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The rise in vancomycin-resistant Enterococcus faecium in Germany: data from the German Antimicrobial Resistance Surveillance (ARS)

The rise in vancomycin-resistant Enterococcus faecium in Germany: data from the German... Background: Due to limited therapeutic options, vancomycin-resistant Enterococcus faecium (VREF) is of great clinical significance. Recently, rising proportions of vancomycin resistance in enterococcal infections have been reported worldwide. This study aims to describe current epidemiological trends of VREF in German hospitals and to identify factors that are associated with an increased likelihood of vancomycin resistance in clinical E. faecium isolates. Methods: 2012 to 2017 data from routine vancomycin susceptibility testing of 35,906 clinical E. faecium isolates from 148 hospitals were analysed using data from the German Antimicrobial Resistance Surveillance System. Descriptive statistical analyses and uni- and multivariable regression analyses were performed to investigate the impact of variables, such as year of sampling, age and region, on vancomycin resistance in clinical E. faecium isolates. Results: From 2014 onwards the proportions of clinical E. faecium isolates exhibiting resistance to vancomycin increased from 11.2% (95% confidence interval [CI] 9.4–13.3%) to 26.1% (95% CI 23.1–29.4%) in 2017. The rise of VREF proportions is primarily observed in the southern regions of Germany, whereas northern regions do not show a major increase. In the Southwest and Southeast, VREF proportions increased from 10.8% (95% CI 6.9–16.5%) and 3.8% (95% CI 3.0–11.5%) in 2014 to 36.7% (95% CI 32.9–40.8%) and 36.8% (95% CI 29.2–44.7%) in 2017, respectively. VREF proportions were considerably higher in isolates from patients aged 40–59 years compared to younger patients. Further regression analyses show that in relation to secondary care hospitals, E. faecium samples collected in specialist care hospitals and prevention and rehabilitation care centres are more likely to be vancomycin-resistant (odds ratios: 2.4 [95% CI 1.2–4.6] and 2.4 [95% CI 1.9–3.0], respectively). No differences in VREF proportions were found between female and male patients as well as between different clinical specimens. Conclusion: The proportion of VREF is increasing in German hospitals, particularly in southern regions in Germany. Increased efforts in infection control and antibiotic stewardship activities accounting for local resistance patterns are necessary to combat the spread of VREF in Germany. Keywords: Enterococcus faecium, Vancomycin resistance, Antimicrobial resistance, Surveillance, Epidemiology, ARS * Correspondence: MarkwartR@rki.de Robert Koch Institute, Department 3: Infectious Disease Epidemiology, Unit 37: Healthcare-associated Infections, Surveillance of Antibiotic Resistance and Consumption, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany Full list of author information is available at the end of the article © The Author(s). 2019 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. Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 2 of 11 Background available data from the German hospital payment system Enterococcus faecium is a Gram-positive, facultative an- based on fee-for-case on diagnosis related groups. aerobic, catalase-negative bacterium that commonly in- habits the intestinal tracts of healthy humans [1]. In Methods addition to its role as a commensal in humans, E. fae- Study design and the German antimicrobial resistance cium has been described as an emerging pathogen that surveillance database causes a significant number of nosocomial infections, in- In order to investigate the epidemiology of vancomycin- cluding infections of the bloodstream, urinary tract, skin resistant E. faecium, a retrospective observational study and endocardium [2]. Data from the United States [3] was conducted analysing data from the Antimicrobial and Germany [4] show that E. faecium is among the Resistance Surveillance (ARS) database from 2012 to most frequent causes of healthcare-associated infections 2017. ARS is the national surveillance system for anti- with considerable potential for healthcare-acquired out- microbial resistance in Germany established by the breaks. Evidence indicates that E. faecium strains that Robert Koch-Institute in 2008 [14]. Voluntarily partici- cause nosocomial infections are different from strains that pating microbiology laboratories submit results from colonize healthy humans highlighting the role of health- routine pathogen identifications and antimicrobial sus- care centres in the spread of E. faecium infections [5–7]. ceptibility testing. In addition to microbiological results, The clinical relevance of E. faecium is directly linked to participating laboratories provide various pseudonymised its intrinsically low susceptibility to a broad spectrum of information including clinical specimen material (e. g. antimicrobial agents, including low-dose penicillin and blood, urine and swabs), patient data (age, gender), hos- ampicillin, aminoglycosides, sulphonamides and cephalos- pital type (e. g. secondary or tertiary care hospitals) and porines [8, 9]. After its first detection in the late 1980’s, geographical location of patient care [15, 16]. As of vancomycin resistance in Enterococci (VRE), including E. 2017, more than 50 laboratories contribute to the ARS faecium, started to emerge in hospitals in the United database, which includes data from more than 600 out States eventually spreading to Europe and worldwide lim- of a total of 1924 hospitals in Germany. Since ARS par- iting therapeutic options against enterococcal infections ticipation is based on laboratories rather than active [10]. Due to its clinical significance, the World Health participation of hospitals, a major selection bias towards Organization (WHO) assigned vancomycin-resistant E. certain hospitals (e.g. only those with implemented anti- faecium (VREF) as a high priority pathogen on its global biotic stewardship programs) can be excluded. All partici- priority list of antibiotic-resistant bacteria [11]. pating laboratories possess accreditation for performing According to 2017 data from the European Antimicro- microbiological analyses. Data transmitted to the ARS bial Resistance Surveillance Network (EARS-Network), database are routinely validated and checked for plausibil- the mean proportion of vancomycin-resistant E. faecium ity, completeness and consistency. ARS data are used to in blood and cerebrospinal fluid isolates is 14.9% (95% CI generate reference resistance data and feedback reports to 14–16) in participating European countries and 16.5% support hospitals in their antibiotic stewardship programs. (95% CI 15–18) in Germany [12]. Findings from the ARS resistance data of common pathogens are also avail- German national nosocomial infection surveillance system able to the public (https://ars.rki.de/). (Krankenhaus-Infektions-Surveillance-System,acrony- mized as “KISS”) show continuously increasing rates of Selection of E. faecium isolates vancomycin-resistant Enterococci from nosocomial blood- The participation of individual laboratories in ARS can stream and urinary tract infections acquired in intensive change over time which can potentially alter the set of care units (ICU) between 2007 and 2016 [13]. hospitals that provide clinical samples to ARS. In order Despite the data available for Germany, a comprehen- to avoid systematic changes in the case mix, only E. sive picture of the epidemiological situation of vanco- faecium isolates from hospitals with continuous yearly mycin-resistant E. faecium in German hospitals is participation in ARS between 2012 and 2017 were in- lacking. In particular, it is not known whether distinct cluded for the main analyses. To avoid biases through patient characteristics (e.g. gender, age, site of infection) inclusion of multiple E. faecium isolates from one pa- or other factors (e.g. hospital care type) are associated tient during one disease episode, only the patient’s first with an increased risk of VREF. Therefore, this study isolate for each quarter of the year was included. How- aims to analyse trends and risk factors of vancomycin re- ever, since vancomycin-resistant enterococci are known sistance of Enterococcus faecium in Germany using data to persist in the human gut for several months [17], it from the German national Antimicrobial Resistance cannot be fully excluded that a specific VREF strain has Surveillance (ARS) System. Furthermore, the study ana- been counted repeatedly from the same patient. Further- lyses trends in the number of infections or colonisations more, isolates were excluded if they were likely derived with VREF diagnosed in German hospitals using publicly for screening purposes (labelled as screening, anal swabs Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 3 of 11 and stool samples). E. faecium isolates without vanco- variables from the univariable analyses. For the multivar- mycin susceptibility testing were excluded. iable analysis assessing the interaction between region and year of sampling, the year was treated as a continu- Outcomes and co-variables ous predictor and the interaction between region and The primary outcome is the proportion of vancomycin- year was included. The same variables as in the model resistant E. faecium isolates among all E. faecium isolates without interaction were otherwise included. expressed as percentages (%). An E. faecium isolate was defined vancomycin resistant if it was tested resistant Sensitivity analyses against vancomycin in antimicrobial susceptibility testing It is important to note that some laboratories do not according to the applied standard, i. e. standards by routinely differentiate Enterococcus isolates into species European Committee on Antimicrobial Susceptibility level. Systematic bias in VREF proportions therefore Testing (EUCAST) or Clinical and Laboratory Standards cannot be excluded, such as those introduced by species Institute (CLSI). differentiation only in selected Enterococcus samples. To Clinical specimens were grouped by sample site into address this issue, time trend analyses of VREF propor- urine (urine samples), blood (blood cultures), swabs tions were analysed for E. faecium isolates identified in (swabs from eye, nose, throat, ear, tongue, urogenital laboratories that consistently differentiate more than sites as well as intraoperative swabs and other/unspeci- 95% of all Enterococcus isolates into species level (n = fied swabs), wound (swabs from wounds and abscesses) 8492). In addition, sensitivity analyses were performed and other specimens (e. g. punctures, respiratory mate- that comprised E. faecium isolates (n = 89,450) from all rials, unspecified). Patient age was grouped into age hospitals including hospitals that did not continuously categories (0–19, 20–39, 40–59, 60–79 and, ≥80 years). participated in ARS between 2012 and 2017. Patient gender was classified into female and male. The geographical origin of the isolates was grouped into five major regions based on the distribution of hospitals: Northeast (federal states of Mecklenburg-West Pomer- Data from the hospital payment system based on fee-for- ania, Brandenburg, Berlin, Saxony-Anhalt), Northwest case on diagnosis related groups (federal states of Lower Saxony, Bremen, Hamburg, In order to estimate the number of diagnosed Schleswig-Holstein), West (North Rhine-Westphalia), infections or colonisations with VREF between 2013 Southwest (Hesse, Rhineland-Palatinate, Saarland, and 2017, publicly available data from the hospital Baden-Wuerttemberg) and Southeast (Bavaria, Saxony, payment system based on fee-for-case on diagnosis re- Thuringia). Hospital care type was categorised into sec- lated groups (DRG) were analysed. German hospitals ondary care, tertiary care, specialist care, and prevention receive a fee-for-case on DRG based on diagnoses ac- and rehabilitation care. All variables were considered as cording to the International Statistical Classification of categorical variables for statistical analyses. Diseases and Related Health Problems Version 10 - German Modification (ICD-10-GM). According to §21 Statistical analyses Hospital Reimbursement Act (Krankenhausentgeltge- All statistical analyses were performed using R version setz) aggregated data must be made publicly available 3.5.1 [18]. Estimates of vancomycin resistance propor- for scientific use by the Insitute for Reimbursement in tions are expressed as percentages with 95% confidence the Hospital (Institut für das Entgeltsystem im intervals (95% CI) accounting for clustering on hospital Krankenhaus, InEK) [20]. The dataset contains diagno- level using routines in the survey package (version 3.35). sis data from approximately 1500 out of 1924 German Proportions of vancomycin-resistant E. faecium isolates hospitals. The diagnosis code U80.30 (E. faecium with between female and male were compared using the resistance to glycopeptide antibiotics, available since Pearson χ test with the Rao-Scott second-order correc- 2013) was used to identify cases of E. faecium with re- tion [19] for different age groups. The resulting p-values sistance to glycopeptide antibiotics. Importantly, a diag- were adjusted for multiple testing using a Bonferroni nosis code for E. faecium with resistance to glycopeptide correction. Risk factors for vancomycin resistance were antibiotics has been implemented since the beginning of analysed using univariable and multivariable logistic re- the DRG system in Germany in 2004 (U.80.3!: E. faecium gression models accounting for clustering at hospital with resistance to glycopeptide antibiotics, oxazolidinone, level as implemented in the survey package. For univari- streptogramine, or high-level-aminoglycoside-resistance). able analyses the following predictors for vancomycin re- Therefore, the diagnosis of glycopeptide-resistant E. fae- sistance were considered: year of sampling, gender, age cium is well established in German hospitals and a report- group, specimen (sample site), region and hospital care ing bias through introduction of the fee-for-case on DRG type. The multivariable analysis model included all can be excluded. Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 4 of 11 Results Table 1 Baseline characteristics of clinical E. faecium isolates Baseline characteristics N 35,906 total In total 35,906 E. faecium isolates from 33,643 patients Year of sampling and 148 continuously participating hospitals were in- 2012 (n, %) 4139 11.53 cluded in the study. The baseline characteristics are out- 2013 (n, %) 5452 15.18 lined in Table 1. Samples predominantly originated from 2014 (n, %) 6326 17.62 elderly patients (median: 74 years), although isolates 2015 (n, %) 6932 19.31 from younger age categories were also available. With a female / male ratio of 1.16 patients’ gender was nearly 2016 (n, %) 6806 18.96 equally distributed in the sample set. The majority of 2017 (n, %) 6251 17.41 hospitals and isolates originated from Western and Gender of patient Southwestern regions in Germany, regions where the Female (n, %) 17,892 49.83 most populated federal states are located, including Male (n, %) 15,370 42.81 North Rhine Westphalia (~ 18 m inhabitants) and NA (n, %) 2644 7.36 Baden-Wuerttemberg (~ 11 m). The largest number of E. faecium isolates was provided by secondary care hospi- Sex ratio (f/m) 1.16 tals (n = 31,182) followed by tertiary care hospitals (n = Age of patient 3.283), and specialist care hospitals (1109). The most 0–19 yrs. (n, %) 527 1.47 common clinical sources of E. faecium were urine sam- 20–39 yrs. (n, %) 1183 3.29 ples (n = 16,261), swabs (n = 5687) and wound material 40–59 yrs. (n, %) 5547 15.45 (n = 5550). It is worth mentioning that the ratio of the 60–79 yrs. (n, %) 17,785 49.53 total numbers of clinical E. faecium and E. faecalis iso- lates recorded in ARS did not change between 2012 and 80+ yrs. (n, %) 10,864 30.26 2017 (Additional file 1: Table S1). Compared to other re- Age (median, IQR) 74.0 63.0–81.0 gions in Germany, in the West and Southwest slightly Specimen (sampling site) higher proportions of E. faecium were observed. Blood (n, %) 3011 8.39 Urine (n, %) 16,261 45.29 Swab (n, %) 5687 15.84 Temporal trend and regional analyses The proportion of E. faecium isolates with resistance Wound (n, %) 5550 15.46 against vancomycin decreased from 15.2% (95% CI 12.0– Other (n, %) 5280 14.71 19.2%) in 2012 to 11.2% (95% CI 9.4–13.4%) in 2014 NA (n, %) 117 0.33 (Fig. 1). However, from 2014 onwards, the percentage of Region vancomycin-resistant clinical E. faecium isolates con- Southwest (n, %) 11,868 33.05 tinuously increased reaching 26.1% (95% CI 23.1–29.4%) Southeast (n, %) 395 1.10 in 2017, more than twice that observed 2014. This find- ing is supported by univariable and multivariable ana- West (n, %) 19,508 54.33 lyses, which show that isolates collected after 2014 were Northwest (n, %) 2400 6.68 increasingly more likely to be tested resistant against Northeast (n, %) 1594 4.44 vancomycin than isolates in 2014 (Table 2). A similar NA (n, %) 141 0.39 rise of VREF proportions between 2014 and 2017 was Hospital care type found in sensitivity analyses including E. faecium isolates Secondary care (n, %) 31,182 86.84 that (i) were identified in laboratories that consistently differentiate more than 95% of all Enterococcus isolates Tertiary care (n, %) 3283 9.14 into species level (Additional file 2: Figure S1A) or (ii) Specialist care 1109 3.09 were provided by all hospitals also including hospitals Prevention and rehabilitation care (n, %) 158 0.44 that did not continuously participated in ARS between Other (n, %) 33 0.09 2012 and 2017 (Additional file 2: Figure S1B). Since NA (n, %) 141 0.39 bloodstream infections are of particular clinical interest, Hospitals (n) 148 it is noteworthy that in the included hospitals the num- ber of VREF blood isolates increased from 57 to 120 be- Patients (n) 33,643 tween 2014 and 2017 accompanied by a marked rise in VREF proportions from 11.0% (95% CI 7.2–16.6) in 2014 to 21.1% (95% CI 17.2–25.7%) in 2017. Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 5 of 11 analysed for different age categories. The results displayed in Fig. 3 show that E. faecium isolates from children and adolescents (0–19 years) exhibit markedly lower vancomycin resistance proportions (7.6% [95% CI 5.4–10.6%]) than young adults (20–39 years) (15.4% [95% CI 11.1–21.0%]) and older age categories. Multivar- iable analyses reveal that E. faecium samples from patient age categories of 0–19 years and 20–39 years are less likely to be vancomycin-resistant than samples from patients with an age between 40 and 59 years (Table 2). Interestingly, the likelihood of vancomycin resistance Fig. 1 Time trend of vancomycin-resistant E. faecium. Time trend of tends to decrease in age groups above 60 years, although vancomycin-resistant E. faecium as a proportion (%) of all E. faecium the differences are not statistical significant. Further ana- isolates with corresponding 95% confidence intervals lyses of all age categories combined do not indicate that female and male patients differ in VREF proportions (16.5 Regional analyses of E. faecium isolates collected between [95% CI 14.2–19.1%] vs. 16.9 [95% CI 14.1–20.1%]), re- 2012 and 2017 reveal that Germany shows a strong north- spectively. However, male young adults (20–39 years) have south disparity in VREF proportions. VREF proportions are higher proportions of vancomycin resistance than their fe- noticeably lower in the Northwest (10.8% [95% CI 6.7– male counterparts (19.8 vs. 13.6%, adjusted p-value: 14.8]) and Northeast (10.0% [95% CI 6.7–14.8]) compared 0.013), while no differences between both genders were to the Southwest where 20.7% (95% CI 17.1–24.9) of all iso- observed in older age categories (Fig. 3). lates were tested resistant against vancomycin (Fig. 2A). Uni- and multivariable regression analyses confirm that E. Clinical specimen faecium isolates from the Northeastand Northwestregions Since the frequency of drug-resistance pathogens can are less likely to be tested vancomycin resistant than iso- differ between infection sites, VREF proportions were lates from the Southwest (Table 2). Importantly, temporal analysed in different clinical specimens, including blood dynamics of VREF proportions differ between the analysed cultures, urine samples, wound material and swabs. No regions (Fig. 2B). While in the Southwest and Southeast a major differences in vancomycin resistance proportions pronounced increase of VREF proportions was observed were found between the analysed sampling sites (blood: between 2014 and 2017, the northern regions do not show 14.9% [95% CI 11.3–19.6%], urine: 17.2% [95% CI 14.6– ariseof VREFduringthatsameperiod. In theSouthwest 20.2%], wound: 16.5% [95% CI 13.6–19.9%], swabs: and Southeast, VREF proportions increased from 10.8% 16.1% [95% CI 13.5–19.0%], other: 15.5% [95% CI 12.2– (95% CI 6.9–16.5%) and 3.8% (95% CI 3.0–11.5%) in 2014 19.5%]). Therefore, no associations between clinical spe- to 36.7% (95% CI 32.9–40.8%) and 36.8% (95% CI 29.2– cimen and the likelihood of VREF resistance were found 44.7%) in 2017, respectively. This finding is supported by a in uni- and multivariable regression analyses (Table 2). multivariable analysis controlling for interaction between year and region (Additional file 3: Table S2). It is important Hospital care type to note that southern regions feature considerably higher To study vancomycin resistance patterns in different VREF proportions than northern regions only from 2016 hospital care types, VREF proportions were analysed for onwards. secondary care, tertiary care and specialist care hospitals The absolute number of VREF isolates in the ARS data- as well as prevention and rehabilitation care centres. E. base continuously increased from 631 to 1634 between faecium isolates from secondary care hospitals exhibited 2012 and 2017, suggesting that numbers of infections with lower proportions of vancomycin resistance (15.2% [95% vancomycin-resistant E. faecium in German hospitals have CI 12.8–18.0%]) than isolates from tertiary care hospitals been annually increasing. This trend is supported by our (22.8% [95% CI 10.0–44.1%]) and specialist care hospi- analysis of publicly available data from the hospital payment tals (31.2% [95% CI 16.9–50.4%]) (Fig. 4). Univariable system based on fee-for-case on DRGs [20]thatshowa analyses show that E. faecium samples from tertiary hos- four-fold increase of diagnoses of glycopeptide-resistant E. pital care and specialist hospital care are more likely to faecium infections or colonisations in German hospitals be- exhibit vancomycin resistance than isolates from second- tween 2013 and 2017 (Table 3). ary care (Table 2). However, in multivariable analyses, no statistical evidence was found that VREF proportions Age and gender differ between secondary and tertiary care hospitals (p = In order to study the influence of the patient age on 0.191). Interestingly, remarkably high proportions of vancomycin resistance patterns, VREF proportions were VREF were observed in isolates from patients treated in Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 6 of 11 Table 2 Uni- and multivariable analyses of factors associated with vancomycin resistance in clinical E. faecium isolates univariable analysis multivariable analysis OR (95% CI) p-value OR (95% CI) p-value Year of sampling 2012 1.42 (1.12–1.80) 0.004 1.58 (1.16–2.14) 0.004 2013 1.26 (1.01–1.58) 0.044 1.27 (0.99–1.63) 0.061 2014 1 –– 1 –– 2015 1.22 (0.98–1.51) 0.072 1.24 (0.99–1.55) 0.060 2016 1.81 (1.46–2.23) < 0.001 1.80 (1.45–2.25) < 0.001 2017 2.79 (2.26–3.46) < 0.001 2.74 (2.22–3.39) < 0.001 Region Southwest 1 –– 1 –– Southeast 0.71 (0.53–0.95) 0.022 0.74 (0.54–1.01) 0.057 West 0.68 (0.46–1.00) 0.051 0.82 (0.55–1.20) 0.303 Northwest 0.46 (0.35–0.61) < 0.001 0.51 (0.36–0.72) < 0.001 Northeast 0.43 (0.27–0.67) < 0.001 0.47 (0.31–0.71) 0.001 Gender Female 1 –– 1 –– Male 0.97 (0.90–1.06) 0.533 1.03 (0.94–1.11) 0.554 Age 0–19 years 0.38 (0.26–0.58) < 0.001 0.33 (0.23–0.48) < 0.001 20–39 years 0.85 (0.71–1.01) 0.071 0.84 (0.71–0.99) 0.043 40–59 years 1 –– 1 –– 60–79 years 0.96 (0.82–1.12) 0.626 0.94 (0.83–1.06) 0.324 80+ years 0.86 (0.67–1.10) 0.234 0.83 (0.69–1.01) 0.062 Specimen (sampling site) Blood 1 –– 1 –– Urine 1.18 (0.92–1.52) 0.20276 1.22 (0.94–1.48) 0.134 Swab 1.09 (0.78–1.51) 0.62974 0.93 (0.74–1.17) 0.547 Wound 1.12 (0.93–1.36) 0.22761 1.08 (0.90–1.29) 0.426 Other 1.04 (0.88–1.23) 0.65102 1.01 (0.85–1.19) 0.952 Hospital care type Secondary care 1 –– 1 –– Tertiary care 1.65 (1.01–2.69) 0.047 1.33 (0.87–2.04) 0.191 Specialist care 2.53 (1.15–5.56) 0.023 2.37 (1.22–4.60) 0.012 Prevention and rehabilitation care 3.23 (2.42–4.33) < 0.001 2.39 (1.91–2.98) < 0.001 prevention and rehabilitation care centres, where more 2014 onwards the proportions of clinical E. faecium iso- than one third of all E. faecium isolates are found to be lates exhibiting resistance to vancomycin increased from resistant to vancomycin (36.7% [CI 95% 26.8–47.9%]. In 11 to 26% in 2017. Regional analyses reveal that, in par- line with that, the multivariable regression analysis iden- ticular, southern regions of Germany have been affected tified prevention and rehabilitation care centres as an in- by a pronounced rise of VREF proportions, whereas dependent risk factor of increased likelihood of VREF northern regions do not feature substantial increases of resistance in relation to secondary care hospitals. VREF. Middle aged adults (40–59 years) exhibit mark- edly higher VREF proportions than children and adoles- Discussion cents (0–20 years) and young adults (20–39 years). By analysing data from the German Antibiotic Resistance While VREF proportions do not differ between female Surveillance system the present study shows that from and male patients in the whole dataset, subgroup Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 7 of 11 Fig. 2 Vancomycin-resistant E. faecium stratified into geographical region. Vancomycin-resistant E. faecium as a proportion (%) of all E. faecium isolates with corresponding 95% confidence intervals by German region (2012–2017 data) (a) and time trend by German region (b) analyses show that E. faecium isolates from young adult men have higher vancomycin resistance proportions than their female counterparts. Rising proportions of vancomycin-resistant E. faecium have also been observed in many other European coun- tries between 2014 and 2017 as reported by EARS-Net, Table 3 Analyses of diagnoses of glycopeptide-resitant E. faecium in German hospitals Year Number of diagnoses 2013 7074 2014 8488 Fig. 3 Vancomycin-resistant E. faecium stratified into age and gender. Vancomycin-resistant E. faecium (VREF) as a proportion (%) 2015 11,697 of all E. faecium isolates with corresponding 95% confidence 2016 19,747 intervals from male and female patients stratified into age categories. Proportions of VREF between female and male were 2017 28,907 compared using the Pearson χ test with the Rao-Scott second- The number of diagnoses of infections or colonisations with glycopeptide- order correction in different age groups. The resulting p-values were resistant E. faecium between 2013 and 2017 were analysed using publicly adjusted for multiple testing using a Bonferroni correction. P-values available data from the hospital payment system based on fee-for-case on diagnosis related groups. The dataset contains diagnosis data of ~ 1500 out of ≤0.05 are indicated with an “*”. Adjusted p-Values (female vs. male a total of 1924 existing (2017) German hospitals. The diagnoses code U80.30! patients): 0–19 yrs.: p = 0.768, 20–39 yrs.: p = 0.013, 40–59 yrs.: p = 1, according ICD-10-GM was used to identify cases of E. faecium with resistance 60–79 yrs.: p = 1, 80+ yrs.: p = 1 to glycopeptide antibiotics Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 8 of 11 information about the development of VRE(F) screening habits are available. However, in Germany, the Commission for Hospital Hygiene and Infection Prevention only recom- mends a VRE(F) screening for risk populations (e.g. patients with severe comorbidities and haematological diseases) ra- ther than a general screening for all hospitalized patients [26]. Rising numbers of infections with vancomycin-resist- ant enterococci and/or E. faecium have been also reported for other countries around the world, including Switzerland [27], Australia [28]and Canada [29, 30]. Interestingly, our data show that the ratio of clinical E. faecium and E. faecalis isolates recorded in ARS is higher in West and South Germany suggesting a more prominent role of E. faecium in enterococcal infections in these regions. Analyses of resistance trends between different geo- Fig. 4 Vancomycin-resistant E. faecium stratified into hospital care graphical regions in Germany between 2012 and 2017 type. Vancomycin-resistant E. faecium as a proportion (%) of all E. reveal that VREF proportions significantly vary within faecium isolates with corresponding 95% confidence intervals by Germany exhibiting a pronounced north-south disparity. hospital care type While VREF proportions remained stable in northern re- gions, a marked increase of VREF proportions was ob- including neighbouring countries to Germanys, such as served in hospitals in the Southwest. From 2016 onwards Denmark, Belgium, Poland and Czech Republic [12]. VREF proportions in the South were significantly higher Only two countries, Ireland and Portugal, in the EU and than in the North. VREF strain characterization based on European Economic Area (EU/EEA) show a decreasing whole genome sequencing performed at the National Ref- trend of VREF proportions between 2014 and 2017 erence Centre for Enterococci for all bloodstream isolates (Portugal 20.1 to 7.2%, Ireland 45.1 to 38.2%). In EARS- between 2015 and 2018 (n = 448) revealed prevalence of Net AMR data are exclusively collected from invasive certain strain types associated to specific regions. Whereas isolates. In line with the findings from EARS-Net our ST117/CT71 was mainly spread throughout Germany and analyses of VREF proportions in blood isolates also show found in at least nine Federal States, isolates of ST117/ increasing trends between 2014 and 2017 in German CT469, ST80/CT1065 and ST80/CT1066 were mainly hospitals. prevalent in Southwestern Germany ([7]and Jennifer K. Since infections with VREF are associated with worse Bender und Guido Werner, unpublished data). Therefore, clinical outcomes compared to infections with vanco- the increase in VREF rates in certain regions in Germany mycin-sensitive strains [21–23], rising vancomycin re- might be associated with a preferred prevalence of certain sistance is of great clinical concern in the management strain types. of patients with nosocomial E. faecium infections. As a Increasing proportions of enterococci infections with matter of fact, a recent population-level study using data vancomycin-resistant strains in Germany are also ob- from EARS-Net showed that there were about 16,000 served in data from the national Nosocomial infection nosocomial infections with vancomycin-resistant entero- surveillance system (KISS). In contrast to our findings, cocci, which were associated with 1065 attributable KISS identified a belt of states with higher proportions deaths in the EU/EEA in the year 2015, nearly twice as of vancomycin-resistant enterococci infections in the many as 2007 [24]. Current German data show increas- centre of Germany spanning from west to east [13]. The ing trends of nosocomial infections with vancomycin-re- different results to our surveillance system might be ex- sistant Enterococci in German hospitals [13, 25]. These plained by different methodological approaches used in findings are strongly supported by our analyses of pub- the KISS study, such as only inclusion of bloodstream licly available data from German hospitals, which show a and urinary tract infections from ICUs and wound infec- four-fold increase of diagnoses of infections or colonisa- tions from surgical departments. The reasons for the re- tions with glycopeptide-resistant E. faecium between gional differences observed in our study are largely 2013 and 2017 underlining the growing significance of unknown. However, a large representative population- vancomycin-resistant E. faecium in Germany. It is im- based study analysing German antibiotic prescription portant to note that rising numbers of diagnoses of in- data reported higher outpatient antibiotic prescription of fections or colonisations with glycopeptide-resistant E. fluoroquinolones in southwestern regions of Germany faecium may be partly explained by increased screening [31]. The extensive use of fluoroquinolones has been efforts in German hospitals, although no representative shown to be associated with the emergence of vancomycin- Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 9 of 11 resistant enterococci in the hospital setting [32]. This find- vancomycin resistance does not further increase the risk ing underlines the importance of the implementing of in- of in-hospital mortality and infection-attributed hospital terventions that improve outpatient antibiotic prescribing stay in bloodstream infections with E. faecium but is asso- [33]. It is important to note that the analyses of regional re- ciated with increased overall hospital costs [49]. sistance patterns are based on the location of the hospital This study indicates that VREF proportions are higher rather than the residence of the patient. Nevertheless, hos- in specialist care hospitals and prevention and rehabilita- pital density in Germany is relatively high and it has been tion care centres, a finding that is possibly explained by reported that the majority of patients are treated in hospi- the larger number of patients with comorbidities and tals fewer than 60 km from the patients places of residence other factors (e. g. age) that are associated with acquiring [34]. This suggests that the described regional VREF pro- resistant bacteria. Specialist care hospitals and preven- portions are a true reflection of the acquisition of VREF in tion and rehabilitation care centres have also been iden- the respective regions, irrespective of whether they were ac- tified as risk factors for antimicrobial resistance in quired in the hospital or in the community. Klebsiella pneumoniae in Germany [16]. Very little is known about factors associated with in- creased vancomycin resistance in clinical E. faecium iso- Strengths and limitations lates in Germany. This study did not find any differences This study used data from the ARS database which is in VREF proportions between female and male patients. the largest and most comprehensive surveillance system This finding is also reported in other studies from differ- for antimicrobial resistance in Germany [14, 50]. As of ent regions in the world [35–38]. In contrast, a study 2017, ARS comprised of data from more than 600 par- analysing data from three New York hospitals found that ticipating hospitals across all regions in Germany allow- isolates from female patients have a higher likelihood of ing for detailed analyses of epidemiological trends. To being vancomycin-resistant than samples from men [39]. our knowledge, with more than 35.000 clinical isolates However, that particular study analysed infections with of E. faecium collected from more than 33,000 patients Enterococcus faecalis or Enterococcus faecium. Interest- our study represents the most comprehensive analysis of ingly, we observed that young male adults (20–39 years) recent trends of VREF in German hospitals. However, it exhibit markedly higher proportions of VREF than is important to consider the limitations of this study. young female adults (20% vs. 14%), a finding that has First, participation in ARS is voluntary, and thus, partici- not been described for E. faecium yet. pating laboratories and hospitals are not equally distrib- Since it has been known that different age groups ex- uted resulting in a clustering in certain regions. In hibit different microbial susceptibility proportions, VREF particular, northern regions are under-represented in the resistance patterns were analyzed for different age cat- sample set, while the Western region is overrepresented. egories. Patients older than 40 years exhibit higher VREF Therefore, statistical analyses were used that accounted proportions than children and adolescents (> 15% vs. for clustering effects. Second, since information on 7%). Similar age trends have been reported for other underlying diagnoses is not collected in ARS, it is not bacterial pathogens, including Staphylococcus aureus, possible to differentiate between colonisation and infec- Escherichia coli, Streptococcus pneumoniae, Pseudo- tion. To address this issue, isolates were excluded if they monas aeruginosa, Helicobacter pylori and Klebsiella were likely collected for screening purposes. Third, al- pneumonia [16, 40–42]. A possible explanation is that though the analyses were restricted to hospitals that older patients are more likely to be colonised with drug- continuously participated in ARS between 2012 and resistant pathogens due to more frequent exposure to 2017, it cannot ruled out that changes in hospital struc- antibiotics throughout their lives, thereby promoting the tures and case mix might have biased the longitudinal selection of drug-resistant bacteria as described for en- observations results. To account for these limitations the terococci [43]. In addition, in comparison to younger pa- key finding of increasing VREF proportion and different tients elderlypatientsarelikelytohavemorecomorbidities regional patterns were confirmed by sensitivity analyses and are more likely to reside in nursing homes or other and regression analyses assessing the interaction be- healthcare facilities, both factors that have been shown to tween region and year which underlines the robustness be associated with increased antibiotic resistance [44]. of the results presented in this study. Since nosocomial bloodstream infections are of particu- lar public health relevance and are often associated with Conclusion worse outcomes than other infection types [45–48], VREF Proportions of vancomycin resistance in clinical E. proportions were analysed in clinical blood samples and faecium isolates from German hospitals are increasing other specimen. Blood samples do not show higher VREF underlining the growing significance of E. faecium infec- proportions compared with urine samples, wound mater- tions for public health. VREF proportions differ consid- ial and swabs. Interestingly, it has been shown that erable among German regions with a particular focus of Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 10 of 11 high vancomycin resistance in Southwest and Southeast Diseases, Unit 13: Nosocomial Pathogens and Antibiotic Resistances, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany. Germany. Continued surveillance and implementation of effective infection prevention and control measures ac- Received: 13 June 2019 Accepted: 9 August 2019 counting for local resistance differences are needed to reduce the spread of vancomycin-resistant E. faecium in German hospitals. References 1. Fisher K, Phillips C. The ecology, epidemiology and virulence of Enterococcus. 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Lee T, et al. Antimicrobial-resistant CC17 Enterococcus faecium: the past, the the interaction between region and year of sampling. (DOCX 18 kb) present and the future. J Glob Antimicrob Resist. 2019;16:36–47. 6. Lebreton F, et al. Emergence of epidemic multidrug-resistant Enterococcus faecium from animal and commensal strains. MBio. 2013;4(4). Abbreviations 7. Liese J, et al. Expansion of Vancomycin-Resistant Enterococcus faecium in an AMR: Antimicrobial Resistance; ARS: Antimicrobial Resistance Surveillance; Academic Tertiary Hospital in Southwest Germany: a Large-Scale Whole-Genome- CI: Confidence intervals; CLSI: Clinical & Laboratory Standards Institute; EARS- Based Outbreak Investigation. Antimicrob Agents Chemother. 2019;63(5). Net: European Antimicrobial Resistance Surveillance Network; 8. O'Driscoll T, Crank CW. 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Lancet We thank all the laboratories and hospitals for contributing data to this Infect Dis. 2018;18(3):318–27. analysis. We thank our colleagues at the Robert Koch Institute for their input 12. Control, E.C.f.D.P.a., Surveillance of antimicrobial resistance in Europe – Annual during this study, namely Angelina Taylor and Hans-Peter Blank. report of the European Antimicrobial Resistance Surveillance Network (EARS- Net) 2017,in Stockholm: ECDC. 2018. Authors’ contributions 13. Remschmidt C, et al. Continuous increase of vancomycin resistance in RM and AR were responsible for conceptualisation of the study and enterococci causing nosocomial infections in Germany - 10 years of formulate the research goals and aims. RM, NW, UK, AR developed the surveillance. Antimicrob Resist Infect Control. 2018;7:54. methodology and models. RM, NW, IN worked on the data curation. RM and 14. Noll I, et al. Antimicrobial resistance in Germany. 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Huang SS, et al. Improving the assessment of vancomycin-resistant Aggregated ARS data are available online (https://ars.rki.de). All raw data can enterococci by routine screening. J Infect Dis. 2007;195(3):339–46. be provided on reasonable request. 18. Team, R.C., R: A language and environment for statistical computing. R Foundation for Statistical Computing. Available online at https://www.R- Ethics approval and consent to participate project.org/.2018. The study only includes anonymised routine surveillance data. Ethical 19. Rao, J.N.K. and A. Scott, On Chi-squared Tests For Multiway Contigency Tables approval for analysis of such surveillance data is not required according to with Proportions Estimated From Survey Data. Vol. 12. 1984. the Medical Association’s professional code of conduct. 20. Datenlieferung gem. § 21 KHEntgG. 2019 [cited 2019 March 15th 2019]; Available from: https://www.g-drg.de/Datenlieferung_gem._21_KHEntgG. Consent for publication 21. Prematunge C, et al. VRE and VSE bacteremia outcomes in the era of All authors read and approved the final manuscript and gave consent for effective VRE therapy: a systematic review and meta-analysis. Infect Control publication. Hosp Epidemiol. 2016;37(1):26–35. 22. Linden PK, et al. Differences in outcomes for patients with bacteremia due Competing interests to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. The authors declare that they have no competing interests. faecium. Clin Infect Dis. 1996;22(4):663–70. 23. Garbutt JM, et al. Association between resistance to vancomycin and death in Author details cases of Enterococcus faecium bacteremia. Clin Infect Dis. 2000;30(3):466–72. Robert Koch Institute, Department 3: Infectious Disease Epidemiology, Unit 24. Cassini A, et al. Attributable deaths and disability-adjusted life-years 37: Healthcare-associated Infections, Surveillance of Antibiotic Resistance and caused by infections with antibiotic-resistant bacteria in the EU and the Consumption, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany. European economic area in 2015: a population-level modelling analysis. Robert Koch Institute, Department 3: Infectious Disease Epidemiology, Unit Lancet Infect Dis. 2019;19(1):56–66. 34: HIV/AIDS, STI and Blood-borne Infections, Robert Koch Institute, Nordufer 25. Behnke M, et al. The prevalence of nosocomial infection and antibiotic use in 20, 13353 Berlin, Germany. Robert Koch Institute, Department 1: Infectious German hospitals. Dtsch Arztebl Int. 2017;114(50):851–7. Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 11 of 11 26. Infektionsprävention, K.f.K.u., Hygienemaßnahmen zur Prävention der Infektion durch Enterokokken mit speziellen Antibiotikaresistenzen. Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz, 2018. 61(10): p. 1310–1361. 27. Buetti N, et al. Emergence of vancomycin-resistant enterococci in Switzerland: a nation-wide survey. Antimicrobial Resistance & Infection Control. 2019;8(1):16. 28. Leong KWC, et al. Emergence of vancomycin-resistant Enterococcus faecium at an Australian hospital: a whole genome sequencing analysis. Sci Rep. 2018;8(1):6274. 29. Canada, P.H.A.o., Canadian Antimicrobial Resistance - 2017 Report,in CANADIAN ANTIMICROBIAL RESISTANCE SURVEILLANCE SYSTEM. 2018, Public Health Agency of Canada Ottawa, ON K1A 0K9. 30. Canada, P.H.A.o., Canadian Antimicrobial Resistance Surveillance System - Update 2018, in Canadian Antimicrobial Resistance Surveillance System. 2018, Public Health Agency of Canada: Ottawa, Canada. 31. Batzing-Feigenbaum J, et al. Outpatient Antibiotic Prescription. Dtsch Arztebl Int. 2016;113(26):454–9. 32. Forstner C, et al. 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Indian J Med Microbiol. 2016;34(1):38–45. 38. Lucas GM, et al. Vancomycin-resistant and vancomycin-susceptible enterococcal bacteremia: comparison of clinical features and outcomes. Clin Infect Dis. 1998;26(5):1127–33. 39. Monteserin N, Larson E. Temporal trends and risk factors for healthcare-associated vancomycin-resistant enterococci in adults. J Hosp Infect. 2016;94(3):236–41. 40. Adam HJ, et al. Comparison of pathogens and their antimicrobial resistance patterns in paediatric, adult and elderly patients in Canadian hospitals. J Antimicrob Chemother. 2013;68(Suppl 1):i31–7. 41. Ji Z, et al. The Association of age and Antibiotic Resistance of helicobacter pylori: a study in Jiaxing City, Zhejiang Province, China. Medicine (Baltimore). 2016;95(8):e2831. 42. Garcia A, Delorme T, Nasr P. Patient age as a factor of antibiotic resistance in methicillin-resistant Staphylococcus aureus. J Med Microbiol. 2017;66(12):1782–9. 43. Karki S, et al. Prevalence and risk factors for VRE colonisation in a tertiary hospital in Melbourne, Australia: a cross sectional study. Antimicrob Resist Infect Control. 2012;1(1):31. 44. Laudisio A, et al. The burden of comorbidity is associated with antibiotic resistance among institutionalized elderly with urinary infection: a retrospective cohort study in a single Italian nursing home between 2009 and 2014. Microb Drug Resist. 2017;23(4):500–6. 45. Koch AM, et al. Mortality related to hospital-associated infections in a tertiary hospital; repeated cross-sectional studies between 2004-2011. Antimicrob Resist Infect Control. 2015;4:57. 46. Goto M, Al-Hasan MN. Overall burden of bloodstream infection and nosocomial bloodstream infection in North America and Europe. Clin Microbiol Infect. 2013;19(6):501–9. 47. Klevens RM, et al. Estimating health care-associated infections and deaths in U.S. hospitals, 2002. Public Health Rep. 2007;122(2):160–6. 48. Alon D, et al. Predictors and outcomes of infection-related hospital admissions of heart failure patients. PLoS One. 2013;8(8):e72476. 49. Kramer TS, et al. 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. Antimicrob Resist Infect Control. 2018;7:133. 50. Noll I, et al. Antibiotic consumption and antimicrobial resistance in human and veterinary medicine : an overview of established national surveillance systems in Germany. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2018;61(5):522–32. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antimicrobial Resistance & Infection Control Springer Journals

The rise in vancomycin-resistant Enterococcus faecium in Germany: data from the German Antimicrobial Resistance Surveillance (ARS)

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Biomedicine; Medical Microbiology; Drug Resistance; Infectious Diseases
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Abstract

Background: Due to limited therapeutic options, vancomycin-resistant Enterococcus faecium (VREF) is of great clinical significance. Recently, rising proportions of vancomycin resistance in enterococcal infections have been reported worldwide. This study aims to describe current epidemiological trends of VREF in German hospitals and to identify factors that are associated with an increased likelihood of vancomycin resistance in clinical E. faecium isolates. Methods: 2012 to 2017 data from routine vancomycin susceptibility testing of 35,906 clinical E. faecium isolates from 148 hospitals were analysed using data from the German Antimicrobial Resistance Surveillance System. Descriptive statistical analyses and uni- and multivariable regression analyses were performed to investigate the impact of variables, such as year of sampling, age and region, on vancomycin resistance in clinical E. faecium isolates. Results: From 2014 onwards the proportions of clinical E. faecium isolates exhibiting resistance to vancomycin increased from 11.2% (95% confidence interval [CI] 9.4–13.3%) to 26.1% (95% CI 23.1–29.4%) in 2017. The rise of VREF proportions is primarily observed in the southern regions of Germany, whereas northern regions do not show a major increase. In the Southwest and Southeast, VREF proportions increased from 10.8% (95% CI 6.9–16.5%) and 3.8% (95% CI 3.0–11.5%) in 2014 to 36.7% (95% CI 32.9–40.8%) and 36.8% (95% CI 29.2–44.7%) in 2017, respectively. VREF proportions were considerably higher in isolates from patients aged 40–59 years compared to younger patients. Further regression analyses show that in relation to secondary care hospitals, E. faecium samples collected in specialist care hospitals and prevention and rehabilitation care centres are more likely to be vancomycin-resistant (odds ratios: 2.4 [95% CI 1.2–4.6] and 2.4 [95% CI 1.9–3.0], respectively). No differences in VREF proportions were found between female and male patients as well as between different clinical specimens. Conclusion: The proportion of VREF is increasing in German hospitals, particularly in southern regions in Germany. Increased efforts in infection control and antibiotic stewardship activities accounting for local resistance patterns are necessary to combat the spread of VREF in Germany. Keywords: Enterococcus faecium, Vancomycin resistance, Antimicrobial resistance, Surveillance, Epidemiology, ARS * Correspondence: MarkwartR@rki.de Robert Koch Institute, Department 3: Infectious Disease Epidemiology, Unit 37: Healthcare-associated Infections, Surveillance of Antibiotic Resistance and Consumption, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany Full list of author information is available at the end of the article © The Author(s). 2019 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. Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 2 of 11 Background available data from the German hospital payment system Enterococcus faecium is a Gram-positive, facultative an- based on fee-for-case on diagnosis related groups. aerobic, catalase-negative bacterium that commonly in- habits the intestinal tracts of healthy humans [1]. In Methods addition to its role as a commensal in humans, E. fae- Study design and the German antimicrobial resistance cium has been described as an emerging pathogen that surveillance database causes a significant number of nosocomial infections, in- In order to investigate the epidemiology of vancomycin- cluding infections of the bloodstream, urinary tract, skin resistant E. faecium, a retrospective observational study and endocardium [2]. Data from the United States [3] was conducted analysing data from the Antimicrobial and Germany [4] show that E. faecium is among the Resistance Surveillance (ARS) database from 2012 to most frequent causes of healthcare-associated infections 2017. ARS is the national surveillance system for anti- with considerable potential for healthcare-acquired out- microbial resistance in Germany established by the breaks. Evidence indicates that E. faecium strains that Robert Koch-Institute in 2008 [14]. Voluntarily partici- cause nosocomial infections are different from strains that pating microbiology laboratories submit results from colonize healthy humans highlighting the role of health- routine pathogen identifications and antimicrobial sus- care centres in the spread of E. faecium infections [5–7]. ceptibility testing. In addition to microbiological results, The clinical relevance of E. faecium is directly linked to participating laboratories provide various pseudonymised its intrinsically low susceptibility to a broad spectrum of information including clinical specimen material (e. g. antimicrobial agents, including low-dose penicillin and blood, urine and swabs), patient data (age, gender), hos- ampicillin, aminoglycosides, sulphonamides and cephalos- pital type (e. g. secondary or tertiary care hospitals) and porines [8, 9]. After its first detection in the late 1980’s, geographical location of patient care [15, 16]. As of vancomycin resistance in Enterococci (VRE), including E. 2017, more than 50 laboratories contribute to the ARS faecium, started to emerge in hospitals in the United database, which includes data from more than 600 out States eventually spreading to Europe and worldwide lim- of a total of 1924 hospitals in Germany. Since ARS par- iting therapeutic options against enterococcal infections ticipation is based on laboratories rather than active [10]. Due to its clinical significance, the World Health participation of hospitals, a major selection bias towards Organization (WHO) assigned vancomycin-resistant E. certain hospitals (e.g. only those with implemented anti- faecium (VREF) as a high priority pathogen on its global biotic stewardship programs) can be excluded. All partici- priority list of antibiotic-resistant bacteria [11]. pating laboratories possess accreditation for performing According to 2017 data from the European Antimicro- microbiological analyses. Data transmitted to the ARS bial Resistance Surveillance Network (EARS-Network), database are routinely validated and checked for plausibil- the mean proportion of vancomycin-resistant E. faecium ity, completeness and consistency. ARS data are used to in blood and cerebrospinal fluid isolates is 14.9% (95% CI generate reference resistance data and feedback reports to 14–16) in participating European countries and 16.5% support hospitals in their antibiotic stewardship programs. (95% CI 15–18) in Germany [12]. Findings from the ARS resistance data of common pathogens are also avail- German national nosocomial infection surveillance system able to the public (https://ars.rki.de/). (Krankenhaus-Infektions-Surveillance-System,acrony- mized as “KISS”) show continuously increasing rates of Selection of E. faecium isolates vancomycin-resistant Enterococci from nosocomial blood- The participation of individual laboratories in ARS can stream and urinary tract infections acquired in intensive change over time which can potentially alter the set of care units (ICU) between 2007 and 2016 [13]. hospitals that provide clinical samples to ARS. In order Despite the data available for Germany, a comprehen- to avoid systematic changes in the case mix, only E. sive picture of the epidemiological situation of vanco- faecium isolates from hospitals with continuous yearly mycin-resistant E. faecium in German hospitals is participation in ARS between 2012 and 2017 were in- lacking. In particular, it is not known whether distinct cluded for the main analyses. To avoid biases through patient characteristics (e.g. gender, age, site of infection) inclusion of multiple E. faecium isolates from one pa- or other factors (e.g. hospital care type) are associated tient during one disease episode, only the patient’s first with an increased risk of VREF. Therefore, this study isolate for each quarter of the year was included. How- aims to analyse trends and risk factors of vancomycin re- ever, since vancomycin-resistant enterococci are known sistance of Enterococcus faecium in Germany using data to persist in the human gut for several months [17], it from the German national Antimicrobial Resistance cannot be fully excluded that a specific VREF strain has Surveillance (ARS) System. Furthermore, the study ana- been counted repeatedly from the same patient. Further- lyses trends in the number of infections or colonisations more, isolates were excluded if they were likely derived with VREF diagnosed in German hospitals using publicly for screening purposes (labelled as screening, anal swabs Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 3 of 11 and stool samples). E. faecium isolates without vanco- variables from the univariable analyses. For the multivar- mycin susceptibility testing were excluded. iable analysis assessing the interaction between region and year of sampling, the year was treated as a continu- Outcomes and co-variables ous predictor and the interaction between region and The primary outcome is the proportion of vancomycin- year was included. The same variables as in the model resistant E. faecium isolates among all E. faecium isolates without interaction were otherwise included. expressed as percentages (%). An E. faecium isolate was defined vancomycin resistant if it was tested resistant Sensitivity analyses against vancomycin in antimicrobial susceptibility testing It is important to note that some laboratories do not according to the applied standard, i. e. standards by routinely differentiate Enterococcus isolates into species European Committee on Antimicrobial Susceptibility level. Systematic bias in VREF proportions therefore Testing (EUCAST) or Clinical and Laboratory Standards cannot be excluded, such as those introduced by species Institute (CLSI). differentiation only in selected Enterococcus samples. To Clinical specimens were grouped by sample site into address this issue, time trend analyses of VREF propor- urine (urine samples), blood (blood cultures), swabs tions were analysed for E. faecium isolates identified in (swabs from eye, nose, throat, ear, tongue, urogenital laboratories that consistently differentiate more than sites as well as intraoperative swabs and other/unspeci- 95% of all Enterococcus isolates into species level (n = fied swabs), wound (swabs from wounds and abscesses) 8492). In addition, sensitivity analyses were performed and other specimens (e. g. punctures, respiratory mate- that comprised E. faecium isolates (n = 89,450) from all rials, unspecified). Patient age was grouped into age hospitals including hospitals that did not continuously categories (0–19, 20–39, 40–59, 60–79 and, ≥80 years). participated in ARS between 2012 and 2017. Patient gender was classified into female and male. The geographical origin of the isolates was grouped into five major regions based on the distribution of hospitals: Northeast (federal states of Mecklenburg-West Pomer- Data from the hospital payment system based on fee-for- ania, Brandenburg, Berlin, Saxony-Anhalt), Northwest case on diagnosis related groups (federal states of Lower Saxony, Bremen, Hamburg, In order to estimate the number of diagnosed Schleswig-Holstein), West (North Rhine-Westphalia), infections or colonisations with VREF between 2013 Southwest (Hesse, Rhineland-Palatinate, Saarland, and 2017, publicly available data from the hospital Baden-Wuerttemberg) and Southeast (Bavaria, Saxony, payment system based on fee-for-case on diagnosis re- Thuringia). Hospital care type was categorised into sec- lated groups (DRG) were analysed. German hospitals ondary care, tertiary care, specialist care, and prevention receive a fee-for-case on DRG based on diagnoses ac- and rehabilitation care. All variables were considered as cording to the International Statistical Classification of categorical variables for statistical analyses. Diseases and Related Health Problems Version 10 - German Modification (ICD-10-GM). According to §21 Statistical analyses Hospital Reimbursement Act (Krankenhausentgeltge- All statistical analyses were performed using R version setz) aggregated data must be made publicly available 3.5.1 [18]. Estimates of vancomycin resistance propor- for scientific use by the Insitute for Reimbursement in tions are expressed as percentages with 95% confidence the Hospital (Institut für das Entgeltsystem im intervals (95% CI) accounting for clustering on hospital Krankenhaus, InEK) [20]. The dataset contains diagno- level using routines in the survey package (version 3.35). sis data from approximately 1500 out of 1924 German Proportions of vancomycin-resistant E. faecium isolates hospitals. The diagnosis code U80.30 (E. faecium with between female and male were compared using the resistance to glycopeptide antibiotics, available since Pearson χ test with the Rao-Scott second-order correc- 2013) was used to identify cases of E. faecium with re- tion [19] for different age groups. The resulting p-values sistance to glycopeptide antibiotics. Importantly, a diag- were adjusted for multiple testing using a Bonferroni nosis code for E. faecium with resistance to glycopeptide correction. Risk factors for vancomycin resistance were antibiotics has been implemented since the beginning of analysed using univariable and multivariable logistic re- the DRG system in Germany in 2004 (U.80.3!: E. faecium gression models accounting for clustering at hospital with resistance to glycopeptide antibiotics, oxazolidinone, level as implemented in the survey package. For univari- streptogramine, or high-level-aminoglycoside-resistance). able analyses the following predictors for vancomycin re- Therefore, the diagnosis of glycopeptide-resistant E. fae- sistance were considered: year of sampling, gender, age cium is well established in German hospitals and a report- group, specimen (sample site), region and hospital care ing bias through introduction of the fee-for-case on DRG type. The multivariable analysis model included all can be excluded. Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 4 of 11 Results Table 1 Baseline characteristics of clinical E. faecium isolates Baseline characteristics N 35,906 total In total 35,906 E. faecium isolates from 33,643 patients Year of sampling and 148 continuously participating hospitals were in- 2012 (n, %) 4139 11.53 cluded in the study. The baseline characteristics are out- 2013 (n, %) 5452 15.18 lined in Table 1. Samples predominantly originated from 2014 (n, %) 6326 17.62 elderly patients (median: 74 years), although isolates 2015 (n, %) 6932 19.31 from younger age categories were also available. With a female / male ratio of 1.16 patients’ gender was nearly 2016 (n, %) 6806 18.96 equally distributed in the sample set. The majority of 2017 (n, %) 6251 17.41 hospitals and isolates originated from Western and Gender of patient Southwestern regions in Germany, regions where the Female (n, %) 17,892 49.83 most populated federal states are located, including Male (n, %) 15,370 42.81 North Rhine Westphalia (~ 18 m inhabitants) and NA (n, %) 2644 7.36 Baden-Wuerttemberg (~ 11 m). The largest number of E. faecium isolates was provided by secondary care hospi- Sex ratio (f/m) 1.16 tals (n = 31,182) followed by tertiary care hospitals (n = Age of patient 3.283), and specialist care hospitals (1109). The most 0–19 yrs. (n, %) 527 1.47 common clinical sources of E. faecium were urine sam- 20–39 yrs. (n, %) 1183 3.29 ples (n = 16,261), swabs (n = 5687) and wound material 40–59 yrs. (n, %) 5547 15.45 (n = 5550). It is worth mentioning that the ratio of the 60–79 yrs. (n, %) 17,785 49.53 total numbers of clinical E. faecium and E. faecalis iso- lates recorded in ARS did not change between 2012 and 80+ yrs. (n, %) 10,864 30.26 2017 (Additional file 1: Table S1). Compared to other re- Age (median, IQR) 74.0 63.0–81.0 gions in Germany, in the West and Southwest slightly Specimen (sampling site) higher proportions of E. faecium were observed. Blood (n, %) 3011 8.39 Urine (n, %) 16,261 45.29 Swab (n, %) 5687 15.84 Temporal trend and regional analyses The proportion of E. faecium isolates with resistance Wound (n, %) 5550 15.46 against vancomycin decreased from 15.2% (95% CI 12.0– Other (n, %) 5280 14.71 19.2%) in 2012 to 11.2% (95% CI 9.4–13.4%) in 2014 NA (n, %) 117 0.33 (Fig. 1). However, from 2014 onwards, the percentage of Region vancomycin-resistant clinical E. faecium isolates con- Southwest (n, %) 11,868 33.05 tinuously increased reaching 26.1% (95% CI 23.1–29.4%) Southeast (n, %) 395 1.10 in 2017, more than twice that observed 2014. This find- ing is supported by univariable and multivariable ana- West (n, %) 19,508 54.33 lyses, which show that isolates collected after 2014 were Northwest (n, %) 2400 6.68 increasingly more likely to be tested resistant against Northeast (n, %) 1594 4.44 vancomycin than isolates in 2014 (Table 2). A similar NA (n, %) 141 0.39 rise of VREF proportions between 2014 and 2017 was Hospital care type found in sensitivity analyses including E. faecium isolates Secondary care (n, %) 31,182 86.84 that (i) were identified in laboratories that consistently differentiate more than 95% of all Enterococcus isolates Tertiary care (n, %) 3283 9.14 into species level (Additional file 2: Figure S1A) or (ii) Specialist care 1109 3.09 were provided by all hospitals also including hospitals Prevention and rehabilitation care (n, %) 158 0.44 that did not continuously participated in ARS between Other (n, %) 33 0.09 2012 and 2017 (Additional file 2: Figure S1B). Since NA (n, %) 141 0.39 bloodstream infections are of particular clinical interest, Hospitals (n) 148 it is noteworthy that in the included hospitals the num- ber of VREF blood isolates increased from 57 to 120 be- Patients (n) 33,643 tween 2014 and 2017 accompanied by a marked rise in VREF proportions from 11.0% (95% CI 7.2–16.6) in 2014 to 21.1% (95% CI 17.2–25.7%) in 2017. Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 5 of 11 analysed for different age categories. The results displayed in Fig. 3 show that E. faecium isolates from children and adolescents (0–19 years) exhibit markedly lower vancomycin resistance proportions (7.6% [95% CI 5.4–10.6%]) than young adults (20–39 years) (15.4% [95% CI 11.1–21.0%]) and older age categories. Multivar- iable analyses reveal that E. faecium samples from patient age categories of 0–19 years and 20–39 years are less likely to be vancomycin-resistant than samples from patients with an age between 40 and 59 years (Table 2). Interestingly, the likelihood of vancomycin resistance Fig. 1 Time trend of vancomycin-resistant E. faecium. Time trend of tends to decrease in age groups above 60 years, although vancomycin-resistant E. faecium as a proportion (%) of all E. faecium the differences are not statistical significant. Further ana- isolates with corresponding 95% confidence intervals lyses of all age categories combined do not indicate that female and male patients differ in VREF proportions (16.5 Regional analyses of E. faecium isolates collected between [95% CI 14.2–19.1%] vs. 16.9 [95% CI 14.1–20.1%]), re- 2012 and 2017 reveal that Germany shows a strong north- spectively. However, male young adults (20–39 years) have south disparity in VREF proportions. VREF proportions are higher proportions of vancomycin resistance than their fe- noticeably lower in the Northwest (10.8% [95% CI 6.7– male counterparts (19.8 vs. 13.6%, adjusted p-value: 14.8]) and Northeast (10.0% [95% CI 6.7–14.8]) compared 0.013), while no differences between both genders were to the Southwest where 20.7% (95% CI 17.1–24.9) of all iso- observed in older age categories (Fig. 3). lates were tested resistant against vancomycin (Fig. 2A). Uni- and multivariable regression analyses confirm that E. Clinical specimen faecium isolates from the Northeastand Northwestregions Since the frequency of drug-resistance pathogens can are less likely to be tested vancomycin resistant than iso- differ between infection sites, VREF proportions were lates from the Southwest (Table 2). Importantly, temporal analysed in different clinical specimens, including blood dynamics of VREF proportions differ between the analysed cultures, urine samples, wound material and swabs. No regions (Fig. 2B). While in the Southwest and Southeast a major differences in vancomycin resistance proportions pronounced increase of VREF proportions was observed were found between the analysed sampling sites (blood: between 2014 and 2017, the northern regions do not show 14.9% [95% CI 11.3–19.6%], urine: 17.2% [95% CI 14.6– ariseof VREFduringthatsameperiod. In theSouthwest 20.2%], wound: 16.5% [95% CI 13.6–19.9%], swabs: and Southeast, VREF proportions increased from 10.8% 16.1% [95% CI 13.5–19.0%], other: 15.5% [95% CI 12.2– (95% CI 6.9–16.5%) and 3.8% (95% CI 3.0–11.5%) in 2014 19.5%]). Therefore, no associations between clinical spe- to 36.7% (95% CI 32.9–40.8%) and 36.8% (95% CI 29.2– cimen and the likelihood of VREF resistance were found 44.7%) in 2017, respectively. This finding is supported by a in uni- and multivariable regression analyses (Table 2). multivariable analysis controlling for interaction between year and region (Additional file 3: Table S2). It is important Hospital care type to note that southern regions feature considerably higher To study vancomycin resistance patterns in different VREF proportions than northern regions only from 2016 hospital care types, VREF proportions were analysed for onwards. secondary care, tertiary care and specialist care hospitals The absolute number of VREF isolates in the ARS data- as well as prevention and rehabilitation care centres. E. base continuously increased from 631 to 1634 between faecium isolates from secondary care hospitals exhibited 2012 and 2017, suggesting that numbers of infections with lower proportions of vancomycin resistance (15.2% [95% vancomycin-resistant E. faecium in German hospitals have CI 12.8–18.0%]) than isolates from tertiary care hospitals been annually increasing. This trend is supported by our (22.8% [95% CI 10.0–44.1%]) and specialist care hospi- analysis of publicly available data from the hospital payment tals (31.2% [95% CI 16.9–50.4%]) (Fig. 4). Univariable system based on fee-for-case on DRGs [20]thatshowa analyses show that E. faecium samples from tertiary hos- four-fold increase of diagnoses of glycopeptide-resistant E. pital care and specialist hospital care are more likely to faecium infections or colonisations in German hospitals be- exhibit vancomycin resistance than isolates from second- tween 2013 and 2017 (Table 3). ary care (Table 2). However, in multivariable analyses, no statistical evidence was found that VREF proportions Age and gender differ between secondary and tertiary care hospitals (p = In order to study the influence of the patient age on 0.191). Interestingly, remarkably high proportions of vancomycin resistance patterns, VREF proportions were VREF were observed in isolates from patients treated in Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 6 of 11 Table 2 Uni- and multivariable analyses of factors associated with vancomycin resistance in clinical E. faecium isolates univariable analysis multivariable analysis OR (95% CI) p-value OR (95% CI) p-value Year of sampling 2012 1.42 (1.12–1.80) 0.004 1.58 (1.16–2.14) 0.004 2013 1.26 (1.01–1.58) 0.044 1.27 (0.99–1.63) 0.061 2014 1 –– 1 –– 2015 1.22 (0.98–1.51) 0.072 1.24 (0.99–1.55) 0.060 2016 1.81 (1.46–2.23) < 0.001 1.80 (1.45–2.25) < 0.001 2017 2.79 (2.26–3.46) < 0.001 2.74 (2.22–3.39) < 0.001 Region Southwest 1 –– 1 –– Southeast 0.71 (0.53–0.95) 0.022 0.74 (0.54–1.01) 0.057 West 0.68 (0.46–1.00) 0.051 0.82 (0.55–1.20) 0.303 Northwest 0.46 (0.35–0.61) < 0.001 0.51 (0.36–0.72) < 0.001 Northeast 0.43 (0.27–0.67) < 0.001 0.47 (0.31–0.71) 0.001 Gender Female 1 –– 1 –– Male 0.97 (0.90–1.06) 0.533 1.03 (0.94–1.11) 0.554 Age 0–19 years 0.38 (0.26–0.58) < 0.001 0.33 (0.23–0.48) < 0.001 20–39 years 0.85 (0.71–1.01) 0.071 0.84 (0.71–0.99) 0.043 40–59 years 1 –– 1 –– 60–79 years 0.96 (0.82–1.12) 0.626 0.94 (0.83–1.06) 0.324 80+ years 0.86 (0.67–1.10) 0.234 0.83 (0.69–1.01) 0.062 Specimen (sampling site) Blood 1 –– 1 –– Urine 1.18 (0.92–1.52) 0.20276 1.22 (0.94–1.48) 0.134 Swab 1.09 (0.78–1.51) 0.62974 0.93 (0.74–1.17) 0.547 Wound 1.12 (0.93–1.36) 0.22761 1.08 (0.90–1.29) 0.426 Other 1.04 (0.88–1.23) 0.65102 1.01 (0.85–1.19) 0.952 Hospital care type Secondary care 1 –– 1 –– Tertiary care 1.65 (1.01–2.69) 0.047 1.33 (0.87–2.04) 0.191 Specialist care 2.53 (1.15–5.56) 0.023 2.37 (1.22–4.60) 0.012 Prevention and rehabilitation care 3.23 (2.42–4.33) < 0.001 2.39 (1.91–2.98) < 0.001 prevention and rehabilitation care centres, where more 2014 onwards the proportions of clinical E. faecium iso- than one third of all E. faecium isolates are found to be lates exhibiting resistance to vancomycin increased from resistant to vancomycin (36.7% [CI 95% 26.8–47.9%]. In 11 to 26% in 2017. Regional analyses reveal that, in par- line with that, the multivariable regression analysis iden- ticular, southern regions of Germany have been affected tified prevention and rehabilitation care centres as an in- by a pronounced rise of VREF proportions, whereas dependent risk factor of increased likelihood of VREF northern regions do not feature substantial increases of resistance in relation to secondary care hospitals. VREF. Middle aged adults (40–59 years) exhibit mark- edly higher VREF proportions than children and adoles- Discussion cents (0–20 years) and young adults (20–39 years). By analysing data from the German Antibiotic Resistance While VREF proportions do not differ between female Surveillance system the present study shows that from and male patients in the whole dataset, subgroup Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 7 of 11 Fig. 2 Vancomycin-resistant E. faecium stratified into geographical region. Vancomycin-resistant E. faecium as a proportion (%) of all E. faecium isolates with corresponding 95% confidence intervals by German region (2012–2017 data) (a) and time trend by German region (b) analyses show that E. faecium isolates from young adult men have higher vancomycin resistance proportions than their female counterparts. Rising proportions of vancomycin-resistant E. faecium have also been observed in many other European coun- tries between 2014 and 2017 as reported by EARS-Net, Table 3 Analyses of diagnoses of glycopeptide-resitant E. faecium in German hospitals Year Number of diagnoses 2013 7074 2014 8488 Fig. 3 Vancomycin-resistant E. faecium stratified into age and gender. Vancomycin-resistant E. faecium (VREF) as a proportion (%) 2015 11,697 of all E. faecium isolates with corresponding 95% confidence 2016 19,747 intervals from male and female patients stratified into age categories. Proportions of VREF between female and male were 2017 28,907 compared using the Pearson χ test with the Rao-Scott second- The number of diagnoses of infections or colonisations with glycopeptide- order correction in different age groups. The resulting p-values were resistant E. faecium between 2013 and 2017 were analysed using publicly adjusted for multiple testing using a Bonferroni correction. P-values available data from the hospital payment system based on fee-for-case on diagnosis related groups. The dataset contains diagnosis data of ~ 1500 out of ≤0.05 are indicated with an “*”. Adjusted p-Values (female vs. male a total of 1924 existing (2017) German hospitals. The diagnoses code U80.30! patients): 0–19 yrs.: p = 0.768, 20–39 yrs.: p = 0.013, 40–59 yrs.: p = 1, according ICD-10-GM was used to identify cases of E. faecium with resistance 60–79 yrs.: p = 1, 80+ yrs.: p = 1 to glycopeptide antibiotics Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 8 of 11 information about the development of VRE(F) screening habits are available. However, in Germany, the Commission for Hospital Hygiene and Infection Prevention only recom- mends a VRE(F) screening for risk populations (e.g. patients with severe comorbidities and haematological diseases) ra- ther than a general screening for all hospitalized patients [26]. Rising numbers of infections with vancomycin-resist- ant enterococci and/or E. faecium have been also reported for other countries around the world, including Switzerland [27], Australia [28]and Canada [29, 30]. Interestingly, our data show that the ratio of clinical E. faecium and E. faecalis isolates recorded in ARS is higher in West and South Germany suggesting a more prominent role of E. faecium in enterococcal infections in these regions. Analyses of resistance trends between different geo- Fig. 4 Vancomycin-resistant E. faecium stratified into hospital care graphical regions in Germany between 2012 and 2017 type. Vancomycin-resistant E. faecium as a proportion (%) of all E. reveal that VREF proportions significantly vary within faecium isolates with corresponding 95% confidence intervals by Germany exhibiting a pronounced north-south disparity. hospital care type While VREF proportions remained stable in northern re- gions, a marked increase of VREF proportions was ob- including neighbouring countries to Germanys, such as served in hospitals in the Southwest. From 2016 onwards Denmark, Belgium, Poland and Czech Republic [12]. VREF proportions in the South were significantly higher Only two countries, Ireland and Portugal, in the EU and than in the North. VREF strain characterization based on European Economic Area (EU/EEA) show a decreasing whole genome sequencing performed at the National Ref- trend of VREF proportions between 2014 and 2017 erence Centre for Enterococci for all bloodstream isolates (Portugal 20.1 to 7.2%, Ireland 45.1 to 38.2%). In EARS- between 2015 and 2018 (n = 448) revealed prevalence of Net AMR data are exclusively collected from invasive certain strain types associated to specific regions. Whereas isolates. In line with the findings from EARS-Net our ST117/CT71 was mainly spread throughout Germany and analyses of VREF proportions in blood isolates also show found in at least nine Federal States, isolates of ST117/ increasing trends between 2014 and 2017 in German CT469, ST80/CT1065 and ST80/CT1066 were mainly hospitals. prevalent in Southwestern Germany ([7]and Jennifer K. Since infections with VREF are associated with worse Bender und Guido Werner, unpublished data). Therefore, clinical outcomes compared to infections with vanco- the increase in VREF rates in certain regions in Germany mycin-sensitive strains [21–23], rising vancomycin re- might be associated with a preferred prevalence of certain sistance is of great clinical concern in the management strain types. of patients with nosocomial E. faecium infections. As a Increasing proportions of enterococci infections with matter of fact, a recent population-level study using data vancomycin-resistant strains in Germany are also ob- from EARS-Net showed that there were about 16,000 served in data from the national Nosocomial infection nosocomial infections with vancomycin-resistant entero- surveillance system (KISS). In contrast to our findings, cocci, which were associated with 1065 attributable KISS identified a belt of states with higher proportions deaths in the EU/EEA in the year 2015, nearly twice as of vancomycin-resistant enterococci infections in the many as 2007 [24]. Current German data show increas- centre of Germany spanning from west to east [13]. The ing trends of nosocomial infections with vancomycin-re- different results to our surveillance system might be ex- sistant Enterococci in German hospitals [13, 25]. These plained by different methodological approaches used in findings are strongly supported by our analyses of pub- the KISS study, such as only inclusion of bloodstream licly available data from German hospitals, which show a and urinary tract infections from ICUs and wound infec- four-fold increase of diagnoses of infections or colonisa- tions from surgical departments. The reasons for the re- tions with glycopeptide-resistant E. faecium between gional differences observed in our study are largely 2013 and 2017 underlining the growing significance of unknown. However, a large representative population- vancomycin-resistant E. faecium in Germany. It is im- based study analysing German antibiotic prescription portant to note that rising numbers of diagnoses of in- data reported higher outpatient antibiotic prescription of fections or colonisations with glycopeptide-resistant E. fluoroquinolones in southwestern regions of Germany faecium may be partly explained by increased screening [31]. The extensive use of fluoroquinolones has been efforts in German hospitals, although no representative shown to be associated with the emergence of vancomycin- Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 9 of 11 resistant enterococci in the hospital setting [32]. This find- vancomycin resistance does not further increase the risk ing underlines the importance of the implementing of in- of in-hospital mortality and infection-attributed hospital terventions that improve outpatient antibiotic prescribing stay in bloodstream infections with E. faecium but is asso- [33]. It is important to note that the analyses of regional re- ciated with increased overall hospital costs [49]. sistance patterns are based on the location of the hospital This study indicates that VREF proportions are higher rather than the residence of the patient. Nevertheless, hos- in specialist care hospitals and prevention and rehabilita- pital density in Germany is relatively high and it has been tion care centres, a finding that is possibly explained by reported that the majority of patients are treated in hospi- the larger number of patients with comorbidities and tals fewer than 60 km from the patients places of residence other factors (e. g. age) that are associated with acquiring [34]. This suggests that the described regional VREF pro- resistant bacteria. Specialist care hospitals and preven- portions are a true reflection of the acquisition of VREF in tion and rehabilitation care centres have also been iden- the respective regions, irrespective of whether they were ac- tified as risk factors for antimicrobial resistance in quired in the hospital or in the community. Klebsiella pneumoniae in Germany [16]. Very little is known about factors associated with in- creased vancomycin resistance in clinical E. faecium iso- Strengths and limitations lates in Germany. This study did not find any differences This study used data from the ARS database which is in VREF proportions between female and male patients. the largest and most comprehensive surveillance system This finding is also reported in other studies from differ- for antimicrobial resistance in Germany [14, 50]. As of ent regions in the world [35–38]. In contrast, a study 2017, ARS comprised of data from more than 600 par- analysing data from three New York hospitals found that ticipating hospitals across all regions in Germany allow- isolates from female patients have a higher likelihood of ing for detailed analyses of epidemiological trends. To being vancomycin-resistant than samples from men [39]. our knowledge, with more than 35.000 clinical isolates However, that particular study analysed infections with of E. faecium collected from more than 33,000 patients Enterococcus faecalis or Enterococcus faecium. Interest- our study represents the most comprehensive analysis of ingly, we observed that young male adults (20–39 years) recent trends of VREF in German hospitals. However, it exhibit markedly higher proportions of VREF than is important to consider the limitations of this study. young female adults (20% vs. 14%), a finding that has First, participation in ARS is voluntary, and thus, partici- not been described for E. faecium yet. pating laboratories and hospitals are not equally distrib- Since it has been known that different age groups ex- uted resulting in a clustering in certain regions. In hibit different microbial susceptibility proportions, VREF particular, northern regions are under-represented in the resistance patterns were analyzed for different age cat- sample set, while the Western region is overrepresented. egories. Patients older than 40 years exhibit higher VREF Therefore, statistical analyses were used that accounted proportions than children and adolescents (> 15% vs. for clustering effects. Second, since information on 7%). Similar age trends have been reported for other underlying diagnoses is not collected in ARS, it is not bacterial pathogens, including Staphylococcus aureus, possible to differentiate between colonisation and infec- Escherichia coli, Streptococcus pneumoniae, Pseudo- tion. To address this issue, isolates were excluded if they monas aeruginosa, Helicobacter pylori and Klebsiella were likely collected for screening purposes. Third, al- pneumonia [16, 40–42]. A possible explanation is that though the analyses were restricted to hospitals that older patients are more likely to be colonised with drug- continuously participated in ARS between 2012 and resistant pathogens due to more frequent exposure to 2017, it cannot ruled out that changes in hospital struc- antibiotics throughout their lives, thereby promoting the tures and case mix might have biased the longitudinal selection of drug-resistant bacteria as described for en- observations results. To account for these limitations the terococci [43]. In addition, in comparison to younger pa- key finding of increasing VREF proportion and different tients elderlypatientsarelikelytohavemorecomorbidities regional patterns were confirmed by sensitivity analyses and are more likely to reside in nursing homes or other and regression analyses assessing the interaction be- healthcare facilities, both factors that have been shown to tween region and year which underlines the robustness be associated with increased antibiotic resistance [44]. of the results presented in this study. Since nosocomial bloodstream infections are of particu- lar public health relevance and are often associated with Conclusion worse outcomes than other infection types [45–48], VREF Proportions of vancomycin resistance in clinical E. proportions were analysed in clinical blood samples and faecium isolates from German hospitals are increasing other specimen. Blood samples do not show higher VREF underlining the growing significance of E. faecium infec- proportions compared with urine samples, wound mater- tions for public health. VREF proportions differ consid- ial and swabs. Interestingly, it has been shown that erable among German regions with a particular focus of Markwart et al. Antimicrobial Resistance and Infection Control (2019) 8:147 Page 10 of 11 high vancomycin resistance in Southwest and Southeast Diseases, Unit 13: Nosocomial Pathogens and Antibiotic Resistances, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany. Germany. Continued surveillance and implementation of effective infection prevention and control measures ac- Received: 13 June 2019 Accepted: 9 August 2019 counting for local resistance differences are needed to reduce the spread of vancomycin-resistant E. faecium in German hospitals. References 1. Fisher K, Phillips C. The ecology, epidemiology and virulence of Enterococcus. 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Lee T, et al. Antimicrobial-resistant CC17 Enterococcus faecium: the past, the the interaction between region and year of sampling. (DOCX 18 kb) present and the future. J Glob Antimicrob Resist. 2019;16:36–47. 6. Lebreton F, et al. Emergence of epidemic multidrug-resistant Enterococcus faecium from animal and commensal strains. MBio. 2013;4(4). Abbreviations 7. Liese J, et al. Expansion of Vancomycin-Resistant Enterococcus faecium in an AMR: Antimicrobial Resistance; ARS: Antimicrobial Resistance Surveillance; Academic Tertiary Hospital in Southwest Germany: a Large-Scale Whole-Genome- CI: Confidence intervals; CLSI: Clinical & Laboratory Standards Institute; EARS- Based Outbreak Investigation. Antimicrob Agents Chemother. 2019;63(5). Net: European Antimicrobial Resistance Surveillance Network; 8. O'Driscoll T, Crank CW. Vancomycin-resistant enterococcal infections: epidemiology, EUCAST: European Committee on Antimicrobial Susceptibility Testing; ICD- clinical manifestations, and optimal management. Infect Drug Resist. 2015;8:217–30. 10-GM: International Statistical Classification of Diseases and Related Health 9. Hollenbeck BL, Rice LB. Intrinsic and acquired resistance mechanisms in Problems Version 10 - German Modification; IQR: interquartile range; enterococcus. Virulence. 2012;3(5):421–33. KISS: Nosocomial Infection Surveillance System; OR: Odds ratio; 10. Werner G, et al. Emergence and spread of vancomycin resistance among VREF: Vancomycin-resistant Enterococcus faecium enterococci in Europe. Euro Surveill. 2008;13(47). 11. Tacconelli E, et al. Discovery, research, and development of new antibiotics: Acknowledgements the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet We thank all the laboratories and hospitals for contributing data to this Infect Dis. 2018;18(3):318–27. analysis. We thank our colleagues at the Robert Koch Institute for their input 12. Control, E.C.f.D.P.a., Surveillance of antimicrobial resistance in Europe – Annual during this study, namely Angelina Taylor and Hans-Peter Blank. report of the European Antimicrobial Resistance Surveillance Network (EARS- Net) 2017,in Stockholm: ECDC. 2018. Authors’ contributions 13. Remschmidt C, et al. Continuous increase of vancomycin resistance in RM and AR were responsible for conceptualisation of the study and enterococci causing nosocomial infections in Germany - 10 years of formulate the research goals and aims. RM, NW, UK, AR developed the surveillance. Antimicrob Resist Infect Control. 2018;7:54. methodology and models. RM, NW, IN worked on the data curation. RM and 14. Noll I, et al. Antimicrobial resistance in Germany. Four years of antimicrobial NW performed the statistical analysis. RM wrote the original draft. NW, IN, UK, resistance surveillance (ARS). Bundesgesundheitsblatt Gesundheitsforschung SH, GW, TE and AR reviewed and commented the draft and gave input on Gesundheitsschutz. 2012;55(11–12):1370–6. editing. All authors read and approved the final manuscript. 15. Schweickert B, et al. MRSA-surveillance in Germany: data from the antibiotic resistance surveillance system (ARS) and the mandatory surveillance of Funding MRSA in blood. Eur J Clin Microbiol Infect Dis. 2012;31(8):1855–65. The analysis was conducted by internal funds of the Robert Koch Institute as 16. Koppe U, et al. Carbapenem non-susceptibility of Klebsiella pneumoniae a Federal Institute within the portfolio of the Ministry of Health. isolates in hospitals from 2011 to 2016, data from the German antimicrobial resistance surveillance (ARS). Antimicrob Resist Infect Control. 2018;7:71. Availability of data and materials 17. 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Published: Aug 28, 2019

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