Carbapenemase-producing Enterobacteriaceae in Europe : a survey among national experts from 39 countries , February 2013

C Glasner1, B Albiger2, G Buist1, A Tambić Andrašević3, R Canton4,5, Y Carmeli6, A W Friedrich1, C G Giske7,8, Y Glupczynski9, M Gniadkowski10, D M Livermore11,12, P Nordmann13,14, L Poirel13,14, G M Rossolini15, H Seifert16, A Vatopoulos17, T Walsh12, N Woodford18, T Donker1, D L Monnet2, H Grundmann (h.grundmann@umcg.nl)1, the European Survey on Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) working group19 1. Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 2. European Centre for Disease Prevention and Control, Stockholm, Sweden 3. Department of Clinical Microbiology, University Hospital for Infectious Diseases, Zagreb, Croatia 4. Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain 5. Unidad de Resistencia a Antibióticos y Virulencia Bacteriana asociada al Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain 6. Division of Epidemiology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel 7. Clinical Microbiology, MTC Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 8. Swedish Institute for Communicable Disease Control, Solna, Sweden 9. National Reference Laboratory for Antibiotic Resistance Monitoring in Gram-negative Bacteria, CHU Mont Godinne, Université Catholique de Louvain, Yvoir, Belgium 10. Department of Molecular Microbiology, National Medicines Institute, Warsaw, Poland 11. Norwich Medical School, University of East Anglia, Norwich, United Kingdom 12. Section of Medical Microbiology IIB, School of Medical Sciences, Cardiff University, Heath Park Hospital, Cardiff, United Kingdom 13. INSERM U914 «Emerging Resistance to Antibiotics», Associated National Reference Center for Antibiotic Resistance, Faculté de Médecine et Université Paris-Sud, K. Bicêtre, France 14. Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland 15. Dipartimento di Biotecnologie Mediche, Università di Siena, Siena; Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze; SOD Microbiologia e Virologia, Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy 16. Institute for Medical Microbiology, Immunology and Hygiene, Cologne University, Cologne, Germany 17. Department of Microbiology, National School of Public Health, Athens, Greece 18. Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, United Kingdom 19. The EuSCAPE working group participants are listed at the end of the article

The spread of carbapenemase-producing Enterobacteriaceae (CPE) is a threat to healthcare delivery, although its extent differs substantially from country to country.In February 2013, national experts from 39 European countries were invited to self-assess the current epidemiological situation of CPE in their country.Information about national management of CPE was also reported.The results highlight the urgent need for a coordinated European effort on early diagnosis, active surveillance, and guidance on infection control measures.
The present report summarises the results from 39 European countries of a self-assessment of the epidemiological stage and the management of carbapenemase-producing Enterobacteriaceae (CPE) at national level.

Background
CPE are an emerging threat to healthcare and are frequently resistant to many other antibiotics than carbapenems [1,2] leaving few treatment options.The extent, to which healthcare systems have already been affected, however, differs substantially from country to country.Following a previous initiative, a group of European experts is implementing the European Survey on CPE (EuSCAPE) in an effort to update assessments of the nature and scale of CPE spread in Europe [3].The current programme receives financial support from the European Centre for Disease Prevention and Control (ECDC).The aim of this study is to obtain a more accurate and timely estimate of CPE prevalence in European countries and to support reference laboratory-capacity building to prevent and control the spread of CPE in Europe.

Development of a questionnaire and collection of information
A Scientific Advisory Board of European experts in the field of carbapenemase-producing bacteria was invited to provide scientific advice in support of the EuSCAPE programme management team.A questionnaire was devised and modified from a 'field-tested' version used during previous similar surveys [3].The questionnaire was divided into two sections.The first section (13 questions) explored the experts' knowledge and awareness of the current occurrence of CPE according to a previously-established epidemiological staging system [1,3].In brief, the system captures seven consecutive stages in the national spread of these organisms.The seven stages are described in Table 1.
The second section (22 questions) collected information about existing requirements, structures and guidance documents for reporting, surveillance, use of reference laboratory services and infection control for CPE.The questionnaire is available from the corresponding author.Answers from the NEs were compiled and analysed.When necessary, NEs were contacted by e-mail or telephone for clarification, and corrections were made accordingly.The epidemiological stage of some countries was considered as uncertain when (i) the NE reported a lack of awareness about the current epidemiology of CPE in their country, (ii) the answer of the NE indicated considerable underdetection and underreporting of CPE in their country, (iii) the comments made by the NE by e-mail or telephone indicated uncertainty and/or (iv) when frequent introductions into other countries have been described but the NE could not independently support this observation by own sources.In the maps (Figure ), this uncertainty was indicated by displaying the respective country as hatched.

Results
All NEs completed the online questionnaire.Thirtyseven NEs declared that they were aware of the current epidemiology of CPE in their country and all rated the occurrence and spread of CPE in their country using the previously established epidemiological staging system (Figure and Table 1).Nevertheless, only 26 NEs could self-assess their current situation with certainty.
Three countries (Iceland, Montenegro and the former Yugoslav Republic of Macedonia) reported no cases of CPE in their country.Sporadic cases, single or sporadic hospital outbreaks were reported by NEs from 22 countries.For 11 countries, regional or national spread was reported, whereas for three countries (Greece, Italy and Malta) NEs reported that CPE are regularly isolated from patients in most hospitals, corresponding to the endemic stage (Table 2*).
Among the 31 countries that participated in both the 2010 and 2013 assessments, 17 reported a higher stage by 2013; likewise, by 2013, the number of countries with regional or inter-regional spread or an endemic situation increased from seven to 13 (Table 2 Sporadic hospital outbreaks Unrelated hospital outbreaks with independent, i.e. epidemiologically unrelated introduction or different strains, no autochthonous inter-institutional transmission reported 2b

*). Some countries expressed concerns that underdetection or
Regional spread More than one epidemiologically related outbreak confined to hospitals that are part of a regional referral network, suggestive of regional autochthonous inter-institutional transmission 3 Inter-regional spread Multiple epidemiologically related outbreaks occurring in different health districts, suggesting inter-regional autochthonous inter-institutional transmission 4 Endemic situation Most hospitals in a country are repeatedly seeing cases admitted from autochthonous sources 5 The table was reproduced from reference [3].More details on the epidemiological stages are given in the manuscript Table 1.

Figure
In some countries, the epidemiological stage might not represent the true extent of the spread of CPE as it is a subjective judgment by national experts.Uncertainty about the epidemiological stage of a country is indicated by hatching.Results presented here reflect the uncertainty at the time of the survey.For Portugal, case notification and submission of isolates became mandatory on 21 February 2013.NA: not available.
The epidemiological staging system, developed in 2010, is based on seven levels [3].Stage 0: no case reported; stage 1: sporadic occurrence whereby only single cases are reported; stage 2a: single hospital outbreak reported whereby an outbreak is defined as two or more epidemiologically-associated cases with indistinguishable geno-or phenotype; stage 2b: sporadic hospital outbreaks reported whereby more than one hospital outbreak is reported but all outbreaks are epidemiologically unrelated or caused by different clones (no autochthonous interinstitutional transmission); stage 3: regional spread whereby more than one epidemiologically-related hospital outbreak is reported, but confined to the same region or health district (regional autochthonous inter-institutional transmission); stage 4: inter-regional spread whereby multiple epidemiologicallyrelated hospital outbreaks are reported from different regions or health districts (inter-regional autochthonous inter-institutional transmission); and stage 5: endemic situation whereby most hospitals in a country are constantly seeing cases admitted from autochthonous sources.The epidemiological stage of a country may not reflect the true extent of the spread of CPE, as it is based on the subjective judgment of the responding national expert in 2010 and 2013 and the opinion of the authors of a review in 2012.Some of the countries were not included in the 2010 survey and/or the 2012 review and their epidemiological stage is consequently indicated as 'not available' (NA).Countries that were uncertain about their epidemiological stages had on average 1.9 national management documents regulating surveillance and response structures.In contrast, those who were more certain about their epidemiological stages had on average 4.7 (p-value < 0.001; Wilcoxon Rank Sum Test).

Discussion
The results of this online survey, performed in February 2013, show that, based on the knowledge and judgment of NEs, CPE are continuing to spread in Europe.
Although most countries reported only single hospital outbreaks, the epidemiological situation has deteriorated over the past three years.Among the 31 countries that participated in both 2010 and 2013 assessments, 17 countries were upgraded to a higher epidemiological stage (Table 2).Three countries that reported sporadic occurrence or single hospital outbreaks of CPE in 2010 are now witnessing regional or inter-regional spread, or even an endemic situation.Malta moved from having sporadic cases to an endemic situation, although by nature of its small size, the intermediate epidemiological stages have little relevance.The influx of injured refugees from Libya in 2011, is believed to have contributed to an increase in carbapenem-hydrolysing oxacillinase (OXA)-48-positive Enterobacteriaceae (M.Borg, personal communication, April 2013).In Italy, a sporadic occurrence of Verona integron-encoded metallo-beta-lactamase (VIM)producing Enterobacteriaceae from 2008, accentuated by a single hospital outbreak, has been overtaken by the wide dissemination of KPC-positive K. pneumoniae strains to many healthcare institutions.[4][5][6][7][8][9].The situation in Hungary has evolved in the opposite direction: in 2010, concern centred upon a single clone of KPC-2-positive K. pneumoniae that had attained regional distribution, whereas VIM-4-positive strains were only reported sporadically, but have now spread nationwide [3,10].Overall, KPC-positive Enterobacteriaceae still have the widest distribution among CPE in Europe, but rising numbers of OXA-48-positive isolates are reported, making OXA-48 the most frequently detected carbapenemase in Belgium, France and Malta.Despite the attention that NDM has received when associated with introductions from the Indian subcontinent, the current numbers of reports by European countries are still relatively modest compared to the other carbapenemases [11].The United Kingdom, however, continues to report more NDM-positive isolates than most other European countries [3,12].
The NEs completed the questionnaire to the best of their knowledge, but these were subjective assessments that may have underestimated the true extent of the spread of CPE.Underdetection and underreporting were pointed out by respondents in several countries, leading to uncertainty about the true epidemiological stage (Figure).In particular, this applied to countries from which introductions into other countries have been described but where NEs could not independently assess the extent of CPE spread.Underdetection and underreporting of CPE also coincided with weaker reference laboratory infrastructures and the absence of national recommendations for submission to national reference laboratories and for reporting to health authorities, thus suggesting that the true extent of CPE occurrence in Europe is still underestimated.At the same time, countries with strict screening policies and good surveillance are more likely to report advanced epidemiological stages also affecting the comparability of the assessment.
The keys to success in preventing the establishment of CPE are, firstly, early detection through good diagnostic practices, secondly, containment of spread through patient and contact screening as well as infection control measures.An increasing number of countries have reacted and implemented measures as indicated by the increasing availability of a recommendation or guideline on infection control measures to prevent the spread of CPE [12].Still 17 countries surveyed lacked such guidance and the same number of countries lacked relevant guidance for submission of isolates to national reference laboratories [12].The results of the present report underscore the urgent need for an upgrading of laboratory standards to enable active surveillance and preventive action.To this purpose, the EuSCAPE programme aims to build a laboratory-based network for CPE detection in Europe.

a
The results were based on data obtained through a Europeanwide consultation during a workshop at the Netherlands's National Institute for Public Health and the Environment (RIVM) on 29 and 30 April 2010[3].bThe results were based on the subjective analyses of the literature available at the time of the publication[1].c This online survey (February 2013).d = increase in the epidemiological stage, = decrease in the epidemiological stage and = unchanged epidemiological stage.A dash indicates that there are discrepancies between the results of the 2012 review and the 2013 survey, whereby no direction of change can be given.e For France and Poland, discrepancies between results from the 2012 review and the 2013 survey are probably due to the subjective assessment by different experts.f This designation is without prejudice to positions on status, and is in line with United Nations Security Council resolution 1244/99 and the International Court of Justice Opinion on the Kosovo declaration of independence.g For Montenegro and Turkey, discrepancies between results from the 2012 review and the 2013 survey underline the uncertainty of stage designation for these countries.underreporting, or both, could affect the certainty of the stage of their countries (Figure).Thirty-three of the NEs indicated that Klebsiella pneumoniae was the most frequent Enterobacteriaceae species to produce carbapenemases in their country.Overall, K. pneumoniae carbapenemase-producing Enterobacteriaceae (KPC) have attained the widest distribution, whereas strains with New Delhi metallo (NDM)-beta-lactamase -although responsible for occasional hospital outbreaks in few countries -have not reached such a wide distribution in European countries (Figure).
cells, a dot in signifies 'in place' and the absence of a dot signifies 'absent'.a Agreed criteria or policy (including minimum inhibitory concentration (MIC) cut-off, species and resistance confirmation, epidemiological typing) to submit CPE isolates to a national reference laboratory.b Voluntary notification to health authorities.c Mandatory notification to health authorities.d Country reporting carbapenem-resistant invasive isolates (Klebsiella pneumoniae and Escherichia coli to the European Antimicrobial Resistance Surveillance Network (EARS-Net)).e Only in case of outbreaks.f Only for bacteraemia cases.g This designation is without prejudice to positions on status, and is in line with United Nations Security Council resolution 1244/99 and the International Court of Justice Opinion on the Kosovo declaration of independence.

Table 1
Description of the epidemiological stages of carbapenemase-producing Enterobacteriaceae (CPE) Occurrence of carbapenemase-producing Enterobacteriaceae (CPE) in 39 European countries based on self-assessment by respective national experts, 2013