Prevalence of Vancomycin-Resistant Enterococci in Europe

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1 Eur J Clin Microbiol Infect Dis (2000) 19 : Q Springer-Verlag 2000 Article Prevalence of Vancomycin-Resistant Enterococci in Europe M.A. Schouten, J.A.A. Hoogkamp-Korstanje, J.F.G. Meis, A. Voss, and the European VRE Study Group Abstract The aim of the present study was to determine the prevalence of vancomycin-resistant enterococci (VRE) in Europe. Overall, 49 laboratories in 27 countries collected 4,208 clinical isolates of enterococci. Species identification, susceptibility testing, and van gene determination by polymerase chain reaction were performed in a central laboratory. Overall, 18 vana and 5 vanb isolates of VRE were found. The prevalence of vana VRE was highest in the UK (2.7%), while the prevalence of vanb VRE was highest in Slovenia (2%). Most vana and vanb VRE were identified as Enterococcus faecium. Most VRE isolates originated from the patient s urogenital tract, skin, or digestive tract. VRE were equally distributed among clinical departments, with no clear preponderance in any single patient group. A total of 71 isolates containing the vanc gene were identified. The prevalence of vanc VRE was highest in Latvia and Turkey, where rates were 14.3 and 11.7%, respectively. Two-thirds of these isolates were identified as Enterococcus gallinarum and one-third as Enterococcus casseliflavus; the majority of these isolates were cultured from feces. Almost all isolates were obtained from hospitalized patients, mostly children. The highest prevalence of high-level gentamicin-resistant enterococci was seen in Turkey and Greece. In general, the distribution of this resistance type seemed unrelated to the occurrence of VRE. The prevalence of vana/ vanb VRE in Europe is still low; the majority of the VRE isolates exhibit the vanc genotype and colonize the gastrointestinal tract of hospitalized children. Introduction During the last decade, enterococci have become important nosocomial pathogens, representing the third leading cause of bacteremia and the second leading cause of urinary tract infections in the USA [1, 2]. This increasing prevalence has been paralleled by the occurrence of vancomycin-resistant strains (VRE), which were first reported in 1988 [3, 4]. Since then, strains resistant to teicoplanin and/or vancomycin have appeared throughout the world. VRE frequently M.A. Schouten, J.A.A. Hoogkamp-Korstanje, J.F.G. Meis, A. Voss (Y) University Medical Center St Radboud, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands a.voss6mmb.azn.nl Tel: c Fax: c express additional resistance to multiple antibiotics, including ampicillin and aminoglycosides (including high-level resistance) [5 20], thereby causing therapeutical problems. Between 1989 and 1993, the incidence of VRE colonization among patients in U.S. hospitals increased 26-fold, from 0.3 to 7.9% [21]. Higher incidences (13.6%) were reported among patients admitted to intensive care units (ICUs) [21]. Whereas the rapid emergence of VRE in the USA is probably attributable to the excessive use of vancomycin and/or cephalosporins [22, 23], the occurrence of VRE in Europe is possibly boosted by the (former) use of glycopeptide analogs (e.g. avoparcin) as growth promoters in bioindustry and the consequent transmission of VRE via the food chain [24 26]. Until now, information on the prevalence of VRE in Europe has been limited to the results of several studies performed in single European countries or as a part of unspecific antimicrobial susceptibility surveys. In general, the

2 817 prevalence seems to be low, ranging from 2 to 5% in the community as well as in hospitalized patients [8, 9, 12 14, 16]. Still, higher prevalences ( 1 30%) in hospitals, while unusual, have been reported [27]. The aim of the present study was to determine the prevalence of both VRE and high-level aminoglycoside-resistant enterococci in a prospective, pan-european study, using a single center for identification, susceptibility testing, and further evaluation of all clinical isolates suspected to be enterococci. Materials and Methods Enterococcal Strain Collection. From 1 January to 1 April 1997, a total of 61 European hospitals were invited to participate in collecting enterococci. Strains had to be isolated from clinical material, with a maximum of 100 consecutive isolates per center and one isolate per patient. A patient record form was used to collect additional information on patient demography, clinical details, and previous glycopeptide usage. Species Identification. Collected strains, presumptively identified as Enterococcus species, were sent to our laboratory, where confirmation of the genus and identification to species level was performed by biochemical characterization using Facklam s recommendations [28] and additional testing for methyl-a-dglucopyranoside [29]. In addition, identification of all VRE isolates was confirmed by the API 20 Strep system (biomérieux, France). The final identification of Enterococcus casseliflavus and Enterococcus gallinarum was based on PCR results (vanc1p Enterococcus gallinarum, vanc2penterococcus casseliflavus) when biochemical reaction patterns were nondiscriminatory. Susceptibility Testing. Susceptibility testing of vancomycin (Sigma Chemie, The Netherlands), teicoplanin (Hoechst Marion Merrell Dow, The Netherlands), amoxicillin (SmithKline Beecham, UK), and gentamicin (Ducheva, The Netherlands) was performed by microbroth dilution [30] with Mueller-Hinton broth (BBL ; Becton & Dickinson, The Netherlands), following NCCLS guidelines. Drugs were reconstituted according to the manufacturers directions. High-level gentamicin resistance was defined as MIC 6500 mg/l. Plates were incubated at 37 7C, and growth was assessed after 24 h of incubation. All strains for which the MIC of vancomycin was 14 mg/l were also tested by the E test (AB Biodisk, Sweden), using an inoculum of 0.5 McFarland turbidity and Mueller-Hinton agar (BBL ; Becton & Dickinson). After 24 h of incubation, the MIC was obtained by rounding to the nearest higher doubling dilution. Enterococcus faecalis ATCC and Staphylococcus aureus ATCC were used as reference strains. The presence of van genes was investigated by PCR as described elsewhere [31], using primers from the vana, vanb, and vanc genes. Table 1 Distribution of the 4,208 enterococcal isolates included in the study Enterococcus species No. of isolates Percent E. faecalis 3, E. faecium E. gallinarum E. durans E. casseliflavus E. avium E. faecalis variant E. hirae E. pseudavium E. mundtii E. raffinosum (np49), while the highest number originated from Germany (np371, from 4 centers). Most participating laboratories (87%) were located at teaching hospitals. Eighty-three percent (np3,493) of all isolates were identified as Enterococcus faecalis. The second most frequently isolated species was Enterococcus faecium, accounting for 13.6% (np574) of all enterococcal isolates (Table 1). Vancomycin-Resistant Enterococci. The MIC of vancomycin was 68 mg/l for 51 strains: 18 possessed a vana gene, 5 a vanb gene, and the remaining 28 a vanc gene. Most vana and all vanb VRE were identified as Enterococcus faecium (Table 2). In one isolate, which was initially identified as Enterococcus casseliflavus (vancomycin MIC, 16 mg/l; teicoplanin MIC, 1 mg/l), a multiplex PCR detected the vana gene but not the vanc gene. This strain was classified as vana VRE. The majority of the vanc VRE were Enterococcus gallinarum strains. In addition to the 28 vanc VRE, we identified 43 isolates, either Enterococcus gallinarum or Enterococcus casseliflavus, that were vanc positive but for which the MICs of vancomycin were ^4 mg/l. In the analysis of results, vana- and vanb-containing enterococci are grouped together and will be evaluated separately from the 71 vanc-containing Enterococcus gallinarum and Enterococcus casseliflavus isolates, which are grouped together irrespective of the vancomycin MICs for these isolates. The prevalence of vana and vanb VRE in Europe is shown in Figure 1. Overall, vana/vanb-vre were isolated in only 10 of the 27 participating countries. vana VRE were isolated in eight countries (Table 3). Results Forty-nine centers from 27 European countries participated (range, 1 4 centers per country), collecting a total of 4,208 enterococcal strains. An average of isolates (SD 89.3) per country were included. The lowest number of isolates from a single country originated from Latvia (np42), followed by Greece Table 2 Species distribution of vancomycin-resistant enterococci Resistance type No. (%) of isolates E. faecalis E. faecium E. casseliflavus E. gallinarum vana 2 (11) 15 (83) 1 (6) vanb 5 (100) vanc 22 (31) 49 (69)

3 818 Figure 1 Prevalence (%) of VRE (vanacvanb) in Europe (including Turkey and Israel) The UK had the highest prevalence (2.9%), followed by Israel (2%). The other European countries had prevalence rates of 1% or lower. vanb VRE were isolated in four countries (Slovenia, Finland, Sweden, UK), of which Slovenia had the highest prevalence (2%). vanc VRE were encountered in most countries participating, with the exception of Belgium, Finland, Greece, Slovenia, Sweden, and Switzerland (Table 3). The highest prevalence was seen in Latvia (14.3%), followed by Turkey (11.7%). The highest prevalence of high-level gentamicinresistant enterococci (HLGRE) was found in Greece (48.9%), followed by Turkey (48.1%). The lowest prevalence of HLGRE was found in Norway, followed by Russia, Denmark, and France (Table 3). Table 4 shows the distribution of glycopeptide-susceptible enterococci and VRE by patient characteristics and culture sites. In general, the isolates were equally distributed between the sexes, with slightly more men being colonized with vanc VRE. Susceptible and resistant isolates originated mainly from patients between 16 and 65 years of age, with the exception of vanc VRE, which were isolated predominately from patients between the ages of 1 and 16. Compared to the age distribution of GSE, the prevalence of VRE was slightly lower among elderly patients. Three-quarters of the glycopeptide-susceptible enterococci were isolated from hospitalized patients, whereas 83% of all vana/vanb VRE were isolated from admitted patients, including all vanb isolates. The percentage of vanc VRE originating from hospitalized patients was even higher, namely 91%. Overall, glycopeptide use was documented in 3.5% of the patients whose isolates were included in the study. In 10% of the patients with vanc VRE and in 16% of the patients with vana VRE, prior glycopeptide use was documented. vana/vanb VRE were equally distributed throughout nine different departments. vanc VRE were distributed among 12 departments, with one-third of these

4 819 Table 3 Distribution of vancomycin-resistant enterococci (VRE) and high-level gentamicin-resistant enterococci (HLGRE) by country Country No. (%) of isolates VanA VanB VanC HLGRE Austria 1 (0.7) 26 (17.6) Belgium 1 (1) 8 (8.0) Bulgaria 5 (5.3) 32 (33.7) Croatia 1 (1.1) 25 (26.9) Czech Republic 1 (1) 3 (3.0) 29 (29.3) Denmark 1 (0.4) 12 (5.3) Finland 1 (1) 37 (18.7) France 1 (0.3) 16 (5.5) 17 (5.9) Germany 3 (0.5) 9 (3.3) 68 (18.3) Greece 24 (48.9) Hungary 2 (1.0) 55 (27.9) Israel 4 (2) 1 (0.5) 43 (21.9) Italy 3 (1) 2 (0.7) 54 (18.9) Latvia 6 (14.3) 12 (28.6) Lithuania 3 (4.0) 29 (38.7) Netherlands 1 (0.4) 75 (27.0) Norway 1 (1.0) 1 (1.0) Poland 1 (0.5) 50 (26.7) Portugal 1 (1.0) 24 (24.7) Russia 1 (1.5) 1 (1.5) Slovak Republic 1 (1) 3 (3.0) 8 (8.4) Slovenia 2 (2) 25 (26.3) Spain 2 (0.9) 62 (27.7) Sweden 1 (0.3) 19 (19.0) Switzerland 23 (7.9) Turkey 9 (11.7) 37 (48.1) UK 4 (2.7) 1 (0.7) 2 (1.5) 50 (36.8) isolates originating from pediatric patients. No VRE were found among patients from neurologic/neurosurgical ICUs, gynecology, or geriatric wards. The urogenital tract was the major source of the enterococci isolated, independent of their resistance to glycopeptides. Significantly more vana/vanb VRE were isolated from patients blood and skin cultures. vanc VRE could be isolated from five different sites, with the majority (58%) from the digestive tract, followed by the urogenital tract (20%). Microepidemiological Evaluation. A more detailed evaluation of the British vana VRE, which originated from two different centers, showed that the four isolates came from four different departments, different body sites, and from patients of different age groups, thus giving no indication of a cluster or epidemiological relatedness. Similarly, no epidemiological relation was seen among the Israeli VRE isolates. Multiple patients with vanb VRE were found only in Slovenia. Two Enterococcus faecium isolates came from the same center and culture source (skin), but from different departments. Results of the PCR fingerprinting suggested that they were not related. When looking further at vanc VRE, it appeared that the 33% peak prevalence seen among children included isolates recovered from the digestive tract (74%), the urogenital tract (17%), and blood (9%). Strains isolated from the last two sites were all vancomycin susceptible, while half of the strains from the digestive tract were vancomycin resistant (MIC, 8 mg/l). The resistant strains (np8), isolated from the digestive tract, originated from a single French center and were distributed equally between boys and girls. All strains were identified as Enterococcus gallinarum. The susceptible strains (np7) came from the same French center and were identified either as Enterococcus casseliflavus or Enterococcus gallinarum. The vanc VRE isolated from the urogenital tract comprised four strains, three of which were derived from one Turkish center. All three isolates were identified as Enterococcus gallinarum. The blood isolates (np2) came from the same Turkish center and were also identified as Enterococcus gallinarum. The high prevalence of vanc VRE in Latvia (14.3%) resulted from six strains isolated from the digestive tract of children. One child was admitted to the pediatric ICU; wards to which the other children were admitted were not specified. Both Enterococcus gallinarum and Enterococcus casseliflavus were isolated. Discussion Since the first reports in 1988 [3, 4], VRE has become a common clinical pathogen in the USA [1, 2, 21]. Whereas VRE in the USA seems to be a hospital problem, probably caused by the extensive use of vancomycin and other antimicrobial agents such as cephalosporins [22, 23], VRE in Europe are present among hospitalized as well as nonhospitalized patients [16]. Furthermore, the prevalence of VRE in Europe is comparably low, but this assumption is based solely on studies performed in single European countries or conducted as a part of unspecific antimicrobial susceptibility surveys [8, 9, 12 14, 16]. Until now, no prospective pan-european VRE surveillance study using a central laboratory for identification and susceptibility testing has been performed. Furthermore, not all investigators differentiate between the particular types of VRE. Certainly, vana- and vanbcontaining enterococci, especially the primarily multiresistant Enterococcus faecium strains, have a much higher clinical impact than vanc VRE, such as Enterococcus casseliflavus or Enterococcus gallinarum. The latter only rarely cause clinical infections. In the present study, only 23 (0.5%) isolates were of the vana/vanb resistance type, whereas the overall prevalence of van-gene-containing VRE (23 vana/vanb c 71 vanc isolates) would have been 2.2%. Thus, the inclusion of all enterococci that harbor a van gene may lead to an overestimation of the clinical problem.

5 820 Table 4 Distribution of enterococci by patient characteristics and clinical variables (%) Variable vanacvanb VRE vanc VRE VSE Total (np23) (np71) (np4,114) (np4,208) Sex Male Female Age ~1 year years years years Glycopeptide use Yes No Unknown Hospitalized Yes No Source of isolate Blood Digestive tract Respiratory tract Skin Spinal fluid Urogenital tract Other Unknown Department Internal medicine Hematology Geriatrics Intensive care Surgery Orthopedics Urology Gynecology Pediatrics Other VRE, vancomycin-resistant enterococci; VSE, vancomycin-sensitive enterococci Furthermore, only 28 of the 71 (40%) vanc-containing isolates were actually vancomycin resistant (MIC68 mg/l) and therefore rightfully referred to as VRE. In contrast to the occurrence of MRSA among European countries [32], the prevalence of VRE shows no special geographical distribution. Theoretically, VRE and MRSA could be two links of the same chain, since a high MRSA prevalence may augment an excessive vancomycin use that consequently could lead to the occurrence of VRE. Such a phenomenon is clearly not reflected in the distribution of VRE among European countries, as shown in the present study. In general, vana/vanb VRE seem to be equally distributed with regard to patients sex and age, clinical department of origin, and site of isolation. An exception is the morethan-twofold higher occurrence of vana/vanb VRE in blood cultures, possibly indicating a higher risk of serious infections due to enterococcal isolates resistant to even the ultimate treatment option. The distribution of HLGRE in Europe follows neither that of VRE nor that of MRSA. Some countries like the UK have a high prevalence of VRE and HLGRE, while others, like Greece, have no VRE yet have the highest prevalence of HLGRE in Europe. Thus, no correlation between the prevalence of any type of VRE and HLGRE can be made. The use of vancomycin or cephalosporins has been described as a risk factor for the selection of VRE [33]. In the present study, patients colonized or infected with VRE (especially vana/vanb VRE) had a higher rate of prior glycopeptide use, namely 13% versus 3.5% in patients with vancomycin-susceptible isolates. With regard to the above-mentioned study, these findings might be accurate, but the number of patients for whom no data on vancomycin use could be documented is too high to consider these results reliable. In contrast to vana/vanb VRE, which were equally distributed by patient and clinical characteristics, vanc VRE were found more frequently in young males. Accordingly, isolates came predominately from pediatric patients, with more than 50% of the patients ranging from 1 to 16 years of age. The proportion of vanc VRE in children, therefore, was 3.2- and 3.9-fold

6 821 higher than the proportion vana and vanb VRE, respectively. Furthermore, with only 13.2% of all enterococci isolated from the digestive tract, the proportion of vanc VRE isolated from this source was 4.4-fold higher. In general, the pan-european VRE prevalence is still very low, but considering the high prevalence of HLGRE in Europe, enterococci may pose a serious threat to the treatment of patients with invasive infections. In such patients, combination therapy may be warranted, especially in those countries where the prevalence of both resistance types is high. Acknowledgement The members of the European VRE Study Group are as follows: Austria: Dr. C. Jebelean, Prof. Dr. M. Rotter; Belgium: Prof. Dr. M.J. Struelens; Bulgaria: Dr. E.E. Keuleyan; Croatia: Dr. A. Boras; Czech Republic: Prof. Dr. J. Schindler; Denmark: Dr. A. Bremmelgaard, Dr. N. Frimodt- Moller, Dr. A. Lester; Finland: Dr. O.O. Liimatainen, Dr. J. Vuopio-Varkila; France: Prof. Dr. A. Andremont/Dr. C. Muller- Serleys, Prof. Dr. J. Etienne, Dr. J. Raymond; Germany: Dr. L. Bader, Prof. Dr. R. Lütticken/Dr. R.R. Reinert, Prof. Dr. G. Peters/Dr. R. Gross, Prof. Dr. Shah; Greece: Dr. G. Syrogiannopoulos, Dr. O. Vavatsi-Manou; Hungary: Dr. A. Marton, Prof. Dr. E. Nagy; Israel: Dr. C. Block, Prof. Dr. P. Yagupsky; Italy: Prof. Dr. G.A. Botta, Prof. Dr. G. Marchiaro, Prof. Dr. S. Stefani; Latvia: Dr. D. Gardovska/Dr. L. Drukalska; Lithuania: Prof. Dr. V. Usonis; Netherlands: Dr. H.P. Endtz, Dr. J.G.M. Koeleman; Norway: Dr. A. Sundsfjord; Poland: Dr. M. Basta, Dr. E. Torbicka, Dr. A. Rokosz, Dr. A. Sawicka-Grzelak; Portugal: Prof. J. Melo-Cristino; Russia: Dr. I.A. Popova; Slovak Republic: Prof. Dr. V. Krcmercy; Slovenia: Prof. Dr. M. Gubina; Spain: Dr. F. Asensi-Botet, Prof. Dr. C. Riestra, Dr. J. Villa; Sweden: Prof. Dr. L.G. Burman, Dr. M.H. Laurel, Dr. M. Rylander; Switzerland: Dr. R. Frei; Turkey: Dr. G. Kanra; UK: Dr. P.R. Chadwick, Dr. E.H. Price References 1. 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