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Vancomycin-resistant enterococci (VRE) in hospital settings across European borders: a scoping review comparing the epidemiology in the Netherlands and Germany

Vancomycin-resistant enterococci (VRE) in hospital settings across European borders: a scoping... The rising prevalence of vancomycin-resistant enterococci ( VRE) is a matter of concern in hospital settings across Europe without a distinct geographical pattern. In this scoping review, we compared the epidemiology of vancomycin-resistant Enterococcus spp. in hospitals in the Netherlands and Germany, between 1991 and 2022. We searched PubMed and summarized the national antibiotic resistance surveillance data of the two countries. We included 46 studies and summarized national surveillance data from the NethMap in the Netherlands, the National Antimicrobial Resistance Surveillance database in Germany, and the EARS-Net data. In total, 12 studies were con- ducted in hospitals in the Netherlands, 32 were conducted in German hospitals, and an additional two studies were conducted in a cross-border setting. The most significant difference between the two countries was that studies in Germany showed an increasing trend in the prevalence of VRE in hospitals, and no such trend was observed in studies in the Netherlands. Furthermore, in both Dutch and German hospitals, it has been revealed that the molec- ular epidemiology of VREfm has shifted from a predominance of vanA towards vanB over the years. According to national surveillance reports, vancomycin resistance in Enterococcus faecium clinical isolates fluctuates below 1% in Dutch hospitals, whereas it follows an increasing trend in German hospitals (above 20%), as supported by indi- vidual studies. This review demonstrates that VRE is more frequently encountered in German than in Dutch hospitals and discusses the underlying factors for the difference in VRE occurrence in these two neighboring countries by com- paring differences in healthcare systems, infection prevention control (IPC) guidelines, and antibiotic use in the Neth- erlands and Germany. Keywords Vancomycin-resistant enterococci, VRE, Antibiotic resistance, Epidemiology, Prevalence, Dutch-German cross-border region, Germany, The Netherlands Corinna Glasner and Axel Hamprecht these authors contributed equally. *Correspondence: Corinna Glasner c.glasner@umcg.nl Full list of author information is available at the end of the article © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 2 of 20 [24]. Although Germany and the Netherlands have many Background common historical, cultural, and social values, they differ Enterococci are among the most common nosocomial in many aspects regarding healthcare. These differences pathogens in the world [1]. The spread of multidrug- include amongst others the healthcare structure, antibi- resistant enterococci in healthcare, the majority attrib- otic prescription habits, and local and national infection uted to Enterococcus faecium, and their adaptation to prevention and control (IPC) guidelines for multidrug- the hospital environment have been of concern since the resistant microorganisms (MDRO) [25–27]. All these 1970s [1, 2]. aspects taken together may be the cause for the differ - Enterococci can acquire antibiotic resistance by spo- ences in VRE rates encountered in these two neighboring radic chromosomal mutations or exogenous gene countries [25, 27–29]. exchange, besides being intrinsically resistant to many Despite the available evidence for the difference in antibiotics such as cephalosporins, trimethoprim-sul- the prevalence of VRE in the Netherlands and Germany, famethoxazole, and lincosamides [3]. High-level resist- there are no nationwide comparative studies detail- ance to aminoglycosides and resistance to ampicillin ing this situation to date. Therefore, this review aims to and glycopeptides are well-known examples of acquired describe the epidemiology of vancomycin-resistant Ente- antibiotic resistance in enterococci [3, 4]. The first case rococcus spp. by presenting the outbreaks, VRE coloniza- of vancomycin-resistant enterococci (VRE) was reported tion prevalence, and VRE proportions in clinical isolates in France in 1986; since then, it has emerged as a major in hospitals in Germany and the Netherlands based on cause of nosocomial infections worldwide [5–7]. Vanco- the literature and national and European surveillance mycin resistance has been attributed to the acquisition data. of gene clusters that alter the nature of peptidoglycan precursors; and to date, nine different gene clusters have Methods been identified [8]: vanA, vanB, vanC, vanD, vanE, vanG, We performed a scoping review using PubMed to search vanL, vanM, vanN. However, vanA and vanB are the for publications in English, Dutch, and German provid- major circulating gene clusters in human VRE coloniza- ing data on VRE colonization and infection prevalence, tion and infections, both in Europe and worldwide [5, 9]. incidence, surveillance, and outbreaks in hospital set- Given the fact that VRE are resistant to first-line anti - tings in the Netherlands and Germany. The review was biotics in hospital settings, there are a limited number performed following the recommendations of PRISMA- of therapeutic options, such as linezolid, tigecycline, and ScR [30]. We performed a peer-reviewed search strategy, daptomycin [10]. However, increasing resistance to these executed on December 30, 2022. The search term (Addi - last-resort antibiotics has been reported [10–14]. There - tional file  1) was externally reviewed by a research librar- fore, prevention of VRE infections is crucial to avoid ian from the University of Groningen. The authors (CC treatment challenges [15]. and MSB) independently searched and extracted data Over the past two decades, studies have provided infor- using a peer-reviewed search strategy to avoid missing mation on the burden of VRE infections in hospitals [5, any relevant studies. No inconsistencies were encoun- 16–20]. Compared to vancomycin-susceptible entero- tered with this strategy. The dataset is available in Addi - cocci (VSE) infections, VRE infections are associated tional file  2, and those who are interested can reach out with higher morbidity, cost of care, longer length of hos- to the corresponding author for any further inquiries. pital stay, and mortality [19, 21, 22]. Unsurprisingly, the The relevance of the publications was assessed and World Health Organization (WHO) included VRE as a included following a defined flowchart (Fig.  1). First, high-priority pathogen in its global list of important anti- inclusion was based on title and abstract reading. biotic-resistant bacteria in 2017 [23]. Data from the Euro- Selected articles were then accessed in full text to deter- pean Antimicrobial Resistance Surveillance Network mine eligibility and extract the data. The reference lists (EARS-Net) justified the WHO’s decision by showing of eligible publications were screened for additional that the prevalence of VRE across Europe doubled from articles. The scientific publications had to meet all the 2015 to 2019 [24]. According to this report, an increase following criteria for inclusion: reported data had to in vancomycin resistance was reported across Europe include the number of VRE isolates and/or cases, and due to the increasing prevalence of vancomycin-resistant studies had to be conducted in a hospital. The following E. faecium (VREfm) [24]. Interestingly, two neighbor- data were extracted from the selected publications: the ing countries, Germany and the Netherlands, are at both first author’s name, country of origin, province of where ends of the scale of the proportion of VREfm in all inva- the study was conducted, time frame for conducting the sive E. faecium isolates according to EARS-Net (< 1% in study, study methodology (outbreak report, surveillance the Netherlands and 22.3% in Germany). The underlying report, prevalence/incidence study), hospital type, ward/ reasons for this difference are not yet fully understood C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 3 of 20 database established by the Robert Koch-Institute (RKI) in Germany and for both countries from EARS-Net data [31–33]. Results Study inclusion and characteristics The initial search yielded 156 potentially relevant pub - lications, 80 of which were excluded based on title and abstract reading (Fig.  1). A further 32 publications were excluded after full-text evaluation. The reference lists of the  eligible studies were screened, and four additional  studies were included. Ultimately, 46 publications were included (Figs. 1, 2). Of the selected publications, 12 were conducted in the Netherlands, and 32 in Germany. Two further studies were cross-border studies that included data from both countries. In total, there were one eco- logical, one pre-post study, one longitudinal study, four cohort studies, 14 outbreak reports, and 25 cross-sec- tional studies. Outbreaks due to vancomycin‑resistant E. faecium (VREfm) Of the 12 studies conducted in the Netherlands, eight Fig. 1 Summary of the literature search and selection process were outbreak reports (Table  1) [34–41]. Of the 32 Ger- man publications, six were outbreak reports (Table  2) [42–47]. All outbreaks in both countries were caused by ICU type, number of cases/samples involved in the study, VREfm. In three of eight outbreaks observed in Dutch the number and prevalence, incidence or proportion of hospitals and in four of six outbreaks observed in Ger- VRE, and presence of resistance genes when available. man hospitals, VREfm infections were reported along- In addition, the national surveillance data from side patients colonized with VREfm [34, 37, 40, 42, the two countries were reviewed by extracting infor- 45–47]. One common factor observed in these reports mation from NethMap in the Netherlands and the was that colonization played a pivotal role in the occur- National Antimicrobial Resistance Surveillance (ARS) rence of outbreaks in both countries. Year of Publication The Netherlands GermanyCross-border region Fig. 2 Publication dates of the included articles Number of articles 2022 Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 4 of 20 Table 1 Summary of the studies on VRE carried out in Dutch hospitals (1991–2021) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Outbreak Reports Timmers et al. Outbreak report 1999 1 university Hematology Anal, BSI Infection, coloni- E. faecium 287 isolates VRE isolates: 76 vanA (100%) [34] hospital ward zation patients: 24 (2 infections) preva- lence: 26.4% Van der Steen Outbreak report 2000 1 non-university Nephrology Rectal, fecal, Colonization E. faecium 91 patients Patients:8 preva- ND et al. [35] hospital ward urine lence: 19.8% Mascini et al. [36] Outbreak report 2000–2003 1 university ICU, wards Rectal Colonization E. faecium 183 patients Patients:27 ND hospital prevalence: 14.8% Frakking et al. Outbreak report 2012–2014 1 teaching ICU, wards Rectal, BSI Infection, coloni- E. faecium ND Patients: 242 (22 vanA (76%), vanB [37] hospital zation infections) preva- (13%) lence: 4.3% Zhou et al. [39] Outbreak report 2014 1 university Wards Rectal, fecal, Colonization E. faecium ND VRE isolates: 36 vanB (94%), hospital sputum, bile patients: 34 vanA + vanB (4%) Weterings et al. Outbreak report 2014–2017 1 general hos- ND Rectal Colonization E. faecium 158 patients Patients: 13 ND [38] pital prevalence: 8% Lisotto et al. [40] Outbreak report 2014, 2017 1 university Wards Rectal, fecal, bile, Infection, coloni- E. faecium ND VRE isolates: 39 vanB (100%) hospital pus, BSI zation (3 infections) Gast et al. [41] Outbreak report 2018 1 teaching ICU, oncology Rectal, urine Colonization E. faecium ND Patients: 19 vanB (100%) hospital ward Studies reporting on the prevalence of VRE colonization Guiot et al. [49] Cross-sectional 1991 1 university Hematology Fecal Colonization E. faecium, E. 70 patients Patients: 9 preva- ND hospital ward faecalis lence: 12.9% Van den Braak Cross-sectional 1995–1998 5 university, 4 ICU, hematol- Rectal, fecal Colonization E. faecium, E. 1112 patients Patients: 15 (E ND et al. [50] regional teach- ogy-oncology faecalis faecium, 11, E. ing hospitals ward faecalis, 4) preva- lence: 1.3% Nys et al. [48] Cohort 1999–2002 3 university Surgical wards Fecal Colonization E. faecalis 261 patients Patients: 3 preva- ND hospital lence: 1.1% Studies reporting the frequency of VRE among all clinical and screening cultures Aardema et al. Cross-sectional 2009–2010 1 university ICU ND Infection, coloni- ND 962 patients Patients: 3 preva- ND [69] hospital zation lence: 0.3% VRE isolates: number of detected isolates of VRE, patients: number of patients colonized/infected with VRE ICU: intensive care unit, ND: not determined, VRE: vancomycin-resistant enterococci C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 5 of 20 Table 2 Summary of the studies on VRE carried out in German hospitals and hospitals in the Dutch-German cross-border region (1999–2022) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Outbreak Reports Elsner et al. [42] Outbreak report 1993–1997 1 university Pediatric ICU/ ND Infection, colo- E. faecium ND Patients: 32 (5 vanA (100%) hospital wards nization infections) Knoll et al. [43] Outbreak report 1999–2001 1 university Hematology Urine, fecal, Colonization E. faecium 1124 patients Patients: 44 vanA (100%) hospital axilla prevalence: 3.9% Borgmann et al. Outbreak report 2001 1 university NICU Fecal Colonization E. faecium ND Patients: 24 vanA (100%) [44] hospital Borgmann et al. Outbreak report 2004–2005 1 university ICU, wards Rectal, fecal, Infection, colo- E. faecium ND Patients: 248 (94 vanA (90%) [45] hospital wound, organ nization infections) swabs Liese et al. [46] Outbreak report 2010–2016 1 university All hospital Rectal, fecal, Infection, colo- E. faecium ND VRE isolates*: vanB (78.5%), vanA hospital intraoperative nization 773 patients: 796 (21.5%) samples, ascites, (159 infections) aspirates, BSI Bender et al. [47] Outbreak report 2015–2019 2 hospitals ND Rectal, clinical Infection, colo- E. faecium ND Patients: 2905 vanB (98%), vanA specimen nization (127 infections) (2%) Studies reporting on the prevalence of VRE colonization Wendt et al. [51] Cross-sectional 1995 1 university, ICU, surgical- Rectal Colonization E. faecium, E. 552 isolates Prevalence: vanA (80%), vanB 1 community medical wards faecalis 8.63% (university (20%) hospital h), 1.77% (com- munity h) Gruber et al. [52] Cross-sectional 2006–2007 1 non-university Geriatric clinic Rectal Colonization E. faecium 46 patients Patients: 7 preva- ND hospital lence: 15.2% Liss et al. [53] Cross-sectional 2008–2009 1 university Hematology- Fecal Colonization ND 513 patients Patients: 51 ND hospital oncology prevalence: 9.9% Messler et al. [61] Pre-post 2012–2013 1 university Surgical ICU Rectal, clinical Colonization E. faecium 2485 patients Patients: 86. vanA (61%), vanB hospital specimen prevalence: 3.6% (39%) Neumann et al. Cohort 2014–2015 1 tertiary care Hematology- Rectal Colonization E. faecium 1606 patients Patients: 111 vanB (91%), vanA [54] hospital oncology prevalence: (9%) 23.8% Bui et al. [55] Cross-sectional 2014–2015 1 university Wards (exc. ICU) Rectal Colonization E. faecium 4013 patients Patients: 48. ND hospital prevalence: 1.2% Xanthopoulou Cross-sectional 2014–2018 6 university Wards (exc. ICU) Rectal Colonization E. faecium 16,350 patients Patients: 263; vanB (78.5%), et al. [56] hospitals prevalence: vanA (20.2%), 2014, 0.8%; 2015, vanA + vanB (1.2%) 1.2%; 2016, 1.3%; 2017, 1.5%; 2018, 2.6% Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 6 of 20 Table 2 (continued) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Biehl et al. [62] Cohort 2016 4 university Hematology- Rectal, fecal Colonization E. faecium, E. 2928 patients Patients: 176 (E. vanB (77.8%), vanA hospitals oncology wards faecalis faecium, 173; (22%) vanA + vanB E faecalis, 3). (0.2%) prevalence: 6% Sommer et al. Cross-sectional 2017–2018 25 hospitals All hospital Rectal, wound Colonization E. faecium 629 patients Prevalence: 5.7% ND [57] Heininger et al. Cross-sectional 2018 1 university High risk Rectal Colonization E. faecium 2572 patients Patients: 712 ND [58] hospital patients prevalence: at admission 27.7% Chhatwal et al. Cross-sectional 2018–2019 1 university Hematology, Rectal, anal, Colonization E. faecium 555 patients Patients: 132 vanB (93%), vanA [59] hospital oncology wards fecal prevalence: (7%) 23.8% Trautmanns- Cross-sectional 2019–2020 1 university chil- NICU, PICU, Rectal Colonization E. faecium 693 patients Patients: 33 vanB (54.5%), vanA berger et al. [60] dren’s hospital surgical-medical prevalence: 4.8% (45.5%) wards Studies reporting the proportion of VRE in nosocomial infections and the incidence of VREfm in BSIs Gastmeier et al. Cross-sectional 2007–2012 ICU-KISS, OP- ICU, surgical Rectal, BSI, SSI Infection, colo- E. faecium E. ND Nosocomial VRE ND [67] KISS, Pathogen- wards UTI nization faecalis infections: 2007– KISS 08, 79; 2009–10, 106; 2011–12, 14 proportion of VRE from 2007 to 2012: in SSI, 0.87% to 4.58%; in BSI, 4.91% to 12.99%; in UTI, 2.23% to 6.19% C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 7 of 20 Table 2 (continued) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Remschmidt Cross-sectional 2007–2016 ICU-KISS, OP-KISS ICU (857), surgi- BSI, SSI, UTI Infection E. faecium, E. ND VRE infec- ND et al. [65] cal wards (1119) faecalis tions: 2007–08, 79; 2009–10, 106; 2011–12, 143; 2013–14, 187; 2014–15, 318 propor- tion of VRE from 2007/2008 to 2015/2016: overall, 1.4% to 10%; in BSI, 5.9% to 16.7%; in UTI, 2.9% to 9.9%; in SSI, 0.9% to 5% Correa-Martinez, Longitudinal 2016–2019 31 microbiology ND BSI Infection E. faecium ND VRE isolates: 2016, vanA et al.[66] laboratories 755 incidence (64.5%); 2017, per 100,000 vanB (68.8%); inhabitants: 2018, vanB 2016, 0.48; 2019, (83.1%); 2019, 1.48 vanB (74.7) Brinkwirth et al. Cross-sectional 2015–2020 ARS ND BSI Infection E. faecium ND VRE isolates: ND [68] 3417 incidence per 100,000 inhabitants: 2015, 1.4%; 2020, 29% Studies reporting the frequency of VRE among all clinical and screening cultures Jones et al. [70] Cross-sectional 2000–2002 169 hospitals ICU ND Infection, colo- E. faecium E. 621,636 isolates Proportion of E. ND (surveillance) nization faecalis faecium, 4.8; proportion of E. faecalis, 0.3 Remschmidt Cohort 2001–2015 SARI (44 hospi- ICU (77) ND Infection, colo- E. faecium, E. 263,639 isolates ND ND et al. [75] tals) nization faecalis Kohlenberg et al. Cross-sectional 2005–2006 MDR-KISS ICU ICU (176) Rectal, clinical Infection, colo- E. faecium, E. 284,142 patients Patients: 301 ND [71] specimen nization faecalis incidence per 1000 patient days: 0.1 Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 8 of 20 Table 2 (continued) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Scharlach et al. Cross-sectional 2006–2010 ARMIN—9 labo- ND ND Infection, colo- E. faecium 6,672,431 VRE isolates: ND [79] ratories in Lower nization isolates 2006, 667; 2010, Saxony 2431 proportion of VRE: 2006, 13.6; 2010, 5.6% Meyer et al. [74] Cross-sectional 2007–2009 4 university All hospital ND Infection, colo- E. faecium 896,822 patients Patients: 2007, ND hospitals nization 159; 2008, 277; 2009, 423 incidence per 10.000 patients: 2007, 5; 2008, 9; 2009,14) Kramer et al. [76] Cross-sectional 2010 5 tertiary, 4 ICU, surgical- ND Infection, colo- E. faecium, E. 3411 patients Patients: 12 ND (point preva- secondary care medical wards nization faecalis prevalence: lence survey) hospitals 0.49% Huebner et al. Cross-sectional 2012 37 acute-care ICU, surgical- ND Infection, colo- E. faecium 7154 patients Prevalence: ND [73] (point preva- hospitals medical wards nization 0.38% lence survey) Wegner et al. Cross-sectional 2012 10 tertiary, 20 ICU, surgical- ND Infection, colo- E. faecium, E. 12,968 patients Prevalence: ND [77] (point preva- secondary, 26 medical wards nization faecalis 0.27% lence survey) primary care hospitals Huebner et al. Cross-sectional 2014 45 tertiary, 76 ICU, surgical- ND Infection, colo- E. faecium, E. 73,938 patients/ VRE isolates: ND [78] (point preva- secondary, 208 medical wards nization faecalis isolates 207 prevalence, lence survey) primary care 0.25% hospitals Remschmidt Ecologic 2014–2015 1 university ICU, surgical- Rectal, clinical Infection, colo- E. faecium, E. 204,054 patients Patients (n): 1430 ND et al. [72] hospital medical specimen nization faecalis prevalence: 0.7% and hematol- ogy-oncology wards VRE isolates: number of detected isolates of VRE, patients: number of patients diagnosed with VRE. *available ARMIN: Antimicrobial Resistance Monitoring in Lower Saxony, BSI: blood-stream infection, ICU: intensive care unit, KISS: Krankenhaus-Infektions-Surveillance System (German national nosocomial surveillance system), ND: not determined, NICU: neonatal intensive care unit, OP-KISS: data on surgical site infections, PICU: pediatric intensive care unit, SARI: the surveillance of antibiotic use and resistance in intensive care units, UTI: urinary tract infection, SSI: surgical site infection, VRE: vancomycin-resistant enterococci C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 9 of 20 Table 3 Summary of the studies on VRE carried out in hospitals in the Dutch-German cross-border region (2012–2018) Study Design Year Setting Patient population Sample site Clinical relevance Species Sample size Outcome Resistance gene (%) Studies reporting on the prevalence of VRE colonization Zhou et al. [63] Cross-sectional 2012–2013 2 university hospitals ICU, wards Rectal Colonization ND NL: 445, DE: 102 VRE isolates: NL, 6; NL: vanB isolates DE, 4 prevalence: (100%), DE: NL, 1.3%; DE, 3.9% vanB (75%) Glasner et al. [64] Cross-sectional 2017–2018 8 Dutch, 15 German ICU Rectal Colonization E. faecium NL: 1110, DE: 2035 VRE isolates: NL, 1; ND hospitals isolates DE, 55 prevalence: NL, 0.1%; DE, 2.7% VRE isolates: number of detected isolates of VRE, patients: number of patients diagnosed with VRE ICU: intensive care unit, ND: not determined, DE: Germany, NL: the Netherlands Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 10 of 20 Summary on the epidemiology of VRE between 2012 and 2013, the prevalence of VRE colo- Thirty-two studies reported prevalence or incidence of nization in the German hospital (3.9%) was three times VRE among inpatients: 17 studies reported the preva- higher than in the Dutch hospital (1.3%) [63]. The differ - lence of VRE colonization, three studies reported the ence was even more significant in the study carried out in proportion of VRE in nosocomial infections, 11 studies 23 hospitals’ ICUs (8 Dutch and 15 German) in the cross- reported the frequency of VRE among all clinical and border region between 2017 and 2018: VRE colonization screening cultures,  and one study reported both the prevalence was almost 30 times higher in the German proportion of VRE in nosocomial infections and the fre- hospitals (2.7%) than in the Dutch hospitals (0.1%) [64]. quency of VRE among clinical and screening cultures. Table 1, Table 2 and Table 3, which provide detailed epi- Studies reporting the proportion of VRE in nosocomial demiological data, indicate whether the numbers pre- infections and the incidence of VREfm in bloodstream sented correspond to VRE isolates or to the total number infections (BSIs) of patients diagnosed with VRE. The studies that reported the proportion of nosoco - mial, invasive VRE were all conducted in German hos- Studies reporting on the prevalence of VRE colonization pitals and presented an increase in VRE infections in Of the 17 studies that reported on the prevalence of VRE Germany over the years (Table  2) [65–68]. Two studies colonization, three were from Dutch hospitals  and 14 analyzed  data from the German National Nosocomial were from German hospitals. One cohort study and two Surveillance System (KISS, Krankenhaus-Infektions-Sur- cross-sectional studies investigated VRE colonization in veillance-System, https:// www. nrz- hygie ne. de/ kiss/ kiss- different patient groups in Dutch hospitals (Table  1). In module) and reported the proportion of VRE (E. faecium the cohort study, the prevalence of vancomycin-resistant and E. faecalis) in nosocomial infections. The first study E. faecalis colonization was 1.1% in surgical patients from analyzed the proportion of VRE in nosocomial infections three university hospitals [48]. In the cross-sectional in ICUs and surgical departments between 2007 and studies, the prevalence of VRE colonization (E. faeca- 2012 [67]. This study found not only an increasing trend lis and E. faecium) was 12.9% in the study conducted in of VRE (from 2007 to 2012: in SSI, 0.87% to 4.58%; in BSI, hematology patients of the university hospital in Leiden 4.91% to 12.99%; in UTI, 2.23% to 6.19%) in Germany in 1991 [49] and 1.3% in the study involving intensive in general, but also a diversity between federal states care and hematology-oncology patients from nine differ - including a “VRE belt” in the middle of the country, rang- ent hospitals between 1995 and 1998 [50]. ing from the West (North Rhine-Westphalia) to East The prevalence of VRE colonization in different patient (Saxony) [67]. The second study described a continuous groups was investigated in nine cross-sectional stud- increase in nosocomial infections caused by VRE in Ger- ies, two cohort studies and one pre-post study in Ger- man ICUs and surgical wards from 1.4% in 2007 to 10% man hospitals. The prevalence ranged between 1.2% and in 2016 [65]. 27.7% (Table  2) [51–62]. All studies reported the preva- The remaining two studies reported the incidence den - lence of VREfm colonization, except for three studies, sity of VREfm in bloodstream infections (BSI). The first one that did not specify the species and the other two study was a prospective longitudinal study in 31 labora- that  reported both E. faecalis and E. faecium [51–62]. tories in North Rhine-Westphalia, Germany [66]. This The highest prevalence was reported in studies among study found an increase in the incidence density (per hematology-oncology patients (23.8%), geriatric patients 100,000 inhabitants) of VREfm BSI from 0.52 in 2016 to (15.2%), and patients at high risk (27.7%) for VREfm col- 1.48 in 2019 [66]. The second study   analyzed the ARS onization [52, 54, 58, 59]. The lowest VREfm colonization surveillance system, which reported an increasing esti- (1.2% and 1.6%) prevalence was reported in two hospital- mated incidence density (per 100,000 inhabitants) of wide studies, which did not include intensive care unit VREfm BSI from 1.4 in 2015 to 2.9 in 2020 across the (ICU) patients [55, 56]. One of these studies was carried country [68]. out in six university hospitals throughout Germany and found an increase in VREfm colonization prevalence Studies reporting the frequency of VRE among all clinical (0.8% in 2014, 1.2% in 2015, 1.3% in 2016, 1.5% in 2017, and screening cultures 2.6% in 2018) in inpatients over the years between 2014 All 12 studies (one conducted in a Dutch hospital and 11 to 2018 [56]. in German hospitals) analyzed microbiology data with- Two cross-border studies compared the prevalence of out distinguishing between VRE infection or VRE colo- VRE colonization among hospitalized patients (Table  3). nization. Unless otherwise stated, the reported numbers In one of the studies conducted at two university hospi- represent the combined rate of VRE in both E.  faecium tals in the Northern Dutch-German cross-border region and E. faecalis isolates. The study conducted at the Dutch C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 11 of 20 hospital (University Hospital Groningen) was a cross- In the Netherlands, of the eight reported outbreaks, six sectional study, reporting a prevalence of 0.3% VRE in reported the vanA/B status of isolates. In an outbreak in ICU patients [69]. 1999 at the university hospital in Amsterdam, all VREfm Of the 11 German studies, nine were cross-sectional isolates were vanA-positive [34], and in another outbreak studies, one was a cohort study, and one was an ecologic at a non-university hospital in Utrecht between 2012 and study (investigating the impact of antibiotic use on VRE 2014, the majority of the VREfm isolates were vanA-posi- prevalence). An international surveillance study, includ- tive [37]. In contrast, two outbreaks at the university hos- ing data from 169 German hospitals between 2000 and pital in Groningen in 2014 and 2017 were predominantly 2002, reported a  VRE prevalence of 4.8% for E. faecium caused by vanB-VREfm [39, 40]. Similarly, in an outbreak and 0.3% for E. faecalis [70] and a study that analyzed at a tertiary hospital in Tilburg in 2018, all VREfm iso- MDR-KISS data between 2005 and 2006 reported a VRE lates were vanB-positive [41]. prevalence of 0.1% in ICU patients [71]. The ecologic In Germany, all reported VREfm outbreaks provided study that was conducted at the university hospital Ber- molecular data. The outbreaks at the university pediatric lin in 2012 reported a VRE prevalence of 0.7% [72]; in a hospital in Hamburg (1993–1997), at the university hos- point prevalence study conducted in 37 acute-care hospi- pital in Halle (1999–2001), and at the university hospital tals in Munich in 2012 a VREfm prevalence of 0.38% was in Tübingen (2001) were all caused solely by vanA VRE recorded in inpatients, including ICU patients [73]. [42–44]. In another outbreak at the university hospital Three of the cross-sectional studies reported an in Tübingen in 2004, most VREfm isolates were vanA- increasing incidence of VRE over several years. In one positive [45]. In a hospital-wide outbreak at a university of the studies that was conducted at four university hos- hospital in south-west Germany in 2015 [46] and in a pitals across different regions in Germany (East, North, VREfm outbreak in two regional hospitals in southern Southwest, Southeast), an increase in the incidence (with Germany between 2015 and 2019, vanB was most fre- rates rising from 5 to 9 to 14 per 10,000 patients) of quently detected [47]. VREfm was observed between 2007 and 2009 [74]. Two Apart from the above-mentioned outbreak reports, no studies that analyzed the data from KISS and the Surveil- other studies from the Netherlands reported molecular lance of Antibiotic use and Resistance in ICUs (SARI) data of VRE. However, a shift from vanA to vanB over project also recorded an increase in VRE in German time was also observed in German non-outbreak stud- hospitals [67, 75]. The incidence of VRE cases (per 100 ies (Table  2). In a cross-sectional study at two hospitals admitted patients) in ICUs rose from 0.11 in 2007 to 0.31 in Berlin in 1995 [51] and another at the university hos- in 2012 [67], whereas the resistance density of VRE in pital in Cologne between 2012  and 2013, most isolates German ICUs increased from 0.1 in 2001 to 1.1 per 1000 were vanA-positive [61]. In contrast, most studies after patient days in 2015 in the other study, which included 2013 reported a predominance of vanB, including a study the SARI cohort [75]. In contrast, three nationwide one- at a tertiary care hospital in southern Germany (2014– day point prevalence studies conducted in 2010, 2012, 2015) [54], a cohort study at the university hospitals in and 2014 using the same study protocol but with differ - Cologne, Freiburg, Hamburg, and Tübingen (2016) [62], ent numbers of participating hospitals did not show an and a cross-sectional study at six university hospitals increase in VRE colonization or infection among hos- throughout Germany (2014–2018) [56]. In a longitudinal pitalized patients [76–78]. In addition to these national study in 31 microbiology laboratories in North Rhine- studies, a regional study was conducted to identify Westphalia, vanA was predominant in 2016, while vanB regional trends of AMR in Lower Saxony. In this study, was most prevalent in 2017–2019 in VRE BSIs [66]. Simi- the data of the Antimicrobial Resistance Monitoring larly, in a study in 2018–2019 at the university hospital in in Lower Saxony (ARMIN) project in the period 2006– Hannover [59] and another study in 2019 in Munich [60], 2010 were analyzed, and strikingly, this study reported a vanB was more frequent than vanA. decreasing proportion of VREfm cases within those years in Lower Saxony from 13.6% in 2006 to 5.6% in 2010 [79]. VRE surveillance data reports on the national level Both countries have their own national antibiotic resist- ance surveillance systems, including VREfm, and both Molecular epidemiology of VRE over time submit their results to EARS-Net. Data from outbreaks in both Dutch and German hospi- tals revealed that the molecular epidemiology of VREfm The Netherlands causing outbreaks has changed from a predominance Microbiological data of all isolates from medical micro- of vanA towards vanB over the years (Table 1–2) [34, 37, biology laboratories in the Netherlands are collected in 39–47]. Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 12 of 20 the Infectious Diseases Surveillance Information System potential decrease in reporting due to the burden of the for Antimicrobial Resistance (ISIS-AR) [80]. Based on pandemic, as reporting is voluntary. these data and in collaboration with the Dutch Work- There is currently no nationwide surveillance of the ing Group on Antibiotic Policy of the Dutch Society of molecular epidemiology of VRE in the Netherlands. Medical Microbiology, a SWAB/RIVM report (NethMap) Centrally collected national data on VREfm molecular has been published annually to monitor AMR since 2003 typing were available only between 2012 and 2018, and [81]. Data regarding VRE from clinical isolates have been vanA was always more frequent than vanB during this available since 2003 in NethMap reports (Fig. 3). period [81]. According to the NethMap reports, there was a signifi - cant increase (from 0.1–0.8% to 1.5%) in the proportion of vanB-positive VREfm in hospitals between 2008 and Germany 2011. This increase  was attributed to VREfm outbreaks, Microbiological data of all isolates from participat- particularly occurring in hospitals in the northern region ing medical microbiology laboratories and hospitals in of the country [81]. As Fig.  3 shows, numerous VREfm Germany are collected in the ARS database established outbreaks have been reported in the Netherlands over by the RKI since 2008 [33]. Pre-2008 national data are the years. However, the proportion of VREfm in clini- available in so-called Epidemiology Bulletins, which cal isolates of E. faecium in hospitals remained below have been periodically published by the RKI. Accord- 1% and has not changed in the last decade. To manage ing to these reports, there was an increase in the num- and prevent large-scale outbreaks of AMR in healthcare ber of VREfm isolates observed in 2003 and 2004 (both facilities and contain its spread to other institutions at an screening and clinical samples) compared to the previ- early stage, the Early Warning and Intervention Meet- ous years [83]. Following a short decrease in the follow- ing for Nosocomial Infections and Antimicrobial Resist- ing two years, numbers increased again in 2007 [84]. ance (SO-ZI/AMR), was established in the Netherlands The ARS database, available since 2008, provides data in 2012 [82]. Participating hospitals have voluntarily regarding the proportion (%) of VREfm in all E. faecium committed to the SO-ZI/AMR system, which includes isolates obtained from inpatient blood cultures (Fig. 4). reporting obligations and regular updates until the out- Since 2009 an overall increasing trend of the VREfm break is resolved. Of all VREfm outbreaks in the last dec- proportion could be observed. ade, the lowest numbers were recorded in 2020 and 2021. A National Reference Center (NRC) for staphylo- This decrease could potentially be influenced by multiple cocci and enterococci was assigned by RKI in 2012 [86]. factors such as the implementation of enhanced infection According to the NRC, significantly more vanB-VREfm control measures during the COVID-19 pandemic or a than vanA-VREfm isolates were sent to the NRC for the 1999-2003 2012 2013-15 2015-17 2017 2018-20 2020 2021 vanA- vanB- 9 VREfm 23 VREfm 26 VREfm 13 VREfm 34 VREfm 5 VREfm 8 VREfm VREfm VREfm outbreaks outbreaks outbreaks outbreaks outbreaks outbreaks outbreaks outbreaks outbreaks 2004, 2011 2012 2008-2010 2015 2016 2017 2013-2015 2018-2020 2020 2021 VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: sporadic 0.1-0.8% 1.5% <0.5% <1% <0.5% 1% 0.6% <1% VREF cases 0.9% 0.8% Fig. 3 Summary of the number of VREfm outbreaks (blue boxes) and VREfm proportion (orange boxes) in clinical isolates in Dutch hospitals between 2003 and 2021 (NethMap reports) [81]. The data in the boxes represent the temporal distribution of VRE data over the years. (VREF: vancomycin resistant E. faecalis, VREfm: vancomycin- resistant E. faecium) C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 13 of 20 2008 2009 2010 2011 2012 2013 20142015201620172018201920202021 Year Fig. 4 VREfm as the proportion (%) of all E. faecium isolates from inpatients’ blood cultures between 2008 and 2021 in Germany (ARS-RKI Statistics) [85]. ( VREfm: vancomycin- resistant E. faecium) first time in 2017, and the situation has remained the In this review, the studies from the two countries did same since then [87, 88]. not only differ in number but also in the type of design. While most of the studies in the Netherlands were out- EARS‑net break reports, cross-sectional prevalence studies were The national AMR data represented in EARS-Net are predominant in Germany. The larger number of cross- obtained from the RIVM and RKI in the Netherlands sectional prevalence studies in German hospitals may and Germany, respectively [24]. In 2021, the popula- indicate that VRE is a more pertinent problem in Ger- tion coverage in the EARS-Net surveillance data was man than in Dutch hospitals. 68% for the Netherlands and 35% for Germany [89]. Analysis of outbreak reports revealed that all out- Throughout the years, the coverage percentages have breaks in both countries were caused by VREfm. This remained relatively stable, with the Netherlands con- is not surprising because of the high tenacity of E. sistently having higher coverage compared to Germany faecium to survive in the hospital environment [93]. [90]. The Netherlands is among 13 out of 30 countries Although the rate of infections differed within and that have maintained a VRE rate below 5% in clinical between countries, colonization was a common cause E. faecium isolates over the course of several years. In of VREfm outbreaks in both countries. Studies on contrast, in Germany, the percentage increased con- prevalence or incidence of VRE varied considerably tinuously between 2016 (11.9%) and 2019 (26.3%) and depending on the patient population and time. Gener- surpassed the European average since 2017 (Fig. 5) [24]. ally, high VRE prevalences were reported in high-risk Interestingly, this percentage (22.3%) decreased in 2020 wards such as haemato-oncology and geriatric wards in for the first time since 2014 [91]. both countries [49, 52–54, 59]. This finding is consist - ent with previous studies, which have identified age and Discussion haemato-oncological malignancies as risk factors for Given the limited treatment options and increasing both VRE colonization and infection [94–96]. prevalence of VRE in Europe, VRE remains a severe The most prominent difference between the two problem in healthcare [5, 24]. Despite this overall countries was that the German studies showed an increase, large variations have been reported between increasing trend of VRE prevalence in German hospi- countries [24]. To the best of our knowledge, we pro- tals, yet such a trend was not observed in the Dutch vide the first comparative overview of the epidemiology studies. It is important to acknowledge that the smaller of VRE in hospital settings in the Netherlands and Ger- number of Dutch studies restricts the ability to draw many, covering 102 million EU inhabitants, by review- conclusive observations regarding this matter. Cross- ing the literature and national surveillance data. border studies have also demonstrated this difference Resistant isolates, proportion (%) Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 14 of 20 Year Germany The Netherlands EU/EAA average Fig. 5 The percentage of VREfm in clinical (invasive) E. faecium isolates in the Netherlands and Germany between 2001 and 2021. EU/EAA average was only reported between 2013 and 2020. Data from the ECDC Surveillance Atlas [92] when applying the same screening strategy for hospital- in Dutch hospitals [28, 98]. Secondly, despite the high ized patients [63, 64]. This observation is supported by number of hospitalizations and longer hospital stays, the national data of both countries and EARS-Net data. German hospitals suffer more compared to Dutch hospi - EARS-Net data shows that the proportion of VREfm tals from a shortage of HCPs, resulting in understaffing, in clinical E. faecium isolates from patients with inva- particularly in nursing care [28]. The interaction between sive infections has remained stable,  with slight fluctua - patients and HCPs has a crucial role in VRE transmis- tions below 1% in the Netherlands over the past decade, sion, which may be one of the factors contributing to the while in Germany, it has risen to over 25% with an high VRE prevalence in German hospitals, due to the low increasing trend [24, 65]. nurse-to-patient ratio [99]. In the following paragraphs, we will elaborate on some points that may explain the difference in epidemiology of VRE between these two neighboring countries. Infection control guidelines In addition to the differences in healthcare structure, Healthcare system there are also variations in the national German and The inherent differences in healthcare structures could Dutch IPC guidelines for the prevention of VRE in hos- serve as a primary explanation for this difference [25, 28]. pitals [25]. The frequency of MDROs in hospitals could Both Germany and the Netherlands have well-established serve as an indicator of the effectiveness of IPC meas - healthcare systems, however, they differ in important ures. In Germany, the Commission for Hospital Hygiene aspects [28]. Firstly, the density of inpatient care (num- and Infection Prevention (KRINKO, Kommission für ber of cases), the average length of hospital stay, and bed Krankenhaushygiene und Infektionsprävention), and occupancy rate were found to be significantly higher in in the Netherlands the Infection Prevention Working Germany-all factors that could increase the risk of VRE Group (WIP, Werkgroep Infectie Preventie, Samen- transmission through increased patient-to patient and werkingsverband Richtlijnen Infectiepreventie), issue patient-to-healthcare professional (HCP) contact [28]. these national IPC guidelines [98, 100, 101]. In general, As the hospital environment is one of the key factors for while the application of IPC rules in the German guide- VRE transmission via surfaces, a high occupancy rate in line varies according to the epidemiological situation of hospitals would also facilitate the spread of VRE [16]. In the hospital and region, there is no such exception in the addition, high bed occupancy rates result in fewer sin- Dutch guideline. The KRINKO guidelines primarily focus gle rooms available to isolate patients with VRE, making on prevention of infections requiring antibiotic therapy, it challenging to implement adequate IPC rules in Ger- classifying patient groups according to their risk of evolv- man hospitals [97]. In contrast, even pre-emptive isola- ing VRE infection, whereas the WIP guidelines recom- tion is implemented for at risk patients upon admission mend a search and detect strategy. For instance, in the Resistant isolates, percentage (%) C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 15 of 20 WIP guidelines, there is no distinction between high-risk contributing to variations in the reported number of VRE wards and normal-care wards in VRE screening, whereas cases between the two countries. the KRINKO guidelines recommend VRE screening only on patients in high-risk wards. The management of VRE Commonalities carriers also differs in the two guidelines; the WIP guide - Even though the general development in VRE epide- lines recommend contact isolation without exception, miology in the Netherlands and Germany differed sub - but the KRINKO guidelines leaves the decision to clini- stantially in the last decades, two common trends have cians, based on the patient’s risk assessment. Thus, the emerged. The first trend is the potential impact of the stricter infection control rules applied in Dutch hospitals COVID-19 pandemic on VRE epidemiology. Data from could contribute to the lower prevalence of VRE. EARS-Net reports for 2020 and 2021 indicate that the number of VRE outbreaks and the proportion of VRE among all E. faecium isolates from clinical isolates have Antibiotic consumption decreased in both countries compared to the previous In addition to well-established IPC measures and the year [110]. This  decline could be due to an increased level of compliance with these measures, appropriate awareness of IPC measures among healthcare profes- use of antibiotics plays a significant role in preventing sionals and the disruption of healthcare services due to colonization with VRE and, hence, infection [102]. For the COVID-19 pandemic. However, it is also possible instance, the use of broad-spectrum cephalosporins has that deprioritization of AMR surveillance in hospitals been linked to an increased VRE prevalence, both by and less engagement to national surveillance systems facilitating the acquisition of VRE and by exerting high may have led to an underestimation of actual situation. selective pressure on the gastrointestinal flora [103–106]. The second trend is the change in the molecular epi - Data from the European Surveillance of Antimicrobial demiology of VRE over time. In Germany, molecular Consumption Network (ESAC-Net) from 1997 to 2020 typing analyses have been performed on all entero- indicate that the use of broad-spectrum cephalosporins cocci submitted to the NRC, while in the Netherlands, in the community in Germany was higher than in the such analyses were only available for centrally collected Netherlands [107]. Given this difference in the use of this enterococci between 2012 and 2018. Apart from the particular antibiotic group between the two countries, it national surveillance data, identified publications illus - is possible that this will also have an impact on the differ - trated that vanB began to be reported as the leading ence in VRE prevalence observed between them. cluster both in the Netherlands and in Germany, since 2014 [39–41, 54, 56, 59]. This shift in molecular epide - miology has led to debate about whether this change Diagnostics is a result of an actual rise in the circulation of vanB Apart from the aforementioned differences that have strains or limitations in the detection of vanB-VRE in been outlined between the Netherlands and Germany, the laboratory [111]. Comparative studies have revealed it is important to consider that variations in the diag- that gradient strip assays and automated antibiotic sus- nostic laboratory protocols, guidelines, and availabil- ceptibility testing methods commonly used in the rou- ity of resources for detecting VRE may also play a role tine laboratory setting fail to detect vanB-mediated in influencing the reported VRE cases in each country vancomycin resistance [112, 113]. EUCAST has also [64]. Variations in diagnostic protocols, including sam- acknowledged these issues and revised recommenda- ple collection, culturing techniques, and antimicrobial tions to reduce the error rate in detecting vanB-VRE susceptibility testing, can impact VRE detection. For [114]. example, variances in media and selective agents used for VRE isolation affect sensitivity and specificity [108]. Differences in the adoption and implementation of sur - Limitations veillance guidelines can also affect VRE detection and There are limitations to this study. Firstly, a meta-analysis reporting, particularly in screening frequency and extent was not possible due to the heterogeneity in study design, for VRE colonization in specific patient populations [98, patient populations, timeframes, and outcome definitions 100]. Additionally, the availability of resources (financial, across the publications. Secondly, comparing the national technological, and human) plays a significant role in a surveillance data might cause biases owing to the chang- laboratory’s capacity to detect VRE, with advanced tech- ing number of participating hospitals and laboratories nologies like PCR assays improving sensitivity and speed and different data collection compliance in the two coun - [109]. These factors can potentially impact the accuracy tries. Thirdly, a comprehensive comparison of implemen - and thoroughness of VRE detection and reporting, thus tation and compliance to the national IPC guidelines at Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 16 of 20 Acknowledgements the hospital level was beyond the scope of the current We gratefully acknowledge the support and cooperation with the CHARE- study, disallowing us to compare the real-life records of GD (Comparison of healthcare structures, processes and outcomes in the hospital practice. Northern German and Dutch cross-border region) Study Group. This study was conducted in partnership with the CrossBorder Institute of Healthcare Systems and Prevention (CBI), Groningen/Oldenburg. Conclusion In conclusion, this review has provided an overview of the Author contributions CC, AH and CG designed the study. CC and MSB performed literature epidemiology of VRE in the hospital setting in the Nether- screening independently, study selection and data extraction. CC wrote the lands and Germany, highlighting the potential causes for manuscript, which was critically reviewed and revised by MSB, AH, CG, EB, ML, the difference in VRE prevalence between these neighbor - AV, and AWF. All authors approved the final version. ing countries. Given the increasing prevalence of VRE in Funding Europe, we demonstrate that VRE remains a serious prob- This project is funded by the Ministry of Science and Culture of Lower Saxony lem in healthcare and call for further research to under- (MWK) as part of the Niedersachsen ‘Vorab’ Program. (Grant Agreement No. ZN3831). stand the underlying factors driving the difference in VRE prevalence between countries to develop effective strate - Availability of data and materials gies to control the spread of VRE. Not applicable. Declarations Abbreviations AMR Antimicrobial resistance Ethics approval and consent to participate BSI Blood-stream infection Not applicable. ARMIN Antimicrobial Resistance Monitoring in Lower Saxony ARS National Antimicrobial Resistance Surveillance Consent for Publication CHARE-GD Comparison of healthcare structures, processes and outcomes in Not applicable. the Northern German and Dutch cross-border region EARS-Net E uropean Antimicrobial Resistance Surveillance Network Competing interests ESAC-Net E uropean Surveillance of Antimicrobial Consumption Network The authors declare that they have no competing interests. HCP Healthcare professional ICU Intensive care unit Author details IPC Infection prevention and control Institute for Medical Microbiology and Virology, University of Oldenburg, ISIS-AR I nfectious Diseases Surveillance Information System for Antimicro- Oldenburg, Germany. Department of Medical Microbiology and Infection bial Resistance Prevention, University of Groningen, University Medical Center Groningen, MDRO Multidrug-resistant microorganism Groningen, The Netherlands. Department of Medical Epidemiology, Certe NICU Neonatal intensive care unit Medical Diagnostics and Advice Foundation, Groningen, The Netherlands. KISS Krankenhaus-Infektions-Surveillance-System (Hospital Infection University Hospital Muenster, University of Muenster, Muenster, Germany. Surveillance System from Germany) KRINKO Kommission für Krankenhaushygiene und Infektionsprävention Received: 12 May 2023 Accepted: 19 July 2023 (Commission for Hospital Hygiene and Infection Prevention in Germany) PICU Pediatric intensive care unit RIVM Rijksinstituut voor Volksgezondheid en Milieu (National Institute for Public Health and the Environment in the Netherlands) References RKI Robert Koch Institute 1. Cattoir V. 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Vancomycin-resistant enterococci (VRE) in hospital settings across European borders: a scoping review comparing the epidemiology in the Netherlands and Germany

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Abstract

The rising prevalence of vancomycin-resistant enterococci ( VRE) is a matter of concern in hospital settings across Europe without a distinct geographical pattern. In this scoping review, we compared the epidemiology of vancomycin-resistant Enterococcus spp. in hospitals in the Netherlands and Germany, between 1991 and 2022. We searched PubMed and summarized the national antibiotic resistance surveillance data of the two countries. We included 46 studies and summarized national surveillance data from the NethMap in the Netherlands, the National Antimicrobial Resistance Surveillance database in Germany, and the EARS-Net data. In total, 12 studies were con- ducted in hospitals in the Netherlands, 32 were conducted in German hospitals, and an additional two studies were conducted in a cross-border setting. The most significant difference between the two countries was that studies in Germany showed an increasing trend in the prevalence of VRE in hospitals, and no such trend was observed in studies in the Netherlands. Furthermore, in both Dutch and German hospitals, it has been revealed that the molec- ular epidemiology of VREfm has shifted from a predominance of vanA towards vanB over the years. According to national surveillance reports, vancomycin resistance in Enterococcus faecium clinical isolates fluctuates below 1% in Dutch hospitals, whereas it follows an increasing trend in German hospitals (above 20%), as supported by indi- vidual studies. This review demonstrates that VRE is more frequently encountered in German than in Dutch hospitals and discusses the underlying factors for the difference in VRE occurrence in these two neighboring countries by com- paring differences in healthcare systems, infection prevention control (IPC) guidelines, and antibiotic use in the Neth- erlands and Germany. Keywords Vancomycin-resistant enterococci, VRE, Antibiotic resistance, Epidemiology, Prevalence, Dutch-German cross-border region, Germany, The Netherlands Corinna Glasner and Axel Hamprecht these authors contributed equally. *Correspondence: Corinna Glasner c.glasner@umcg.nl Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 2 of 20 [24]. Although Germany and the Netherlands have many Background common historical, cultural, and social values, they differ Enterococci are among the most common nosocomial in many aspects regarding healthcare. These differences pathogens in the world [1]. The spread of multidrug- include amongst others the healthcare structure, antibi- resistant enterococci in healthcare, the majority attrib- otic prescription habits, and local and national infection uted to Enterococcus faecium, and their adaptation to prevention and control (IPC) guidelines for multidrug- the hospital environment have been of concern since the resistant microorganisms (MDRO) [25–27]. All these 1970s [1, 2]. aspects taken together may be the cause for the differ - Enterococci can acquire antibiotic resistance by spo- ences in VRE rates encountered in these two neighboring radic chromosomal mutations or exogenous gene countries [25, 27–29]. exchange, besides being intrinsically resistant to many Despite the available evidence for the difference in antibiotics such as cephalosporins, trimethoprim-sul- the prevalence of VRE in the Netherlands and Germany, famethoxazole, and lincosamides [3]. High-level resist- there are no nationwide comparative studies detail- ance to aminoglycosides and resistance to ampicillin ing this situation to date. Therefore, this review aims to and glycopeptides are well-known examples of acquired describe the epidemiology of vancomycin-resistant Ente- antibiotic resistance in enterococci [3, 4]. The first case rococcus spp. by presenting the outbreaks, VRE coloniza- of vancomycin-resistant enterococci (VRE) was reported tion prevalence, and VRE proportions in clinical isolates in France in 1986; since then, it has emerged as a major in hospitals in Germany and the Netherlands based on cause of nosocomial infections worldwide [5–7]. Vanco- the literature and national and European surveillance mycin resistance has been attributed to the acquisition data. of gene clusters that alter the nature of peptidoglycan precursors; and to date, nine different gene clusters have Methods been identified [8]: vanA, vanB, vanC, vanD, vanE, vanG, We performed a scoping review using PubMed to search vanL, vanM, vanN. However, vanA and vanB are the for publications in English, Dutch, and German provid- major circulating gene clusters in human VRE coloniza- ing data on VRE colonization and infection prevalence, tion and infections, both in Europe and worldwide [5, 9]. incidence, surveillance, and outbreaks in hospital set- Given the fact that VRE are resistant to first-line anti - tings in the Netherlands and Germany. The review was biotics in hospital settings, there are a limited number performed following the recommendations of PRISMA- of therapeutic options, such as linezolid, tigecycline, and ScR [30]. We performed a peer-reviewed search strategy, daptomycin [10]. However, increasing resistance to these executed on December 30, 2022. The search term (Addi - last-resort antibiotics has been reported [10–14]. There - tional file  1) was externally reviewed by a research librar- fore, prevention of VRE infections is crucial to avoid ian from the University of Groningen. The authors (CC treatment challenges [15]. and MSB) independently searched and extracted data Over the past two decades, studies have provided infor- using a peer-reviewed search strategy to avoid missing mation on the burden of VRE infections in hospitals [5, any relevant studies. No inconsistencies were encoun- 16–20]. Compared to vancomycin-susceptible entero- tered with this strategy. The dataset is available in Addi - cocci (VSE) infections, VRE infections are associated tional file  2, and those who are interested can reach out with higher morbidity, cost of care, longer length of hos- to the corresponding author for any further inquiries. pital stay, and mortality [19, 21, 22]. Unsurprisingly, the The relevance of the publications was assessed and World Health Organization (WHO) included VRE as a included following a defined flowchart (Fig.  1). First, high-priority pathogen in its global list of important anti- inclusion was based on title and abstract reading. biotic-resistant bacteria in 2017 [23]. Data from the Euro- Selected articles were then accessed in full text to deter- pean Antimicrobial Resistance Surveillance Network mine eligibility and extract the data. The reference lists (EARS-Net) justified the WHO’s decision by showing of eligible publications were screened for additional that the prevalence of VRE across Europe doubled from articles. The scientific publications had to meet all the 2015 to 2019 [24]. According to this report, an increase following criteria for inclusion: reported data had to in vancomycin resistance was reported across Europe include the number of VRE isolates and/or cases, and due to the increasing prevalence of vancomycin-resistant studies had to be conducted in a hospital. The following E. faecium (VREfm) [24]. Interestingly, two neighbor- data were extracted from the selected publications: the ing countries, Germany and the Netherlands, are at both first author’s name, country of origin, province of where ends of the scale of the proportion of VREfm in all inva- the study was conducted, time frame for conducting the sive E. faecium isolates according to EARS-Net (< 1% in study, study methodology (outbreak report, surveillance the Netherlands and 22.3% in Germany). The underlying report, prevalence/incidence study), hospital type, ward/ reasons for this difference are not yet fully understood C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 3 of 20 database established by the Robert Koch-Institute (RKI) in Germany and for both countries from EARS-Net data [31–33]. Results Study inclusion and characteristics The initial search yielded 156 potentially relevant pub - lications, 80 of which were excluded based on title and abstract reading (Fig.  1). A further 32 publications were excluded after full-text evaluation. The reference lists of the  eligible studies were screened, and four additional  studies were included. Ultimately, 46 publications were included (Figs. 1, 2). Of the selected publications, 12 were conducted in the Netherlands, and 32 in Germany. Two further studies were cross-border studies that included data from both countries. In total, there were one eco- logical, one pre-post study, one longitudinal study, four cohort studies, 14 outbreak reports, and 25 cross-sec- tional studies. Outbreaks due to vancomycin‑resistant E. faecium (VREfm) Of the 12 studies conducted in the Netherlands, eight Fig. 1 Summary of the literature search and selection process were outbreak reports (Table  1) [34–41]. Of the 32 Ger- man publications, six were outbreak reports (Table  2) [42–47]. All outbreaks in both countries were caused by ICU type, number of cases/samples involved in the study, VREfm. In three of eight outbreaks observed in Dutch the number and prevalence, incidence or proportion of hospitals and in four of six outbreaks observed in Ger- VRE, and presence of resistance genes when available. man hospitals, VREfm infections were reported along- In addition, the national surveillance data from side patients colonized with VREfm [34, 37, 40, 42, the two countries were reviewed by extracting infor- 45–47]. One common factor observed in these reports mation from NethMap in the Netherlands and the was that colonization played a pivotal role in the occur- National Antimicrobial Resistance Surveillance (ARS) rence of outbreaks in both countries. Year of Publication The Netherlands GermanyCross-border region Fig. 2 Publication dates of the included articles Number of articles 2022 Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 4 of 20 Table 1 Summary of the studies on VRE carried out in Dutch hospitals (1991–2021) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Outbreak Reports Timmers et al. Outbreak report 1999 1 university Hematology Anal, BSI Infection, coloni- E. faecium 287 isolates VRE isolates: 76 vanA (100%) [34] hospital ward zation patients: 24 (2 infections) preva- lence: 26.4% Van der Steen Outbreak report 2000 1 non-university Nephrology Rectal, fecal, Colonization E. faecium 91 patients Patients:8 preva- ND et al. [35] hospital ward urine lence: 19.8% Mascini et al. [36] Outbreak report 2000–2003 1 university ICU, wards Rectal Colonization E. faecium 183 patients Patients:27 ND hospital prevalence: 14.8% Frakking et al. Outbreak report 2012–2014 1 teaching ICU, wards Rectal, BSI Infection, coloni- E. faecium ND Patients: 242 (22 vanA (76%), vanB [37] hospital zation infections) preva- (13%) lence: 4.3% Zhou et al. [39] Outbreak report 2014 1 university Wards Rectal, fecal, Colonization E. faecium ND VRE isolates: 36 vanB (94%), hospital sputum, bile patients: 34 vanA + vanB (4%) Weterings et al. Outbreak report 2014–2017 1 general hos- ND Rectal Colonization E. faecium 158 patients Patients: 13 ND [38] pital prevalence: 8% Lisotto et al. [40] Outbreak report 2014, 2017 1 university Wards Rectal, fecal, bile, Infection, coloni- E. faecium ND VRE isolates: 39 vanB (100%) hospital pus, BSI zation (3 infections) Gast et al. [41] Outbreak report 2018 1 teaching ICU, oncology Rectal, urine Colonization E. faecium ND Patients: 19 vanB (100%) hospital ward Studies reporting on the prevalence of VRE colonization Guiot et al. [49] Cross-sectional 1991 1 university Hematology Fecal Colonization E. faecium, E. 70 patients Patients: 9 preva- ND hospital ward faecalis lence: 12.9% Van den Braak Cross-sectional 1995–1998 5 university, 4 ICU, hematol- Rectal, fecal Colonization E. faecium, E. 1112 patients Patients: 15 (E ND et al. [50] regional teach- ogy-oncology faecalis faecium, 11, E. ing hospitals ward faecalis, 4) preva- lence: 1.3% Nys et al. [48] Cohort 1999–2002 3 university Surgical wards Fecal Colonization E. faecalis 261 patients Patients: 3 preva- ND hospital lence: 1.1% Studies reporting the frequency of VRE among all clinical and screening cultures Aardema et al. Cross-sectional 2009–2010 1 university ICU ND Infection, coloni- ND 962 patients Patients: 3 preva- ND [69] hospital zation lence: 0.3% VRE isolates: number of detected isolates of VRE, patients: number of patients colonized/infected with VRE ICU: intensive care unit, ND: not determined, VRE: vancomycin-resistant enterococci C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 5 of 20 Table 2 Summary of the studies on VRE carried out in German hospitals and hospitals in the Dutch-German cross-border region (1999–2022) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Outbreak Reports Elsner et al. [42] Outbreak report 1993–1997 1 university Pediatric ICU/ ND Infection, colo- E. faecium ND Patients: 32 (5 vanA (100%) hospital wards nization infections) Knoll et al. [43] Outbreak report 1999–2001 1 university Hematology Urine, fecal, Colonization E. faecium 1124 patients Patients: 44 vanA (100%) hospital axilla prevalence: 3.9% Borgmann et al. Outbreak report 2001 1 university NICU Fecal Colonization E. faecium ND Patients: 24 vanA (100%) [44] hospital Borgmann et al. Outbreak report 2004–2005 1 university ICU, wards Rectal, fecal, Infection, colo- E. faecium ND Patients: 248 (94 vanA (90%) [45] hospital wound, organ nization infections) swabs Liese et al. [46] Outbreak report 2010–2016 1 university All hospital Rectal, fecal, Infection, colo- E. faecium ND VRE isolates*: vanB (78.5%), vanA hospital intraoperative nization 773 patients: 796 (21.5%) samples, ascites, (159 infections) aspirates, BSI Bender et al. [47] Outbreak report 2015–2019 2 hospitals ND Rectal, clinical Infection, colo- E. faecium ND Patients: 2905 vanB (98%), vanA specimen nization (127 infections) (2%) Studies reporting on the prevalence of VRE colonization Wendt et al. [51] Cross-sectional 1995 1 university, ICU, surgical- Rectal Colonization E. faecium, E. 552 isolates Prevalence: vanA (80%), vanB 1 community medical wards faecalis 8.63% (university (20%) hospital h), 1.77% (com- munity h) Gruber et al. [52] Cross-sectional 2006–2007 1 non-university Geriatric clinic Rectal Colonization E. faecium 46 patients Patients: 7 preva- ND hospital lence: 15.2% Liss et al. [53] Cross-sectional 2008–2009 1 university Hematology- Fecal Colonization ND 513 patients Patients: 51 ND hospital oncology prevalence: 9.9% Messler et al. [61] Pre-post 2012–2013 1 university Surgical ICU Rectal, clinical Colonization E. faecium 2485 patients Patients: 86. vanA (61%), vanB hospital specimen prevalence: 3.6% (39%) Neumann et al. Cohort 2014–2015 1 tertiary care Hematology- Rectal Colonization E. faecium 1606 patients Patients: 111 vanB (91%), vanA [54] hospital oncology prevalence: (9%) 23.8% Bui et al. [55] Cross-sectional 2014–2015 1 university Wards (exc. ICU) Rectal Colonization E. faecium 4013 patients Patients: 48. ND hospital prevalence: 1.2% Xanthopoulou Cross-sectional 2014–2018 6 university Wards (exc. ICU) Rectal Colonization E. faecium 16,350 patients Patients: 263; vanB (78.5%), et al. [56] hospitals prevalence: vanA (20.2%), 2014, 0.8%; 2015, vanA + vanB (1.2%) 1.2%; 2016, 1.3%; 2017, 1.5%; 2018, 2.6% Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 6 of 20 Table 2 (continued) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Biehl et al. [62] Cohort 2016 4 university Hematology- Rectal, fecal Colonization E. faecium, E. 2928 patients Patients: 176 (E. vanB (77.8%), vanA hospitals oncology wards faecalis faecium, 173; (22%) vanA + vanB E faecalis, 3). (0.2%) prevalence: 6% Sommer et al. Cross-sectional 2017–2018 25 hospitals All hospital Rectal, wound Colonization E. faecium 629 patients Prevalence: 5.7% ND [57] Heininger et al. Cross-sectional 2018 1 university High risk Rectal Colonization E. faecium 2572 patients Patients: 712 ND [58] hospital patients prevalence: at admission 27.7% Chhatwal et al. Cross-sectional 2018–2019 1 university Hematology, Rectal, anal, Colonization E. faecium 555 patients Patients: 132 vanB (93%), vanA [59] hospital oncology wards fecal prevalence: (7%) 23.8% Trautmanns- Cross-sectional 2019–2020 1 university chil- NICU, PICU, Rectal Colonization E. faecium 693 patients Patients: 33 vanB (54.5%), vanA berger et al. [60] dren’s hospital surgical-medical prevalence: 4.8% (45.5%) wards Studies reporting the proportion of VRE in nosocomial infections and the incidence of VREfm in BSIs Gastmeier et al. Cross-sectional 2007–2012 ICU-KISS, OP- ICU, surgical Rectal, BSI, SSI Infection, colo- E. faecium E. ND Nosocomial VRE ND [67] KISS, Pathogen- wards UTI nization faecalis infections: 2007– KISS 08, 79; 2009–10, 106; 2011–12, 14 proportion of VRE from 2007 to 2012: in SSI, 0.87% to 4.58%; in BSI, 4.91% to 12.99%; in UTI, 2.23% to 6.19% C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 7 of 20 Table 2 (continued) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Remschmidt Cross-sectional 2007–2016 ICU-KISS, OP-KISS ICU (857), surgi- BSI, SSI, UTI Infection E. faecium, E. ND VRE infec- ND et al. [65] cal wards (1119) faecalis tions: 2007–08, 79; 2009–10, 106; 2011–12, 143; 2013–14, 187; 2014–15, 318 propor- tion of VRE from 2007/2008 to 2015/2016: overall, 1.4% to 10%; in BSI, 5.9% to 16.7%; in UTI, 2.9% to 9.9%; in SSI, 0.9% to 5% Correa-Martinez, Longitudinal 2016–2019 31 microbiology ND BSI Infection E. faecium ND VRE isolates: 2016, vanA et al.[66] laboratories 755 incidence (64.5%); 2017, per 100,000 vanB (68.8%); inhabitants: 2018, vanB 2016, 0.48; 2019, (83.1%); 2019, 1.48 vanB (74.7) Brinkwirth et al. Cross-sectional 2015–2020 ARS ND BSI Infection E. faecium ND VRE isolates: ND [68] 3417 incidence per 100,000 inhabitants: 2015, 1.4%; 2020, 29% Studies reporting the frequency of VRE among all clinical and screening cultures Jones et al. [70] Cross-sectional 2000–2002 169 hospitals ICU ND Infection, colo- E. faecium E. 621,636 isolates Proportion of E. ND (surveillance) nization faecalis faecium, 4.8; proportion of E. faecalis, 0.3 Remschmidt Cohort 2001–2015 SARI (44 hospi- ICU (77) ND Infection, colo- E. faecium, E. 263,639 isolates ND ND et al. [75] tals) nization faecalis Kohlenberg et al. Cross-sectional 2005–2006 MDR-KISS ICU ICU (176) Rectal, clinical Infection, colo- E. faecium, E. 284,142 patients Patients: 301 ND [71] specimen nization faecalis incidence per 1000 patient days: 0.1 Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 8 of 20 Table 2 (continued) Study Design Year Setting Patient Sample site Clinical Species Sample size Outcome Resistance gene population relevance (%) Scharlach et al. Cross-sectional 2006–2010 ARMIN—9 labo- ND ND Infection, colo- E. faecium 6,672,431 VRE isolates: ND [79] ratories in Lower nization isolates 2006, 667; 2010, Saxony 2431 proportion of VRE: 2006, 13.6; 2010, 5.6% Meyer et al. [74] Cross-sectional 2007–2009 4 university All hospital ND Infection, colo- E. faecium 896,822 patients Patients: 2007, ND hospitals nization 159; 2008, 277; 2009, 423 incidence per 10.000 patients: 2007, 5; 2008, 9; 2009,14) Kramer et al. [76] Cross-sectional 2010 5 tertiary, 4 ICU, surgical- ND Infection, colo- E. faecium, E. 3411 patients Patients: 12 ND (point preva- secondary care medical wards nization faecalis prevalence: lence survey) hospitals 0.49% Huebner et al. Cross-sectional 2012 37 acute-care ICU, surgical- ND Infection, colo- E. faecium 7154 patients Prevalence: ND [73] (point preva- hospitals medical wards nization 0.38% lence survey) Wegner et al. Cross-sectional 2012 10 tertiary, 20 ICU, surgical- ND Infection, colo- E. faecium, E. 12,968 patients Prevalence: ND [77] (point preva- secondary, 26 medical wards nization faecalis 0.27% lence survey) primary care hospitals Huebner et al. Cross-sectional 2014 45 tertiary, 76 ICU, surgical- ND Infection, colo- E. faecium, E. 73,938 patients/ VRE isolates: ND [78] (point preva- secondary, 208 medical wards nization faecalis isolates 207 prevalence, lence survey) primary care 0.25% hospitals Remschmidt Ecologic 2014–2015 1 university ICU, surgical- Rectal, clinical Infection, colo- E. faecium, E. 204,054 patients Patients (n): 1430 ND et al. [72] hospital medical specimen nization faecalis prevalence: 0.7% and hematol- ogy-oncology wards VRE isolates: number of detected isolates of VRE, patients: number of patients diagnosed with VRE. *available ARMIN: Antimicrobial Resistance Monitoring in Lower Saxony, BSI: blood-stream infection, ICU: intensive care unit, KISS: Krankenhaus-Infektions-Surveillance System (German national nosocomial surveillance system), ND: not determined, NICU: neonatal intensive care unit, OP-KISS: data on surgical site infections, PICU: pediatric intensive care unit, SARI: the surveillance of antibiotic use and resistance in intensive care units, UTI: urinary tract infection, SSI: surgical site infection, VRE: vancomycin-resistant enterococci C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 9 of 20 Table 3 Summary of the studies on VRE carried out in hospitals in the Dutch-German cross-border region (2012–2018) Study Design Year Setting Patient population Sample site Clinical relevance Species Sample size Outcome Resistance gene (%) Studies reporting on the prevalence of VRE colonization Zhou et al. [63] Cross-sectional 2012–2013 2 university hospitals ICU, wards Rectal Colonization ND NL: 445, DE: 102 VRE isolates: NL, 6; NL: vanB isolates DE, 4 prevalence: (100%), DE: NL, 1.3%; DE, 3.9% vanB (75%) Glasner et al. [64] Cross-sectional 2017–2018 8 Dutch, 15 German ICU Rectal Colonization E. faecium NL: 1110, DE: 2035 VRE isolates: NL, 1; ND hospitals isolates DE, 55 prevalence: NL, 0.1%; DE, 2.7% VRE isolates: number of detected isolates of VRE, patients: number of patients diagnosed with VRE ICU: intensive care unit, ND: not determined, DE: Germany, NL: the Netherlands Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 10 of 20 Summary on the epidemiology of VRE between 2012 and 2013, the prevalence of VRE colo- Thirty-two studies reported prevalence or incidence of nization in the German hospital (3.9%) was three times VRE among inpatients: 17 studies reported the preva- higher than in the Dutch hospital (1.3%) [63]. The differ - lence of VRE colonization, three studies reported the ence was even more significant in the study carried out in proportion of VRE in nosocomial infections, 11 studies 23 hospitals’ ICUs (8 Dutch and 15 German) in the cross- reported the frequency of VRE among all clinical and border region between 2017 and 2018: VRE colonization screening cultures,  and one study reported both the prevalence was almost 30 times higher in the German proportion of VRE in nosocomial infections and the fre- hospitals (2.7%) than in the Dutch hospitals (0.1%) [64]. quency of VRE among clinical and screening cultures. Table 1, Table 2 and Table 3, which provide detailed epi- Studies reporting the proportion of VRE in nosocomial demiological data, indicate whether the numbers pre- infections and the incidence of VREfm in bloodstream sented correspond to VRE isolates or to the total number infections (BSIs) of patients diagnosed with VRE. The studies that reported the proportion of nosoco - mial, invasive VRE were all conducted in German hos- Studies reporting on the prevalence of VRE colonization pitals and presented an increase in VRE infections in Of the 17 studies that reported on the prevalence of VRE Germany over the years (Table  2) [65–68]. Two studies colonization, three were from Dutch hospitals  and 14 analyzed  data from the German National Nosocomial were from German hospitals. One cohort study and two Surveillance System (KISS, Krankenhaus-Infektions-Sur- cross-sectional studies investigated VRE colonization in veillance-System, https:// www. nrz- hygie ne. de/ kiss/ kiss- different patient groups in Dutch hospitals (Table  1). In module) and reported the proportion of VRE (E. faecium the cohort study, the prevalence of vancomycin-resistant and E. faecalis) in nosocomial infections. The first study E. faecalis colonization was 1.1% in surgical patients from analyzed the proportion of VRE in nosocomial infections three university hospitals [48]. In the cross-sectional in ICUs and surgical departments between 2007 and studies, the prevalence of VRE colonization (E. faeca- 2012 [67]. This study found not only an increasing trend lis and E. faecium) was 12.9% in the study conducted in of VRE (from 2007 to 2012: in SSI, 0.87% to 4.58%; in BSI, hematology patients of the university hospital in Leiden 4.91% to 12.99%; in UTI, 2.23% to 6.19%) in Germany in 1991 [49] and 1.3% in the study involving intensive in general, but also a diversity between federal states care and hematology-oncology patients from nine differ - including a “VRE belt” in the middle of the country, rang- ent hospitals between 1995 and 1998 [50]. ing from the West (North Rhine-Westphalia) to East The prevalence of VRE colonization in different patient (Saxony) [67]. The second study described a continuous groups was investigated in nine cross-sectional stud- increase in nosocomial infections caused by VRE in Ger- ies, two cohort studies and one pre-post study in Ger- man ICUs and surgical wards from 1.4% in 2007 to 10% man hospitals. The prevalence ranged between 1.2% and in 2016 [65]. 27.7% (Table  2) [51–62]. All studies reported the preva- The remaining two studies reported the incidence den - lence of VREfm colonization, except for three studies, sity of VREfm in bloodstream infections (BSI). The first one that did not specify the species and the other two study was a prospective longitudinal study in 31 labora- that  reported both E. faecalis and E. faecium [51–62]. tories in North Rhine-Westphalia, Germany [66]. This The highest prevalence was reported in studies among study found an increase in the incidence density (per hematology-oncology patients (23.8%), geriatric patients 100,000 inhabitants) of VREfm BSI from 0.52 in 2016 to (15.2%), and patients at high risk (27.7%) for VREfm col- 1.48 in 2019 [66]. The second study   analyzed the ARS onization [52, 54, 58, 59]. The lowest VREfm colonization surveillance system, which reported an increasing esti- (1.2% and 1.6%) prevalence was reported in two hospital- mated incidence density (per 100,000 inhabitants) of wide studies, which did not include intensive care unit VREfm BSI from 1.4 in 2015 to 2.9 in 2020 across the (ICU) patients [55, 56]. One of these studies was carried country [68]. out in six university hospitals throughout Germany and found an increase in VREfm colonization prevalence Studies reporting the frequency of VRE among all clinical (0.8% in 2014, 1.2% in 2015, 1.3% in 2016, 1.5% in 2017, and screening cultures 2.6% in 2018) in inpatients over the years between 2014 All 12 studies (one conducted in a Dutch hospital and 11 to 2018 [56]. in German hospitals) analyzed microbiology data with- Two cross-border studies compared the prevalence of out distinguishing between VRE infection or VRE colo- VRE colonization among hospitalized patients (Table  3). nization. Unless otherwise stated, the reported numbers In one of the studies conducted at two university hospi- represent the combined rate of VRE in both E.  faecium tals in the Northern Dutch-German cross-border region and E. faecalis isolates. The study conducted at the Dutch C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 11 of 20 hospital (University Hospital Groningen) was a cross- In the Netherlands, of the eight reported outbreaks, six sectional study, reporting a prevalence of 0.3% VRE in reported the vanA/B status of isolates. In an outbreak in ICU patients [69]. 1999 at the university hospital in Amsterdam, all VREfm Of the 11 German studies, nine were cross-sectional isolates were vanA-positive [34], and in another outbreak studies, one was a cohort study, and one was an ecologic at a non-university hospital in Utrecht between 2012 and study (investigating the impact of antibiotic use on VRE 2014, the majority of the VREfm isolates were vanA-posi- prevalence). An international surveillance study, includ- tive [37]. In contrast, two outbreaks at the university hos- ing data from 169 German hospitals between 2000 and pital in Groningen in 2014 and 2017 were predominantly 2002, reported a  VRE prevalence of 4.8% for E. faecium caused by vanB-VREfm [39, 40]. Similarly, in an outbreak and 0.3% for E. faecalis [70] and a study that analyzed at a tertiary hospital in Tilburg in 2018, all VREfm iso- MDR-KISS data between 2005 and 2006 reported a VRE lates were vanB-positive [41]. prevalence of 0.1% in ICU patients [71]. The ecologic In Germany, all reported VREfm outbreaks provided study that was conducted at the university hospital Ber- molecular data. The outbreaks at the university pediatric lin in 2012 reported a VRE prevalence of 0.7% [72]; in a hospital in Hamburg (1993–1997), at the university hos- point prevalence study conducted in 37 acute-care hospi- pital in Halle (1999–2001), and at the university hospital tals in Munich in 2012 a VREfm prevalence of 0.38% was in Tübingen (2001) were all caused solely by vanA VRE recorded in inpatients, including ICU patients [73]. [42–44]. In another outbreak at the university hospital Three of the cross-sectional studies reported an in Tübingen in 2004, most VREfm isolates were vanA- increasing incidence of VRE over several years. In one positive [45]. In a hospital-wide outbreak at a university of the studies that was conducted at four university hos- hospital in south-west Germany in 2015 [46] and in a pitals across different regions in Germany (East, North, VREfm outbreak in two regional hospitals in southern Southwest, Southeast), an increase in the incidence (with Germany between 2015 and 2019, vanB was most fre- rates rising from 5 to 9 to 14 per 10,000 patients) of quently detected [47]. VREfm was observed between 2007 and 2009 [74]. Two Apart from the above-mentioned outbreak reports, no studies that analyzed the data from KISS and the Surveil- other studies from the Netherlands reported molecular lance of Antibiotic use and Resistance in ICUs (SARI) data of VRE. However, a shift from vanA to vanB over project also recorded an increase in VRE in German time was also observed in German non-outbreak stud- hospitals [67, 75]. The incidence of VRE cases (per 100 ies (Table  2). In a cross-sectional study at two hospitals admitted patients) in ICUs rose from 0.11 in 2007 to 0.31 in Berlin in 1995 [51] and another at the university hos- in 2012 [67], whereas the resistance density of VRE in pital in Cologne between 2012  and 2013, most isolates German ICUs increased from 0.1 in 2001 to 1.1 per 1000 were vanA-positive [61]. In contrast, most studies after patient days in 2015 in the other study, which included 2013 reported a predominance of vanB, including a study the SARI cohort [75]. In contrast, three nationwide one- at a tertiary care hospital in southern Germany (2014– day point prevalence studies conducted in 2010, 2012, 2015) [54], a cohort study at the university hospitals in and 2014 using the same study protocol but with differ - Cologne, Freiburg, Hamburg, and Tübingen (2016) [62], ent numbers of participating hospitals did not show an and a cross-sectional study at six university hospitals increase in VRE colonization or infection among hos- throughout Germany (2014–2018) [56]. In a longitudinal pitalized patients [76–78]. In addition to these national study in 31 microbiology laboratories in North Rhine- studies, a regional study was conducted to identify Westphalia, vanA was predominant in 2016, while vanB regional trends of AMR in Lower Saxony. In this study, was most prevalent in 2017–2019 in VRE BSIs [66]. Simi- the data of the Antimicrobial Resistance Monitoring larly, in a study in 2018–2019 at the university hospital in in Lower Saxony (ARMIN) project in the period 2006– Hannover [59] and another study in 2019 in Munich [60], 2010 were analyzed, and strikingly, this study reported a vanB was more frequent than vanA. decreasing proportion of VREfm cases within those years in Lower Saxony from 13.6% in 2006 to 5.6% in 2010 [79]. VRE surveillance data reports on the national level Both countries have their own national antibiotic resist- ance surveillance systems, including VREfm, and both Molecular epidemiology of VRE over time submit their results to EARS-Net. Data from outbreaks in both Dutch and German hospi- tals revealed that the molecular epidemiology of VREfm The Netherlands causing outbreaks has changed from a predominance Microbiological data of all isolates from medical micro- of vanA towards vanB over the years (Table 1–2) [34, 37, biology laboratories in the Netherlands are collected in 39–47]. Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 12 of 20 the Infectious Diseases Surveillance Information System potential decrease in reporting due to the burden of the for Antimicrobial Resistance (ISIS-AR) [80]. Based on pandemic, as reporting is voluntary. these data and in collaboration with the Dutch Work- There is currently no nationwide surveillance of the ing Group on Antibiotic Policy of the Dutch Society of molecular epidemiology of VRE in the Netherlands. Medical Microbiology, a SWAB/RIVM report (NethMap) Centrally collected national data on VREfm molecular has been published annually to monitor AMR since 2003 typing were available only between 2012 and 2018, and [81]. Data regarding VRE from clinical isolates have been vanA was always more frequent than vanB during this available since 2003 in NethMap reports (Fig. 3). period [81]. According to the NethMap reports, there was a signifi - cant increase (from 0.1–0.8% to 1.5%) in the proportion of vanB-positive VREfm in hospitals between 2008 and Germany 2011. This increase  was attributed to VREfm outbreaks, Microbiological data of all isolates from participat- particularly occurring in hospitals in the northern region ing medical microbiology laboratories and hospitals in of the country [81]. As Fig.  3 shows, numerous VREfm Germany are collected in the ARS database established outbreaks have been reported in the Netherlands over by the RKI since 2008 [33]. Pre-2008 national data are the years. However, the proportion of VREfm in clini- available in so-called Epidemiology Bulletins, which cal isolates of E. faecium in hospitals remained below have been periodically published by the RKI. Accord- 1% and has not changed in the last decade. To manage ing to these reports, there was an increase in the num- and prevent large-scale outbreaks of AMR in healthcare ber of VREfm isolates observed in 2003 and 2004 (both facilities and contain its spread to other institutions at an screening and clinical samples) compared to the previ- early stage, the Early Warning and Intervention Meet- ous years [83]. Following a short decrease in the follow- ing for Nosocomial Infections and Antimicrobial Resist- ing two years, numbers increased again in 2007 [84]. ance (SO-ZI/AMR), was established in the Netherlands The ARS database, available since 2008, provides data in 2012 [82]. Participating hospitals have voluntarily regarding the proportion (%) of VREfm in all E. faecium committed to the SO-ZI/AMR system, which includes isolates obtained from inpatient blood cultures (Fig. 4). reporting obligations and regular updates until the out- Since 2009 an overall increasing trend of the VREfm break is resolved. Of all VREfm outbreaks in the last dec- proportion could be observed. ade, the lowest numbers were recorded in 2020 and 2021. A National Reference Center (NRC) for staphylo- This decrease could potentially be influenced by multiple cocci and enterococci was assigned by RKI in 2012 [86]. factors such as the implementation of enhanced infection According to the NRC, significantly more vanB-VREfm control measures during the COVID-19 pandemic or a than vanA-VREfm isolates were sent to the NRC for the 1999-2003 2012 2013-15 2015-17 2017 2018-20 2020 2021 vanA- vanB- 9 VREfm 23 VREfm 26 VREfm 13 VREfm 34 VREfm 5 VREfm 8 VREfm VREfm VREfm outbreaks outbreaks outbreaks outbreaks outbreaks outbreaks outbreaks outbreaks outbreaks 2004, 2011 2012 2008-2010 2015 2016 2017 2013-2015 2018-2020 2020 2021 VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: VREfm: sporadic 0.1-0.8% 1.5% <0.5% <1% <0.5% 1% 0.6% <1% VREF cases 0.9% 0.8% Fig. 3 Summary of the number of VREfm outbreaks (blue boxes) and VREfm proportion (orange boxes) in clinical isolates in Dutch hospitals between 2003 and 2021 (NethMap reports) [81]. The data in the boxes represent the temporal distribution of VRE data over the years. (VREF: vancomycin resistant E. faecalis, VREfm: vancomycin- resistant E. faecium) C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 13 of 20 2008 2009 2010 2011 2012 2013 20142015201620172018201920202021 Year Fig. 4 VREfm as the proportion (%) of all E. faecium isolates from inpatients’ blood cultures between 2008 and 2021 in Germany (ARS-RKI Statistics) [85]. ( VREfm: vancomycin- resistant E. faecium) first time in 2017, and the situation has remained the In this review, the studies from the two countries did same since then [87, 88]. not only differ in number but also in the type of design. While most of the studies in the Netherlands were out- EARS‑net break reports, cross-sectional prevalence studies were The national AMR data represented in EARS-Net are predominant in Germany. The larger number of cross- obtained from the RIVM and RKI in the Netherlands sectional prevalence studies in German hospitals may and Germany, respectively [24]. In 2021, the popula- indicate that VRE is a more pertinent problem in Ger- tion coverage in the EARS-Net surveillance data was man than in Dutch hospitals. 68% for the Netherlands and 35% for Germany [89]. Analysis of outbreak reports revealed that all out- Throughout the years, the coverage percentages have breaks in both countries were caused by VREfm. This remained relatively stable, with the Netherlands con- is not surprising because of the high tenacity of E. sistently having higher coverage compared to Germany faecium to survive in the hospital environment [93]. [90]. The Netherlands is among 13 out of 30 countries Although the rate of infections differed within and that have maintained a VRE rate below 5% in clinical between countries, colonization was a common cause E. faecium isolates over the course of several years. In of VREfm outbreaks in both countries. Studies on contrast, in Germany, the percentage increased con- prevalence or incidence of VRE varied considerably tinuously between 2016 (11.9%) and 2019 (26.3%) and depending on the patient population and time. Gener- surpassed the European average since 2017 (Fig. 5) [24]. ally, high VRE prevalences were reported in high-risk Interestingly, this percentage (22.3%) decreased in 2020 wards such as haemato-oncology and geriatric wards in for the first time since 2014 [91]. both countries [49, 52–54, 59]. This finding is consist - ent with previous studies, which have identified age and Discussion haemato-oncological malignancies as risk factors for Given the limited treatment options and increasing both VRE colonization and infection [94–96]. prevalence of VRE in Europe, VRE remains a severe The most prominent difference between the two problem in healthcare [5, 24]. Despite this overall countries was that the German studies showed an increase, large variations have been reported between increasing trend of VRE prevalence in German hospi- countries [24]. To the best of our knowledge, we pro- tals, yet such a trend was not observed in the Dutch vide the first comparative overview of the epidemiology studies. It is important to acknowledge that the smaller of VRE in hospital settings in the Netherlands and Ger- number of Dutch studies restricts the ability to draw many, covering 102 million EU inhabitants, by review- conclusive observations regarding this matter. Cross- ing the literature and national surveillance data. border studies have also demonstrated this difference Resistant isolates, proportion (%) Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 14 of 20 Year Germany The Netherlands EU/EAA average Fig. 5 The percentage of VREfm in clinical (invasive) E. faecium isolates in the Netherlands and Germany between 2001 and 2021. EU/EAA average was only reported between 2013 and 2020. Data from the ECDC Surveillance Atlas [92] when applying the same screening strategy for hospital- in Dutch hospitals [28, 98]. Secondly, despite the high ized patients [63, 64]. This observation is supported by number of hospitalizations and longer hospital stays, the national data of both countries and EARS-Net data. German hospitals suffer more compared to Dutch hospi - EARS-Net data shows that the proportion of VREfm tals from a shortage of HCPs, resulting in understaffing, in clinical E. faecium isolates from patients with inva- particularly in nursing care [28]. The interaction between sive infections has remained stable,  with slight fluctua - patients and HCPs has a crucial role in VRE transmis- tions below 1% in the Netherlands over the past decade, sion, which may be one of the factors contributing to the while in Germany, it has risen to over 25% with an high VRE prevalence in German hospitals, due to the low increasing trend [24, 65]. nurse-to-patient ratio [99]. In the following paragraphs, we will elaborate on some points that may explain the difference in epidemiology of VRE between these two neighboring countries. Infection control guidelines In addition to the differences in healthcare structure, Healthcare system there are also variations in the national German and The inherent differences in healthcare structures could Dutch IPC guidelines for the prevention of VRE in hos- serve as a primary explanation for this difference [25, 28]. pitals [25]. The frequency of MDROs in hospitals could Both Germany and the Netherlands have well-established serve as an indicator of the effectiveness of IPC meas - healthcare systems, however, they differ in important ures. In Germany, the Commission for Hospital Hygiene aspects [28]. Firstly, the density of inpatient care (num- and Infection Prevention (KRINKO, Kommission für ber of cases), the average length of hospital stay, and bed Krankenhaushygiene und Infektionsprävention), and occupancy rate were found to be significantly higher in in the Netherlands the Infection Prevention Working Germany-all factors that could increase the risk of VRE Group (WIP, Werkgroep Infectie Preventie, Samen- transmission through increased patient-to patient and werkingsverband Richtlijnen Infectiepreventie), issue patient-to-healthcare professional (HCP) contact [28]. these national IPC guidelines [98, 100, 101]. In general, As the hospital environment is one of the key factors for while the application of IPC rules in the German guide- VRE transmission via surfaces, a high occupancy rate in line varies according to the epidemiological situation of hospitals would also facilitate the spread of VRE [16]. In the hospital and region, there is no such exception in the addition, high bed occupancy rates result in fewer sin- Dutch guideline. The KRINKO guidelines primarily focus gle rooms available to isolate patients with VRE, making on prevention of infections requiring antibiotic therapy, it challenging to implement adequate IPC rules in Ger- classifying patient groups according to their risk of evolv- man hospitals [97]. In contrast, even pre-emptive isola- ing VRE infection, whereas the WIP guidelines recom- tion is implemented for at risk patients upon admission mend a search and detect strategy. For instance, in the Resistant isolates, percentage (%) C imen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 15 of 20 WIP guidelines, there is no distinction between high-risk contributing to variations in the reported number of VRE wards and normal-care wards in VRE screening, whereas cases between the two countries. the KRINKO guidelines recommend VRE screening only on patients in high-risk wards. The management of VRE Commonalities carriers also differs in the two guidelines; the WIP guide - Even though the general development in VRE epide- lines recommend contact isolation without exception, miology in the Netherlands and Germany differed sub - but the KRINKO guidelines leaves the decision to clini- stantially in the last decades, two common trends have cians, based on the patient’s risk assessment. Thus, the emerged. The first trend is the potential impact of the stricter infection control rules applied in Dutch hospitals COVID-19 pandemic on VRE epidemiology. Data from could contribute to the lower prevalence of VRE. EARS-Net reports for 2020 and 2021 indicate that the number of VRE outbreaks and the proportion of VRE among all E. faecium isolates from clinical isolates have Antibiotic consumption decreased in both countries compared to the previous In addition to well-established IPC measures and the year [110]. This  decline could be due to an increased level of compliance with these measures, appropriate awareness of IPC measures among healthcare profes- use of antibiotics plays a significant role in preventing sionals and the disruption of healthcare services due to colonization with VRE and, hence, infection [102]. For the COVID-19 pandemic. However, it is also possible instance, the use of broad-spectrum cephalosporins has that deprioritization of AMR surveillance in hospitals been linked to an increased VRE prevalence, both by and less engagement to national surveillance systems facilitating the acquisition of VRE and by exerting high may have led to an underestimation of actual situation. selective pressure on the gastrointestinal flora [103–106]. The second trend is the change in the molecular epi - Data from the European Surveillance of Antimicrobial demiology of VRE over time. In Germany, molecular Consumption Network (ESAC-Net) from 1997 to 2020 typing analyses have been performed on all entero- indicate that the use of broad-spectrum cephalosporins cocci submitted to the NRC, while in the Netherlands, in the community in Germany was higher than in the such analyses were only available for centrally collected Netherlands [107]. Given this difference in the use of this enterococci between 2012 and 2018. Apart from the particular antibiotic group between the two countries, it national surveillance data, identified publications illus - is possible that this will also have an impact on the differ - trated that vanB began to be reported as the leading ence in VRE prevalence observed between them. cluster both in the Netherlands and in Germany, since 2014 [39–41, 54, 56, 59]. This shift in molecular epide - miology has led to debate about whether this change Diagnostics is a result of an actual rise in the circulation of vanB Apart from the aforementioned differences that have strains or limitations in the detection of vanB-VRE in been outlined between the Netherlands and Germany, the laboratory [111]. Comparative studies have revealed it is important to consider that variations in the diag- that gradient strip assays and automated antibiotic sus- nostic laboratory protocols, guidelines, and availabil- ceptibility testing methods commonly used in the rou- ity of resources for detecting VRE may also play a role tine laboratory setting fail to detect vanB-mediated in influencing the reported VRE cases in each country vancomycin resistance [112, 113]. EUCAST has also [64]. Variations in diagnostic protocols, including sam- acknowledged these issues and revised recommenda- ple collection, culturing techniques, and antimicrobial tions to reduce the error rate in detecting vanB-VRE susceptibility testing, can impact VRE detection. For [114]. example, variances in media and selective agents used for VRE isolation affect sensitivity and specificity [108]. Differences in the adoption and implementation of sur - Limitations veillance guidelines can also affect VRE detection and There are limitations to this study. Firstly, a meta-analysis reporting, particularly in screening frequency and extent was not possible due to the heterogeneity in study design, for VRE colonization in specific patient populations [98, patient populations, timeframes, and outcome definitions 100]. Additionally, the availability of resources (financial, across the publications. Secondly, comparing the national technological, and human) plays a significant role in a surveillance data might cause biases owing to the chang- laboratory’s capacity to detect VRE, with advanced tech- ing number of participating hospitals and laboratories nologies like PCR assays improving sensitivity and speed and different data collection compliance in the two coun - [109]. These factors can potentially impact the accuracy tries. Thirdly, a comprehensive comparison of implemen - and thoroughness of VRE detection and reporting, thus tation and compliance to the national IPC guidelines at Cimen et al. Antimicrobial Resistance & Infection Control (2023) 12:78 Page 16 of 20 Acknowledgements the hospital level was beyond the scope of the current We gratefully acknowledge the support and cooperation with the CHARE- study, disallowing us to compare the real-life records of GD (Comparison of healthcare structures, processes and outcomes in the hospital practice. Northern German and Dutch cross-border region) Study Group. This study was conducted in partnership with the CrossBorder Institute of Healthcare Systems and Prevention (CBI), Groningen/Oldenburg. Conclusion In conclusion, this review has provided an overview of the Author contributions CC, AH and CG designed the study. CC and MSB performed literature epidemiology of VRE in the hospital setting in the Nether- screening independently, study selection and data extraction. CC wrote the lands and Germany, highlighting the potential causes for manuscript, which was critically reviewed and revised by MSB, AH, CG, EB, ML, the difference in VRE prevalence between these neighbor - AV, and AWF. All authors approved the final version. ing countries. Given the increasing prevalence of VRE in Funding Europe, we demonstrate that VRE remains a serious prob- This project is funded by the Ministry of Science and Culture of Lower Saxony lem in healthcare and call for further research to under- (MWK) as part of the Niedersachsen ‘Vorab’ Program. (Grant Agreement No. ZN3831). stand the underlying factors driving the difference in VRE prevalence between countries to develop effective strate - Availability of data and materials gies to control the spread of VRE. Not applicable. Declarations Abbreviations AMR Antimicrobial resistance Ethics approval and consent to participate BSI Blood-stream infection Not applicable. ARMIN Antimicrobial Resistance Monitoring in Lower Saxony ARS National Antimicrobial Resistance Surveillance Consent for Publication CHARE-GD Comparison of healthcare structures, processes and outcomes in Not applicable. the Northern German and Dutch cross-border region EARS-Net E uropean Antimicrobial Resistance Surveillance Network Competing interests ESAC-Net E uropean Surveillance of Antimicrobial Consumption Network The authors declare that they have no competing interests. HCP Healthcare professional ICU Intensive care unit Author details IPC Infection prevention and control Institute for Medical Microbiology and Virology, University of Oldenburg, ISIS-AR I nfectious Diseases Surveillance Information System for Antimicro- Oldenburg, Germany. Department of Medical Microbiology and Infection bial Resistance Prevention, University of Groningen, University Medical Center Groningen, MDRO Multidrug-resistant microorganism Groningen, The Netherlands. Department of Medical Epidemiology, Certe NICU Neonatal intensive care unit Medical Diagnostics and Advice Foundation, Groningen, The Netherlands. KISS Krankenhaus-Infektions-Surveillance-System (Hospital Infection University Hospital Muenster, University of Muenster, Muenster, Germany. Surveillance System from Germany) KRINKO Kommission für Krankenhaushygiene und Infektionsprävention Received: 12 May 2023 Accepted: 19 July 2023 (Commission for Hospital Hygiene and Infection Prevention in Germany) PICU Pediatric intensive care unit RIVM Rijksinstituut voor Volksgezondheid en Milieu (National Institute for Public Health and the Environment in the Netherlands) References RKI Robert Koch Institute 1. Cattoir V. 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Klare I, Bender JK, Fleige C, Kriebel N, Hamprecht A, Gatermann S, et al. Comparison of VITEK 2, three different gradient strip tests and broth microdilution for detecting vanB-positive Enterococcus faecium isolates with low vancomycin MICs. J Antimicrob Chemother. 2019;74(10):2926–9. 113. Walker SV, Wolke M, Plum G, Weber RE, Werner G, Hamprecht A. Failure of Vitek2 to reliably detect vanB-mediated vancomycin resistance in Enterococcus faecium. J Antimicrob Chemother. 2021;76(7):1698–702. 114. EUCAST. Vancomycin susceptibility testing in Enterococcus faecalis and E. faecium using MIC gradient tests–a modified warning 21 May, 2019. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Journal

Antimicrobial Resistance and Infection Control – Springer Journals

Published: Aug 12, 2023

Keywords: Vancomycin-resistant enterococci; VRE; Antibiotic resistance; Epidemiology; Prevalence; Dutch-German cross-border region; Germany; The Netherlands

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