caused by VSEm (< 0,001). As we consideration in future studies assessing the burden were not able to attribute costs to particular agents, of VRE infections. Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 8 of 9 Additional file 3. Bonten MJ, Willems R, Weinstein RA. Vancomycin-resistant enterococci: why are they here, and where do they come from? Lancet Infect Dis. 2001;1:314–25. Additional file 1: Table S1. Susceptibility towards Ampicillin among 4. WHO publishes list of bacteria for which new antibiotics are urgently cases. Table S2. Susceptibility towards Ampicillin among Isolate n=193 needed [http://www.who.int/mediacentre/news/releases/2017/bacteria- missing; AMP= Susceptibility to Ampicillin. R=Resistant. S=Susceptible. antibiotics-needed/en/]. Accessed 5 Mar 2018. RR= relative risk. CI95=95% confidence interval. (DOCX 34 kb) 5. Gastmeier P, Schroder C, Behnke M, Meyer E, Geffers C. Dramatic increase in vancomycin-resistant enterococci in Germany. J Antimicrob Chemother. 2014;69:1660–4. Abbreviations 6. Simon A, Christiansen B. Adaptation and development of German 95% CI: 95% confidence interval; BSI: blood stream infection; CCI: Charlson recommendations on the prevention and control of nosocomial infections comorbidity index; HAI: hospital acquired infection; HR: Hazard ratios; due to multiresistant pathogens. Gesundheitsforschung Gesundheitsschutz. IQR: interquartile range; LOS: length of stay; ME: multiplicative effect; 2012;55:1427–31. VRE: vancomycin-resistant enterococcus; VREm: vancomycin resistant 7. Muto CA, Jernigan JA, Ostrowsky BE, Richet HM, Jarvis WR, Boyce JM, Farr Enterococcus faecium; VSE: vancomycin-susceptible enterococcus; BM. SHEA guideline for preventing nosocomial transmission of multidrug- VSEf: vancomycin susceptible E. faecalis; VSEm: vancomycin susceptible resistant strains of Staphylococcus aureus and enterococcus. Infect Control Enterococcus faecium Hosp Epidemiol. 2003;24:362–86. 8. Cosgrove SE. The relationship between antimicrobial resistance and patient Acknowledgements outcomes: mortality, length of hospital stay, and health care costs. Clin We acknowledge support from the German Research Foundation (DFG) and Infect Dis. 2006;42(Suppl 2):S82–9. the Open Access Publication Fund of Charité – Universitätsmedizin Berlin. 9. Kaye KS, Engemann JJ, Mozaffari E, Carmeli Y. Reference group choice and antibiotic resistance outcomes. Emerg Infect Dis. 2004;10:1125–8. Funding 10. Lloyd-Smith P, Younger J, Lloyd-Smith E, Green H, Leung V, Romney MG. No external funding was received for this study. Economic analysis of vancomycin-resistant enterococci at a Canadian hospital: assessing attributable cost and length of stay. J Hosp Infect. Availability of data and materials 2013;85:54–9. The datasets used and/or analyzed during the current study are available 11. Hayakawa K, Martin ET, Gudur UM, Marchaim D, Dalle D, Alshabani K, from the corresponding author on reasonable request. Muppavarapu KS, Jaydev F, Bathina P, Sundaragiri PR, et al. Impact of different antimicrobial therapies on clinical and fiscal outcomes of patients Authors’ contributions with bacteremia due to vancomycin-resistant enterococci. Antimicrob TSK, CR, PG and RL were responsible for the study design. RL supervised the Agents Chemother. 2014;58:3968–75. study. MB, SW and RL were responsible for data collection and data cleaning. 12. Cheah AL, Spelman T, Liew D, Peel T, Howden BP, Spelman D, Grayson ML, FS and RL conducted the statistical analysis. GW helped writing the Nation RL, Kong DC. Enterococcal bacteraemia: factors influencing mortality, manuscript and contributed significantly to the discussion. All authors length of stay and costs of hospitalization. Clin Microbiol Infect. 2013;19:E181–9. interpreted the data, gave important intellectual content and revised the 13. Lloyd-Smith P. Controlling for endogeneity in attributable costs of manuscript critically. All authors read and approved the final manuscript. vancomycin-resistant enterococci from a Canadian hospital. Am J Infect Control. 2017;45:e161–4. Ethics approval and consent to participate 14. Pelz RK, Lipsett PA, Swoboda SM, Diener-West M, Powe NR, Brower RG, Perl A confirmatory ethics vote was obtained from the Charité University TM, Hammond JM, Hendrix CW. Vancomycin-sensitive and vancomycin- Medicine ethics committee (internal processing key EA4/229/17). resistant enterococcal infections in the ICU: attributable costs and outcomes. Intensive Care Med. 2002;28:692–7. Consent for publication 15. Puchter L, Chaberny IF, Schwab F, Vonberg R-P, Bange F-C, Ebadi E. Not applicable. Economic burden of nosocomial infections caused by vancomycin-resistant enterococci. Antimicrob Resist Infect Control. 2018;7:1. 16. Gandra S, Barter D, Laxminarayan R. Economic burden of antibiotic Competing interests resistance: how much do we really know? Clin Microbiol Infect. The authors declare that they have no competing interests. 2014;20:973–9. 17. Bach PB, Malak SF, Jurcic J, Gelfand SE, Eagan J, Little C, Sepkowitz KA. Publisher’sNote Impact of infection by vancomycin-resistant enterococcus on survival and Springer Nature remains neutral with regard to jurisdictional claims in resource utilization for patients with leukemia. Infect Control Hosp published maps and institutional affiliations. Epidemiol. 2002;23:471–4. 18. Russell DL, Flood A, Zaroda TE, Acosta C, Riley MM, Busuttil RW, Pegues DA. Author details Outcomes of colonization with MRSA and VRE among liver transplant Charité Universitätsmedizin Berlin, Institute of Hygiene and Environmental candidates and recipients. Am J Transplant Off J Am Soc Transplant Medicine, Berlin, Germany. National Reference Center for the Surveillance of Am Soc Transplant Surg. 2008;8:1737–43. Nosocomial Infections, Berlin, Germany. Department of Medical and 19. Chiang HY, Perencevich EN, Nair R, Nelson RE, Samore M, Khader K, Chorazy Financial Controlling, Charité Universitätsmedizin Berlin, Berlin, Germany. ML, Herwaldt LA, Blevins A, Ward MA, Schweizer ML. Incidence and Robert Koch Institute, FG13 Nosocomial Pathogens and Antibiotic outcomes associated with infections caused by vancomycin-resistant Resistance, Wernigerode, Germany. National Reference Centre for enterococci in the United States: systematic literature review and meta- Staphylococci and Enterococci, Berlin, Germany. analysis. Infect Control Hosp Epidemiol. 2017;38:203–15. 20. McNeil SA, Malani PN, Chenoweth CE, Fontana RJ, Magee JC, Punch JD, Received: 19 April 2018 Accepted: 11 October 2018 Mackin ML, Kauffman CA. Vancomycin-resistant enterococcal colonization and infection in liver transplant candidates and recipients: a prospective surveillance study. Clin Infect Dis. 2006;42:195–203. 21. Butler AM, Olsen MA, Merz LR, Guth RM, Woeltje KF, Camins BC, Fraser VJ. References Attributable costs of enterococcal bloodstream infections in a nonsurgical 1. Zasowski EJ, Claeys KC, Lagnf AM, Davis SL, Rybak MJ. Time is of the hospital cohort. Infect Control Hosp Epidemiol. 2010;31:28–35. essence: the impact of delayed antibiotic therapy on patient outcomes in hospital-onset Enterococcal bloodstream infections. Clin Infect Dis. 22. DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of 2016;62:1242–50. mortality associated with vancomycin-resistant and vancomycin-susceptible 2. Maragakis LL, Perencevich EN, Cosgrove SE. Clinical and economic burden enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis. of antimicrobial resistance. Expert Rev Anti-Infect Ther. 2008;6:751–63. 2005;41:327–33. Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 9 of 9 23. Salgado CD, Farr BM. Outcomes associated with vancomycin-resistant enterococci: a meta-analysis. Infect Control Hosp Epidemiol. 2003;24:690–8. 24. Prematunge C, MacDougall C, Johnstone J, Adomako K, Lam F, Robertson J, Garber G. 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. 25. Murray BE. Vancomycin-resistant enterococcal infections. N Engl J Med. 2000;342:710–21. 26. Noskin GA, Peterson LR, Warren JR. Enterococcus faecium and enterococcus faecalis bacteremia: acquisition and outcome. Clin Infect Dis. 1995;20:296–301. 27. Jahresbericht. 2015. [https://www.charite.de/fileadmin/user_upload/portal_ relaunch/Mediathek/publikationen/jahresberichte/Charite_Jahresbericht_ 2015_EN.pdf]. Accessed 27 Mar 2018. 28. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83. 29. Thygesen SK, Christiansen CF, Christensen S, Lash TL, Sorensen HT. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of patients. BMC Med Res Methodol. 2011;11:83. 30. Schulgen G, Kropec A, Kappstein I, Daschner F, Schumacher M. Estimation of extra hospital stay attributable to nosocomial infections: heterogeneity and timing of events. J Clin Epidemiol. 2000;53:409–17. 31. Barnett AG, Beyersmann J, Allignol A, Rosenthal VD, Graves N, Wolkewitz M. The time-dependent bias and its effect on extra length of stay due to nosocomial infection. Value Health. 2011;14:381–6. 32. Jiang HL, Zhou Z, Wang LS, Fang Y, Li YH, Chu CI. The risk factors, costs, and survival analysis of invasive VRE infections at a medical Center in Eastern Taiwan. Int J Infect Dis. 2017;54:18–24. 33. Guzman Prieto AM, van Schaik W, Rogers MR, Coque TM, Baquero F, Corander J, Willems RJ. Global emergence and dissemination of enterococci as nosocomial pathogens: attack of the clones? Front Microbiol. 2016;7:788. 34. von Baum H, Ober JF, Wendt C, Wenzel RP, Edmond MB. Antibiotic-resistant bloodstream infections in hospitalized patients: specific risk factors in a high-risk population? Infection. 2005;33:320–6. 35. Arias CA, Murray BE. The rise of the enterococcus: beyond vancomycin resistance. Nat Rev Microbiol. 2012;10:266–78. 36. Sava IG, Heikens E, Huebner J. Pathogenesis and immunity in enterococcal infections. Clin Microbiol Infect. 2010;16:533–40. 37. Gao W, Howden BP, Stinear TP. Evolution of virulence in enterococcus faecium, a hospital-adapted opportunistic pathogen. Curr Opin Microbiol. 2018;41:76–82. 38. Lebreton F, van Schaik W, McGuire AM, Godfrey P, Griggs A, Mazumdar V, Corander J, Cheng L, Saif S, Young S. Emergence of epidemic multidrug- resistant enterococcus faecium from animal and commensal strains. MBio. 2013;4:e00534–13. 39. Lester CH, Sandvang D, Olsen SS, Schønheyder HC, Jarløv JO, Bangsborg J, Hansen DS, Jensen TG, Frimodt-Møller N, Hammerum AM. Emergence of ampicillin-resistant enterococcus faecium in Danish hospitals. J Antimicrob Chemother. 2008;62:1203–6. 40. Top J, Willems R, Blok H, De Regt M, Jalink K, Troelstra A, Goorhuis B, Bonten M. Ecological replacement of enterococcus faecalis by multiresistant clonal complex 17 enterococcus faecium. Clin Microbiol Infect. 2007;13:316–9. 41. Freitas AR, Novais C, Duarte B, Pereira AP, Coque TM, Peixe L. High rates of colonisation by ampicillin-resistant enterococci in residents of long-term care facilities in Porto, Portugal. Int J Antimicrob Agents. 2018;51:503–7. 42. Zou J, Shankar N. Surface protein Esp enhances pro-inflammatory cytokine expression through NF-κB activation during enterococcal infection. Innate immunity. 2016;22:31–9. 43. Sillanpää J, Nallapareddy SR, Singh KV, Prakash VP, Fothergill T, Ton-that H, Murray BE. Characterization of the ebpfm pilus-encoding operon of enterococcus faecium and its role in biofilm formation and virulence in a murine model of urinary tract infection. Virulence. 2010;1:236–46. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antimicrobial Resistance and Infection Control Springer Journals

The importance of adjusting for enterococcus species when assessing the burden of vancomycin resistance: a cohort study including over 1000 cases of enterococcal bloodstream infections

Loading next page...
 
/lp/springer-journals/the-importance-of-adjusting-for-enterococcus-species-when-assessing-VeMMhEG0ZQ

References (49)

Publisher
Springer Journals
Copyright
Copyright © The Author(s). 2018
Subject
Biomedicine; Medical Microbiology; Drug Resistance; Infectious Diseases
eISSN
2047-2994
DOI
10.1186/s13756-018-0419-9
Publisher site
See Article on Publisher Site

Abstract

Background: Infections caused by vancomycin-resistant enterococci (VRE) are on the rise worldwide. Few studies have tried to estimate the mortality burden as well as the financial burden of those infections and found that VRE are associated with increased mortality and higher hospital costs. However, it is unclear whether these worse outcomes are attributable to vancomycin resistance only or whether the enterococcal species (Enterococcus faecium or Enterococcus faecalis) play an important role. We therefore aimed to determine the burden of enterococci infections attributable to vancomycin resistance and pathogen species (E. faecium and E. faecalis) in cases of bloodstream infection (BSI). Methods: We conducted a retrospective cohort study on patients with BSI caused by Enterococcus faecium or Enterococcus faecalis between 2008 and 2015 in three tertiary care hospitals. Data was collected on true hospital costs (in €), length of stay (LOS), basic demographic parameters, and underlying diseases including the results of the Charlson comorbidity index (CCI). We used univariate and multivariable regression analyses to compare risk factors for in-hospital mortality and length of stay (i) between vancomycin-susceptible E. faecium- (VSEm) and vancomycin-susceptible E. faecalis- (VSEf) cases and (ii) between vancomycin-susceptible E. faecium- (VSEm) and vancomycin-resistant E. faecium-cases (VREm). We calculated total hospital costs for VSEm, VSEf and VREm. Results: Overall, we identified 1160 consecutive cases of BSI caused by enterococci: 596 (51.4%) cases of E. faecium BSI and 564 (48.6%) cases of E. faecalis BSI. 103 cases of E. faecium BSI (17.3%) and 1 case of E. faecalis BSI (0.2%) were infected by vancomycin-resistant isolates. Multivariable analyses revealed (i) that in addition to different underlying diseases E. faecium was an independent risk factor for in-hospital mortality and prolonged hospital stay and (ii) that vancomycin-resistance did not further increase the risk for the described outcomes among E. faecium- isolates. However, the overall hospital costs were significantly higher in VREm-BSI cases as compared to VSEm- and VSEf-BSI cases (80,465€ vs. 51,365€ vs. 31,122€ p < 0.001). (Continued on next page) * Correspondence: tobias.kramer@charite.de Charité Universitätsmedizin Berlin, Institute of Hygiene and Environmental Medicine, Berlin, Germany National Reference Center for the Surveillance of Nosocomial Infections, Berlin, Germany Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 2 of 9 (Continued from previous page) Conclusion: Our data indicates that in-hospital mortality and infection-attributed hospital stay in enterococci BSI might rather be influenced by Enterococcus species and underlying diseases than by vancomycin resistance. Therefore, future studies should consider adjusting for Enterococcus species in addition to vancomycin resistance in order to provide a conservative estimate for the burden of VRE infections. Keywords: Bloodstream infection, Vancomycin-resistant enterococci, Enterococcus faecium Introduction Cases were identified in the Charité microbiology data- Enterococcus spp. are part of the normal gastrointestinal base as hospitalized patients with blood cultures positive flora. Among those pathogens, resistance to antimicrobial for one of these pathogens. Data on costs and hospital substances, notably to vancomycin, results in limited thera- financial accounting was provided by the Charité peutic options [1, 2]. In recent years, hospital-acquired in- Department of Financial Controlling as true hospital fections (HAI) caused by vancomycin-resistant enterococci expenses in Euros. For all patients enrolled in this study, (VRE) have emerged as a relevant burden on patients and the following demographic and clinical characteristics healthcare systems globally [3–5]. In order to reduce the were collected: age, sex, in-hospital death, length of spread of resistant strains in hospitals, infection control hospital stay (LOS), day of BSI onset and stay on an measures, e.g. contact precautions, have been proposed intensive care unit (days). Length of stay in total and [6, 7]. To assess the efficiency of VRE prevention after BSI onset were defined as length of stay until death measures, the mortality- and financial burden of VRE or discharge. The Charlson comorbidity index (CCI) was infections has to be assessed. However, the methodo- obtained on the basis of the patients’ diagnosed comor- logical approach on assessing VRE-burden remains bidities using the method of Charlson et al. and the controversial [2, 8, 9] and only few studies have addressed adaptation for the ICD-10 by Thygesen et al. [28, 29]. economic aspects [10–15]. As costs are often not available The original 17 Charlson comorbidity categories were as infection-attributable costs (costs after onset for cumulated based on the affected organ system in the fol- infection) length of stay (LOS) after onset of infection is lowing ten disease categories: heart disease, cerebrovas- being used as a surrogate parameter [2, 8, 16]. cular disease, neurologic disease, lung disease, rheumatic Although analyses should compare VRE infections disease, gastrointestinal disease, liver disease, diabetes, to VSE-infected patients when the attributable effect renal disease and cancer/immunological disease. of vancomycin resistance is addressed, [2, 8, 16]prior studies also utilized comparisons to cohorts with Definitions and statistical methods non-enterococcus infections [17, 18]or cohorts Cases were defined as patients with BSI caused by without infection [8, 12, 19–24]. Since the course of Enterococcus spp. (Enterococcus faecalis or Enterococcus enterococcal infections may also be influenced by the faecium) during the study period. Each patient was in- enterococcus subspecies itself [2, 8, 9, 25, 26], cluded in the analysis once. Onset of BSI was defined as analyses not considering the pathogen species may the date of the first blood culture positive for the re- therefore be biased as result of the different virulence spective pathogen. BSI was considered hospital-onset if of the pathogens. it occurred after the third day of hospitalization. Mortality In a large cohort of cases with bloodstream infection was assessed based on discharge alive or in-hospital death. (BSI), we therefore studied the influence of vancomycin Data on hospital costs were derived from true hospital resistance and enterococcus subspecies on in-hospital costs (hospital expenses). The costs analyzed cover direct mortality, hospital costs and length of hospital stay. costs to the hospital of treatment and diagnostics as well as indirect hospital costs of activities without patient Methods contact (e.g. administration, hospital maintenance). The Setting, study design and data collection estimated cost of individual cases was based on definite The study was conducted at three different tertiary care performances and on settlement keys (e.g. nurse working hospitals of the Charité university hospital in Berlin, time per patient). Economic data was available on total with 3011-beds in total [27]. After a confirmatory ethics hospital costs and on daily costs. A differentiation of costs vote was obtained from the Charité University Medicine before and after the infection was not available. However, ethics committee (internal processing key EA4/229/17), as length of stay directly correlates with hospital costs, we performed a cohort study that included all cases of length of stay after onset for infection can be applied as BSI caused by Enterococcus faecalis or Enterococcus fae- proxy for infection attributable additional expenditures cium between January 1, 2008 and December 31, 2015. [2, 30, 31]. We therefore assessed the multiplicative Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 3 of 9 effect on length of stay after BSI onset in a multivari- transformation and referred to as the multiplicative able linear regression. effect (ME) of investigated parameters. P-values < 0.05 Descriptive, univariate analyses were performed for the were considered significant. total cohort, stratified by enterococcus species (i.e. Multivariable, binary logistic regression was performed vancomycin susceptible E. faecium vs. vancomycin sus- for in-hospital death by stepwise forward selection. The ceptible E. faecalis) and by vancomycin susceptibility p-values for including a variable in the model was 0.05 (i.e. vancomycin susceptible enterococci vs. vancomycin and for excluding 0.06 respectively. Odds ratios (HR) resistant enterococci). Since among E. faecalis-isolates with 95% confidence intervals (95% CI) were calculated. only one isolate was resistant against vancomycin, only Parameters considered in the model were sex, age, E. faecium (VSEm vs. VREm) were analyzed in the pathogen species (E. faecium vs. E. faecalis) with the second analysis. Additionally, we compared in univariate interaction of the vancomycin resistance and all under- analysis deceased patients and patients discharged alive. lying diseases assessed as described above. The median and the interquartile range (IQR) were cal- All analyses were performed using SPSS (IBM SPSS culated for continuous parameters; number and percent- statistics, Somer, NY, USA) and SAS (SAS Institute, age were calculated for binary parameters. Univariate Cary, NC, USA). differences were tested using the Wilcoxon rank-sum test for continuous variables and the Chi-square test for Microbiological methods binary variables. If a blood stream infection was suspected, blood cultures The two linear regression analyses were performed for were drawn and incubated for up to seven days using length of stay (LOS) after onset of enterococcal BSI by standard blood culture tubes (BACTEC, Becton stepwise forward variable selection. The continuous Dickinson Heidelberg Germany). If growth was detected, parameters LOS after onset of BSI was log transformed gram staining and culturing were performed. MALDI to achieve normal distribution. Only surviving patients TOF MS and Vitek 2 automated system (Biomerieux were included. Parameters considered in the full Marcy l’etoile France) were used for identification and model were vancomycin resistance OR pathogen susceptibility testing of bacterial strains. They were species (E. faecium or E. faecalis), sex, age and all interpreted using EUCAST definitions. underlying diseases assessed as described above. From the full model, parameters with the smallest Results Chi-square statistic and p > 0.05 in the type III test We initially extracted n = 24,086 clinical isolates diag- were removed. The regression coefficients were con- nosed with Enterococcus faecium or Enterococcus faecalis verted to the measures of effect using an exponential from the microbiology database. After excluding all Fig. 1 Flowchart depicting patient recruitment based on blood culture isolates Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 4 of 9 Table 1 Univariate analysis of epidemiologic parameters, length of stay, and direct hospital costs of cases with blood stream infection caused by enterococcus spp. stratified by vancomycin resistance Parameter (A) VS-E. faecium (n = 493) (B) VS-E. faecalis (n = 563) P-Value for A) vs. B) (C) VR-E. faecium (n = 103) P-Value for C) vs. A) P-Value OR (CI 95) P-Value OR (CI 95) In-hospital mortality 39.6% (195) 24.4% (132) 0.000 2.137 (1.638-2.787) 50.5% (52) 0.041 1.558 (1.017–2.387) Male 58.6% (289) 63.1% (355) 0.141 0.830 (0.648-1.063) 66.0% (68) 0.163 1.371 (0.879–2.141) Age in years, median (IQR) 67 (54–75) 64 (53–73) 0.059 n.a. 61 (52–70) 0.107 Cardiac disease 28.2% (139) 29.0% (163) 0.786 0.964 (0.737-1.259) 26.2% (27) 0.683 0.905 (0.559-1.464) Vascular disease 22.1% (109) 22.4% (126) 0.916 0.984 (0.736-1.317) 22.3% (23) 0.961 1.013 (0.608-1.687) Pulmonary disease 20.1% (99) 23.1% (130) 0.236 0.837 (0.623-1.124) 21.4% (22) 0.769 1.081 (0.643-1.818) Rheumatic disease 3.0% (15) 3.6% (20) 0.644 0.852 (0.431-1.683) 2.9% (3) 0.944 0.956 (0.272-3.364) Gastrointestinal disease 5.5% (27) 3.7% (21) 0.174 1.495 (0.834-2.680) 5.8% (6) 0.888 1.068 (0.429-2.656) Diabetes 22.9% (113) 32.0% (180) 0.001 0,633 (0,481-0,833) 19.4% (20) 0.437 0,810 (0.476-1.379) Renal disease 59.0% (291) 52.8% (297) 0.041 1.290 (1.011-1.647) 70.9% (73) 0.025 1.689 (1.065-2.679) Liver disease 29.6% (146) 19.9% (112) 0.000 1.694 (1.276-2.249) 42.7% (44) 0.009 1.772 (1.146-2,74) Cancer/ immunological disease 48.1% (237) 36.1% (203) 0.000 1.642 (1.283-2.101) 53.4% (55) 0.325 1.238 (0.809-1.894) Neurological disease 7.3% (36) 13.0% (73) 0.003 0,529 (0,348-0,804) 8.7% (9) 0.616 1.215 (0.566-2.608) Charlson comorbidity index, median (IQR) 7 (4–9) 7 (4–9) 0.907 n.a. 7 (5–9) 0.377 n.a. Length of stay as Median (IQR) LOS total (days) 42 (23–78) 32 (16–61) 0.000 n.a. 54 (36–85) 0.010 n.a. LOS before BSI (days) 19 (9–34) 10 (2–25) 0.000 n.a. 27 (15–39) 0.003 n.a. LOS after BSI (days) 18 (8–41) 16 (8–33) 0.308 n.a. 23 (8–45) 0.183 n.a. LOS normal ward 15 (1–36) 11 (1–25) 0.010 n.a. 17 (0–44) 0.368 n.a. LOS ICU 18 (1–49) 10 (1–40) 0.016 n.a. 24 (5–57) 0.050 n.a. Hospital costs as median (IQR) Total hospital costs 51,365 (22,535-119,789) 31,122 (11,829-74,344) 0.000 n.a. 80,465 (47,887–157,447) 0.000 n.a. Daily costs 1,237 (729–1,812) 1,014 (614–1,466) 0.000 n.a. 1,484 (1,095–2,186) 0.000 n.a. Medical staff 7,600 (3169-16,468) 5,344 (1841-12,213) 0.000 n.a. 10,390 (6,364–20,983) 0.002 n.a. Nursing staff 11,499 (4,476-26,237) 7,141 (2,610-21,591) 0.000 n.a. 16,661 (8,029–32,905) 0.003 n.a. Assistant medical technicians 2,630 (1,028-5694) 1,906 (646–4,325) 0.000 n.a. 3,665 (1,397–6,795) 0.082 n.a. Pharmacy 6,924 (2,200-20,922) 2,742 (636–7,865) 0.000 n.a. 17,145 (8,087–36,779) 0.000 n.a. Expenses for implants/transplants 0 (0–412) 0 (0–170) 0.005 n.a. 20 (0–605) 0.767 n.a. Medical supply 6,858 (2,820-15,057) 3,926 (− 1,338-9,782) 0.000 n.a. 9,878 (5,104–18,957) 0.002 n.a. Medical infrastructure 1,893 (939–4,128) 1,473 (547–3,271) 0.000 n.a. 2,629 (1,611–5,219) 0.001 n.a. Non-medical infrastructure 8,975 (4,215-18,206) 6,176 (2,576-14,049) 0.000 n.a. 12,244 (6,763–20,002) 0.003 n.a. Categorical variables displayed as percentage and number; continuous variable displayed as median and interquartile range. *P-value, categorical variables tested with Chi-square test, continuous variable tested with Wilcoxon rank sum test. BSI = blood stream infection, IQR = interquartile range, OR = odds ratio, CI95 = 95% confidence interval. VRE = vancomycin-resistant enterococcus, VSE = vancomycin-susceptible enterococcus. N.a. = not applicable Bold entries represent statistically significant factors Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 5 of 9 isolates not derived from blood cultures and correcting studies demonstrate that vancomycin resistance is as- for copy strains, 1242 patients with BSI caused by E. fae- sociated with overall worsened outcome (mortality, cium or E. faecalis were included in the analysis (Fig. 1). length of stay and hospital costs). However, although Sufficient data on all relevant parameters was available former studies indicated that E. faecium isolates for 96.4% of the patients. Overall, this accounted for might be more virulent than E. faecalis isolates irre- 1160 patients, 91% with infections caused by VSE and spective of vancomycin resistance [2, 8, 9, 26], many 9% by VRE. Table 1 gives an overview of the parameters of the above mentioned studies did not adjust for en- for all patients and shows the results of the (i) univariate terococcal subspecies. As Kaye et al. showed in 2004, comparison of VSEm vs. VSEf and (ii) the comparison of this could lead to an overestimation of the outcome VSEm vs. VREm BSI cases. The highest in-hospital effects attributable to vancomycin resistance [9]. Some mortality rate was found among VREm cases (50.5%) of the authors discussed this issue in their articles, ar- followed by VSEm cases (39.6%) and VSEf cases (24.4%). guing that meta-analyses cannot improve the quality Also regarding LOS, highest numbers were found among of data published [22, 24]. VREm cases (total LOS, 54 days) followed by VSEm In our analyses, in-hospital mortality and length of (42 days) and VSEf (32 days). In all three groups, the stay after BSI onset were independently associated with Charlson comorbidity score was similar with a median underlying diseases, age and E. faecium but not with of 7. vancomycin resistance. In multivariable analyses on LOS after BSI onset Regarding mortality vancomycin resistance was among vancomycin-susceptible enterococci cases, some associated with increased in-hospital mortality in the chronic diseases and E. faecium statistically significant univariate analysis. This result is in agreement with increased LOS as compared to E. faecalis (see Table 2). recent studies including three meta-analyses [19, 22, 24]. Vancomycin-resistance was not found to additionally in- However, after adjusting for underlying diseases, age, crease LOS among E. faecium cases (see Table 2 and and species (E. faecium vs. E. faecalis), in-hospital Fig. 2). Regarding in-hospital death, patients with E. mortality was no longer associated with VRE. There are faecium-BSI had a higher chance for death as compared several possible explanations for these differences with to E. faecalis-cases when only vancomycin-susceptible other studies. cases were considered (see Table 3 and 4). Among E. fae- Systemic enterococci infections mainly occur in pa- cium cases, vancomycin-resistant was not found to be tients with severe underlying diseases and comorbidities an additional risk factor for death (Table 4). [33, 34] which also applies to our study cohort. Patients Regarding economic aspects, almost all hospital costs had a very high Charlson comorbidity score with a were significantly higher in the VREm BSI cohort median of 7. In this regard, there was no significant compared to the VSEm BSI and the VSEf cohort. difference between the cases infected with E. faecalis, E. faecium or vancomycin-resistant strains. Furthermore, Discussion infections caused by antimicrobial-resistant bacteria are During the last 15 years (since 2003), 4 meta-analyses often associated with increased morbidity and mortality on mortality- and financial burden of VRE infections [19]. These differences are explained by the delay in or [19, 22–24], and few recent studies on costs associ- even complete lack of an effective antibiotic treatment ated with VRE infections (not included in the despite the availability of effective drugs [1, 24]. meta-analyses) were published [13, 15, 32]. The Prematunge et al. adjusted for appropriate antimicrobial Table 2 Multivariable linear regression on length of stay of surviving patients after BSI onset Parameter VS-E. faecium vs. VS-E. faecalis VS-E. faecium vs. VR-E. faecium ME Sig. CI 95 (lower-upper) ME Sig. CI 95 (lower-upper) Renal Disease 1.588 0000 1.891 – 3.868 1516 0.001 1.472 – 4.201 Age (years) 0.659 0000 0.969 – 0.987 Not significant Lung Disease 1.457 0000 1.800 – 4.342 1333 0.018 1.151 – 4.409 Gastrointestinal Disease 1.323 0001 1.959 – 11.025 Not significant Liver Disease 1.270 0.003 1.256 – 3.100 1370 0.009 1.226 – 4.155 Vascular Disease 1.216 0.016 1.104 – 2.622 Not significant Enterococcus species E. faecium 1.258 0.004 1.170 – 2.324 Not applicable E. faecalis Reference = 1 BSI = bloodstream infection, CI95 = 95% confidence interval, ME multiplicative effect Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 6 of 9 Fig. 2 Kaplan Meier survival curve of patients with enterococcal blood stream infection (BSI). VSE, vancomycin-resistant enterococcus. VRE, vancomycin-susceptible enterococcus. Censored = left the hospital alive therapy but found that the differences remained [24]. we observed significantly increased mortality associated Outcome differences resulting from varying pathogen- with vancomycin-susceptible E. faecium compared to icity of enterococci species is an alternative explanation vancomycin-susceptible E. faecalis. [35, 36]. In the multivariable analysis we found only Possibly because E. faecium is the most common type of small differences for in-hospital mortality resulting VRE worldwide and most E. faecalis isolates from from vancomycin resistance, differences which are infections are vancomycin-susceptible, it might be a limi- insufficient to explain the univariate results. However, tation to most existing studies that this confounder is not Table 3 Univariate analysis on risk factors for in-hospital death Parameter Discharge alive (n = 781) In-hospital death (n = 379) *P-value OR (CI 95) Vancomycin resistance 6.7% (52) 13.7% (52) < 0.001 2.273 (1.512-3.417) E. faecium 44.7% (349) 65.2% (247) < 0.001 2.311 (1.792-2.979) E. faecalis 55.3% (432) 34.8% (132) 1 = Reference Male 61.2% (478) 62.0% (235) 0.792 1.037 (0.805-1.334) Age (years), median (IQR) 64.0 (51–73) 66.0 (56–74) 0.011 n.a. Heart disease 25.1% (196) 35.4% (134) < 0.001 1.641 (1.258-2.14) Vascular disease 19.6% (153) 27.7% (105) 0.002 1,57 (1,18-2.091) Lung disease 19.6% (153) 26.1% (99) 0.011 1.461 (1.093-1.952) Rheumatic disease 2.6% (20) 4.7% (18) 0.050 1.895 (0,99-3.626) Gastrointestinal disease 4.1% (32) 5.8% (22) 0.195 1,44 (0,825-2.515) Diabetes 26.8% (209) 27.4% (104) 0.807 1.033 (0,784-1.361) Renal disease 46.9% (366) 78.1% (296) < 0.001 4.055 (3.061-5.371) Liver disease 18.2% (142) 42.2% (160) < 0.001 3.283 (2.498-4.314) Cancer/Immunological disease 41.4% (323) 45.4% (172) 0.194 1.176 (0,918-1.506) Neurological disease 10.8% (84) 9.0% (34) 0.346 0,817 (0.537-1.241) Categorical variables displayed as percentage and number; continuous variable displayed as median and interquartile range. *P-value, categorical variables tested with Chi-square test, continuous variable tested with Wilcoxon rank sum test. BSI = blood stream infection, IQR = interquartile range, OR = odds ratio, CI95 = 95% confidence interval. VRE = vancomycin-resistant enterococcus, VSE = vancomycin-susceptible enterococcus. N.a. = not applicable Bold entries represent statistically significant factors Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 7 of 9 Table 4 Results of multivariable binary logistic regression of risk factors for in-hospital death after enterococcal bloodstream infection Parameter VS-E. faecium vs. VS-E. faecalis VS-E. faecium vs. VR-E. faecium OR P-value CI95 (lower-upper) OR P-value CI95 (lower-upper) Age 1015 0,002 1005 – 1025 1016 0,010 1004 – 1029 Vascular disease 1407 0,042 1012 – 1956 Not significant Renal disease 3120 0,000 2274 – 4280 4005 0,000 2708 – 5922 Liver disease 2909 0,000 2109 – 4011 2390 0,000 1618 – 3529 Enterococcus species VS-E. faecium 2023 0,000 1519 – 2695 Not applicable VS-E. faecalis Reference = 1 Not applicable Vancomycin-resistant Not applicable 1.283 0.300 0.801 – 2.057 Vancomycin-susceptible Not applicable Reference = 1 OR = odds ratio, CI95 = 95% confidence interval considered [10–16, 18–24, 32]. Prematunge et al. already these differences could be due to higher antibiotics costs pointed out in their 2016 meta-analysis, that it is possible or to differences in underlying conditions treated. For that many observations on VRE-associated outcome are this reason, we analyzed the length of stay before and based on differences in the infection-causing species after onset of BSI. Our data showed increased lengths of rather than on vancomycin resistance [24]. stay overall and before onset of VREm-BSI, but not after. Attempts to assess the pathogenicity of enterococci go Interestingly, all BSIs were classified as HAIs as none far back in time. In some of the previous studies, the occurred prior to day 3 after hospital admission. On pathogenic potential of commensal E. faecium was average, the BSI episodes occurred on day 16 of determined, whereas most of nowadays HAIs are caused hospitalization. Moreover, the same phenomenon was by isolates of a different E. faecium lineage [37, 38]. observed in the analysis of the infection-attributable These so-called hospital-associated strain types (formerly LOS stratified by the two clinically relevant Entero- known as clonal complex CC17) differ from commensal coccus species. Cases with vancomycin susceptible E. human and animal isolates by a distinct core and accessory faecium BSI were in-hospital longer before onset of in- genome content. Ampicillin resistance is a phenotypic fection than vancomycin susceptible E. faecalis cases. No marker of these hospital-associated strain types [39–41]. It difference in LOS was observed after onset of infection. has been shown that AMP-R E. faecium isolates causing This study has several limitations. The cases were identi- healthcare-associated infections are in fact more pathogenic fied retrospectively through a microbiological database and than commensal variants [42, 43]. In a supplementary ana- 6.6% lacked sufficient data for this analysis. We did not lysis (Additional file 1: Tables S1 and S2) we found that have data on the course or severity of infection and the 95% of our E. faecium isolates were ampicillin-resistant antibiotic treatment performed. We did not have separate (AMP-R), in contrast to only 1% of the E. faecalis isolates. data on true costs before and after the bloodstream infec- Due to the uneven distribution of ampicillin resistance tion. We did not perform molecular analyses on the entero- over the two pathogens we were not able to assess cocci isolates to assess their potential virulence traits. potential virulence differences between commensal and hospital-associated isolates. However, our results are sup- Conclusion portive to previous population-based and molecular ana- In our study, vancomycin resistance in patients with lyses of E. faecium from hospital-acquired infections. Enterococcus faecium bloodstream infection was asso- Several reports have linked VRE infections with in- ciated with increased total costs, length of stay before creased costs [13, 15, 19, 32]. In the univariate analyses, onset of infection, but not with infection-attributable our data showed similar results as almost all costs were LOS or in-hospital mortality. We observed that significantly higher in VREm-BSI patients than in vancomycin-susceptible E. faecium infections were patients with VSEm-BSI. Butler et al. reported that more strongly associated with increased LOS and pharmacy costs are the second most relevant driver of mortality than vancomycin susceptible E. faecalis increased costs, making up to 18% of the total amount infections and might indicate higher virulence of E. [21]. In our cohort, the percentage of pharmaceutical faecium as compared to E. faecalis. In order to avoid costs for patients with VREm made up 21% of the total overestimation of VRE-attributable effects, in addition hospital costs while they made up only 9% of the costs to vancomycin-resistance species should be taken into of patents with BSI caused by VSEm (< 0,001). As we consideration in future studies assessing the burden were not able to attribute costs to particular agents, of VRE infections. Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 8 of 9 Additional file 3. Bonten MJ, Willems R, Weinstein RA. Vancomycin-resistant enterococci: why are they here, and where do they come from? Lancet Infect Dis. 2001;1:314–25. Additional file 1: Table S1. Susceptibility towards Ampicillin among 4. WHO publishes list of bacteria for which new antibiotics are urgently cases. Table S2. Susceptibility towards Ampicillin among Isolate n=193 needed [http://www.who.int/mediacentre/news/releases/2017/bacteria- missing; AMP= Susceptibility to Ampicillin. R=Resistant. S=Susceptible. antibiotics-needed/en/]. Accessed 5 Mar 2018. RR= relative risk. CI95=95% confidence interval. (DOCX 34 kb) 5. Gastmeier P, Schroder C, Behnke M, Meyer E, Geffers C. Dramatic increase in vancomycin-resistant enterococci in Germany. J Antimicrob Chemother. 2014;69:1660–4. Abbreviations 6. Simon A, Christiansen B. Adaptation and development of German 95% CI: 95% confidence interval; BSI: blood stream infection; CCI: Charlson recommendations on the prevention and control of nosocomial infections comorbidity index; HAI: hospital acquired infection; HR: Hazard ratios; due to multiresistant pathogens. Gesundheitsforschung Gesundheitsschutz. IQR: interquartile range; LOS: length of stay; ME: multiplicative effect; 2012;55:1427–31. VRE: vancomycin-resistant enterococcus; VREm: vancomycin resistant 7. Muto CA, Jernigan JA, Ostrowsky BE, Richet HM, Jarvis WR, Boyce JM, Farr Enterococcus faecium; VSE: vancomycin-susceptible enterococcus; BM. SHEA guideline for preventing nosocomial transmission of multidrug- VSEf: vancomycin susceptible E. faecalis; VSEm: vancomycin susceptible resistant strains of Staphylococcus aureus and enterococcus. Infect Control Enterococcus faecium Hosp Epidemiol. 2003;24:362–86. 8. Cosgrove SE. The relationship between antimicrobial resistance and patient Acknowledgements outcomes: mortality, length of hospital stay, and health care costs. Clin We acknowledge support from the German Research Foundation (DFG) and Infect Dis. 2006;42(Suppl 2):S82–9. the Open Access Publication Fund of Charité – Universitätsmedizin Berlin. 9. Kaye KS, Engemann JJ, Mozaffari E, Carmeli Y. Reference group choice and antibiotic resistance outcomes. Emerg Infect Dis. 2004;10:1125–8. Funding 10. Lloyd-Smith P, Younger J, Lloyd-Smith E, Green H, Leung V, Romney MG. No external funding was received for this study. Economic analysis of vancomycin-resistant enterococci at a Canadian hospital: assessing attributable cost and length of stay. J Hosp Infect. Availability of data and materials 2013;85:54–9. The datasets used and/or analyzed during the current study are available 11. Hayakawa K, Martin ET, Gudur UM, Marchaim D, Dalle D, Alshabani K, from the corresponding author on reasonable request. Muppavarapu KS, Jaydev F, Bathina P, Sundaragiri PR, et al. Impact of different antimicrobial therapies on clinical and fiscal outcomes of patients Authors’ contributions with bacteremia due to vancomycin-resistant enterococci. Antimicrob TSK, CR, PG and RL were responsible for the study design. RL supervised the Agents Chemother. 2014;58:3968–75. study. MB, SW and RL were responsible for data collection and data cleaning. 12. Cheah AL, Spelman T, Liew D, Peel T, Howden BP, Spelman D, Grayson ML, FS and RL conducted the statistical analysis. GW helped writing the Nation RL, Kong DC. Enterococcal bacteraemia: factors influencing mortality, manuscript and contributed significantly to the discussion. All authors length of stay and costs of hospitalization. Clin Microbiol Infect. 2013;19:E181–9. interpreted the data, gave important intellectual content and revised the 13. Lloyd-Smith P. Controlling for endogeneity in attributable costs of manuscript critically. All authors read and approved the final manuscript. vancomycin-resistant enterococci from a Canadian hospital. Am J Infect Control. 2017;45:e161–4. Ethics approval and consent to participate 14. Pelz RK, Lipsett PA, Swoboda SM, Diener-West M, Powe NR, Brower RG, Perl A confirmatory ethics vote was obtained from the Charité University TM, Hammond JM, Hendrix CW. Vancomycin-sensitive and vancomycin- Medicine ethics committee (internal processing key EA4/229/17). resistant enterococcal infections in the ICU: attributable costs and outcomes. Intensive Care Med. 2002;28:692–7. Consent for publication 15. Puchter L, Chaberny IF, Schwab F, Vonberg R-P, Bange F-C, Ebadi E. Not applicable. Economic burden of nosocomial infections caused by vancomycin-resistant enterococci. Antimicrob Resist Infect Control. 2018;7:1. 16. Gandra S, Barter D, Laxminarayan R. Economic burden of antibiotic Competing interests resistance: how much do we really know? Clin Microbiol Infect. The authors declare that they have no competing interests. 2014;20:973–9. 17. Bach PB, Malak SF, Jurcic J, Gelfand SE, Eagan J, Little C, Sepkowitz KA. Publisher’sNote Impact of infection by vancomycin-resistant enterococcus on survival and Springer Nature remains neutral with regard to jurisdictional claims in resource utilization for patients with leukemia. Infect Control Hosp published maps and institutional affiliations. Epidemiol. 2002;23:471–4. 18. Russell DL, Flood A, Zaroda TE, Acosta C, Riley MM, Busuttil RW, Pegues DA. Author details Outcomes of colonization with MRSA and VRE among liver transplant Charité Universitätsmedizin Berlin, Institute of Hygiene and Environmental candidates and recipients. Am J Transplant Off J Am Soc Transplant Medicine, Berlin, Germany. National Reference Center for the Surveillance of Am Soc Transplant Surg. 2008;8:1737–43. Nosocomial Infections, Berlin, Germany. Department of Medical and 19. Chiang HY, Perencevich EN, Nair R, Nelson RE, Samore M, Khader K, Chorazy Financial Controlling, Charité Universitätsmedizin Berlin, Berlin, Germany. ML, Herwaldt LA, Blevins A, Ward MA, Schweizer ML. Incidence and Robert Koch Institute, FG13 Nosocomial Pathogens and Antibiotic outcomes associated with infections caused by vancomycin-resistant Resistance, Wernigerode, Germany. National Reference Centre for enterococci in the United States: systematic literature review and meta- Staphylococci and Enterococci, Berlin, Germany. analysis. Infect Control Hosp Epidemiol. 2017;38:203–15. 20. McNeil SA, Malani PN, Chenoweth CE, Fontana RJ, Magee JC, Punch JD, Received: 19 April 2018 Accepted: 11 October 2018 Mackin ML, Kauffman CA. Vancomycin-resistant enterococcal colonization and infection in liver transplant candidates and recipients: a prospective surveillance study. Clin Infect Dis. 2006;42:195–203. 21. Butler AM, Olsen MA, Merz LR, Guth RM, Woeltje KF, Camins BC, Fraser VJ. References Attributable costs of enterococcal bloodstream infections in a nonsurgical 1. Zasowski EJ, Claeys KC, Lagnf AM, Davis SL, Rybak MJ. Time is of the hospital cohort. Infect Control Hosp Epidemiol. 2010;31:28–35. essence: the impact of delayed antibiotic therapy on patient outcomes in hospital-onset Enterococcal bloodstream infections. Clin Infect Dis. 22. DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of 2016;62:1242–50. mortality associated with vancomycin-resistant and vancomycin-susceptible 2. Maragakis LL, Perencevich EN, Cosgrove SE. Clinical and economic burden enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis. of antimicrobial resistance. Expert Rev Anti-Infect Ther. 2008;6:751–63. 2005;41:327–33. Kramer et al. Antimicrobial Resistance and Infection Control (2018) 7:133 Page 9 of 9 23. Salgado CD, Farr BM. Outcomes associated with vancomycin-resistant enterococci: a meta-analysis. Infect Control Hosp Epidemiol. 2003;24:690–8. 24. Prematunge C, MacDougall C, Johnstone J, Adomako K, Lam F, Robertson J, Garber G. 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. 25. Murray BE. Vancomycin-resistant enterococcal infections. N Engl J Med. 2000;342:710–21. 26. Noskin GA, Peterson LR, Warren JR. Enterococcus faecium and enterococcus faecalis bacteremia: acquisition and outcome. Clin Infect Dis. 1995;20:296–301. 27. Jahresbericht. 2015. [https://www.charite.de/fileadmin/user_upload/portal_ relaunch/Mediathek/publikationen/jahresberichte/Charite_Jahresbericht_ 2015_EN.pdf]. Accessed 27 Mar 2018. 28. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83. 29. Thygesen SK, Christiansen CF, Christensen S, Lash TL, Sorensen HT. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of patients. BMC Med Res Methodol. 2011;11:83. 30. Schulgen G, Kropec A, Kappstein I, Daschner F, Schumacher M. Estimation of extra hospital stay attributable to nosocomial infections: heterogeneity and timing of events. J Clin Epidemiol. 2000;53:409–17. 31. Barnett AG, Beyersmann J, Allignol A, Rosenthal VD, Graves N, Wolkewitz M. The time-dependent bias and its effect on extra length of stay due to nosocomial infection. Value Health. 2011;14:381–6. 32. Jiang HL, Zhou Z, Wang LS, Fang Y, Li YH, Chu CI. The risk factors, costs, and survival analysis of invasive VRE infections at a medical Center in Eastern Taiwan. Int J Infect Dis. 2017;54:18–24. 33. Guzman Prieto AM, van Schaik W, Rogers MR, Coque TM, Baquero F, Corander J, Willems RJ. Global emergence and dissemination of enterococci as nosocomial pathogens: attack of the clones? Front Microbiol. 2016;7:788. 34. von Baum H, Ober JF, Wendt C, Wenzel RP, Edmond MB. Antibiotic-resistant bloodstream infections in hospitalized patients: specific risk factors in a high-risk population? Infection. 2005;33:320–6. 35. Arias CA, Murray BE. The rise of the enterococcus: beyond vancomycin resistance. Nat Rev Microbiol. 2012;10:266–78. 36. Sava IG, Heikens E, Huebner J. Pathogenesis and immunity in enterococcal infections. Clin Microbiol Infect. 2010;16:533–40. 37. Gao W, Howden BP, Stinear TP. Evolution of virulence in enterococcus faecium, a hospital-adapted opportunistic pathogen. Curr Opin Microbiol. 2018;41:76–82. 38. Lebreton F, van Schaik W, McGuire AM, Godfrey P, Griggs A, Mazumdar V, Corander J, Cheng L, Saif S, Young S. Emergence of epidemic multidrug- resistant enterococcus faecium from animal and commensal strains. MBio. 2013;4:e00534–13. 39. Lester CH, Sandvang D, Olsen SS, Schønheyder HC, Jarløv JO, Bangsborg J, Hansen DS, Jensen TG, Frimodt-Møller N, Hammerum AM. Emergence of ampicillin-resistant enterococcus faecium in Danish hospitals. J Antimicrob Chemother. 2008;62:1203–6. 40. Top J, Willems R, Blok H, De Regt M, Jalink K, Troelstra A, Goorhuis B, Bonten M. Ecological replacement of enterococcus faecalis by multiresistant clonal complex 17 enterococcus faecium. Clin Microbiol Infect. 2007;13:316–9. 41. Freitas AR, Novais C, Duarte B, Pereira AP, Coque TM, Peixe L. High rates of colonisation by ampicillin-resistant enterococci in residents of long-term care facilities in Porto, Portugal. Int J Antimicrob Agents. 2018;51:503–7. 42. Zou J, Shankar N. Surface protein Esp enhances pro-inflammatory cytokine expression through NF-κB activation during enterococcal infection. Innate immunity. 2016;22:31–9. 43. Sillanpää J, Nallapareddy SR, Singh KV, Prakash VP, Fothergill T, Ton-that H, Murray BE. Characterization of the ebpfm pilus-encoding operon of enterococcus faecium and its role in biofilm formation and virulence in a murine model of urinary tract infection. Virulence. 2010;1:236–46.

Journal

Antimicrobial Resistance and Infection ControlSpringer Journals

Published: Nov 14, 2018

Keywords: Bloodstream infection; Vancomycin-resistant enterococci; Enterococcus faecium

There are no references for this article.