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Continuous increase of vancomycin resistance in enterococci causing nosocomial infections in Germany − 10years of surveillance

Continuous increase of vancomycin resistance in enterococci causing nosocomial infections in... Background: Enterococci are frequent pathogens causing nosocomial infections in Germany. Infections due to strains with vancomycin resistance are high when compared with other European states. Therefore, the study aimed to describe the recent progression of nosocomial infections due to vancomycin-resistant enterococci (VRE) in Germany. Methods: We analyzed data from two components of the German national nosocomial infection surveillance system for the period 2007–2016. For primary bloodstream infections (BSIs) and urinary tract infections (UTIs) we used data from intensive care units and for surgical site infections (SSIs) data from surgical departments. In a sensitivity analysis, we considered only data from participants that participated continuously from 2007 to 2016 (“core group”). We calculated proportions of VRE among all nosocomial enterococcal infections with 95% confidence intervals (95% CIs) and trends over time. A multivariable logistic regression was used to compare occurrence of VRE proportions among German federal states. Results: Enterococcal infections from 857 ICUs and 1119 surgical departments were analyzed. On ICUs, the proportion of vancomycin resistance in enterococci causing nosocomial infections significantly increased for BSIs from 5.9 to 16.7% and for UTIs from 2.9 to 9.9%; for surgical site infections, the proportion of VRE increased from 0.9 to 5.2% (P < 0.001 for all). In the core group, the increase of VRE was more pronounced in ICUs (BSIs: 5.5 to 21.6%; UTIs: 2 to 11.2%) but was not seen in surgical departments (SSIs: 1.5 to 2.8%). Compared with the most populous German federal state North Rhine Westphalia, enterococcal infections in Hesse (Odds Ratio (OR) 2.3, 95% CI 1.7–3.1), Saxony (OR 2.5, 95% CI 1.8–3.5) and Thuringia (OR 1.9, 95% CI 1.4–2.6) were more likely to be caused by vancomycin-resistant strains. Conclusion: In Germany, the proportion of VRE in nosocomial infection due to enterococci is still increasing. It remains unclear, why a large variation in the proportion of VRE exists between German federal states. Keywords: Vancomycin-resistant enterococci, Multiresistant, Surveillance, Epidemiology * Correspondence: cornelius.remschmidt@charite.de Institute of Hygiene and Environmental Medicine, Charité – University Medicine Berlin, Hindenburgdamm 27, 12203 Berlin, Germany German National Reference Centre for Surveillance of Nosocomial Infections (NRZ), Hindenburgdamm 27, 12203 Berlin, Germany © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 2 of 7 Background with the German “Protection against Infection Act” §23. Vancomycin-resistant enterococci (VRE) have emerged as Therefore, ethical approval by an institutional board was important multiresistant pathogens causing nosocomial not necessary. infections [1, 2]. Infections with VRE are associated with increased length of stay and excess in-hospital mortality Statistical analysis and therefore pose a rising public health threat [3]. In We pooled data recorded in ICU-KISS and OP-KISS 2017, the World Health Organization identified VRE as and analyzed the proportion of VRE for each type of in- one of the most important resistant bacteria in their fection (BSI, UTI, SSI) by dividing the number of entero- “Global Priority list of antibiotic-resistant bacteria list” [4]. coccal infections resistant against vancomycin by the According to the 2016 surveillance report of the Euro- number of all enterococcal infections multiplied by 100. pean Antimicrobial Resistance Network (EARS-Net), a 95% confidence intervals (CIs) were calculated. Data significant increasing trend for VRE between 2013 and were univariate tested for a yearly linear trend by using 2016 was not identified among invasive isolates for the Cochrane-Armitage-test [6]. EU/EEA population-weighted mean percentage [5]; how- A multivariable logistic regression was used to com- ever, in seven out of 30 participating countries a signifi- pare VRE proportions among German federal states. In cant increase of VRE was observed. Ireland (VRE rate of addition to the risk factor federal state, the following po- 44.1%), Greece (27.9%), Slovakia (26.4%), Poland (25.2%) tential confounders were considered: year of the surgical and Hungary (22.5%) showed the highest resistance rates procedure, gender and age group for the patient (0–50, in the EARS-Net 2016 report, if only countries with 51–65, 66–70 and 71–120 years), type of hospital (uni- more than 100 reported isolates were considered. In versity hospital, other hospital), season, type of ICU or Germany, the proportion of VRE among invasive Entero- type of surgical department, and hospital size (400 beds coccus (E.) faecium isolates was 12.1% and comparable and ≥ 400 beds). Stepwise forward-backward selection with the EU/EEA mean. was used to derive the final logistic regression model. Previously, we observed a dramatic increase of the Parameters were entered into the model at a significance proportion of VRE among blood-stream infections and level of P ≤ 0.05 and were removed at P > 0.05. Odds surgical site infections between 2007 and 2012 [6]. Ratios (OR) with 95% CIs were calculated. Therefore, the objective of this study was to investigate Since not all hospitals reported data for the entire the recent development of different nosocomial infec- study period, we conducted a sensitivity analysis in tionscausedbyVRE in Germanybyusing data from which only hospitals were included that had reported the large German national nosocomial infection surveil- data continuously from 2007 to 2016 for at least 6 month lance system. per year (“core group”). P-values less than 0.05 were considered statistically significant. Methods All analyses were performed with R 3.4.3 [R Core We analyzed data that were recorded into two surveil- Team (2013); R Foundation for statistical computing, lance components of the German national nosocomial Vienna, Austria] and SAS 9.4 (SAS Institute Inc., Cary, infection surveillance system (Krankenhaus-Infektions- NC, USA). Surveillance-System, KISS) between 2007 and 2016. Detailed information on KISS and its above-mentioned Results components have been described elsewhere [7]. Briefly, Between 2007 and 2016 a total of 1121 ICUs and 1412 data on nosocomial primary blood stream-infections surgical departments from all German federal states re- (BSI) and nosocomial urinary tract-infections (UTIs) on ported data on nosocomial infections to ICU-KISS and intensive care units (ICUs) were recorded in the ICU OP-KISS, respectively (Table 1). Of those, 12,659 infec- component of KISS (ICU-KISS). Data on nosocomial tions were due to enterococcus species. Overall, the surgical site infections (SSIs) on surgical departments proportion of VRE increased from 1.4% in 2007/2008 were recorded in OP-KISS. Infections were documented to 10% in 2015/2016 (Fig. 1). In BSI, the proportion of according to definitions by the CDC [8]. In KISS, entero- VRE increased from 5.9 to 16.7% (P <0.001). Among coccal infections are not documented on a species level. UTIs and SSIs, the proportion of VRE increased from Therefore, the term VRE is defined as all infections due 2.9 to 9.9% (P <0.001) and from 0.9 to 5% (P < 0.001), to enterococci resistant against vancomycin regardless of respectively (Table 2). the underlying mechanism or species. According to our sensitivity analysis, 218 ICUs and 174 surgical wards reported data continuously on an an- Ethics and data protection nual basis (core group). Overall, the core group showed We analyzed aggregated and anonymous data that are a comparable increase regarding the proportion of VRE collected by the participating hospitals in accordance from 4 to 10%; however, the increase in the core group Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 3 of 7 Table 1 ICUs and surgical departments providing VRE infection data for 2007–16 per year from the German national nosocomial infection surveillance system (KISS) Year/number (n) 2007/08 2009/10 2011/12 2013/14 2015/16 Total Number (n) of ICUs 465 533 645 764 857 1121 Number (n) of surgical departments 432 558 681 919 1119 1412 Nosocomial enterococcal infections Total number (N) of nosocomial enterococcal infections 2047 2559 2253 2639 3161 12,659 Number of VRE infections, n (% (n/N)) 79 (3.9) 106 (4.1) 143 (6.4) 187 (7.1) 318 (10.1) 833 (6.6) Total number (N) of enterococcal infections on ICUs 1520 1927 1574 1700 1929 8650 Number of VRE infections on ICUs, n (% (n/N)) 74 (4.9) 90 (4.7) 119 (7.6) 158 (9.3) 229 (11.9) 670 (7.8) Total number (N) of nosocomial enterococcal infections 527 637 679 939 1232 4009 in surgical wards Number of nosocomial VRE infections in surgical wards, 5 (1.0) 16 (2.5) 24 (3.5) 30 (3.2) 57 (4.6) 132 (3.3) n (% (n/N)) ICU intensive care unit, VRE vancomycin-resistant enterococci; Total number of ICUs/surgical departments that reported data for at least 6 month in any year was more pronounced in BSIs and UTIs whereas the internal medicine ICU: OR: 1.8 (95% CI 1.5–2.2) and proportion of VRE among SSI showed only a small in- calendar year (OR 1.1, 95% CI 1.1–1.2) statistically sig- crease (Fig. 2). VRE proportions increased significantly nificant increased the chance for VRE. in primary BSI from 5.5 to 21.6% (P < 0.001) and in UTI from 2 to 11.2% (P = 0.001). Discussion Regarding differences in the proportion of VRE among Our analysis of the German national nosocomial infec- German federal states, we found that proportion of VRE tion surveillance system revealed a continuous increase infections were > 10% in the 6 federal states of Berlin, of VRE proportions in nosocomial infections caused by Hesse, Saarland, Saxony-Anhalt, Saxony and Thuringia, enterococci in Germany between 2007 and 2016. This all of which are in the center of Germany (Fig. 3). Com- development has become even more apparent since our pared with the most populous federal state North Rhine last report [6]. Westphalia, enterococcal infections in Hesse (OR 2.3, The results on VRE are concordant with other reports 95% CI 1.7–3.1), Saxony (OR 2.5, 95% CI 1.8–3.5) and from Germany. Behnke et al. showed in two consecutive Thuringia (OR 1.9, 95% CI 1.4–2.6) were more likely to national point prevalence studies that vancomycin resist- be caused by VRE. Additionally, the final multivariable ance in E. faecium causing nosocomial infections in- logistic regression indicated that type of hospital (univer- creased from 10.2% in 2011 to 23.1% in 2016 [9, 10]. sity hospital vs. non-university hospital: OR 2.1, 95% CI Another study which analyzed data on antibiotic con- 1.7–2.5), type of ICU (internal medicine ICU vs. non- sumption and antimicrobial resistance in German ICUs Fig. 1 Time trend for percentage of vancomycin-resistant entercoccal (VRE) infections according to the German national nosocomial infection surveillance system (KISS), by infection site Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 4 of 7 Table 2 Data on nosocomial infections due to Enterococci for 2007–16 per year from the German national nosocomial infection surveillance system (KISS), by infection site Surgical site infections Bloodstream infections Urinary tract infections Year Enterococci VRE (n) Proportion in % Enterococci VRE (n) Proportion in % Enterococci VRE (n) Proportion in % (n) (95% CI) (n) (95% CI) (n) (95% CI) 2007 231 2 0.87 (0.15, 2.83) 170 10 5.88 (3.03, 10.23) 450 13 2.89 (1.62, 4.78) 2008 296 3 1.01 (0.26, 2.73) 206 15 7.28 (4.29, 11.47) 540 29 5.37 (3.69, 7.52) 2009 301 7 2.33 (1.02, 4.55) 273 23 8.42 (5.55, 12.18) 591 19 3.21 (2.00, 4.88 2010 336 9 2.68 (1.31, 4.86) 261 20 7.66 (4.88, 11.38) 627 26 4.15 (2.78, 5.93) 2011 357 11 3.08 (1.63, 5.29) 303 32 10.56 (7.46, 14.41) 379 18 4.75 (2.93, 7.26) 2012 322 13 4.04 (2.26, 6.63) 265 33 12.45 (8.88, 16.85) 434 27 6.22 (4.22, 8.80) 2013 420 20 4.76 (3.02, 7.13) 338 30 8.88 (6.18, 12.27) 462 37 8.01 (5.79, 10.76) 2014 519 10 1.93 (0.98, 3.41) 335 30 8.96 (6.24, 12.38) 439 44 10.02 (7.47, 13.10) 2015 615 26 4.23 (2.84, 6.05) 409 57 13.94 (10.83, 17.55) 504 41 8.13 (5.98, 10.77) 2016 617 31 5.02 (3.50, 6.97) 437 73 16.70 (12.39, 18.90) 496 49 9.88 (7.48, 12.75) VRE vancomycin-resistant enterococci found a continuous increase in resistance against vanco- growing sample of hospitals and individual wards report mycin in E. faecium between 2001 and 2016 [11]. Finally, different types of infections (UTIs, SSIs and BSIs). How- comparable results were found in the national anti- ever, even when considering only ICUs that continuously microbial resistance surveillance project [12], where reported data on BSI we observed a continuous increase detection of E. faecium derived from blood-cultures of VRE. (ii) As compared to EARS-net, we considered not has increased by up to 50% in recent years and pro- only BSI but also surgical site infections and urinary tract portion of isolates resistant against vancomycin in- infections. However, when only BSI were analysed in our creased to 11.9% [13]. study, the increase in the last 3 years has been particularly Interestingly, the recent report by the EARS-net de- pronounced and differences to EARS-Net data remain un- scribed a high but stable situation regarding the propor- clear. (iii) Antimicrobial susceptibility testing (AST) in tion of VRE among E. faecium isolates of 12.1% in many microbiological laboratories Germany was per- Germany, which is comparable with the European popula- formed according to Clinical & Laboratory Standards In- tion weighted mean of 11.8% for 2016 [5]. These differ- stitute (CLSI) while EARS-net uses EUCAST-standards ences might be caused by the following reasons. (i) In only [14]. This potentially could influence vancomycin re- EARS-Net, a static representative sample of hospitals from sistance rates especially in low and medium-level resist- defined regions deliver rates of BSI from all wards based ance due to differing recommended AST methods and on laboratory results whereas in KISS a continuously clinical breakpoints [15]. Fig. 2 Time trend for percentage of vancomycin-resistant enterococcal (VRE) infections according to the German national nosocomial infection surveillance system (KISS), by infection site. Data from wards that participated continuously from 2007 to 2016 (“core group”) Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 5 of 7 Fig. 3 Distribution of the proportion of vancomycin-resistant entercoccal (VRE) infections among German federal states according to data from the German national nosocomial infection surveillance system (KISS) 2007–2016 Risk factors that have been described for VRE Nosocomial Infection Surveillance Program (CNISP) colonization or infections are long periods of hospitalization, was analyzed found an increase of VRE in western and hemodialysis, immunosuppression as well as close proximity central Canada [29]. The authors assumed that the to patients infected or colonized with VRE [16]. The fact clonal spread of certain sequence types might have been that enterococci are able to survive on environmental sur- in part responsible for these findings, although a reliable faces for long periods of time [16, 17] highlights the import- explanation was not possible. Kullar et al. evaluated re- ance of adherence to hand hygiene practice to prevent gional variations on VRE across blood, urine and wound transmission. But despite improved adherence to hand- sources in United States Hospitals 2015 and found sig- hygiene and successful reduction of nosocomial infections nificant differences among US states [30]. A potential in Germany [18, 19], VRE continues to gain importance explanation for these results was not discussed. when compared to other multidrug resistant gram-positive The reasons for the regional differences in our study organisms [11]. are also unclear and possible reasons for higher VRE Increased antibiotic consumption has been advocated as rates in the center of Germany are difficult to explain another important risk factor that influence spread of and are likely to be multifactorial [6]. One possible VRE [16, 20, 21]. Many reports have established an indir- explanation might be regional variations in antibiotic ect or direct link between appearance of VRE and the usage in the ambulatory and/or the inpatient setting; for consumption of certain antimicrobial groups but the example, a large population-based study found among connection probably is more complex [21]. Exposure to German federal states differences in outpatient antibiotic substances with a broad gram-negative and anerobic prescription rates [25] of fluoroquinolones and cephalos- microbiological spectrum, but no coverage against E. fae- porines, substances that might influence VRE selection cium are believed to facilitate the colonization of the process [1, 16, 22]. Other reasons for the regional differ- GI-tract with VRE [22]. Particularly carbapenems [20], 3rd ences that have been discussed are differences in the generation cephalosporins [23] but also penicillin’swith proportion of VRE in the environment (e.g. higher pro- beta-lactamase inhibitors such as piperacillin/tazobactam portion of VRE in farm animals) or the spread of new or [24] are likely to trigger this process. In Germany, cepha- clonal VRE strain in certain areas [6]. However, Willems losporins are now the most commonly prescribed in et al. found genetic differences in hospital-acquired VRE German primary care [25] and might have triggered VRE- isolates and community-acquired or animal isolates selection in the outpatient setting already. This would which makes an association between the environment highlight the need of antibiotic stewardship not only in and increased VRE rates in German ICUs unlikely [31]. the inpatient but also in the outpatient setting [26, 27]. Some limitations have to be acknowledged: (i) Since Interestingly, a recent meta-analysis has not found a direct fulfillment of case criteria depends on diagnostic sam- influence of measures within in-hospital antimicrobial pling and documentation there is a risk for underdetec- stewardship and the occurrence of VRE; however, the tion of cases. However, using proportions of VRE for all number of included studies was limited [28]. nosocomial infections caused by enterococci might have Although differences of VRE are obviously among reduce confounding effects for changes in the bacterio- European countries [5], only few studies have assessed logical diagnostic over time, since only pathogen-derived regional differences of VRE within the same country. In infections were included. (ii) We did not record below a a Canadian study, in which the molecular epidemiology genus level of enterococci; therefore, we were unable to of VRE from invasive samples from the National rule out an increase of Enterococcus spp. with intrinsic Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 6 of 7 glycopeptide resistance. However, this is less likely 2. Werner G, Coque TM, Hammerum AM, Hope R, Hryniewicz W, Johnson A, Klare I, Kristinsson KG, Leclercq R, Lester CH, et al. Emergence and since national and international sources have reported spread of vancomycin resistance among enterococci in Europe. Euro an increase vancomycin-resistant E. faecium, while in- Surveill. 2008;13(47). https://www.eurosurveillance.org/content/10.2807/ fections due to vancomycin-resistant E. faecalis and ese.13.47.19046-en. 3. Chiang HY, Perencevich EN, Nair R, Nelson RE, Samore M, Khader K, Chorazy Enterococcus spp. with intrinsic glycopeptid resistance ML, Herwaldt LA, Blevins A, Ward MA, et al. Incidence and outcomes e.g. E. gallinarum remain rare [2, 32]. (iii) Since we associated with infections caused by vancomycin-resistant enterococci in used surveillance definitions to determine infections, the United States: systematic literature review and meta-analysis. Infect Control Hosp Epidemiol. 2017;38(2):203–15. in some cases of UTIs the identified VRE might have 4. World Health Organization (WHO): Global priority list of antibiotic-resistant been a contamination rather than the infection-causing bacteria to guide research, discovery, and development of new antibiotics. pathogen. (iv) Finally, we had no information regarding Available at http://www.who.int/medicines/publications/WHO-PPL-Short_ Summary_25Feb-ET_NM_WHO.pdf?ua=1. Accessed 03 Mar 2017. 2017. strain characteristics, therefore local or regional out- 5. European Centre for Disease Prevention and Control: Antimicrobial resistance breaks cannot be excluded. surveillance in Europe 2016. Annual report of the European antimicrobial resistance surveillance network (EARS-net). Stockholm: ECDC. 2018. 6. Gastmeier P, Schroder C, Behnke M, Meyer E, Geffers C. Dramatic increase in Conclusion vancomycin-resistant enterococci in Germany. J Antimicrob Chemother. To proportion of vancomycin-resistant enterococcal in- 2014;69(6):1660–4. fections has emerged as a relevant threat for patients 7. Gastmeier P, Sohr D, Schwab F, Behnke M, Zuschneid I, Brandt C, Dettenkofer M, Chaberny IF, Ruden H, Geffers C. Ten years of KISS: the most and the healthcare system in Germany. Particularly the important requirements for success. J Hosp Infect. 2008;70(Suppl 1):11–6. increasing rate of VRE in blood stream infections pose a 8. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of serious threat for patients. Although specific recommen- health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309–32. dations and efforts regarding prevention of nosocomial 9. Nationales Referenzzentrum für nosokomiale Infektionen: Deutsche infections, transmission of VRE and improvement in nationale Punkt-Prävalenzerhebung zu nosokomialen Infektionen und antimicrobial prescription are in place in Germany, the Antibiotika-Anwendung 2016; Abschlussbericht. Access at http://www.nrz- hygiene.de/fileadmin/nrz/download/pps2016/PPS_2016_Abschlussbericht_ proportion of VRE continues to increase. To this end, 20.07.2017.pdf. Last Accessed 20 Mar 2018. 2016. implementation of effective strategies are necessary in 10. Behnke M, Aghdassi SJ, Hansen S, Diaz LAP, Gastmeier P, Piening B. The order to reduce the spread of VRE. prevalence of nosocomial infection and antibiotic use in German hospitals. Dtsch Arztebl Int. 2017;114(50):851–7. Abbreviations 11. Remschmidt C, Schneider S, Meyer E, Schroeren-Boersch B, Gastmeier P, 95% CI: 95% confidence interval; BSI: Blood stream infection; ICU: Intensive Schwab F. Surveillance of antibiotic use and resistance in intensive care care unit; OR: Odds ratio; SSI: Surgical site infection; UTI: Urinary tract units (SARI). Dtsch Arztebl Int. 2017;114(50):858–65. infection;; VRE: Vancomycin-resistant enterococcus 12. Noll I, Schweickert B, Abu Sin M, Feig M, Claus H, Eckmanns T. Antimicrobial resistance in Germany. Four years of antimicrobial resistance surveillance Availability of data and materials (ARS). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. The datasets used and/or analyzed during the current study are available 2012;55(11–12):1370–6. from the corresponding author on reasonable request. 13. Klare IBJ, Koppe U, Abu Sin M, Eckmanns T, Werner G. Eigenschaften, Häufigkeit und Verbreitung von Vancomycin-resistenten Enterokokken (VRE) in Deutschland – Update 2015/2016. Epid Bull. 2017;46:519–27. https://doi. Authors’ contributions org/10.17886/EpiBull-2017-063. 2017 CR, PG, CG and TSK were responsible for the study design. PG supervised the study. MB and CS were responsible for data collection and data cleaning. CS 14. European Society of Clinical Microbiology and Infectious Diseases: The conducted the statistical analysis. All authors interpreted the data, gave European Committee on Antimicrobial Susceptibility Testing - EUCAST. important intellectual content and revised the manuscript critically. All Available at http://www.eucast.org/. Last Access 20 Mar 2018. 2017. authors read and approved the final manuscript. 15. Hegstad K, Giske CG, Haldorsen B, Matuschek E, Schonning K, Leegaard TM, Kahlmeter G, Sundsfjord A, Nordic ASTVREDSG. Performance of the EUCAST disk diffusion method, the CLSI agar screen method, and the Ethics approval and consent to participate Vitek 2 automated antimicrobial susceptibility testing system for For this study, we analyzed aggregated and anonymous data that were detection of clinical isolates of enterococci with low- and medium-level collected by the hospital in accordance with the German “Protection against VanB-type vancomycin resistance: a multicenter study. J Clin Microbiol. Infection Act”, §23. 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Hand rub consumption has almost doubled in 132 German Received: 28 March 2018 Accepted: 19 April 2018 hospitals over 9 years. Infect Control Hosp Epidemiol. 2017;38(7):870–2. 19. Gastmeier P, Geffers C, Herrmann M, Lemmen S, Salzberger B, Seifert H, Kern W, Fatkenheuer G. Nosocomial infections and infections with multidrug-resistant pathogens - frequency and mortality. Dtsch Med References Wochenschr. 2016;141(6):421–6. 1. O'Driscoll T, Crank CW. Vancomycin-resistant enterococcal infections: 20. Remschmidt C, Behnke M, Kola A, Pena Diaz LA, Rohde AM, Gastmeier P, epidemiology, clinical manifestations, and optimal management. Infect Schwab F. The effect of antibiotic use on prevalence of nosocomial Drug Resist. 2015;8:217–30. Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 7 of 7 vancomycin-resistant enterococci- an ecologic study. Antimicrob Resist Infect Control. 2017;6:95. 21. Harbarth S, Cosgrove S, Carmeli Y. 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Continuous increase of vancomycin resistance in enterococci causing nosocomial infections in Germany − 10years of surveillance

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Springer Journals
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Copyright © The Author(s). 2018
Subject
Biomedicine; Medical Microbiology; Drug Resistance; Infectious Diseases
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2047-2994
DOI
10.1186/s13756-018-0353-x
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Abstract

Background: Enterococci are frequent pathogens causing nosocomial infections in Germany. Infections due to strains with vancomycin resistance are high when compared with other European states. Therefore, the study aimed to describe the recent progression of nosocomial infections due to vancomycin-resistant enterococci (VRE) in Germany. Methods: We analyzed data from two components of the German national nosocomial infection surveillance system for the period 2007–2016. For primary bloodstream infections (BSIs) and urinary tract infections (UTIs) we used data from intensive care units and for surgical site infections (SSIs) data from surgical departments. In a sensitivity analysis, we considered only data from participants that participated continuously from 2007 to 2016 (“core group”). We calculated proportions of VRE among all nosocomial enterococcal infections with 95% confidence intervals (95% CIs) and trends over time. A multivariable logistic regression was used to compare occurrence of VRE proportions among German federal states. Results: Enterococcal infections from 857 ICUs and 1119 surgical departments were analyzed. On ICUs, the proportion of vancomycin resistance in enterococci causing nosocomial infections significantly increased for BSIs from 5.9 to 16.7% and for UTIs from 2.9 to 9.9%; for surgical site infections, the proportion of VRE increased from 0.9 to 5.2% (P < 0.001 for all). In the core group, the increase of VRE was more pronounced in ICUs (BSIs: 5.5 to 21.6%; UTIs: 2 to 11.2%) but was not seen in surgical departments (SSIs: 1.5 to 2.8%). Compared with the most populous German federal state North Rhine Westphalia, enterococcal infections in Hesse (Odds Ratio (OR) 2.3, 95% CI 1.7–3.1), Saxony (OR 2.5, 95% CI 1.8–3.5) and Thuringia (OR 1.9, 95% CI 1.4–2.6) were more likely to be caused by vancomycin-resistant strains. Conclusion: In Germany, the proportion of VRE in nosocomial infection due to enterococci is still increasing. It remains unclear, why a large variation in the proportion of VRE exists between German federal states. Keywords: Vancomycin-resistant enterococci, Multiresistant, Surveillance, Epidemiology * Correspondence: cornelius.remschmidt@charite.de Institute of Hygiene and Environmental Medicine, Charité – University Medicine Berlin, Hindenburgdamm 27, 12203 Berlin, Germany German National Reference Centre for Surveillance of Nosocomial Infections (NRZ), Hindenburgdamm 27, 12203 Berlin, Germany © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 2 of 7 Background with the German “Protection against Infection Act” §23. Vancomycin-resistant enterococci (VRE) have emerged as Therefore, ethical approval by an institutional board was important multiresistant pathogens causing nosocomial not necessary. infections [1, 2]. Infections with VRE are associated with increased length of stay and excess in-hospital mortality Statistical analysis and therefore pose a rising public health threat [3]. In We pooled data recorded in ICU-KISS and OP-KISS 2017, the World Health Organization identified VRE as and analyzed the proportion of VRE for each type of in- one of the most important resistant bacteria in their fection (BSI, UTI, SSI) by dividing the number of entero- “Global Priority list of antibiotic-resistant bacteria list” [4]. coccal infections resistant against vancomycin by the According to the 2016 surveillance report of the Euro- number of all enterococcal infections multiplied by 100. pean Antimicrobial Resistance Network (EARS-Net), a 95% confidence intervals (CIs) were calculated. Data significant increasing trend for VRE between 2013 and were univariate tested for a yearly linear trend by using 2016 was not identified among invasive isolates for the Cochrane-Armitage-test [6]. EU/EEA population-weighted mean percentage [5]; how- A multivariable logistic regression was used to com- ever, in seven out of 30 participating countries a signifi- pare VRE proportions among German federal states. In cant increase of VRE was observed. Ireland (VRE rate of addition to the risk factor federal state, the following po- 44.1%), Greece (27.9%), Slovakia (26.4%), Poland (25.2%) tential confounders were considered: year of the surgical and Hungary (22.5%) showed the highest resistance rates procedure, gender and age group for the patient (0–50, in the EARS-Net 2016 report, if only countries with 51–65, 66–70 and 71–120 years), type of hospital (uni- more than 100 reported isolates were considered. In versity hospital, other hospital), season, type of ICU or Germany, the proportion of VRE among invasive Entero- type of surgical department, and hospital size (400 beds coccus (E.) faecium isolates was 12.1% and comparable and ≥ 400 beds). Stepwise forward-backward selection with the EU/EEA mean. was used to derive the final logistic regression model. Previously, we observed a dramatic increase of the Parameters were entered into the model at a significance proportion of VRE among blood-stream infections and level of P ≤ 0.05 and were removed at P > 0.05. Odds surgical site infections between 2007 and 2012 [6]. Ratios (OR) with 95% CIs were calculated. Therefore, the objective of this study was to investigate Since not all hospitals reported data for the entire the recent development of different nosocomial infec- study period, we conducted a sensitivity analysis in tionscausedbyVRE in Germanybyusing data from which only hospitals were included that had reported the large German national nosocomial infection surveil- data continuously from 2007 to 2016 for at least 6 month lance system. per year (“core group”). P-values less than 0.05 were considered statistically significant. Methods All analyses were performed with R 3.4.3 [R Core We analyzed data that were recorded into two surveil- Team (2013); R Foundation for statistical computing, lance components of the German national nosocomial Vienna, Austria] and SAS 9.4 (SAS Institute Inc., Cary, infection surveillance system (Krankenhaus-Infektions- NC, USA). Surveillance-System, KISS) between 2007 and 2016. Detailed information on KISS and its above-mentioned Results components have been described elsewhere [7]. Briefly, Between 2007 and 2016 a total of 1121 ICUs and 1412 data on nosocomial primary blood stream-infections surgical departments from all German federal states re- (BSI) and nosocomial urinary tract-infections (UTIs) on ported data on nosocomial infections to ICU-KISS and intensive care units (ICUs) were recorded in the ICU OP-KISS, respectively (Table 1). Of those, 12,659 infec- component of KISS (ICU-KISS). Data on nosocomial tions were due to enterococcus species. Overall, the surgical site infections (SSIs) on surgical departments proportion of VRE increased from 1.4% in 2007/2008 were recorded in OP-KISS. Infections were documented to 10% in 2015/2016 (Fig. 1). In BSI, the proportion of according to definitions by the CDC [8]. In KISS, entero- VRE increased from 5.9 to 16.7% (P <0.001). Among coccal infections are not documented on a species level. UTIs and SSIs, the proportion of VRE increased from Therefore, the term VRE is defined as all infections due 2.9 to 9.9% (P <0.001) and from 0.9 to 5% (P < 0.001), to enterococci resistant against vancomycin regardless of respectively (Table 2). the underlying mechanism or species. According to our sensitivity analysis, 218 ICUs and 174 surgical wards reported data continuously on an an- Ethics and data protection nual basis (core group). Overall, the core group showed We analyzed aggregated and anonymous data that are a comparable increase regarding the proportion of VRE collected by the participating hospitals in accordance from 4 to 10%; however, the increase in the core group Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 3 of 7 Table 1 ICUs and surgical departments providing VRE infection data for 2007–16 per year from the German national nosocomial infection surveillance system (KISS) Year/number (n) 2007/08 2009/10 2011/12 2013/14 2015/16 Total Number (n) of ICUs 465 533 645 764 857 1121 Number (n) of surgical departments 432 558 681 919 1119 1412 Nosocomial enterococcal infections Total number (N) of nosocomial enterococcal infections 2047 2559 2253 2639 3161 12,659 Number of VRE infections, n (% (n/N)) 79 (3.9) 106 (4.1) 143 (6.4) 187 (7.1) 318 (10.1) 833 (6.6) Total number (N) of enterococcal infections on ICUs 1520 1927 1574 1700 1929 8650 Number of VRE infections on ICUs, n (% (n/N)) 74 (4.9) 90 (4.7) 119 (7.6) 158 (9.3) 229 (11.9) 670 (7.8) Total number (N) of nosocomial enterococcal infections 527 637 679 939 1232 4009 in surgical wards Number of nosocomial VRE infections in surgical wards, 5 (1.0) 16 (2.5) 24 (3.5) 30 (3.2) 57 (4.6) 132 (3.3) n (% (n/N)) ICU intensive care unit, VRE vancomycin-resistant enterococci; Total number of ICUs/surgical departments that reported data for at least 6 month in any year was more pronounced in BSIs and UTIs whereas the internal medicine ICU: OR: 1.8 (95% CI 1.5–2.2) and proportion of VRE among SSI showed only a small in- calendar year (OR 1.1, 95% CI 1.1–1.2) statistically sig- crease (Fig. 2). VRE proportions increased significantly nificant increased the chance for VRE. in primary BSI from 5.5 to 21.6% (P < 0.001) and in UTI from 2 to 11.2% (P = 0.001). Discussion Regarding differences in the proportion of VRE among Our analysis of the German national nosocomial infec- German federal states, we found that proportion of VRE tion surveillance system revealed a continuous increase infections were > 10% in the 6 federal states of Berlin, of VRE proportions in nosocomial infections caused by Hesse, Saarland, Saxony-Anhalt, Saxony and Thuringia, enterococci in Germany between 2007 and 2016. This all of which are in the center of Germany (Fig. 3). Com- development has become even more apparent since our pared with the most populous federal state North Rhine last report [6]. Westphalia, enterococcal infections in Hesse (OR 2.3, The results on VRE are concordant with other reports 95% CI 1.7–3.1), Saxony (OR 2.5, 95% CI 1.8–3.5) and from Germany. Behnke et al. showed in two consecutive Thuringia (OR 1.9, 95% CI 1.4–2.6) were more likely to national point prevalence studies that vancomycin resist- be caused by VRE. Additionally, the final multivariable ance in E. faecium causing nosocomial infections in- logistic regression indicated that type of hospital (univer- creased from 10.2% in 2011 to 23.1% in 2016 [9, 10]. sity hospital vs. non-university hospital: OR 2.1, 95% CI Another study which analyzed data on antibiotic con- 1.7–2.5), type of ICU (internal medicine ICU vs. non- sumption and antimicrobial resistance in German ICUs Fig. 1 Time trend for percentage of vancomycin-resistant entercoccal (VRE) infections according to the German national nosocomial infection surveillance system (KISS), by infection site Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 4 of 7 Table 2 Data on nosocomial infections due to Enterococci for 2007–16 per year from the German national nosocomial infection surveillance system (KISS), by infection site Surgical site infections Bloodstream infections Urinary tract infections Year Enterococci VRE (n) Proportion in % Enterococci VRE (n) Proportion in % Enterococci VRE (n) Proportion in % (n) (95% CI) (n) (95% CI) (n) (95% CI) 2007 231 2 0.87 (0.15, 2.83) 170 10 5.88 (3.03, 10.23) 450 13 2.89 (1.62, 4.78) 2008 296 3 1.01 (0.26, 2.73) 206 15 7.28 (4.29, 11.47) 540 29 5.37 (3.69, 7.52) 2009 301 7 2.33 (1.02, 4.55) 273 23 8.42 (5.55, 12.18) 591 19 3.21 (2.00, 4.88 2010 336 9 2.68 (1.31, 4.86) 261 20 7.66 (4.88, 11.38) 627 26 4.15 (2.78, 5.93) 2011 357 11 3.08 (1.63, 5.29) 303 32 10.56 (7.46, 14.41) 379 18 4.75 (2.93, 7.26) 2012 322 13 4.04 (2.26, 6.63) 265 33 12.45 (8.88, 16.85) 434 27 6.22 (4.22, 8.80) 2013 420 20 4.76 (3.02, 7.13) 338 30 8.88 (6.18, 12.27) 462 37 8.01 (5.79, 10.76) 2014 519 10 1.93 (0.98, 3.41) 335 30 8.96 (6.24, 12.38) 439 44 10.02 (7.47, 13.10) 2015 615 26 4.23 (2.84, 6.05) 409 57 13.94 (10.83, 17.55) 504 41 8.13 (5.98, 10.77) 2016 617 31 5.02 (3.50, 6.97) 437 73 16.70 (12.39, 18.90) 496 49 9.88 (7.48, 12.75) VRE vancomycin-resistant enterococci found a continuous increase in resistance against vanco- growing sample of hospitals and individual wards report mycin in E. faecium between 2001 and 2016 [11]. Finally, different types of infections (UTIs, SSIs and BSIs). How- comparable results were found in the national anti- ever, even when considering only ICUs that continuously microbial resistance surveillance project [12], where reported data on BSI we observed a continuous increase detection of E. faecium derived from blood-cultures of VRE. (ii) As compared to EARS-net, we considered not has increased by up to 50% in recent years and pro- only BSI but also surgical site infections and urinary tract portion of isolates resistant against vancomycin in- infections. However, when only BSI were analysed in our creased to 11.9% [13]. study, the increase in the last 3 years has been particularly Interestingly, the recent report by the EARS-net de- pronounced and differences to EARS-Net data remain un- scribed a high but stable situation regarding the propor- clear. (iii) Antimicrobial susceptibility testing (AST) in tion of VRE among E. faecium isolates of 12.1% in many microbiological laboratories Germany was per- Germany, which is comparable with the European popula- formed according to Clinical & Laboratory Standards In- tion weighted mean of 11.8% for 2016 [5]. These differ- stitute (CLSI) while EARS-net uses EUCAST-standards ences might be caused by the following reasons. (i) In only [14]. This potentially could influence vancomycin re- EARS-Net, a static representative sample of hospitals from sistance rates especially in low and medium-level resist- defined regions deliver rates of BSI from all wards based ance due to differing recommended AST methods and on laboratory results whereas in KISS a continuously clinical breakpoints [15]. Fig. 2 Time trend for percentage of vancomycin-resistant enterococcal (VRE) infections according to the German national nosocomial infection surveillance system (KISS), by infection site. Data from wards that participated continuously from 2007 to 2016 (“core group”) Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 5 of 7 Fig. 3 Distribution of the proportion of vancomycin-resistant entercoccal (VRE) infections among German federal states according to data from the German national nosocomial infection surveillance system (KISS) 2007–2016 Risk factors that have been described for VRE Nosocomial Infection Surveillance Program (CNISP) colonization or infections are long periods of hospitalization, was analyzed found an increase of VRE in western and hemodialysis, immunosuppression as well as close proximity central Canada [29]. The authors assumed that the to patients infected or colonized with VRE [16]. The fact clonal spread of certain sequence types might have been that enterococci are able to survive on environmental sur- in part responsible for these findings, although a reliable faces for long periods of time [16, 17] highlights the import- explanation was not possible. Kullar et al. evaluated re- ance of adherence to hand hygiene practice to prevent gional variations on VRE across blood, urine and wound transmission. But despite improved adherence to hand- sources in United States Hospitals 2015 and found sig- hygiene and successful reduction of nosocomial infections nificant differences among US states [30]. A potential in Germany [18, 19], VRE continues to gain importance explanation for these results was not discussed. when compared to other multidrug resistant gram-positive The reasons for the regional differences in our study organisms [11]. are also unclear and possible reasons for higher VRE Increased antibiotic consumption has been advocated as rates in the center of Germany are difficult to explain another important risk factor that influence spread of and are likely to be multifactorial [6]. One possible VRE [16, 20, 21]. Many reports have established an indir- explanation might be regional variations in antibiotic ect or direct link between appearance of VRE and the usage in the ambulatory and/or the inpatient setting; for consumption of certain antimicrobial groups but the example, a large population-based study found among connection probably is more complex [21]. Exposure to German federal states differences in outpatient antibiotic substances with a broad gram-negative and anerobic prescription rates [25] of fluoroquinolones and cephalos- microbiological spectrum, but no coverage against E. fae- porines, substances that might influence VRE selection cium are believed to facilitate the colonization of the process [1, 16, 22]. Other reasons for the regional differ- GI-tract with VRE [22]. Particularly carbapenems [20], 3rd ences that have been discussed are differences in the generation cephalosporins [23] but also penicillin’swith proportion of VRE in the environment (e.g. higher pro- beta-lactamase inhibitors such as piperacillin/tazobactam portion of VRE in farm animals) or the spread of new or [24] are likely to trigger this process. In Germany, cepha- clonal VRE strain in certain areas [6]. However, Willems losporins are now the most commonly prescribed in et al. found genetic differences in hospital-acquired VRE German primary care [25] and might have triggered VRE- isolates and community-acquired or animal isolates selection in the outpatient setting already. This would which makes an association between the environment highlight the need of antibiotic stewardship not only in and increased VRE rates in German ICUs unlikely [31]. the inpatient but also in the outpatient setting [26, 27]. Some limitations have to be acknowledged: (i) Since Interestingly, a recent meta-analysis has not found a direct fulfillment of case criteria depends on diagnostic sam- influence of measures within in-hospital antimicrobial pling and documentation there is a risk for underdetec- stewardship and the occurrence of VRE; however, the tion of cases. However, using proportions of VRE for all number of included studies was limited [28]. nosocomial infections caused by enterococci might have Although differences of VRE are obviously among reduce confounding effects for changes in the bacterio- European countries [5], only few studies have assessed logical diagnostic over time, since only pathogen-derived regional differences of VRE within the same country. In infections were included. (ii) We did not record below a a Canadian study, in which the molecular epidemiology genus level of enterococci; therefore, we were unable to of VRE from invasive samples from the National rule out an increase of Enterococcus spp. with intrinsic Remschmidt et al. Antimicrobial Resistance and Infection Control (2018) 7:54 Page 6 of 7 glycopeptide resistance. However, this is less likely 2. Werner G, Coque TM, Hammerum AM, Hope R, Hryniewicz W, Johnson A, Klare I, Kristinsson KG, Leclercq R, Lester CH, et al. 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World Health Organization (WHO): Global priority list of antibiotic-resistant been a contamination rather than the infection-causing bacteria to guide research, discovery, and development of new antibiotics. pathogen. (iv) Finally, we had no information regarding Available at http://www.who.int/medicines/publications/WHO-PPL-Short_ Summary_25Feb-ET_NM_WHO.pdf?ua=1. Accessed 03 Mar 2017. 2017. strain characteristics, therefore local or regional out- 5. European Centre for Disease Prevention and Control: Antimicrobial resistance breaks cannot be excluded. surveillance in Europe 2016. Annual report of the European antimicrobial resistance surveillance network (EARS-net). Stockholm: ECDC. 2018. 6. Gastmeier P, Schroder C, Behnke M, Meyer E, Geffers C. Dramatic increase in Conclusion vancomycin-resistant enterococci in Germany. J Antimicrob Chemother. To proportion of vancomycin-resistant enterococcal in- 2014;69(6):1660–4. fections has emerged as a relevant threat for patients 7. 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Antimicrobial resistance in Germany. Four years of antimicrobial resistance surveillance Availability of data and materials (ARS). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. The datasets used and/or analyzed during the current study are available 2012;55(11–12):1370–6. from the corresponding author on reasonable request. 13. Klare IBJ, Koppe U, Abu Sin M, Eckmanns T, Werner G. Eigenschaften, Häufigkeit und Verbreitung von Vancomycin-resistenten Enterokokken (VRE) in Deutschland – Update 2015/2016. Epid Bull. 2017;46:519–27. https://doi. Authors’ contributions org/10.17886/EpiBull-2017-063. 2017 CR, PG, CG and TSK were responsible for the study design. PG supervised the study. MB and CS were responsible for data collection and data cleaning. CS 14. European Society of Clinical Microbiology and Infectious Diseases: The conducted the statistical analysis. 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Journal

Antimicrobial Resistance and Infection ControlSpringer Journals

Published: Apr 24, 2018

Keywords: Vancomycin-resistant enterococci; Multiresistant; Surveillance; Epidemiology

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