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EARSS receives funding from the European Commission. Information contained in this publication does not necessarily reflect the opinion or the position of the European Commission. EARSS is also financially supported by the Dutch Ministry of Health, Welfare and Sports.
EARSS receives funding from the European Commission. Information contained in this publication does not necessarily reflect the opinion or the position of the European Commission. EARSS is also financially supported by the Dutch Ministry of Health, Welfare and Sports.
EARSS receives funding from the European Commission. Information contained in this publication does not necessarily reflect the opinion or the position of the European Commission. EARSS is also financially supported by the Dutch Ministry of Health, Welfare and Sports.
Stef Bronzwaer European antimicrobial resistance surveillance as part of a Community strategy Stef Bronzwaer Colofon Stef Bronzwaer, 2003 Lay-out: Studio aan de Werf Cover: Studio RIVM Printing: Wilco, Amersfoort ISBN electronic version: 90-367-1830-9 EARSS receives funding from the European Commission. The information contained in this publication does not necessarily reflect the opinion or the position of the European Commission. EARSS is also financially supported by the Dutch Ministry of Health, Welfare and Sports. RIJKSUNIVERSITEIT GRONINGEN European antimicrobial resistance surveillance as part of a Community strategy Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 1 oktober 2003 om 14.15 uur door Stephan Louis Adrianus Marie Bronzwaer geboren op 28 april 1967 te Heerlen Promotor: Prof. dr. J.E. Degener Co-promotor: Dr. M.A.E. Conyn-van Spaendonck Aan Pa Contents Chapter 1 Introduction 3 Chapter 2 Objectives and set up of the European Antimicrobial Resistance Surveillance System (EARSS) 13 Chapter 3 Standardisation of Streptococcus pneumoniae and Staphylococcus aureus susceptibility data within EARSS 19 Chapter 4 Comparability of antimicrobial susceptibility test results from 22 European countries and Israel: an external quality assurance exercise of EARSS in collaboration with UK NEQAS 29 Chapter 5 Streptococcus pneumoniae susceptibility data in Europe 51 Chapter 6 A European study on the relationship of antimicrobial use and antimicrobial resistance 77 Chapter 7 Staphylococcus aureus susceptibility data in Europe 89 Chapter 8 The Community strategy against antimicrobial resistance concerning human medicine 105 Chapter 9 General discussion 121 Summary 131 Samenvatting 135 Acknowledgements 139 Curriculum Vitae 145 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 1 Chapter 1 Introduction The introduction of penicillin in clinical practice dates back to the 1940s, and almost immediately the possibility for micro-organisms to develop resistance to antibiotics was recognised. Some 60 years later, antimicrobial resistance has become a major public health concern and a world-wide problem, requiring international approaches. The worlds leading health authorities, such as the World Health Organisation (WHO) and the Centers for Disease Control and Prevention (CDC), as well as the European Community have recognised the importance to study the emergence and determinants of antimicrobial resistance and launched strategies for its control (1-3). Antimicrobial resistance makes infections more difficult to treat. It may also increase the length and severity of illness, the period of infectiousness, adverse reactions (due to the need to use less safe alternative drugs), length of hospital admission and costs (4, 5). The emergence of resistance represents adaptive selection by micro-organisms which is to some extent an inevitable result of the therapeutic use of antibiotics. Killing or suppressing drug-sensitive organisms allows naturally drug-resistant ones to emerge which can then not only spread but also transfer their resistance to other organisms. There is an established but complex relation between the consumption of antibiotics and the prevalence of drug resistance in micro-organisms. This problem can not be overcome by continuously developing new drugs, as time needed may come too short. An important complementary step is to avoid further increase in resistance by reducing unnecessary and inappropriate use of antibiotics. This makes it imperative that measures are taken to slow the emergence and spread of resistance to existing antibiotics and to new ones as they come into use. This chapter provides a brief discussion on the concept of resistance and will illustrate some clinical implications of recalcitrant infections with resistant strains as opposed to infections with susceptible strains. Mechanisms of resistance Resistance is considered to be present if a bacterium is not susceptible to a clinically- relevant concentration of an antibiotic and/or when it is possible to demonstrate that the bacterium possesses a mechanism or property which will render the antibiotic ineffective. Resistance of a bacterium to an antibacterial substance may be: Inherent: the species is not normally susceptible to a particular drug. This may be due to an inability of the antibacterial to enter the bacterial cell and reach its target site(s), lack of affinity between the antibacterial drug and its target (site of action), or absence of the target in the cell. This is also called intrinsic resistance. Acquired: the species is normally susceptible to a particular drug but certain strains express drug resistance that may be mediated via a number of mechanisms: i. destroying enzymatically the antimicrobial agent inside or outside the cell; 4 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY ii. lowering the intracellular concentration of an antimicrobial as a result of reduced uptake and/or increased excretion; iii. altering the target site so that the antimicrobial no longer binds to it; iv. creating an alternative metabolic pathway that bypasses the target action. In those strains having an inherent or an acquired mechanism of resistance, minimum inhibitory concentrations (MICs) of the antibiotic may be higher than those which may be achieved for an adequate period at the site of infection and, hence, there is the risk of therapeutic failure. Sometimes two or more mechanisms exist simultaneously in the same organism and may produce an even greater degree of resistance. One single mechanism of resistance may bring about the ability to resist actions of some or all of the drugs of a particular class (cross-resistance). Therefore, exposure of a bacterial population to one single antibiotic may select for organisms that display resistance to a large number of similar agents. Transfer of resistance There is a genetic basis for all bacterial resistance to antimicrobial agents. Inherent resistance is determined by the genetic composition of a particular bacterial species. Acquired resistance is brought about either by random mutation of the DNA of the bacterial genome, which is then passed on to offspring, or by the acquisition of DNA containing a gene or genes which code for a mechanism(s) of resistance. DNA may be transmitted to other bacterial cells by three processes: conjugation, transformation and transduction (6). In conjugative transfer, DNA passes along a tube that links two bacteria, which may occur between bacteria of the same or similar species. Plasmids carrying genes as transposable elements (transposons) may transfer between cells. Those carrying more than one transposon can encode resistance to many, chemically unrelated, antibacterials. Transformation involves the uptake of DNA from the environment. DNA acquired by this process may come from an unrelated species, and antibacterial resistance may be acquired even from species not usually responsible for causing disease. Transduction involves the transfer of DNA by a bacteriophage. Extent of the problem There is no clear answer to the question of the extent of the resistance problem. In the Netherlands, for example, the Rijksinstituut voor Volksgezondheid en Milieu (RIVM, National Institute of Public Health and the Environment) and a number of associated regional laboratories run a resistance monitoring programme. The data can be used in order to formulate antibiotics policy both inside and outside hospitals. However, this concentrates on selected material so that no picture is established of morbidity and mortality in the population as a whole or of financial consequences. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 5 Resistant strains are generally no more virulent than non-resistant ones. However, an infection with a resistant strain can be much more serious because the chance of effective treatment is much lower. Little is known about the frequency of problems of this kind. In addition, it is also possible that patients will remain contagious for longer as a result of inadequate treatment so that an infectious disease can spread more extensively. Mild infections often improve after treatment using antibiotics to which the pathogen is resistant (7). The reason for this may be that, despite the reduction in susceptibility, enough effective concentrations are still attained at the location of the infection (8, 9). Another possible cause is that the natural course of many of these infections - such as bronchitis, otitis and sinusitis - is also generally positive without antibiotics (7). Staphylococcus aureus: resistant (MRSA) or susceptible to methicillin (MSSA) In a case-control study, patients infected with MRSA and MSSA in a hospital in the United States were compared with one another (10). Of the S. aureus infections, 31% were caused by MRSA. Infection was associated with several prior courses of antibiotics and extension of the period of admission by seven days. There was no increase in mortality. Another study produced a comparable result (11). In some hospital departments, the period of admission was increased by 30 days. In a retrospective study Crowcroft and Catchpole used death certificates to examine the evidence that mortality due to MRSA and staphylococcal infections in England and Wales is increasing (12). MRSA was mentioned on 20.6% (1387/6723) of death certificates that included an ICD-9 code for staphylococcal infection, gradually increasing from 7.5% in 1993 to 25.0% in 1998. Although recognising limitations of using routine mortality data for monitoring the impact of MRSA, they conclude that infections due to MRSA seem to be an increasing cause of mortality in England and Wales. It is assumed that there are a number of risk factors for the contraction and selection of MRSA, like frequent and extensive use of wide-spectrum antibiotics, lengthy hospital admission, presence of decubitus ulcers and other pre-existent skin disorders, intravascular endoprotheses, administration systems and indwelling catheters. Recently a number of reports are published on MRSA strains possessing the Panton Valentine Leukocidin (PVL) gene. The PVL gene encodes a highly potent toxin, which is involved in severe skin infections and necrotising pneumonia. PVL positive MRSA strains have been detected in the Netherlands and have also been reported in France (in healthy individuals), in the United States (in the Los Angeles gay community, and in a large prison), and in Scotland (small outbreaks of skin abscesses in healthcare staff ) (13). It has been suggested that the PVL MRSA is acquired in the community (14-16). 6 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Penicillin-resistant and penicillin-sensitive Streptococcus pneumoniae The mechanism for penicillin resistance in pneumococci is comparable to that of MRSA and is based upon the change in the affinity of beta-lactam antibiotics for the penicillin- binding proteins in the bacterial cell wall (6). Penicillin resistance in pneumococci is still only a sporadic phenomenon in the Netherlands (17), but studies in other European countries report resistance rates of 50% or more (18). The fact that the highest MIC value found for pneumococci in European research is 8 mg/l whereas this is normally < 0.1 mg/l shows that resistance is not absolute. That is why, in the treatment of less serious infections with high doses of penicillin or amoxicillin, a beneficial effect is still usually seen. In the case of more complex infections and infections in compartments where the antibiotic penetrates with greater difficulty, as in the case of the central nervous system and pulmonary abscesses in emphysema, therapeutic failure should be kept in mind (8). Penicillin-resistant pneumococci are less susceptible to cephalosporins. Furthermore, a considerable proportion is resistant to other drugs such as the macrolides, quinolones and doxycycline. The diffusion of teicoplanin and clindamycin is poor in cerebrospinal fluid. Susceptibility is universal only in the case of vancomycin. Complications seen in penicillin resistance have been described in systemic pneumococcal infections with bacteraemia. In a retrospective study in Spain (19), mortality was significantly higher (54%, n=24) in patients with infections involving resistant pneumococci than in patients with susceptible pneumococci (25%, n=48). Patients with resistant pneumococci had often been treated with antibiotics before. They had also suffered from pneumonia more often and more of them were seriously ill. In a later prospective study carried out by the same researchers, no increase in mortality was found after the results had been corrected for other causes of death (20). Implications Resistance is a problem with logistical and economical implications. This is true in particular of the severe infections that require hospital admission or which arise in hospitals. In the case of multi-resistance, quarantine measures are required which are not only difficult for the patient in psychosocial terms but which are also accompanied by a higher workload for staff. Often, relatively expensive antimicrobial therapies are required. A number of controlled studies have shown that, in patients with both an infection and resistance, length of admission and costs in general are at least doubled (8). For general practitioners, it is of major importance to follow a restrictive antibiotic policy given the fact that many infections seen in general practice (upper airway infections) are caused by viruses. Antibiotics should only be prescribed upon strict indication. The Standards of the Netherlands Society of General Practitioners, partly available in English, provide guidelines in this respect (21). If an antibiotic is indicated, the classic drugs should be selected first. Where possible, preference will be for drugs with a narrow EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 7 spectrum. In addition, reserve drugs should never be prescribed blindly, since this can contribute to the increase of resistance to these drugs. If an antibiotic therapy that has been started fails, resistance should be tested by means of a culture. Subsequent treatment should be based on the result of this test. For a number of bacterial antigens and clinical situations, it has been demonstrated that resistance to antibiotics is a complicating factor. Resistance constitutes a threat to patients in risk categories such as those with reduced immunity or those who are infected with tuberculosis or salmonella bacteria. Fast treatment that covers the susceptibility spectrum can often save lives here. If the right antibiotic is not prescribed for this patient group given the susceptibility of the bacterium, therapeutic failure with serious consequences is seen more often than if the right choice had been made. Alongside common strains of bacteria such as Staphylococcus aureus and enterococci, it is in the nature of things that more resistant strains are found in this situation, examples being Pseudomonas spp. and Serratia spp. For a few of the species, it has been shown that infections with resistant strains are associated with higher rates of morbidity, mortality and recurrent infections. This applies to the entire range of Gram-positive and -negative species of bacteria that can cause bacteraemia. Not a single one of these species of bacteria is an obligate pathogen; they constitute a part of the indigenous flora or of flora in the environment that colonises the patient. It is only under exceptional circumstances that their pathogenic properties become evident. In the Netherlands, in October 1996, the Dutch Working Party on Antibiotic Policy (Dutch acronym is SWAB) was established as an initiative of the Society of Infectious Diseases and the professional societies of medical microbiologists and hospital pharmacists (22). The mission of the SWAB is to contribute to the containment of the development of antimicrobial resistance and of the expanding costs of the use of antibiotics. This is achieved by optimising the use of antibiotics by means of guideline development, education and antibiotic resistance surveillance. In December 2000, the Council on Health Research advised the government on antibiotic resistance. The Minister of Health responded in November 2001, stating that she would follow this advice to a large extent. This advice by the Council on Health Research as well as the decision made by the Minister of Health are of great importance to the SWAB, because the SWAB has since then been designated to co-ordinate the surveillance of antibiotic resistance in the Netherlands. Background and outline of thesis Pathogens have never recognised the ever more fading European frontiers as barriers. There is a clear need for European collaboration to control infectious diseases. The Treaty of Amsterdam makes provision for action directed towards improving public health, preventing human illness and diseases. At the EU conference The Microbial Threat, held in Copenhagen in 1998, all EU Member States unanimously agreed that antimicrobial 8 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY resistance was no longer a national problem, but a major international issue requiring a common strategy at European level (23). One of the recommendations made at this conference was that a European surveillance system of antimicrobial resistance should be set up. In the same year the RIVM (National Institute of Public Health and the Environment) in the Netherlands had taken the initiative and received funding from the European Commission to start with the European Antimicrobial Resistance Surveillance System (EARSS). In 2001, at a follow-up EU-conference in Visby, Sweden, it was concluded that all Member States should join EARSS as a minimum requirement of national surveillance programmes. Surveillance of antimicrobial resistance is a first step towards containment of the problem and is generally considered to be necessary to provide local data for selection of empirical therapy, to assess the scale of the resistance problem at local, national or international level, to monitor changes in resistance rates, to detect the emergence and spread of new resistances, and to provide a measure of the effectiveness of interventions aimed at reducing resistance. Surveillance can also provide an opportunity to improve the quality of susceptibility testing among participants in the surveillance (24). This thesis aims to explore ways how to set up and improve European surveillance of antimicrobial resistance as a necessary step in the containment of antimicrobial resistance. Microbiological laboratories are using different diagnostic protocols between and even within countries. Indications for taking clinical samples may vary as well as the choice of antibiotics. Criteria for discriminating resistant isolates from susceptible bacteria are often based on national, and not on international consensus. How to address these problems, aiming to provide reproducible and comparable data from the participating laboratories, is studied and discussed in chapters 2 and 3. In chapter 4 the question is asked whether laboratories in different countries are able to provide reliable results when it comes to susceptibility testing of the bacterial species under surveillance. For this reason we initiated an external quality exercise to study the comparability of susceptibility test results among participants. In chapter 5 a survey is described to investigate the European geographical distribution and a trend-analysis of the susceptibility of the community-acquired pathogen S. pneumoniae against a number of indicator antibiotics. In chapter 6 we investigate whether there is a relationship between the level of resistance in a certain country and the level of antimicrobial use. We therefore study the correlation between S. pneumoniae resistance rates and the amount of penicillin and macrolides used at country level. In chapter 7 a survey is described to investigate the European geographical distribution and a trend-analysis of the susceptibility of a common hospital-acquired pathogen S. aureus against key indicator antibiotics. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 9 In chapter 8 we aim to provide the larger framework of which EARSS is part. We present the comprehensive Community strategy against antimicrobial resistance with its actions to contain antimicrobial resistance and discuss how these actions are to be co-ordinated. Finally, in chapter 9 we discuss general findings of the studies and provide recommendations specifically for community- and hospital-acquired pathogens. References 1. European Community. Official Journal of the European Community. Council Resolution of 8 June 1999 on antibiotic resistance A strategy against the microbial threat. Official Journal C 195, 13/07/1999 p.13. Available at: http://europa.eu.int/eur-lex/en/lif/dat/1999/en_ 399Y0713_01.html. Accessed April 29, 2000. 2. World Health Organization. Report on Infectious Diseases 2000: Overcoming antimicrobial resistance. www.who.int/infectious-disease-report/index.html. Accessed September 23, 2000. 3. Centers for Disease Control and Prevention. Preventing Emerging Infectious Diseases. www.cdc.gov/ncidod/emergplan/plan98.pdf. Accessed May 20, 2000. 4. Metly J, Hoffmann J, Cetron M, Fine M, Farley M, Whitney C, Breiman R. Impact of Penicillin Susceptibility on Medical Outcomes for Adult Patients with Bacteremic Pneumococcal Pneumonia. Clin Inf Dis 2000;30:520-8. 5. Kim T, Oh PI, Simor AE. The economic impact of methicillin-resistant Staphylococcus aureus in Canadian hospitals. Infect Control Hosp Epidemiol. 2001 Feb;22(2):99-104. 6. Neu HC. The crisis in antibiotic resistance. Science 1992; 257: 1064-1072. 7. Melker RA de. Effectiviteit van antibiotica bij veel voorkomende luchtweginfecties in de huisartspraktijk. Ned Tijdschr Geneeskd 1998; 142: 452-456. 8. Klugman KP. The clinical relevance of in-vitro resistance to penicillin, ampicillin, amoxycillin, and alternative agents for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. J Antimicrob Chemother 1996; 38 (suppl A): 133-140. 9. Friedland IR, McCracken GH jr. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 1994; 331: 377-382. 10. Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher E. Methicillin-resistant Staphylococcus aureus. Epidemiologic observations during a community-acquired outbreak. Ann Intern Med 1982; 96: 11-16. 11. Holmberg SD, Solomon SL, Blake PA. Health and economic impacts of antimicrobial resistance. Rev Infect Dis 1987; 9: 1065-1078. 12. Crowcroft NS, Catchpole M. Mortality from methicillin resistant Staphylococcus aureus in England and Wales: analysis of death certificates. BMJ 2002;325:1390-1. 13. Wannet W. Virulent MRSA strains containing the Panton Valentine Leukocidin gene in the Netherlands. Eurosurveillance weekly 7;10. www.eurosurveillance.org/ew/2003/030306.asp Accessed 7 April 2003. 14. Dufour P, Gillet Y, Bes M, , et al. Community-acquired methicillin resistant Staphylococcus aureus in France: emergence of a single clone that produces Panton Valentine Leukocidin. Clin Infect Dis 2002; 35: 819-24. 15. Gonzalez-Zorn B, Courvalin P. VanA-mediated high level glycopeptide resistance in MRSA. Lancet Infect Dis 2003; 3: 67-8. 10 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 16. SCIEH. Community MRSA and Panton-Valentin leukocidin. SCIEH Weekly Report 2002; 36: 298. http://www.show.scot.nhs.uk/scieh/PDF/pdf2002/0246.pdf. Accessed 7 April 2003. 17. Neeling AJ de, Pelt W van, Hendrix MGR, Buiting AGM, Hol C, Ligtvoet EEJ et al. Antibiotica resistentie in Nederland. Deel III: Gram-positieve bacterin. Infectieziektenbulletin 1997; 8: 211-215. 18. Goldstein FW, Acar JF. The Alexander Project Collaborative Group. Antimicrobial resistance among lower respiratory tract isolates of Streptococcus pneumoniae: results of a 1992-93 western Europe and USA collaborative surveillance study. J Antimicrob Chemother 1996; 38 (suppl A): 71-84. 19. Pallares R, Gudiol F, Linares J, Ariza J, Rufi G, Murgui L et al. Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med 1987; 317: 18-22. 20. Pallares R, Linares J, Vadillo M, Cabellos C, Manresa F, Viladrich PF. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona in Spain. N Engl J Med 1995; 333: 474-480. 21. Official web site of the Netherlands Society of General Practitioners: http://nhg.artsennet.nl/ index.asp?s=4512. Accessed 6 May 2003. 22. Official SWAB web site: www.swab.nl. Accessed 3 January 2003. 23. State Serum Institut and Danish Veterinary Laboratory, eds. The Copenhagen recommendations the microbial threat. Ministry of Health, Ministry of Food, Agriculture and Fisheries, 1998. 24. Kahlmeter G, Brown D. Resistance surveillance studies comparability of results and quality assurance of methods. J. Antimicrob. Chemother. 2002 50: 775-7. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 11 Chapter 2 Objectives and set up of the European Antimicrobial Resistance Surveillance System (EARSS) Adapted from: Bronzwaer SLAM, Goettsch W, Olsson-Liljequist B, Wale MCJ, Vatopoulos AC, Sprenger MJW. European Antimicrobial Resistance Surveillance System (EARSS): objectives and organisation. Eurosurveillance 1999;4;4:41-4, and from Bronzwaer SLAM, Sprenger MJW. A surveillance system for Europe - textbox. BMJ 1998; 317; 615. Introduction In 1997 a prioritisation exercise was carried out among heads of national surveillance centres in the Member States of the European Union. Antimicrobial resistance ranked in the top five areas in communicable disease surveillance for which the development of a network was deemed a high priority (1). Effective European surveillance must have the agreement and active involvement of all participants, concluded the Microbial Threat conference on the need for surveillance of resistant micro-organisms, held in September 1998 in Denmark (2). Patterns of antibiotic resistance differ widely between member states of the EU (3, 4), and different studies suggest that policies and guidelines on antibiotic usage may affect the prevalence of resistance (5, 6). From an epidemiological and methodological standpoint it is difficult to compare antimicrobial resistance rates because of differences in antimicrobial agents tested, sampling policies, susceptibility test systems used, and breakpoints adopted. To obtain more comparable and validated data, the European Commission, Directorate General Health and Consumer Protection, made funds available to implement a European Antimicrobial Resistance Surveillance System (EARSS). This system is coordinated by the Rijksinstituut voor de Volksgezondheid en Milieu (RIVM), the National Institute of Public Health and the Environment of the Netherlands. In 1998, more than 400 laboratories expressed willingness to take part in this European surveillance network. This chapter describes objectives and set-up of EARSS. Objectives EARSS is an international network of national surveillance systems, aiming to collect comparable and validated antimicrobial resistance data for public health purposes. Taking into account laboratory methods as well as epidemiological principles, EARSS will explore the feasibility of analysing regional differences, assessing risk factors, and providing electronic feedback. EARSS started on 1 April 1998 with an 18-month feasibility study. During the first plenary meeting, with a microbiologist and an epidemiologist representing every country, it was decided that EARSS will concentrate on Streptococcus pneumoniae and Staphylococcus aureus during the pilot phase; with more pathogens added later. The system will use routine data from laboratories so that no changes to the primary diagnostic process will be needed. The participants will gather unbiased samples of isolates by either total or representative coverage. The objective for S. pneumoniae is to collect susceptibility data on penicillin and cephalosporins, and possibly other drugs, from blood and cerebrospinal fluid isolates. For S. aureus, in particular data on methicillin resistance will be collected from isolates from blood. 14 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY EARSS aims to assist in the control of antimicrobial resistance, by performing antimicrobial resistance surveillance at national and European level, and has set the following objectives: collecting susceptibility data in standardised manner, thereby improving comparability providing information to target interventions (at local, national, and EU level) providing official national AMR data that constitute a basis for policy decisions analysing temporal / geographical trends: monitoring AMR data over place (among different European countries) and time (from year to year). providing feedback to those who need to know, for evaluating interventions and follow the effect of policy decisions. Furthermore, EARSS aims to stimulate: national antimicrobial resistance surveillance and provision of information for national policies linkage of antimicrobial resistance data to antibiotic use data European research in the field of antimicrobial resistance Organisation Each participating country has appointed a national representative microbiologist and a representative epidemiologist. One of the representatives from each country acts as the national coordinator. His/her main task is to coordinate activities of the participating laboratories; arrange distribution and collection of questionnaires on susceptibility testing; and to collect and forward resistance data each quarter for international collation. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 15 EARSS Network DG-SANCO (EC) EARSS Management Team WHO ESCMID Public Plenary Meeting QA Committee Advisory board Lab 2 (28) National Co-ordinating Centres (PH institutes) National representatives Data managers Lab ... Lab 1 Figure 2.1: EARSS Network organogram Standardisation and microbiological quality control methods are being developed in consultation with the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). EARSS is a component of the network-of-networks being established by the World Health Organization (WHO) for global surveillance. Selection of participating laboratories EARSS recommended that the national coordinators should select enough laboratories in their countries to cover at least 20% of the total population. For the community acquired pathogens the catchment population of the laboratories (the number of people living in the area they serve) will be considered as the denominator. The 400 or so laboratories participating in EARSS will cover well over 20% of the population in many countries. Epidemiological data EARSS collects the following data by means of isolate record forms and questionnaires: information about an isolate and its susceptibility test results information about patients information about the laboratory methods used and denominator data data about the hospital(s) served by the laboratory used to generate the denominator. Isolate record form. This form collects information about patients and isolates. EARSS requires the following information: sex, month and year of birth, date of specimen collection, name or code of hospital, hospital department, origin of patient, isolate specimen number, laboratory code, and antibiotic susceptibility testing results as specified in the protocol. Furthermore, the isolate record form allows other optional data to be collected: patient identifier, clinical diagnosis, and susceptibility data for other antibiotics. Questionnaire on susceptibility testing. This questionnaire asks about test methods used, and collects denominator data from a laboratory and from the hospital(s) it serves. The facilities the hospital offers (intensive care unit, renal, transplant, cardiac surgery) and the number of bed days are requested. For nosocomial pathogens the number of bed days will be considered as the denominator. Data on patients and isolates can be related to information about the laboratory and hospital by means of a unique laboratory code that will be filled out on all isolate record forms and questionnaires. We are aware that the catchment population estimated by a laboratory may overestimate the true catchment population. True catchment populations can be calculated through postal codes of the patients from whom isolates were obtained. To preserve confidentiality this must be done at a national level. 16 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Duplicates To prevent duplicate isolates from being reported, laboratories are asked to send information only about the first isolate of each strain from each patient. These are referred to as patient-isolates. To be able to correct for duplicate isolates, the isolate record form asks for patient ID/code. This is marked as optional information, since in many countries there are legal limitations on the inclusion of patient identifiers. For the same reason we do not ask for date of birth, but month and year of birth. A code is needed, however, to exclude duplicates at the national level. If a patient identifier cannot be used in a particular country, we ask laboratories to use another (encrypted) code for a specific patient. In other countries the patient identifier may be used to exclude repeat isolates, removing the identifier before sending data to the central database. Data processing Participating laboratories are offered two methods of data entry: electronically and on paper. Details vary from country to country, but if a laboratory opts for electronic data transfer they can use an existing laboratory information system or make use of Whonet (and/or Whonet-Baclink). WHO revised the existing microbiology laboratory database software Whonet for EARSS. Laboratories that do not process data electronically will forward the isolate record forms to their national coordinator, who will perform the data entry and will send data each quarter to the RIVM in ASCII fixed or tab separated format. On receipt, the data will be checked for syntax errors (for example, dates and test results). After this validation, tables, figures, and geographical maps can be generated and published on the internet site. The aggregated data sets will also be used for more complex epidemiological studies, for example investigating relationships between antimicrobial use and resistance. Feedback Sufficient and timely feedback is essential for all surveillance systems. Information on resistance is needed at local, national, and international levels to guide decision making and interventions. As well as information letters and a newsletter, data will be shared using the electronic infrastructure Health Surveillance System of Communicable Diseases (HSSCD) network of the EU. Feedback, in the form of standard reports, is already provided by means of the EARSS web site, newsletters and publications. Results About 400 laboratories will take part by sending data via national coordinators to the central EARSS database. Data collection began in some countries on 1 October 1998. The EARSS protocol and issues like ownership of data and data management were agreed by all national co-ordinators and laid down in the EARSS manual (7). The manual has been EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 17 distributed to participating laboratories. By the end of 1999, questionnaires on test methods and denominators from 283 laboratories had been received. These laboratories serve 450 hospitals, mainly general hospitals (76%) but also academic/tertiary hospitals (20%) and nursing homes (4%). Ninety-five per cent of the 150 laboratories that specified which method they used undertook susceptibility testing of S. aureus against oxacillin and/or methicillin routinely. About half of these laboratories use Mueller-Hinton agar (sometimes with salt) and follow the National Committee for Clinical Laboratory Standards (NCCLS) recommended breakpoints. By the end of the pilot phase, laboratories from 12 countries (Belgium, Denmark, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Portugal, Sweden, United Kingdom) were sending data. Conclusion In developing the protocol and questionnaire, the challenge was to balance scientific validity and feasibility. A first result is that consensus has been reached by leading microbiologists and epidemiologists on the protocol and logistical framework. The feasibility phase yielded a conclusion that EARSS is needed and feasible, and that it must run continuously with guaranteed funding. The number of pathogens under surveillance will be expanded as soon as the data processing has been optimised. EARSS is already acting as a catalyst for national surveillance systems, such as in Ireland (8). References 1. Weinberg J, Grimaud O, Newton L. Establishing priorities for European collaboration in communicable disease surveillance. Eur J Public Health 1999; 9: 236-40. 2. Thamdrup Rosdahl V, Borge Pederson K. Report from the invitational EU conference on he microbial threat. September 1998. 3. Rahal K, Wang F, Schindler J, Rowe B, Cookson B, Houvinen P, et al. Reports on surveillance of antimicrobial resistance in individual countries. Clin Infect Dis 1997; 24 (Suppl 1): S69-75. 4. Kresken M, Wiedemann B. Development of resistance in the past decade in central Europe. J Antimicrob Chemother 1986; 18(suppl C): 235-42. 5. Seppala H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, Lager K, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N Engl J Med 1997; 337: 441-6. 6. Pradier, C, Dunais H, Carsenti-Etesse, Dellamonica P. Pneumococcal resistance in Europe. Eur J Clin Microbiol Infect Dis 1997; 16: 644-7. 7. EARSS Management Team and national co-ordinators. EARSS Manual 1998. 8. OFlanagan D. Development of a strategy to combat antimicrobial resistance in Ireland. Eurosurveillance Weekly 1999; 3: 991104. (http://www.eurosurv.org/1999/991104.html) 18 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Chapter 3 Standardisation of Streptococcus pneumoniae and Staphylococcus aureus susceptibility data within EARSS Adapted from: Goettsch W, Bronzwaer SLAM, Neeling de AJ, Wale MCJ, Aubry-Damon H, Olsson-Liljequist B, Sprenger MJW, Degener JE. Standardisation and quality assurance for antimicrobial resistance of Streptococcus pneumoniae and Staphylococcus aureus within the European Antimicrobial Resistance Surveillance System (EARSS). Clin Microbiol Infect 2000; 6; 59-63. Introduction In several countries of the European Union increased resistance of micro-organisms to antimicrobial agents is reported; the rise of methillicin-resistant Staphylococcus aureus infections, the occurrence of vancomycin resistant enterococci and the presence of penicillin-resistant Streptococcus pneumoniae 1 cause severe problems. In a geographical context it seems that resistance problems become urgent especially in southern European countries. 1,2,3,4 From an epidemiological and methodological standpoint the comparison of antimicrobial resistance from different countries is very difficult. Reasons for these difficulties are that: 1. Different antimicrobial agents are tested. 2. Different systems for antimicrobial susceptibility testing are used. 3. Different breakpoints for antimicrobial susceptibility are used. 4. Data from point prevalence studies are used for longitudinal comparisons; e.g. studies on antibiotic resistance performed in 1970 and 1990 are compared, in spite of differences in study conditions and methodology. 5. Only the resistant strains are tested. 6. Differences between the prevalence of resistant strains from local practices and university hospitals are not taken into account. In order to obtain more comparable and validated data, the European Commission has funded a European Antimicrobial Resistance Surveillance System (EARSS). In this chapter we present how susceptibility data of Staphylococcus aureus and Streptococcus pneumoniae within EARSS are standardised in order to address difficulties as mentioned above. Methods During the feasibility phase of EARSS it is important to use a limited number of pathogenic bacterial species, in order to manage the set-up of the surveillance system. More than 400 laboratories have agreed to participate in this European surveillance network. EARSS depends on national surveillance data, so input of the participants of the different member states is essential. The methodology of the surveillance system was decided during the first plenary EARSS meeting with all national representatives (May 18- 20, 1998). The first decision to be taken was which species are to be to included under surveillance. Before the meeting a working group prepared a discussion paper with objective criteria for selection. The rationale of selection of a community acquired pathogen and a hospital-acquired (nosocomial) pathogen for the pilot phase of EARSS is summarised in the discussion paper: 20 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 1. Relevance for Public Health. Most participants believe that S. pneumoniae and S. aureus are the most relevant species. They are both proven pathogens, clinically relevant on population level for the community or the hospitalised population, have a high potential for spread in community and/or hospital setting and are known to acquire resistance against currently used and recommended antibiotics. Other relevant species are Campylobacter jejuni, Haemophilus influenzae, Streptococcus pyogenes, Pseudomonas aeruginosa and Escherichia coli. 2. Political Interest. Most participants believe that especially S. aureus, S. pneumoniae and Enterococcus faecium/faecalis are of interest to policy makers. These species are the ones most often attracting media and political attention. In addition, in relation to the present discussion on the use of fluoroquinolones in animals and humans, resistance in micro-organisms such as Salmonella typhimurium, C. jejuni and E. coli are of interest. 3. Availability of quantitative data. The participants believe that quantitative resistance data in sufficient numbers are present for several species, including S. aureus, S. pneumoniae, H. influenzae and E. coli. 4. Reliability of data. For some species, such as E. coli in urinary tract infections, sample bias can occur in resistance surveillance. Physicians only send isolated bacteria to the laboratories when they have patients with treatment failures. For S. aureus and S. pneumoniae blood isolates that always cause patients to be severely ill, irrespective of the susceptibility of the isolate, it is to be expected that clinicians in the hospital send all isolates for susceptibility testing. 5. Quality assurance. S. aureus, S. pneumoniae, E. faecium/faecalis, E. coli, P. aeruginosa and H. influenzae are common micro-organisms and are often included in quality assurance systems. Therefore susceptibility data for these species are normally quality-assured. 6. Interaction with other resistance surveillance systems. For some species such as Salmonella spp., Mycobacterium tuberculosis and Neisseria gonorrhoea other well- organised European surveillance systems are already in place, like Enternet (www.phls.co.uk/inter/enter-net/menu.htm) and EuroTB (www.eurotb.org). Results consensus meeting Having circulated the discussion paper on the rationale for selection of pathogens for comments before, consensus was reached relatively fast during the meeting. Realising that in the phase of establishing a surveillance programme not the most complex species should be selected, it was decided that S. pneumoniae and S. aureus are the most relevant species for the pilot phase in EARSS. In the future it is expected that EARSS will be a permanent surveillance system for the most public health relevant species and after the feasibility phase more species will be added. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 21 In order to minimise sample bias, it was decided to test only S. pneumoniae isolates from blood and cerebral spinal fluid (CSF), and S. aureus isolates from blood for antimicrobial resistance. During the same meeting the protocols for antimicrobial testing of S. aureus en S. pneumoniae were developed. Protocol Staphylococcus aureus testing Objective To study the (methicillin)-resistance of S. aureus, in blood isolates in hospitals in Europe. Case definition Resistance data on the first isolate only of each strain from the blood of each patient with a S. aureus infection (confirmed by a coagulase test). We exclude duplicate isolates of the same species from the same patient, and collect information only on the first isolate from each patient (patient-isolate). Test procedure (1) Oxacillin screen plates (6 g/ml according to NCCLS) or oxacillin disks (1 g or 5 g) will be used. When S. aureus is tested for oxacillin resistance a disk with a load of 1 g oxacillin (NCCLS) is used; non-susceptibles are strains with a zone size of 10 mm or less ( 10 mm). When a disk with a load of 5 g oxacillin (according to the French guidelines, SFM) for oxacillin susceptibility testing is used, non- susceptibles are isolates with a zone size of 19 mm or less ( 19 mm). (2) In the case of oxacillin non-susceptible S. aureus, the participating laboratories are asked additionally to determine the MIC for oxacillin (range of dilutions: 0.016-256) and MIC for vancomycin specifying the method used: agardilution, microdilution or E-test (range of dilutions: 0,016 256). A participating country can decide whether the local laboratory will perform the second step of the protocol or that a reference laboratory will collect the non-susceptible strains and perform the MIC for oxacillin and vancomycin. 22 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY S. aureus (blood) oxacillin agar screen plate or oxacillin disk (1) susceptible non-susceptible MIC oxacillin or PCR mecA-gene (2) MIC vancomycin (2) Protocol Streptococcus pneumoniae testing Objective: To study the penicillin-resistance of S. pneumoniae blood- and CSF-isolates in Europe. Case definition Resistance data on the first isolate only from the blood or CSF of each patient with a S. pneumoniae infection (confirmed by an optochin test). We exclude duplicate isolates of the same species from the same patient, and collect information only on the first isolate from each patient (patient-isolate). Test procedure (1) For testing of S. pneumoniae an oxacillin disk (1 g or 5 g) will be used. When S. pneumoniae is tested, non-susceptible penicillin resistant S. pneumoniae are strains with a zone size of 20 mm or less ( 20 mm). An alternative in oxacillin susceptibility testing is a disk with a load of 5 g oxacillin (according to the French guidelines, SFM). Non-susceptible penicillin resistant S. pneumoniae are isolates with a zone size of 26 mm or less ( 26 mm). (2) In the case of oxacillin non-susceptible S. pneumoniae, the participating laboratories are asked additionally to determine the MIC of penicillin, cefotaxime or ceftriaxone and ciprofloxacin, specifying the method used: agardilution, microdilution or E-test (range of dilutions: 0,016256 (penicillin) or 0,00232 (cefotaxime/ ceftriaxone and ciprofloxacin)). A participating country can decide whether the local laboratory will perform the second step of the protocol or that a reference laboratory will collect the non-susceptible strains and perform the MIC for penicillin, cefotaxime/ceftriaxone and ciprofloxacin. Discussion EARSS is designed in order to minimise epidemiological or microbiological difficulties as were summarised in the introduction: EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 23 S. pneumoniae (blood + CSF) oxacillin disk (1) susceptible non-susceptible MIC penicillin (2) MIC cefotaxime/ceftriaxone (2) MIC ciprofloxacin (2) 1. Different antimicrobial agents are tested. In EARSS, resistance for two species (S. aureus and S. pneumoniae) is tested against a restricted set of specified antimicrobials. The choice for oxacillin, instead of methicillin, for determination of MRSA (ORSA) is a practical one. Because methicillin is becoming less available in the near future, we think that oxacillin is a reliable alternative. For S. pneumoniae, testing of oxacillin, as a first step, in combination with a penicillin minimum inhibitory concentration (MIC) for non-susceptibles is now generally accepted. 5 We believe that the introduction of a new generation of fluoroquinolones for the therapy of respiratory tract infections necessitates us to follow ciprofloxacin resistance in S. pneumoniae. 2. Different systems for antimicrobial susceptibility testing are used. The protocols for S. pneumoniae and S. aureus are clearly defined. Next to a simple first line screening method, a second step, in which the MIC is determined, is included. Such a protocol combines easy accessibility with careful quantitative examination of antimicrobial resistance. For a reliable comparison of resistance against oxacillin in S. aureus oxacillin agar screen plates can be used. 6,7 However, results from a survey among national co- ordinators illustrate that agar screen plates are only used in a few countries. Because one of the key features of EARSS is easy accessibility, the protocol will also accept data from the oxacillin disk diffusion test. 7,8 The golden standard for confirmation of an MRSA is testing for the presence of the mecA-gene. However, when a participating laboratory is not able to perform a PCR, determination of a MIC for oxacillin (range of dilutions: 0.016-256) will be done to confirm that an MRSA is not false positive. Testing of MRSA for resistance against vancomycin is very relevant but under debate. Vancomycin intermediate resistant S. aureus (VISA) strains, which were first reported in Japan 9 , are often heterogeneously resistant. Only a very limited percentage of the total population of isolated bacteria is intermediately resistant. 9,10 The presence of these VISAs can be missed measuring a MIC under standard conditions. At this moment there is not an established protocol to test for VISA. We propose to test the MRSA for vancomycin using the E-test, with a standardised protocol which is also used testing the oxacillin MIC, realising that some intermediate VISA strains might be missed. The determination of the vancomycin MIC will preferably be done at a central reference lab in each country. In case of finding a VISA strain, arrangements will be made for further analysis (e.g. sequence analysis). 24 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 3. Different breakpoints for antimicrobial susceptibility are used. Breakpoints are defined in the two protocols, according to US - National Committee for Clinical Laboratory Standards (NCCLS) or in some cases the Socit Francaise de Microbiologie (SFM) guidelines. For all S. pneumoniae and S. aureus isolates, we ask the participating laboratories to register the inhibition zone (in case of the disk method). The collection of zone diameters has an additional value in case medium and disk load are standardised. Firstly, zone diameters will give more insight in the distribution of S. pneumoniae or S. aureus strains with different susceptibilities to oxacillin, e.g. high resistance versus intermediate resistance. 11 Secondly, the distribution of zone diameters may be used to study the quality of resistance data from different participating laboratories. 12 It is acknowledged that laboratories in some participating countries are not able to collect zone diameters. In the second step (MIC testing), the validity of categorising the strains as susceptible or non-susceptible, according to the SFM and the NCCLS guidelines, is evaluated. Correction of false positive (resistant) strains is possible by MIC testing. Also a monthly testing of quality control strains assesses correct use of breakpoints for the categorisation of strains into susceptible and resistant. 4. Data from point prevalence studies are used for longitudinal comparisons; e.g. studies on antibiotic resistance performed in 1970 and 1990 are compared, in spite of differences in study conditions and methodology. For a longitudinal analysis on developments in resistance continuous data are essential. EARSS wants to provide continuous data that is generated according to a standardised protocol. Sudden increases or decreases in resistance percentages could be caused by changes in the surveillance method and should be closely monitored. 5. Only the resistant strains are tested. Selection of strains can easily occur in case of less invasive infections. For instance, antimicrobial susceptibility testing of Enterobacteriaceae from urinary tract infections depends on the response of the patient on the initial therapy. Resistance testing will be more likely performed when the patient returns after therapy failure. Resistance surveillance on basis of routine samples may overestimate the problem. 13,14 In the EARSS pilot, sampling of the species is restricted to invasive isolates, which are routinely tested for antimicrobial susceptibility. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 25 6. Resistance in local practices or general hospitals is compared to resistance in university hospitals. In order to tackle this problem we asked the national co-ordinators to ensure reasonable coverage in their country. In case of the community-acquired pathogen, a coverage of more than 20% of the total national population is necessary. Participating laboratories are providing the national co-ordinator with information on the catchment population (the number of people living in the area they serve). In case of S. aureus we believe that 20% of the total number of patient-days in every country is a minimum. Therefore, the participating laboratories provide the national co-ordinators with information on the number of patient-days of every hospital they serve. The national co-ordinator selects laboratories; not only laboratories that serve university hospitals but also laboratories, which serve small regional hospitals and general practitioners, are part of EARSS. We believe that EARSS can evolve as a good framework to monitor antimicrobial resistance in the EU for the coming years. The first result of EARSS is that this system has activated several countries to establish or to update their national resistance surveillance system in order to follow national resistance patterns and to compare these to developments in Europe. Addendum At the third plenary EARSS meeting in November 2000 it was decided with all the national representatives to extend surveillance to three other species: E. coli, E. faecium and E. faecalis. The protocol for testing for these species was agreed and most countries started data collection in January 2001. The EARSS manual was updated accordingly and sent to the participating laboratories. Next to testing protocols the EARSS Manual 2001 provides an overview of the organisation and infrastructure of EARSS, and of data management. 15 In annex it provides the data exchange format, updated isolate record forms, an updated laboratory/hospital questionnaire and a template Memorandum of Understanding between national EARSS representatives and participating laboratories. In further chapters susceptibility results will be presented only for S. pneumoniae and S. aureus, for which data collection began in 1999. References 1. Appelbaum PC. Antimicrobial resistance in Streptococcus pneumoniae: an Overview. Clin Infect Dis 1992; 15: 77-83. 2. Goldstein FW, Acar JF. Antimicrobial resistance among lower respiratory tract isolates of Streptococcus 26 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY pneumoniae: results of a 1992-93 western Europe and USA collaborative surveillance study. The Alexander Project Collaborative Group. J Antimicrob Chemother 1996: 38 (Suppl A): 71-84. 3. Felmingham D, Gruneberg RN. A multicentre collaborative study of the antimicrobial susceptibility of community-acquired, lower respiratory tract pathogens: The Alexander Project. J Antimicrob Chemother 1996; 38 (Suppl A): 1-57. 4. Rahal K, Wang F, Schindler J, Rowe B, Cookson B, Houvinen P, Marton A, Lalitha MK, Semina N, Kronvall G, Guzman M. Reports on surveillance of antimicrobial resistance in individual countries. CID 1997; 24(Suppl 1): S69-S75. 5. Sinave C, Jette LP. Use of oxacillin disk screening test for detection of penicillin- and cefalosporin-resistant pneumococci. Abstract ICAAC, September 1998, San Diego, D-67. 6. Frebourg NB, Nouet D, Lemee L, Martin E, Lemeland JF. Comparison of ATB Staph, Vitek, and E-test methods for detection of oxacillin heteroresistance in staphylococci possessing mecA. J Clin Microbiol 1998; 36: 52-57. 7. Cormican MG, Wilke WW, Barrett MS, Pfaller MA, Jones RN. Phenotypic detection of mec A-positive staphylococcal blood stream isolates: high accuracy of simple disk diffusion tests. Diagn-Microbiol-Infect- Dis. 1996 Jul; 25(3): 107-112 8. Ramotar K, Bobrowska M, Jessamine P, Toye B. Detection of methicillin resistance in coagulase-negative staphylococci initially reported as methicillin susceptible using automated methods. Diagn-Microbiol- Infect-Dis. 1998 Apr; 30(4): 267-273. 9. Hiramitsu K, Hanaki H, Ino T, Yabuta K, Oguri T, Tenover FC. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chem 1997; 40: 135-136. 10. Hiramitsu K, Aritaka N, Hanaki H, Kawasaki S, Hosoda Y, Hori S, Fukuchi Y, Kobayashi I. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 1997; 350: 1670-1673. 11. Ringertz S, OlssonLiljequist B, Kahlmeter G, Kronvall G. Antimicrobial susceptibility testing in Sweden II. Species-related zone diameter breakpoints to avoid interpretive errors and guard against unrecognized evolution of resistance. Scand J Infect Dis 1997; Suppl. 105 : 8-12. 12. Blanc DS, Petignat C, Moreillon P, Wenger A, Bille J, Francioli P. Quantitative antibiogram as a typing method for the prospective epidemiological surveillance and control of MRSA: Comparison with molecular typing. Infect Cont Hosp-Epidemiol 1996; 17: 654-659. 13. Neeling de AJ, Pelt van W, Hendrix MGR, e.a. Antibiotic resistance in the Netherlands. Part II: Gram- negative bacteria [NL]. Antibioticumresistentie in Nederland. Deel II : Gram-negatieve bacterin. Infectieziekten Bulletin 1997; 8: 192-195. 14. Neeling AJ de, Jong de J, Overbeek BP, Bruin RW de, Dessens-Kroon M, Klingeren B van. Quantitative susceptibility research with intra- and extramural Escherichia coli isolates [NL]. Kwantitatief gevoeligheidsonderzoek met intra- en extramurale isolaten van Escherichia coli. RIVM report nr 359001002, November 1990. 15. EARSS Management Team and Advisory Board EARSS, in collaboration with national representatives. EARSS Manual 2001. January 2001. Pages: 56. Available at www.earss.rivm.nl. Accessed 1 May 2003. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 27 Chapter 4 Comparability of antimicrobial susceptibility test results from 22 European countries and Israel: an external quality assurance exercise of EARSS in collaboration with UK NEQAS S. Bronzwaer, U. Buchholz, P. Courvalin, J. Snell, G. Cornaglia, A. de Neeling, H. Aubry-Damon, J. Degener, and EARSS participants. Journal of Antimicrobial Chemotherapy (2002) 50, 953964 Abstract The goal of this exercise was to organize external quality assurance (QA) of antibiotic susceptibility testing for laboratories participating in EARSS and to assess the comparability of susceptibility test results across countries, and guidelines. In September 2000, UK NEQAS distributed a set of three Streptococcus pneumoniae strains, two Staphylococcus aureus strains and one Staphylococcus haemolyticus strain. Laboratories reported the guideline followed, the interpretation of the susceptibility test result and the MIC, if tested. In this study we considered results concordant if the reported interpretation of the participating laboratory agreed with the designated interpretation of reference laboratories. Overall, 433 (92%) of 471 laboratories from 23 countries reported back. Of the 8685 tests that were assessed, 8322 (96%) were interpreted correctly by the participants. Concordance for detection of penicillin non-susceptibility in the three S. pneumoniae strains was 96%, 90% and 87%, respectively. Laboratories performed extremely well in detecting oxacillin resistance in the homogeneously methicillin-resistant S. aureus (MRSA) strain, but the concordance rate dropped from 100% to 77% in the heterogeneously resistant MRSA strain. Concordance for detection of teicoplanin resistance in the S. haemolyticus strain was 82%. We stratified concordance rates first for country and then for guideline used, but observed only minor differences among countries and guidelines. Quantitative methods yielding an MIC were more concordant than non-MIC methods for penicillin resistance in the S. pneumoniae strains (94% versus 79%). The NCCLS guideline was the most frequently followed, by 61% of laboratories from 19 countries. This exercise shows that, overall, countries participating in EARSS are capable of delivering susceptibility data of good quality. The comparability of susceptibility data for penicillin resistance in S. pneumoniae and for homogeneous methicillin resistance in S. aureus is satisfactory among European countries and across guidelines. However, we emphasize the importance of determining an MIC for suspected penicillin non-susceptible S. pneumoniae and for suspected glycopeptide non-susceptible S. aureus. Laboratories, particularly in some countries, may need to improve their capability to detect oxacillin resistance in heterogeneously resistant MRSA. For continuous external quality assessment we recommend that laboratories participate in national and international schemes with frequent distribution of control strains. 30 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Introduction Since 1999, the European Antimicrobial Resistance Surveillance System (EARSS) has been monitoring antimicrobial resistance in an increasing number of European countries. Funded by the European Commission, EARSS is an international network of national surveillance systems aiming at collecting comparable and valid resistance data. The purpose of EARSS is to document variations in antimicrobial resistance over time and place, to provide the basis for policy decisions and assess the effectiveness of interventions. EARSS is an ongoing system monitoring resistance of invasive infections of Streptococcus pneumoniae and Staphylococcus aureus. Since 2001, invasive isolates of Escherichia coli and enterococci have also been under surveillance, and a similar external quality assurance exercise for these pathogens was organized in September 2001. Summary results from the 2001 quality assurance (QA) exercise as well as the EARSS database are accessible through the EARSS web site (www.earss.rivm.nl). Antibiotic susceptibility of clinical isolates of bacteria is usually tested as part of routine laboratory investigations to establish the most adequate therapy for an infection. Detection of resistance relies on specimen collection from the patient, isolation, identification and susceptibility testing of the bacterial pathogen. Only recently a reference method for the determination of minimum inhibitory concentrations (MIC) has been proposed by the European Committee for Antimicrobial Susceptibility Testing (EUCAST), 1 but there is still no European agreement on breakpoint criteria for interpreting the results into clinical categories [susceptible (S), intermediate (I), or resistant (R)]. As a result, methods for most agents still differ between countries, and interpretation of test results may differ. The goal of this exercise was to organize external quality assurance of antibiotic susceptibility testing for laboratories participating in EARSS and to assess the comparability of susceptibility test results, as collected according to the EARSS protocol 2 across countries and guidelines. Furthermore, this exercise assessed the comparability of MIC-yielding methods versus non-MIC-yielding methods (e.g. agar diffusion tests), and provided an overview of the frequency of use of various guidelines among EARSS laboratories. Quality assessment is essential in order for EARSS to assess the validity of comparing S. pneumoniae and S. aureus susceptibility data from a large number of laboratories from numerous countries and pooling it into a European database. Materials and methods A set of six strains (three S. pneumoniae, two S. aureus and one Staphylococcus haemolyticus) was provided by the French Reference Center for AntibioticsInstitut Pasteur. The strains were characterized and tested by three reference laboratories: one in France, one in Italy, and one in The Netherlands. MICs were determined by an agar dilution method in two laboratories and by Etest in the third. Each reference laboratory EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 31 interpreted the results according to its own breakpoint criteria, respectively: Comit de lAntibiogramme de la Socit Franaise de Microbiologie (CA-SFM), National Committee for Clinical Laboratory Standards (NCCLS) and the Commissie Richtlijnen Gevoeligheidsbepalingen (CRG). A designated interpretation and a reference MIC was determined for every organismantimicrobial combination. In cases where there were differences in MIC between reference laboratories of more than one dilution step, strains were tested repeatedly until agreeing on a reference MIC or accepting a narrow MIC range of reference laboratories. The S. pneumoniae strains UA1283 and UA347 were intermediately resistant to penicillin G, and S. pneumoniae strain UA1449 was fully penicillin resistant. S. aureus strain UA1432 was homogeneously resistant to methicillin, and strain UA1450 was a heterogeneously resistant MRSA strain. The phenotypic expression of methicillin resistance of the S. aureus strains was analysed by performing two independent population analyses on agar plates containing different concentrations of the antibiotic, as described by Tomasz et al. 3 The S. haemolyticus strain UA1434 was resistant to teicoplanin. The United Kingdom National External Quality Assurance Scheme (UK NEQAS) reference laboratory at the Central Public Health Laboratory, Colindale, London, organized the logistics of this study and arranged the shipment of the strains. The strains were prepared as freeze-dried cultures and sent by air-freight to EARSS national co-ordinating centres in 23 countries, who distributed the strains to the 471 laboratories participating in EARSS. Laboratories were asked to identify the control strains and to test them for susceptibility to specified antimicrobials using their routine procedures (for invasive specimens). They were asked to report the clinical categorization (S, I or R) and the MIC, if performed, as well as the breakpoints and guideline(s) followed. Five weeks were allowed for return of the results to UK NEQAS. Immediately after the closing date for return of results, brief details of the intended results were posted to participant laboratories, sent by e-mail to participants with e-mail addresses, and made available on the UK NEQAS web site. Laboratories received their individual results and a summary of the aggregate results. 4 Where 10 or more laboratories within a country participated, tables of coded results specific to the country were produced. Analysis comprised three parts: bacterial identification, antimicrobial susceptibility test results and the use of guidelines. We assessed participants results as being concordant or discrepant with the designated interpretation where all three reference laboratories agreed on the interpretation (S or I/R), and where the range of MICs of the reference laboratories allowed unambiguous interpretation by different guidelines. For assessing concordance we used only two categories: susceptible (S) versus non- susceptible [i.e. intermediate plus resistant (I/R)]. Results were assessed for correct 32 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY interpretation of susceptibility/non-susceptibility for oxacillin, penicillin G and erythromycin against S. pneumoniae; for oxacillin, methicillin, gentamicin, vancomycin, teicoplanin and erythromycin against the S. aureus strains; and for gentamicin, vancomycin, teicoplanin and erythromycin against the S. haemolyticus strain. In this study we considered results concordant if the reported interpretation of the participating laboratory agreed with the designated interpretation of the reference laboratories. The term concordance rate denotes the proportion of susceptibility tests with a correct result. For each countryexcept for France, Hungary and Malta, with only one laboratory participatingwe calculated the average concordance of participating laboratories. We also calculated for every guideline the average of the concordance of laboratories following that guideline, using Microsoft Excel (Microsoft Corporation, Release 97 SR-2; Redmond, WA, USA). We used SAS software (SAS Institute Inc., Release 8.01; Cary, NC, USA) for the calculation of the confidence intervals (CI), weighting the results for the number of tests performed in each country and considering that observations within one country are not independent. Results The designated interpretations and MIC reference values for the strains investigated are listed in Table 4.1. Overall, 433 (92%) of 471 laboratories from 23 countries reported results (Table 4.2). Analysis of results at a national level from countries where only one laboratory participated (France, Hungary and Malta) are not presented, for confidentiality reasons and also because the results from one laboratory may not be a true representation of national performance. Bacterial identification Strains were identified at the genus and species level. The three S. pneumoniae strains were correctly identified by: 425/428 (99%), 421/425 (99%) and 413/419 (99%) of the participating laboratories. Twelve laboratories from different countries did not identify one of the three S. pneumoniae strains correctly at species level and one laboratory failed to identify the genus correctly. Four laboratories identified one of the strains as Streptococcus mitis, four as Streptococcus viridans, two as Streptococcus sanguis, one as Streptococcus oralis, one as Streptococcus sp., and one as Aerococcus sp. The two S. aureus strains were correctly identified by: 422/427 (99%) and 422/423 (100%) of the laboratories. Three laboratories identified one of the strains as coagulase-negative staphylococci, two as S. haemolyticus and one as Staphylococcus intermedius. The S. haemolyticus strain was identified by 364/424 (86%) of the laboratories as S. haemolyticus or coagulase-negative staphylococcus and by 46/424 (11%) of the laboratories as staphylococcus species other than S. aureus. Thirteen laboratories (3%) misidentified the strain as S. aureus and one laboratory misidentified it as Enterococcus faecalis. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 33 34 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Table 4.1. The designated interpretation and reference MIC or MIC range of reference laboratories for every organismantimicrobial combination that was assessed Designated interpretation Reference MIC or MIC range (mg/L) Strain UA1449, S. pneumoniae oxacillin R 16 penicillin G R 34 erythromycin R >256 Strain UA1283, S. pneumoniae oxacillin R 2 penicillin G I 0.250.5 erythromycin R >256 Strain UA347, S. pneumoniae oxacillin R 4 penicillin G I 0.5 erythromycin R >256 Strain UA1432, S. aureus oxacillin R >256 methicillin R >256 gentamicin R 64128 vancomycin S 2 erythromycin R >256 Strain UA1434, S. haemolyticus gentamicin R 64 vancomycin S 24 teicoplanin R 3264 erythromycin R 64256 Strain UA1450, S. aureus oxacillin R 864 methicillin R 3264 gentamicin S 0.120.25 vancomycin S 1 teicoplanin S 0.51 erythromycin S 0.25 Antimicrobial susceptibility testing Of the 8685 tests that were reported and assessed in this exercise, 8322 (96%) were interpreted correctly by the participants. The average of the concordance of all antimicrobial test results across countries surpassed 90% in all control strains (Figure 4.1). This figure shows for every control strain the average and the range across countries of the concordance of all antimicrobial test results that were assessed. The lower end of the ranges in the S. pneumoniae strains varied between 90% and 72%. In the S. aureus strains the lower ends ranged between 96% and 82%. We found similar results after stratification for guidelines (Figure 4.2), with the lowest concordance rate of 67% for one guideline for strain UA347. Oxacillin, penicillin G and erythromycin susceptibility in S. pneumoniae. The overall concordance rate to detect penicillin non-susceptibility with an oxacillin screen disc was 97%, and ranged from 96% to 99% for the three strains tested (Table 4.3). The performance of most countries was excellent, although the group of Greek laboratories showed a lower concordance rate. Ninetyseven per cent of the participants used an oxacillin disc loaded with 1 g. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 35 Table 4.2. Proportion of participants returning reports specified per country Number of Number of Number of Number of QA samples returning QA samples returning Country sent reports (%) Country sent reports (%) Austria 11 10 (91) Israel 3 3 (100) Belgium 59 57 (97) Italy 63 53 (84) Bulgaria 23 20 (87) Luxembourg 5 5 (100) Czech Republic 34 33 (97) Malta 1 1 (100) Denmark 5 5 (100) Netherlands 27 25 (93) Germany 35 31 (89) Poland 20 19 (95) Finland 29 25 (86) Portugal 20 16 (80) France 1 1 (100) Slovenia 10 10 (100) Greece 18 17 (94) Spain 32 31 (97) Hungary 1 1 (100) Sweden 26 25 (96) Iceland 3 3 (100) UK 25 24 (96) Ireland 20 18 (90) Total 471 433 (92) QA, quality assurance 36 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 0 UA347 UA1283 UA1449 UA1432 UA1450 UA1434 90 80 70 60 40 50 30 20 10 100 S. pneumoniae S. aureus S. haemolyticus c o n c o r d a n c e
( % ) 0 UA347 UA1283 UA1449 UA1432 UA1450 UA1434 90 80 70 60 40 50 30 20 10 100 S. pneumoniae S. aureus S. haemolyticus c o n c o r d a n c e
b y
g u i d e l i n e
( % ) Figure 4.1. The average and the range across countries of the con cordance of antimicrobial test results, specified for every control strain. Figure 4.2. The average and the range across guidelines of the concordance of antimicrobial test results, specified for every control strain. The proportion of laboratories that reported penicillin non-susceptibility correctly after testing penicillin G varied from 96% for strain UA1449 to 90% for strain UA1283 and 87% for strain UA347 (Table 4.4). The peak of the frequency distribution of the penicillin G MICs for strain UA1449 (2 mg/L), yielding the highest concordance is well in the non- susceptible region compared with the peak of the frequency distribution of strain UA347 (0.25 mg/L), yielding a lower concordance. Again, almost all countries showed high concordance rates, with the exception of Bulgaria and Greece. The overall concordance rate for the detection of penicillin G non-susceptibility among guidelines followed in Europe was 91%, as specified for all three S. pneumoniae strains and for every guideline in Table 4.5. Again, performance was best for strain UA1449 and decreased for the other two test strains. Guidelines yielding somewhat lower concordance rates, such as those set by the Deutsches Institut fr Normung (DIN), as well as the guidelines specified under Other [Czech 98 and Mesa Espaola de Normalizacion de la Suseptibilitad y Resistencia a los Antimicrobianos (MENSURA)] were used by only a few participants. The guideline used most frequently for penicillin testing of S. pneumoniae was NCCLS, with an average concordance of 91%. Erythromycin resistance in all three S. pneumoniae control strains was detected correctly by 99% of the participants. Oxacillin, gentamicin, erythromycin, teicoplanin and vancomycin susceptibility in S. aureus. The overall concordance for detection of oxacillin (i.e. methicillin) resistance in the homogeneously resistant S. aureus strain UA1432 was 100%. The overall concordance for the heterogeneously resistant MRSA strain UA1450 was much lower, at 77%. Three countries (Czech Republic, Greece and Iceland) yielded notably lower concordance rates (Table 4.6), but no difference was found among different guidelines followed in Europe (data not shown). We found a very high concordance for detection of vancomycin susceptibility in the two MRSA strains, of 98% and 100%, respectively. Respectively 100% and 99% of the participants detected erythromycin and gentamicin resistance in the homogeneously resistant MRSA strain. Erythromycin and gentamicin susceptibility in the heterogeneously resistant MRSA strain was interpreted correctly by 98% and 99% of the participants, respectively. For teicoplanin susceptibility in the heterogeneously resistant MRSA strain, we found a concordance rate of 100%. Teicoplanin, vancomycin, gentamicin and erythromycin susceptibility in S. haemolyticus. For detection of teicoplanin resistance in the S. haemolyticus strain, the overall concordance rate was 82% (Table 4.7), with five countries (Belgium, Denmark, Luxembourg, The Netherlands and UK) scoring low concordance rates. Vancomycin susceptibility of this strain was interpreted correctly by 94% of the participants. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 37 38 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Table 4.3. Detection of penicillin non-susceptibility in S. pneumoniae by country as tested with an oxacillin screen disc Strain UA1449 Strain UA1283 Strain UA347 (oxacillin MIC of (oxacillin MIC of (oxacillin MIC of ref. labs: 16 mg/ L; ref. labs: 2 mg/ L; ref. labs: 4 mg/ L; intended intended intended interpretation: interpretation: interpretation: resistant) resistant) resistant) Total number number number of labs of labs of labs total doing % doing % doing % of % Country test correct test correct test correct tests correct Austria 10 100 10 90 10 100 30 97 Belgium 51 100 50 98 48 100 149 99 Bulgaria 16 100 16 94 15 100 47 98 Czech R. 28 100 28 100 28 100 84 100 Denmark 5 100 4 100 5 100 14 100 Finland 21 100 21 95 20 95 62 97 Germany 30 100 30 87 30 97 90 94 Greece 12 83 12 75 12 67 36 75 Iceland 3 100 3 100 3 100 9 100 Ireland 17 100 17 100 17 100 51 100 Israel 3 100 3 100 3 100 9 100 Italy 43 98 42 95 41 95 126 96 Luxembourg 4 100 4 100 4 100 12 100 Netherlands 22 100 22 95 22 91 66 95 Poland 17 100 17 100 17 100 51 100 Portugal 15 100 15 100 15 100 45 100 Slovenia 7 100 7 100 7 100 21 100 Spain 23 100 23 96 22 100 68 99 Sweden 20 100 20 100 20 100 60 100 UK 21 100 21 100 20 100 62 100 Overall concordance 99 96 97 97 95% Confidence interval 94 99 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 39 Table 4.4. Detection of penicillin non-susceptibility in S. pneumoniae by country after testing for penicillin G Strain UA1449 Strain UA1283 Strain UA347 (penicillin MIC of (penicillin MIC of (penicillin MIC of ref. labs: 4 mg/ L; ref. labs: 0.5 mg/ L; ref. labs: 0.5 mg/ L; intended intended intended interpretation: interpretation: interpretation: resistant) intermediate) intermediate) Total number number number of labs of labs of labs total doing % doing % doing % of % Country test correct test correct test correct tests correct Austria 8 100 8 100 8 88 24 96 Belgium 49 98 48 90 47 87 144 92 Bulgaria 11 82 11 64 11 55 33 67 Czech R. 28 100 27 93 27 93 82 95 Denmark 4 100 4 100 4 100 12 100 Finland 22 95 22 91 21 86 65 91 Germany 29 93 28 82 28 79 85 85 Greece 13 85 13 69 13 54 39 69 Iceland 2 100 2 100 2 100 6 100 Ireland 17 94 17 94 17 94 51 94 Israel 3 100 3 100 3 100 9 100 Italy 47 87 47 79 45 78 139 81 Luxembourg 5 100 5 100 5 100 15 100 Netherlands 24 100 23 96 24 83 71 93 Poland 17 100 17 100 17 100 51 100 Portugal 14 100 14 100 14 100 42 100 Slovenia 10 100 10 100 10 100 30 100 Spain 30 97 30 97 30 93 90 96 Sweden 20 100 21 100 21 100 62 100 UK 22 100 22 95 21 95 65 97 Overall concordance 96 90 87 91 95% Confidence interval 87 95 40 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Table 4.5. Detection of penicillin non-susceptibility in S. pneumoniae by guidelines used Strain UA1449 Strain UA1283 Strain UA347 (penicillin MIC of (penicillin MIC of (penicillin MIC of ref. labs: 4 mg/ L; ref. labs: 0.5 mg/ L; ref. labs: 0.5 mg/ L; intended intended intended interpretation: interpretation: interpretation: resistant) intermediate) intermediate) Total number number number of labs of labs of labs total doing % doing % doing % of % Country test correct test correct test correct tests correct BSAC 10 100 9 100 7 100 26 100 CRG 7 100 7 100 7 100 21 100 DIN 10 100 10 70 10 70 30 80 NCCLS 180 94 170 92 163 87 513 91 SRGA 13 100 14 100 13 100 40 100 Other 23 100 25 76 23 70 71 82 Not indicated 135 96 140 91 148 89 423 92 Overall concordance 96 90 87 91 95% Confidence interval 89 93 Other = participants using NeoSensitabs or the Stokes method or following a different guideline or following more than one guideline. For abbreviations see footnotes to Table 4.9. Gentamicin and erythromycin resistance were detected by 97% and 99% of participants, respectively. The overall concordance for detection of oxacillin susceptibility in the S. haemolyticus strain was 83%, with three countries (Bulgaria, Israel and Slovenia) clearly scoring lower. Concordance of MIC yielding methods versus non-MIC methods. Of the 433 laboratories participating, 375 used methods yielding an MIC: 11 (3%) used agar dilution, 21 (6%) (micro-) broth, 202 (54%) Etest and 52 (14%) used exclusively an automated method. Eightynine laboratories used more than one method. One-quarter of all laboratories (110/433) made use of an automated method. The most frequently used system was one of the different generations of bioMrieux Vitek (Table 4.8). The MICs determined by automated systems should be considered as semi-quantitative data because only a very limited range of dilutions is used. However, in this study we group automated methods under the MIC yielding methods as opposed to non-MIC methods. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 41 Table 4.6. Detection of oxacillin non-susceptibility in S. aureus by country Strain UA1432 Strain UA1450 (oxacillin MIC of ref. labs: (oxacillin MIC of ref. labs: >256 mg/ L; intended 8-64 mg/ L; intended interpretation: resistant) interpretation: resistant) Total number of number of labs doing % labs doing % total % Country test correct test correct of tests correct Austria 10 100 10 70 20 85 Belgium 55 100 56 73 111 86 Bulgaria 19 100 19 95 38 97 Czech R. 33 97 33 42 66 70 Denmark 4 100 4 75 8 88 Finland 26 100 26 81 52 87 Germany 28 100 28 86 56 93 Greece 16 100 16 63 32 81 Iceland 3 100 3 33 6 67 Ireland 10 100 10 80 20 90 Israel 3 100 3 100 6 100 Italy 48 100 47 79 95 89 Luxembourg 5 100 5 80 10 90 Netherlands 22 100 23 87 45 93 Poland 18 100 17 88 35 94 Portugal 15 100 14 71 29 86 Slovenia 10 100 10 90 20 95 Spain 29 100 29 90 58 95 Sweden 24 100 23 91 47 96 UK 10 100 10 70 20 85 Overall concordance 100 77 89 95% Confidence interval 8592 Quantitative methods yielding a penicillin G MIC [number of tests done (n) = 882] were more frequently concordant than non-MIC methods (n = 242) for S. pneumoniae strains (94% versus 79%). The same was true for detection of teicoplanin resistance in the S. haemolyticus strain, with a concordance of 91% for teicoplanin MIC methods (n = 182) versus 71% for non-MIC methods (n = 160). 42 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Table 4.7. Detection of oxacillin susceptibility and teicoplanin resistance in S. haemolyticus by country Strain UA1434 (oxacillin MIC of Strain UA1434 (teicoplanin MIC of ref. labs: 0.5 mg/ L; intended ref. labs: 32-64 mg/ L; intended interpretation: susceptible) interpretation: resistant) number of labs number of labs Country doing test % correct doing test % correct Austria 10 100 9 100 Belgium 55 84 43 65 Bulgaria 19 53 14 93 Czech R. 33 76 31 90 Denmark 4 75 2 50 Finland 26 81 13 77 Germany 28 100 28 96 Greece 16 81 14 79 Iceland 3 100 0 Ireland 10 90 17 71 Israel 2 50 2 100 Italy 46 83 49 90 Luxembourg 5 100 5 60 Netherlands 23 91 18 61 Poland 17 82 9 100 Portugal 15 93 12 83 Slovenia 10 50 8 100 Spain 30 93 28 89 Sweden 25 80 17 76 UK 10 90 20 65 Overall concordance 83 82 For the two S. aureus strains, oxacillin MIC methods (n = 363) reached 99% concordance in the homogeneously resistant MRSA, and 76% concordance in the heterogeneously resistant MRSA. Other methods (n = 405) yielded a concordance of 100% and 78%, respectively. Use of guidelines Of the 395 laboratories specifying which guideline they used, 242 (61%) in 19 countries followed the NCCLS guideline (Table 4.9). Any other guideline was not followed by more than 6% of the laboratories, in at most two countries. With only one reference laboratory participating in France, and Norway not participating, the CA-SFM and Norwegian Working Group on Antibiotics (NWGA) guidelines were not represented. 5 Thirty-eight of the 433 laboratories (9%) did not specify the guideline they followed. Discussion This Europewide QA exercise was characterized by an excellent response rate. It confirmed that an exercise of these dimensions is feasible and demonstrated the commitment of EARSS participants to quality. Strains were identified correctly at the genus and species level, and the average concordances over all control strains were high. We distributed strains that tested the laboratories capability to identify the most clinically relevant resistances (penicillin G in S. pneumoniae, methicillin in S. aureus and glycopeptide in staphylococci) and feel reassured to continue using surveillance data generated by the participating national surveillance systems. In this exercise, 8685 tests were reported and assessed but some 850 more results were expected. Laboratories were asked to test all antimicrobial agents listed on the report form, but in case they normally test for another agent from the same class they were asked to specify the name of this agent in the same box. This may have given rise to misunderstanding. Laboratories were asked furthermore to test the susceptibility using routine procedures. Apparently this was interpreted by a number of laboratories to test only those organismantimicrobial combinations that they test routinely. Laboratories should be solicited in future QA exercises to test and report all the requested organismantimicrobial combinations. To screen for penicillin resistance in S. pneumoniae, almost all participants used the oxacillin 1 g disc, achieving a very high concordance rate. This indicates that the oxacillin screen disc reliably discriminates susceptible from non-susceptible strains. The concordance for penicillin resistance in S. pneumoniae is somewhat lower when laboratories test for penicillin G. This lower concordance rate is partly due to the fact that a substantial number of laboratories use non-MIC-based penicillin confirmation EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 43 techniques. Indeed, we observed a far higher concordance (94%) for quantitative methods yielding a penicillin MIC than for non-MIC-yielding methods (79%), confirming the rationale of the EARSS protocol to perform MIC determination on S. pneumoniae strains found to be non-susceptible by a screen test. The difficulty of laboratories using disc diffusion tests to recognize reduced penicillin susceptibility in S. pneumoniae has recently been described in another international QA survey. 6 The differences in concordance among the three S. pneumoniae control strains are a reflection of how many dilution steps the penicillin MIC for the strain is distant from the susceptible breakpoint. Indeed, more laboratories misinterpreted strain UA347 as being penicillin susceptible than strain UA1449. Some guidelines yielded lower concordance rates for the determination of penicillin resistance, like the DIN guideline as well as the guidelines specified under Other in Table 4.5. For the DIN guideline, this may be related to the susceptible breakpoint, which is one dilution step higher. Almost all national guidelines in Europe, as well as the NCCLS guideline, consider isolates of S. pneumoniae to be non-susceptible to penicillin if the MIC is >0.06 mg/L. 711 The DIN guideline considers isolates to be non-susceptible to penicillin if the MIC is >0.12 mg/L. 12 However, it should be noted that the DIN, as well as the guidelines specified under Other, were used only by relatively small numbers of laboratories, allowing for larger variation. All three S. pneumoniae control strains were non-susceptible, and the high concordance rates represent a high sensitivity of EARSS laboratories to detect penicillin non-susceptibility in S. pneumoniae. It is not possible from this exercise to infer the specificity of EARSS laboratories to detect penicillin susceptibility in S. pneumoniae. Because all three S. pneumoniae strains were highly resistant to erythromycin, they were not really a challenge to participating laboratories. Virtually all laboratories correctly determined erythromycin resistance. For the detection of oxacillin resistance in S. aureus, we included one strain that was homogeneously resistant and another strain that was heterogeneously resistant to oxacillin. Laboratories performed extremely well in detecting oxacillin resistance in the homogeneously MRSA strain, but the concordance rate dropped from 100% to 77% in the heterogeneously resistant MRSA strain. A notable proportion of laboratories in three countries failed to detect the heterogeneously resistant MRSA strain. However, although we observed differences in concordance among countries, we found no significant differences among guidelines. Detecting heterogeneously resistant MRSA possibly depends more on test methods used by individual laboratories than on differences in guidelines. Laboratories in most countries, and in some countries in particular, should scrutinize carefully their capability of detecting low-frequency resistant subpopulations, and ensure that proper laboratory methods are used to detect heterogeneously resistant MRSA strains. 44 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Detection of glycopeptide resistance in staphylococci is of paramount importance. For safety reasons we chose not to distribute a vancomycin intermediate (or resistant) strain among laboratories all over Europe, but instead distributed a S. haemolyticus strain that was resistant to teicoplanin. Vancomycin susceptibility of the two S. aureus control strains was interpreted correctly by participating laboratories, but teicoplanin resistance of the S. haemolyticus strain was often missed. Quantitative methods yielding an MIC were more frequently concordant than non-MIC methods for the detection of teicoplanin resistance against the S. haemolyticus strain (91% versus 71%). Only a few participants misinterpreted gentamicin and erythromycin susceptibility in staphylococci, indicating that most participating laboratories are capable of determining gentamicin and erythromycin resistance. This exercise provides a good overview of the guidelines being followed in Europe, with exception of the French and Norwegian guidelines. The NCCLS guideline is widely followed in Europe. In 10 countries NCCLS seems to be the only guideline in use; but in the countries that have issued national guidelines (Germany, The Netherlands, Sweden and Spain) some laboratories also follow the NCCLS guideline. The BSAC and Swedish Reference Group for Antibiotics (SRGA) guidelines are the only European guidelines used in more than one country. Because France and Norway are not represented in this study, we cannot infer on the use of guidelines there. It is probable, however, that the CA-SFM and NWGA guidelines are not widely followed in other European countries. We found that 9% of participating laboratories did not specify which guideline they follow. Apart from the obvious reason that some laboratories simply may not have reported which guideline is followed, it may also be that some laboratories use in-house guidelines, EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 45 Table 4.8. Manufacturer and type of automated system used by participating laboratories Automatic method Total Automatic method Total BBL/BD Sceptor 14 Dade Behring Microscan 5 Becton Dickinson Pasco 5 Dade Behring Microscan Walkaway 11 bioMrieux ATP 2 Dade Behring Autoscan 2 bioMrieux Vitek1 6 Sensititre Aris 2 bioMrieux Vitek2 8 Soria Helgguipo Wider 8 bioMrieux Vitek32 6 Pasteur-Sanofi Pneumo PAC 1 bioMrieux Mini API 6 >1 method 6 bioMrieux API-ATB 5 bioMrieux Vitek unspecified 23 Total 110 Table 4.9. The usage of guidelines by number of laboratories per country Guideline CZECH MEN- CA- Not used BSAC CRG 98 DIN SURA NCCLS SFM a SRGA Stokes >1 specified Austria 9 1 Belgium 31 10 16 Bulgaria 20 Czech R . 15 4 11 3 Denmark 1 1 3 Finland 25 France 1 Germany 15 6 9 1 Greece 14 3 Hungary 1 Iceland 3 Ireland 5 1 9 2 1 Israel 3 Italy 50 2 1 Luxembourg 5 Malta 1 Netherlands 6 8 9 2 Poland 18 1 Portugal 11 1 4 Slovenia 7 3 Spain 1 25 5 Sweden 25 UK 12 6 3 3 Total 17 6 15 15 1 242 1 26 15 57 38 Grand total 433 a French laboratories did not participate in this QA exercise, with the exception of one national reference centre. BSAC, British Society for Antimicrobial Chemotherapy; CRG, Commissie Richtlijnen Gevoeligheidsbepalingen; DIN, Deutsches Institut fr Normung; MENSURA, Mesa Espaola de Normalizacion de la Suseptibilitad y Resistencia a los Antimicrobianos; NCCLS, National Committee for Clinical Laboratory Standards; CA- SFM, Comit de lAntibiogramme de la Socit Franaise de Microbiologie; SRGA, Swedish Reference Group for Antibiotics; >1, more than one guideline followed. 46 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 47 or other non-documented guidelines. An overview of the antimicrobial susceptibility test breakpoints of national societies has been published recently. 13 The authors recommend that other national guidelines (e.g. Czech 98) are also documented in international literature and that every laboratory works according to well-documented guidelines so that susceptibility test results are reproducible and comparable. Guidelines should also be freely accessible through the Internet. It should be noted that overall the breakpoints defining susceptibility or resistance of bacteria to antimicrobial agents do not differ greatly between guidelines used in Europe. Baquero 14 argued that it is possible to establish a theoretical consensus standard list of breakpoints, such that more than 95% of the breakpoints proposed by the different systems differ from the consensus standard by no more than one dilution. We hope that these findings may add to the process of standardizing breakpoints in Europe as brought forward by the EUCAST. It is shown that, overall, countries participating in EARSS are capable of delivering susceptibility data of good quality. The comparability of susceptibility data for penicillin resistance in S. pneumoniae and for homogeneous methicillin resistance in S. aureus is satisfactory among European countries and across guidelines. However, we emphasize the importance of determining an MIC for suspected penicillin non-susceptible S. pneumoniae and for suspected glycopeptide non-susceptible S. aureus. Laboratories, particularly in some countries, may need to improve their capability of detecting oxacillin resistance in heterogeneously resistant MRSA and teicoplanin resistance in S. haemolyticus. A number of laboratories did not fill out the form completely, for example by not reporting the species identification or not performing all the susceptibility tests requested. Not doing (or reporting) a test is considered as non-performance and hinders the assessment of the performance of laboratories. This should be avoided in future QA studies by organizers and participants. Not every laboratory produced good results in this exercise, and the performance of some individual laboratories could probably be improved. For continuous external quality assessment we recommend that laboratories participate in national and international schemes with frequent distributions of control strains. However, we feel reassured by this exercise that overall the antimicrobial susceptibility testing data as monitored through the national surveillance systems that participate in EARSS are of good quality. It is hoped that laboratories participating in this EARSSUK NEQAS quality assurance are encouraged to maintain and improve their performance, as has been observed in other surveillance schemes. 15,16 Acknowledgements We express our thanks and appreciation for the organization by UK NEQAS, for the countries coordinating centres who distributed the strains swiftly and for the overwhelmingly good response rate of the 471 laboratories participating in EARSS. We thank N. Nagelkerke for help in the statistical analysis and thank the national representatives of EARSS in the participating countries. We also welcome the comments on this article by D. Brown and G. Kahlmeter from EUCAST. EARSS is funded by the European Commission, DG SANCO [Agreement SI2.123794 (99CVF4-018) European Antimicrobial Resistance Surveillance System (EARSS)]. Participating countries and national representatives in EARSS during 2000: Austria, H. Mittermayer, W. Koller; Belgium, H. Goossens, F. van Loock; Bulgaria, B. Markova; Czech Republic, P. Urbaskova; Denmark, T. L. Srensen, D. Monnet; Finland, P. Huovinen, O. Lyytikinen; France, P. Courvalin, H. Aubry-Damon; Germany, W. Witte, T. Breuer; Greece, N. Legakis, G. Vatopoulos; Hungary, M. Konkoly-Thege; Iceland, K. Kristinsson, H. Briem; Ireland, O. Murphy, D. OFlanagan; Israel, R. Raz; Italy, G. Cornaglia, M. L. Moro; Luxembourg, R. Hemmer; Malta, M. Borg; Netherlands, A. de Neeling, W. Goettsch; Norway, E. Hoiby, P. Aavitsland; Poland, V. Hryniewicz; Portugal, M. Cania, M. Paixao; Slovenia, M. Gubina; Spain, F. Baquero, J. Campos; Sweden, B. Olsson-Liljequist, O. Cars; United Kingdom, A. Johnson, M. Wale. References 1. EUCAST. (2000). The setting of antimicrobial breakpoints Clinical Microbiology and Infection 5, 12. 2. EARSS website. (2001). EARSS Manual. EARSS management Team. [Online.] http://www.earss.rivm.nl (21 June 2002, date last accessed). 3. Tomasz, A., Nachman, S. & Leaf, H. (1991). Stable classes of phenotypic expression in methicillin-resistant clinical isolates of staphylococci. Antimicrobial Agents and Chemotherapy 35, 1249. 4. UK-NEQAS website. (2000). Report of External Quality Assessment Exercise EARSS-NEQAS 2000. UK- NEQAS. [Online.] http://www.pcug.co.uk/~ukneqasm/ and at http://www.earss.rivm.nl (21 June 2002, date last accessed). 5. Bergan, T., Bruun, J., Digranes, A., Lingaas, E., Melby, K. & Sander, J. (1997). Susceptibility testing of bacteria and fungi. Report from the Norwegian working group on antibiotics. Scandinavian Journal of Infectious Diseases, Suppl. 1, 103. 6. Tenover, F. C., Mohammed, M. J., Stelling, J., OBrien, T. & Williams, R. (2001). Ability of laboratories to detect emerging anti-microbial resistance: proficiency testing and quality control results from the World Health Organizations external quality assurance system for antimicrobial susceptibility testing. Journal of Clinical Microbiology 39, 24150. 48 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 7. The British Society for Antimicrobial Chemotherapy (BSAC) website. (1998). Standardized disc sensitivity testing method, The Newsletter of the British Society for Antimicrobial Chemotherapy, 1998. BSAC, Birmingham, UK. Update available online at: http://www.bsac.org.uk/discdiff/sensitivity2.pdf (21 June 2002, date last accessed). 8. Commissie Richtlijnen Gevoeligheidsbepalingen. (1996). Nederlands Tijdschrift voor Medische Microbiologie 4, 5. 9. Cars, O. (Ed.) (1997). Antimicrobial susceptibility testing in Sweden. Scandinavian Journal of Infectious Diseases, Suppl. 1, 105. 10. Socit Franaise de Microbiologie. (1996). Report of the Comit de lAntibiogramme de la Socit Franaise de Microbiologie. Clinical Microbiology and Infection 2, Suppl. 1, S149. 11. MENSURA. (2000). Recomendaciones del grupo MENSURA para la seleccin de antimicrobianos en el estudio de la sensibilidad y criterios para la interpretacin del antibiograma. Revista Espaola Quimoterapia 13, 7386. 12. Deutsches Institut fr Normung. (1998). Methods for the Determination of Susceptibility of Pathogens (Except Mycobacteria) to Antimicrobial Agents. MIC Breakpoints of Antibacterial Agents, Suppl. 1, pp. 589404. DIN, Berlin. 13. Degener, J. E. & Phillips, I. (2001). Comparison of antimicrobial susceptibility test breakpoints of national societies. Clinical Microbiology and Infection 7, 514. 14. Baquero, F. (1990). European standards for antibiotic susceptibility testing: towards a theoretical consensus. European Journal of Clinical Microbiology and Infectious Diseases 7, 4925. 15. Forster, D. H., Krause, G., Gastmeier, P., Ebner, W., Rath, A., Wischnewski, N. et al. (2000). Can quality circles improve hospital-acquired infection control? Journal of Hospital Infection 45, 30210. 16. Snell, J. S. & Brown, D. F. J. (2001). External quality assessment of antimicrobial susceptibility testing in Europe. Journal of Antimicrobial Chemotherapy 47, 80110. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 49 Chapter 5 Streptococcus pneumoniae susceptibility data in Europe Introduction Pneumonia has been a major cause of morbidity and mortality among humans throughout history. Despite advances made by medical science it is still the major cause of infection related mortality world-wide. In 1998, the World Health Organisation reported over 3.7 million deaths due to lower respiratory tract infections [1, 2]. Streptococcus pneumoniae is an important pathogen in many community-acquired respiratory infections, including acute bacterial sinusitis, acute otitis media, community acquired pneumonia, and acute exacerbations of chronic bronchitis, as well as more invasive infections such as meningitis and bacteremia [3]. Until the early 1990s, clinical isolates of S. pneumoniae were nearly uniformly susceptible to penicillin [4], but it was only a matter of time until the first reports of penicillin-resistant pneumococci emerged and became more widespread [2, 5]. Together with the emergence of penicillin resistance in pneumococci, strains with multiple resistance, not only to betalactams, but also to macrolides, chloramphenicol, tetracyclines, and cotrimoxazole appeared in various parts of the world [2, 6]. The European Antimicrobial Resistance Surveillance System (EARSS) has been collecting antimicrobial susceptibility data (AST) data for S. pneumoniae since 1999, currently in 26 European countries, and has been monitoring variations in antimicrobial resistance geographically and in time. In this chapter the susceptibility data for S. pneumoniae from 1999, 2000, and 2001 are presented and discussed. Methods EARSS protocol for Streptococcus pneumoniae testing AST data were collected from European countries participating in EARSS of the first invasive S. pneumoniae isolate (from blood or cerebrospinal fluid (CSF)) per patient per quarter over the period 1999-2001. By the EARSS protocol laboratories were asked to report penicillin susceptibility determined with an oxacillin disk test (1 g or 5 g). Using a 1-g oxacillin disc load, a S. pneumoniae strain with a zone size of 20 mm or less is considered presumably non-susceptible to penicillin. With a 5-g oxacillin disk load, the zone size must be 26 mm or less in order to be presumably non-susceptible. If the isolate was oxacillin non-susceptible by the oxacillin disk test, the minimum inhibitory concentration (MIC) of penicillin, cefotaxime or ceftriaxone and ciprofloxacin had to be determined. In addition, participants could also opt to report AST data of: clindamycin, erythromycin, rifampin, tetracycline and vancomycin. EARSS collects routinely generated data and as such accepts the interpretations, sensitive (S), intermediate (I) and resistant (R) of the laboratories. 52 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Antimicrobial susceptibility breakpoints All laboratories perform antimicrobial susceptibility tests and interpret their results according to the guidelines used in their laboratories. Almost all national guidelines in Europe, as well as the United States guideline, consider isolates of S. pneumoniae to be non-susceptible to penicillin if the MIC is >0.06 mg/L [7-11]. The German guideline considers isolates penicillin non-susceptible if the MIC is >0.12 mg/L [12]. An overview of the breakpoints according to the various AST guidelines used by laboratories participating in EARSS is shown in Table 5.1. Table 5.1. Antimicrobial susceptibility testing breakpoints for Streptococcus pneumoniae used in EARSS*. Antibiotic S R National breakpoint committees Range of breakpoints (mg/L) (mg/L) S R Penicillin G 0.06 - NCCLS 0.06 2 MENSURA, SFM 0.06 - 0.12 2 SRGA , BSAC, CRG 0.12 2 DIN Ceftriaxone / 0.12 2 SRGA Cefotaxime 0.5 2 NCCLS 0.5 4 SFM 0.12 - 4 2 - 32 1 2 BSAC 4 32 CRG, DIN Ciprofloxacin 0.12 4 SRGA 0.25 4 NWGA 0.12 - 1 4 1 4 CRG, DIN, MENSURA Erythromycin 0.25 1 NCCLS 0.5 1 BSAC, SRGA 0.5 2 MENSURA 0.25 - 1 1 - 8 1 4 CRG, NWGA 1 8 DIN, SFM BSAC, British Society for Antimicrobial Chemotherapy; CRG, Commissie Richtlijnen Gevoeligheidsbepalingen; DIN, Deutsches Institut fr Normung; MENSURA, Mesa Espaola de Normalizacion de la Suseptibilitad y Resistencia a los Antimicrobianos; NCCLS, National Committee for Clinical Laboratory Standards; NWGA, Norwegian Working Group on antibiotics; SFM, Comit de lAntibiogramme de la Socit Franaise de Microbiologie; SRGA, Swedish Reference Group for Antibiotics. * For comparability, the resistance breakpoints of the SFM and CRG guidelines were adapted, changing the sign > (greater than) into the sign (equal to or greater than) and adding one dilution step. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 53 Data processing and validation Laboratories send data to the national EARSS data manager, who checks and forwards the data to the Dutch National Institute of Public Health and the Environment (RIVM). National data managers receive standard feedback reports for approval. The national data is then collated into the EARSS database and are accessible at the interactive EARSS web site, and are made available for statistical analysis using the SAS software. Data lacking mandatory information i.e., laboratory code, date of sample collection, patient identifier or month and year of birth, pathogen code, antibiotic code, or test result (S, I or R) were rejected. Data were de-duplicated to only the first invasive isolate per patient per year. The proportion of PNSP and erythromycin non-susceptible S. pneumoniae was determined per country per year (1999, 2000 and 2001). Non- susceptible S. pneumoniae isolates include both intermediately and fully resistant isolates. Only the countries that reported AST data for all three years (1999-2001) were included for the trend analysis and seasonal distribution over the years. The AST data from all countries reporting over the years were included for the age distribution analysis. The proportion of PNSP isolates non-susceptible to 3 rd generation cephalosporins and fluoroquinolones was determined. The S. pneumoniae isolates from France could not be included in the age distribution and seasonal variation analysis, because France delivered aggregated data of invasive S. pneumoniae isolates only for the first 2 quarters of 2001. A quality assurance exercise was performed in September 2000 by 471 laboratories from 23 countries participating in EARSS to assess the comparability of susceptibility test results (see chapter 4). The overall concordance rate for detecting penicillin non- susceptibility with an oxacillin screen disk was 97% and ranged from 96% to 99% for the three strains tested. Ninety-seven percent of the participants used an oxacillin disk loaded with 1 g. Erythromycin resistance was detected correctly by 99% of the participants. Results Streptococcus pneumoniae penicillin susceptibility In total 26 European countries reported AST data of 15 288 invasive S. pneumoniae isolates to EARSS over the period 1999-2001 (3899, 5449, and 5940 respectively), of which 1712 were reported non-susceptible to penicillin (11.4% overall). Confirmation of the penicillin non-susceptible S. pneumoniae (PNSP) isolates by determining the penicillin MIC, as specified in the EARSS protocol, was performed for 91% of the PNSP isolates. In total 93% of the S. pneumoniae isolates were derived from blood samples versus 7% from cerebrospinal fluid (CSF) (French data not included). The highest average proportions of PNSP isolates (> 30%) were found for the Mediterranean countries. The lowest average proportions of PNSP isolates were found in northern countries (<3%) (Figures 5.1 and 5.2). 54 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY The exact number of invasive penicillin non-susceptible S. pneumoniae (PNSP) isolates reported to EARSS in the period 1999-2001, per country, per year can be found in Appendix 5.1. Time trends in country-specific PNSP proportions Figure 5.3 displays S. pneumoniae penicillin non-susceptibility in invasive isolates from 1999 to 2001 and shows a stable pattern in most countries. The total number of S. pneumoniae isolates reported (by the countries with data of all three years) in 1999, 2000 and 2001 were 3871, 3839, and 3611, respectively. The average proportion of PNSP was 7%, 8% and 6% for the respective years. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 55 LU MT < 3 % I, R Missing 3 9 10 30 > 30 Figure 5.1. Mean proportion (1999-2001) of Streptococcus pneumoniae penicillin non-susceptibility (PNSP) in invasive isolates reported per country. France delivered aggregated data for the first 2 quarters of 2001. 56 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 0 n o n - s u s c e p t i b l e
i s o l a t e s
( % ) country code (number of isolates) 40 35 30 25 20 15 10 5 45 50 F R
( 6 9 3 ) B G
( 2 9 ) E S
( 1 2 3 3 ) H U
( 3 6 ) L U
( 7 2 ) I L
( 1 6 9 ) B E
( 2 3 2 8 ) U K
( 1 3 1 6 ) I E
( 6 0 5 ) I T
( 4 2 3 ) D E
( 6 8 4 ) F I
( 7 7 0 ) N O
( 4 1 6 ) D K
( 7 3 7 ) C Z
( 2 6 5 ) N L
( 2 2 1 5 ) S E
( 2 3 9 6 ) P T
( 3 7 9 ) S I
( 1 9 6 ) H R
( 2 0 ) M T
( 2 3 ) I S
( 1 3 3 ) A T
( 1 1 6 ) E E
( 2 0 ) % intermediate % resistant Figure 5.2. S. pneumoniae penicillin susceptibility in invasive isolates reported per country over 1999-2001, with a minimum of 10 S. pneumoniae isolates (number of isolates indicated between brackets). France delivered aggregated data for the first 2 quarters of 2001. For the country codes, see appendix 5.0 at the end of this chapter. Figure 5.3. Streptococcus pneumoniae penicillin non-susceptibility in invasive isolates from 1999 to 2001. Only countries that reported to EARSS for all three years of surveillance are presented (number of isolates indicated between brackets). 0 20 25 15 10 5 30 n o n - s u s c e p t i b l e
i s o l a t e s
( % ) year of sample collection country code (mean sample-size per year) 1999 2000 2001 BE (776) DE (228) FI (257) IE (202) IS (44) IT (141) LU (24) NL (738) PT (126) SE (799) UK (439) Seasonal variation Figure 5.4 shows the total number of invasive S. pneumoniae isolates and the proportion of PNSP isolates reported per month over a period of three years from 9 countries (Germany, Finland, Iceland, Ireland, Luxembourg, the Netherlands, Portugal, Sweden, and the United Kingdom). The distribution of the S. pneumoniae isolates that are reported displays a clear seasonal variation with a peak around the turn of the year, a constant decline of isolates until August, and a successive regular increase in the fall and winter months. Figure 5.4. The total number of invasive Streptococcus pneumoniae (SPN) isolates and the proportion of penicillin non-susceptible S. pneumoniae isolates (PNSP) per month (only the 9 countries with data of all quarters over the period 1999-2001 were included). A two-fold increase of the average number of S. pneumoniae isolates reported during the winter months (January to March) was observed in comparison with the summer months (June to August) (Table 5.2). No significant differences (P > 0.05) were found for the average proportion of PNSP isolates during the winter and summer months (Table 5.2). Every August there appears to be a repeated high prevalence of PNSP. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 57 0 n u m b e r
o f
S P N
i s o l a t e s %
P N S P month of sample collection 350 300 250 200 10 400 0 10,5 7,5 6 4,5 1,5 12 1 9 9 9
j a n f e b m a r a p r m a y j u n j u l a u g s e p o c t n o v d e c
2 0 0 0
j a n f e b m a r a p r m a y j u n j u l a u g s e p o c t n o v d e c 2 0 0 1
j a n f e b m a r a p r m a y j u n j u l a u g s e p o c t n o v d e c 350 9 200 3 number of SPN isolates % PNSP 58 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Table 5.2. The average number of invasive Streptococcus pneumoniae isolates and the proportion of penicillin non-susceptible S. pneumoniae isolates (PNSP) during the winter (Jan-March) and summer months (Jun-Aug) over the years. Winter Summer Year Average number Average number S. pneumoniae %PNSP S. pneumoniae %PNSP 1999 301 5% 139 3% 2000 320 5% 143 5% 2001 341 6% 164 7% Age distribution The invasive S. pneumoniae isolates (n= 14 595, French isolates not included) reported to EARSS over the years 1999-2001 show that S. pneumoniae isolates were most common in the age group 4 years and younger (Figure 5.5). Also the likelihood of having PNSP was greatest for the age group 4 years and younger (20%, p<0.05). A steadily increasing number of S. pneumoniae isolates were reported for those between the ages of 49 and 79. Streptococcus pneumoniae cephalosporin susceptibility In total, 1627 of the 1712 (95%) PNSP isolates reported to EARSS were tested for ceftriaxone or cefatoxime in the period 1999-2001. Figure 5.6 shows the proportion of PNSP isolates non-susceptible to 3 rd generation cephalosporins per country. Three percent of the PNSP isolates were reported resistant and 28% intermediately resistant to these agents (Appendix 5.2). Streptococcus pneumoniae fluoroquinolone susceptibility In total 915 of the 1324 PNSP isolates reported to EARSS in 1999-2001 were tested for ciprofloxacin or ofloxacin. Figure 5.7 shows the proportion of PNSP isolates non- susceptible to fluoroquinolones per country. Two percent of these isolates were reported as resistant and 10% as intermediately resistant to these agents (Appendix 5.3). Streptococcus pneumoniae erythromycin susceptibility For 76% of all S. pneumoniae isolates also AST data of erythromycin was reported. Therefore, it was decided at the 2001 EARSS plenary meeting to display as well erythromycin susceptibility data. In total 11 781 of 15 288 (77%) S. pneumoniae isolates reported to EARSS were tested for erythromycin in the years 1999, 2000, and 2001 (2419, EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 59 0 n u m b e r
o f
S P N
i s o l a t e s %
P N S P age categories 1800 1600 1200 1000 800 200 2000 0 15 10 25 0 - 4 5 - 9 1 0 - 1 4 1 5 - 1 9 2 0 - 2 4 2 5 - 2 9 3 0 - 3 4 3 5 - 3 9 4 0 - 4 4 4 5 - 4 9 5 0 - 5 4 5 5 - 5 9 6 0 - 6 4 6 5 - 6 9 7 0 - 7 4 7 5 - 7 9 8 0 - 8 4 8 5 + 20 1400 600 400 5 number of SPN isolates % PNSP 0 60 50 40 30 20 10 70 % intermediate % resistant n o n - s u s c e p t i b l e
i s o l a t e s
( % ) country code (number of isolates) U K
( 6 5 ) P T
( 8 8 ) D E
( 1 2 ) C Z
( 1 5 ) E S
( 4 1 6 ) B E
( 3 3 6 ) I L
( 6 5 ) F R
( 3 1 5 ) S E
( 4 1 ) N L
( 1 5 ) S I
( 4 0 ) I E
( 7 4 ) I T
( 4 7 ) F I
( 3 6 ) D K
( 2 3 ) Figure 5.6. 3 rd generation cephalosporin susceptibility in invasive penicillin non-susceptible Streptococcus pneumoniae (PNSP) isolates reported per country in 1999-2001, with a minimum of 10 PNSP isolates (number of isolates indicated between brackets). France delivered aggregated data for the first 2 quarters of 2001. Figure 5.5. The total number of invasive Streptococcus pneumoniae isolates and the proportion of penicillin non- susceptible S. pneumoniae isolates (PNSP) by age reported to EARSS from 1999 to 2001. 60 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 0 90 80 70 60 40 50 30 20 10 100 % intermediate % resistant n o n - s u s c e p t i b l e
i s o l a t e s
( % ) country code (nr of isolates) C Z
( 1 3 ) I L
( 1 3 ) D K
( 2 3 ) P T
( 8 8 ) S I
( 3 8 ) I T
( 4 3 ) E S
( 2 0 4 ) B E
( 3 3 7 ) S E
( 3 4 ) F I
( 1 3 ) I E
( 7 3 ) LU MT < 3 % I, R Missing 3 9 10 30 > 30 Figure 5.7. Fluoroquinolone susceptibility in invasive penicillin non-susceptible Streptococcus pneumoniae (PNSP) isolates reported per country in 1999-2001, with a minimum of 10 PNSP isolates. Note that the Swedish guideline recommends that pneumococci should never be reported as clinically susceptible to ciprofloxacin. Figure 5.8. Mean proportion (1999-2001) of Streptococcus pneumoniae erythromycin non-susceptibility in invasive isolates per country reported to EARSS. France delivered aggregated data for the first 2 quarters of 2001. 4431 and 4931 respectively). In the period 1999-2001, 2071 S. pneumoniae isolates were reported non-susceptible to erythromycin (17.6% overall). The highest average proportions of erythromycin non-susceptible S. pneumoniae isolates were found in Italy, France and Belgium (>30%), whereas the lowest proportion of erythromycin non-susceptible isolates was found in the Czech Republic (<3%), followed by the Scandinavian countries, the Netherlands, Germany, Austria and Iceland (3-10%) (Figure 5.8). More than half of the PNSP isolates with reported erythromycin data in the period 1999- 2001 (1558/1712, 91%) were reported to be erythromycin resistant (54%) and 1% was reported to be intermediately resistant. Figure 5.9 reports the proportions of erythromycin resistance among PNSP isolates by country. For some countries the ratio of reported erythromycin AST data was unequal for penicillin susceptible and non-susceptible isolates. Therefore the erythromycin AST data in Appendix 5.4 is categorised as penicillin susceptible and penicillin non-susceptible. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 61 0 70 60 50 40 30 20 10 80 % intermediate % resistant n o n - s u s c e p t i b l e
i s o l a t e s
( % ) country code (nr of isolates) F R
( 3 1 5 ) B E
( 3 3 7 ) I T
( 4 6 ) F I
( 4 7 ) E S
( 4 1 0 ) S I
( 3 0 ) N L
( 1 4 ) U K
( 6 4 ) I L
( 6 1 ) P T
( 4 8 ) C Z
( 1 4 ) I E
( 6 4 ) D K
( 2 5 ) S E
( 4 5 ) Figure 5.9. Erythromycin susceptibility in invasive penicillin non-susceptible Streptococcus pneumoniae (PNSP) isolates reported per country in 1999-2001, with a minimum of 10 PNSP isolates (number of isolates indicated between brackets). France delivered aggregated data for the first 2 quarters of 2001. Discussion There was a clear north-south gradient for the proportion of invasive penicillin non- susceptible S. pneumoniae. The highest proportion of penicillin non-susceptibility was found in the southern European countries. Most countries (with data for all three years) did not show any increase in resistance during the relatively short observation time. Some countries reported low numbers of invasive S. pneumoniae isolates, possibly leading to an overestimation of the proportion of non-susceptible isolates. However, in the majority of countries only a relatively small proportion of the isolates was reported as fully resistant to penicillin. The prevalence of invasive S. pneumoniae was seasonal with clear peaks during winter. The prevalence of penicillin non-susceptible S. pneumoniae displayed no seasonality. The seasonal variation analysis of the total number of invasive S. pneumoniae isolates and the proportion of PNSP per month includes mainly data from northern European countries with the only exception being Portugal. Epidemiology of S. pneumoniae infections in northern countries may possibly be different from southern and/or central European countries also with regard to PNSP-seasonality. The same analysis should be repeated once trend-data is available from more countries. To what degree the number of reported S. pneumoniae strains over the years/months follow a comparable seasonality as do upper respiratory viral infections, respiratory syncytial virus, and influenza remains to be elucidated. The prevalence of invasive infections with S. pneumoniae was highest in children 4 years and younger. Elderly are also at higher risk for invasive S. pneumoniae infections. It is known from literature that the highest rates of invasive pneumococcal disease (i.e. bacteremia and meningitis) occur among young children, especially those less than 2 years old [13]. EARSS data show that also the likelihood of having PNSP was greatest for the age group 4 years and younger. This emphasises the importance of physician and parent education about the prudent use of antimicrobial agents, as well as the importance of new conjugate vaccines from which children could benefit. Since February 2000, a new vaccine to protect children of less than 2 years against invasive pneumococcal disease has been widely used in the United States [14]. This vaccine has also been granted final marketing authorisation by the European Commission in 15 European countries, and is currently on the market in several of them. The standard treatment for pneumococcal illnesses in infants and young children has relied on the use of antibiotics, such as penicillin and erythromycin. According to WHO, increasing pneumococcal resistance to antimicrobial drugs, and the rapid spread of resistant strains throughout the world underlines the importance of the prudent use of antimicrobial agents and vaccination [15]. There were large differences in the resistance proportions among penicillin non- 62 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY susceptible S. pneumoniae for 3 rd generation cephalosporins and fluoroquinolones. When interpreting proportion rates from the different countries it is essential to be aware of recommendations of the different national breakpoints. Regarding cephalosporin susceptibility, national breakpoint committees recommend laboratories in case of finding a PNSP either to: a) report 3 rd generation cephalosporins automatically as non-susceptible (unless MIC determination has shown otherwise), such as is common practise in the UK; or b) determine the cefotaxim or ceftriaxone MIC, leading most PNSPs in Sweden to be classified as intermediate resistant because the SRGA susceptible breakpoint for cephalosporins is low (S <0.12 mg/L) compared to other national susceptible breakpoints. These recommendations explain the high proportion of intermediate resistance to 3 rd generation cephalosporins in Sweden and the UK. Regarding fluoroquinolone susceptibility it is essential to know that the national guideline SRGA, used by all Swedish laboratories participating in EARSS, recommends that pneumococci should never be reported as clinically susceptible to ciprofloxacin. For this reason all PNSP isolates from Sweden were reported as intermediately resistant. Taking these recommendations into account, considerable differences remain among countries in resistance proportions among penicillin non-susceptible S. pneumoniae for 3 rd generation cephalosporins and fluoroquinolones. Fluoroquinolone resistance is a problem in many areas warranting the prudent use of these agents. In many countries the proportion of macrolide resistant S. pneumoniae is high. It is apparent also from the EARSS data that penicillin and macrolide resistance is often associated. This high macrolide resistance prevalence has cast doubt on the efficacy of macrolide antibiotics for serious pneumococcal infections. Based on surveillance data from EARSS and on outpatient antibiotic sales, a strong correlation between antimicrobial resistance in S. pneumoniae and the use of beta-lactam antibiotics and macrolides was demonstrated in Europe, see chapter 6. Thus, in situations where penicillin and erythromycin resistance is common, the empirical use of macrolides should be discouraged. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 63 Appendix 5.0. EARSS country codes Austria AT Italy IT Belgium BE Luxembourg LU Bulgaria BG Malta MT Croatia HR Netherlands NL Czech Republic CZ Norway NO Denmark DK Poland PL Estonia EE Portugal PT Finland FI Rumania RO France FR Russia RU Germany DE Slovakia SK Greece GR Slovenia SI Hungary HU Spain ES Iceland IS Sweden SE Ireland IE Switzerland CH Israel IL United Kingdom UK 64 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Appendix 5.1. Invasive penicillin non-susceptible S. pneumoniae (PNSP) isolates reported to EARSS in the period 1999-2001, per country, per year (SP = S. pneumoniae). Total SP country year Nr of tested Nr % Labs for PNSP Nr I Nr R % I % R PNSP PNSP AT 2000 9 53 1 0 2% 0% 1 2% 2001 9 63 2 0 3% 0% 2 3% BE 1999 96 938 87 44 9% 5% 131 14% 2000 92 973 100 51 10% 5% 151 16% 2001 83 417 55 0 13% 0% 55 13% BG 2000 8 13 0 3 0% 23% 3 23% 2001 8 16 0 1 0% 6% 1 6% CZ 2000 26 111 4 0 4% 0% 4 4% 2001 32 154 10 1 6% 1% 11 7% DE 1999 11 363 5 3 1% 1% 8 2% 2000 9 168 3 1 2% 1% 4 2% 2001 9 153 4 1 3% 1% 5 3% DK 2000 5 410 14 1 3% 0% 15 4% 2001 5 327 8 2 2% 1% 10 3% EE 2001 5 20 0 0 0% 0% 0 0% ES 2000 33 584 126 64 22% 11% 190 33% 2001 38 649 167 74 26% 11% 241 37% FI 1999 14 245 8 2 3% 1% 10 4% 2000 9 176 9 0 5% 0% 9 5% 2001 9 349 27 2 8% 1% 29 8% FR 2001 329 693 211 104 31% 15% 315 46% HR 2001 10 20 3 0 15% 0% 3 15% HU 2001 14 36 5 3 14% 8% 8 22% IE 1999 10 157 26 4 17% 3% 30 19% 2000 18 202 16 10 8% 5% 26 13% 2001 21 246 24 6 10% 2% 30 12% IL 2001 5 169 59 8 35% 5% 67 40% IS 1999 2 49 1 0 2% 0% 1 2% 2000 2 36 3 0 8% 0% 3 8% 2001 3 48 3 0 6% 0% 3 6% EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 65 Total SP country year Nr of tested Nr % Labs for PNSP Nr I Nr R % I % R PNSP PNSP IT 1999 42 183 21 3 11% 2% 24 13% 2000 38 119 12 1 10% 1% 13 11% 2001 39 121 6 5 5% 4% 11 9% LU 1999 1 9 1 1 11% 11% 2 22% 2000 5 22 3 0 14% 0% 3 14% 2001 8 41 2 3 5% 7% 5 12% MT 2000 1 11 1 0 9% 0% 1 9% 2001 1 12 1 0 8% 0% 1 8% NL 1999 21 762 6 2 1% 0% 8 1% 2000 23 739 7 3 1% 0% 10 1% 2001 20 714 5 2 1% 0% 7 1% NO 1999 1 28 0 0 0% 0% 0 0% 2000 1 388 7 2 2% 1% 9 2% PL 2001 5 8 0 1 0% 13% 1 13% PT 1999 12 119 20 0 17% 0% 20 17% 2000 11 98 28 0 29% 0% 28 29% 2001 16 162 40 0 25% 0% 40 25% SE 1999 24 805 11 1 1% 0% 12 1% 2000 19 803 16 0 2% 0% 16 2% 2001 20 788 18 4 2% 1% 22 3% SI 2000 7 40 9 0 23% 0% 9 23% 2001 10 156 31 0 20% 0% 31 20% SK 2001 4 6 0 0 0% 0% 0 0% UK 1999 22 241 8 9 3% 4% 17 7% 2000 28 503 11 20 2% 4% 31 6% 2001 26 572 10 15 2% 3% 25 4% 26 countries Total 15288 1255 457 8% 3% 1712 11% 66 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Appendix 5.2. Invasive penicillin non-susceptible S. pneumoniae (PNSP) isolates non-susceptible to 3 rd generation cephalosporins (CEP) reported to EARSS in the period 1999-2001 per country per year Total PNSP Proportion Nr of tested PNSP tested country year Labs for CEP for CEP Nr I Nr R % I % R AT 2000 9 1 100% 0 0 0% 0% 2001 9 2 100% 0 0 0% 0% BE 1999 96 130 99% 44 0 34% 0% 2000 92 151 100% 44 7 29% 5% 2001 83 55 100% 2 0 4% 0% BG 2000 8 1 33% 0 0 0% 0% 2001 8 1 100% 0 0 0% 0% CZ 2000 26 4 100% 0 1 0% 25% 2001 32 11 100% 4 0 36% 0% DE 1999 11 5 63% 1 1 20% 20% 2000 9 2 50% 0 0 0% 0% 2001 9 5 100% 0 0 0% 0% DK 2000 5 14 93% 0 0 0% 0% 2001 5 9 90% 1 0 11% 0% EE 2001 5 0 0% ES 2000 33 179 94% 58 6 32% 3% 2001 38 237 98% 56 11 24% 5% FI 1999 14 6 60% 0 0 0% 0% 2000 9 7 78% 0 0 0% 0% 2001 9 23 79% 2 0 9% 0% FR 2001 329 315 100% 151 2 48% 0.6% HR 2001 10 3 100% 0 0 0% 0% HU 2001 14 5 63% 0 0 0% 0% IE 1999 10 27 90% 2 0 7% 0% 2000 18 22 85% 5 0 23% 0% 2001 21 25 83% 1 0 4% 0% IL 2001 5 65 97% 7 1 11% 2% IS 1999 2 1 100% 0 0 0% 0% 2000 2 2 67% 0 0 0% 0% 2001 3 3 100% 0 0 0% 0% EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 67 Total SP country year Nr of tested Nr % Labs for PNSP Nr I Nr R % I % R PNSP PNSP IT 1999 42 24 100% 2 0 8% 0% 2000 38 13 100% 0 0 0% 0% 2001 39 10 91% 3 0 30% 0% LU 1999 1 2 100% 0 0 0% 0% 2000 5 3 100% 0 0 0% 0% 2001 8 4 80% 1 1 25% 25% MT 2000 1 1 100% 0 0 0% 0% 2001 1 0 0% NL 1999 21 4 50% 0 0 0% 0% 2000 23 7 70% 2 0 29% 0% 2001 20 4 57% 2 0 50% 0% NO 1999 1 0 0% 2000 1 9 100% 4 0 44% 0% PL 2001 5 1 100% 0 0 0% 0% PT 1999 12 20 100% 0 0 0% 0% 2000 11 28 100% 5 3 18% 11% 2001 16 40 100% 0 10 0% 25% SE 1999 24 10 83% 7 0 70% 0% 2000 19 14 88% 8 0 57% 0% 2001 20 17 77% 10 0 59% 0% SI 2000 7 9 100% 1 0 11% 0% 2001 10 31 100% 6 0 19% 0% SK 2001 4 0 0% UK 1999 22 15 88% 6 1 40% 7% 2000 28 29 94% 11 8 38% 28% 2001 26 21 84% 12 3 57% 14% 26 countries Total 1627 95% 458 55 28% 3% 68 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Appendix 5.3. Invasive penicillin non-susceptible S. pneumoniae (PNSP) isolates non-susceptible to fluoroquinolones (FLUO) reported to EARSS in the period 1999-2001 per country per year. Total PNSP Proportion Nr of tested PNSP tested country year Labs for FLUO for FLUO Nr I Nr R % I % R AT 2000 9 0 0% 2001 9 2 100% 1 0 50% 0% BE 1999 96 131 100% 5 4 4% 3% 2000 92 151 100% 1 1 1% 1% 2001 83 55 100% 1 0 2% 0% BG 2000 8 1 33% 0 0 0% 0% 2001 8 1 100% 0 0 0% 0% CZ 2000 26 2 50% 0 0 0% 0% 2001 32 11 100% 0 3 0% 27% DE 1999 11 1 13% 0 0 0% 0% 2000 9 1 25% 0 0 0% 0% 2001 9 3 60% 2 0 67% 0% DK 2000 5 14 93% 1 1 7% 7% 2001 5 9 90% 0 0 0% 0% EE 2001 5 0 0% ES 2000 33 136 72% 20 4 15% 3% 2001 38 68 28% 1 0 1% 0% FI 1999 14 1 10% 1 0 100% 0% 2000 9 3 33% 0 0 0% 0% 2001 9 9 31% 0 0 0% 0% HR 2001 10 3 100% 0 0 0% 0% HU 2001 14 1 13% 1 0 100% 0% IE 1999 10 27 90% 0 0 0% 0% 2000 18 21 81% 1 0 5% 0% 2001 21 25 83% 0 0 0% 0% IL 2001 5 13 19% 0 1 0% 8% IS 1999 2 0 0% 2000 2 0 0% 2001 3 0 0% EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 69 Total PNSP Proportion Nr of tested PNSP tested country year Labs for FLUO for FLUO Nr I Nr R % I % R IT 1999 42 24 100% 3 0 13% 0% 2000 38 13 100% 2 1 15% 8% 2001 39 6 55% 1 0 17% 0% LU 1999 1 0 0% 2000 5 3 100% 0 0 0% 0% 2001 8 4 80% 0 0 0% 0% MT 2000 1 1 100% 0 0 0% 0% 2001 1 1 100% 0 0 0% 0% NL 1999 21 2 25% 0 1 0% 50% 2000 23 2 20% 1 0 50% 0% 2001 20 1 14% 0 0 0% 0% NO 1999 1 0 0% 2000 1 9 100% 9 0 100% 0% PL 2001 5 0 0% PT 1999 12 20 100% 4 3 20% 15% 2000 11 28 100% 3 0 11% 0% 2001 16 40 100% 2 0 5% 0% SE 1999 24 5 42% 5 0 100% 0% 2000 19 16 100% 16 0 100% 0% 2001 20 13 59% 13 0 100% 0% SI 2000 7 7 78% 1 0 14% 0% 2001 10 31 100% 1 1 3% 3% SK 2001 4 0 0% 25 countries Total 915 69% 96 20 10% 2% The proportion of PNSP isolates (n=315) non-susceptible for France was 7.3%. 70 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Appendix 5.4. Invasive S. pneumoniae (SP) erythromycin non-susceptible isolates reported to EARSS in the period 1999-2001 per country per year, categorised by susceptibility to penicillin. country year PNSP Total SP Total SP Proportion tested isolates tested for erythro for erythro Nr I (%) Nr R (%) AT 2000 I 1 1 100% 1(100%) S 52 49 94% 1 (2%) 2001 I 2 1 50% S 61 30 49% 3(10%) BE 1999 I 87 87 100% 58(67%) R 44 44 100% 30(68%) S 807 807 100% 203 (25%) 2000 I 100 100 100% 59(59%) R 51 51 100% 36( 71%) S 822 822 100% 236(29%) 2001 I 55 55 100% 44(80%) S 362 362 100% 95(26%) BG 2000 R 3 3 100% 1(33%) 1 (33%) S 10 9 90% 1 (11%) 2001 R 1 0 0% S 15 11 73% 1 (9%) CZ 2000 I 4 4 100% 1 (25%) S 107 89 83% 2001 I 10 9 90% 2(22%) R 1 1 100% S 143 135 94% 1 (1%) DE 1999 I 5 1 20% R 3 0 0% S 355 235 66% 1 (0%) 16 (7%) 2000 I 3 2 67% R 1 1 100% S 164 132 80% 13(10%) 2001 I 4 1 25% R 1 0 0% S 148 74 50% 1 (1%) 9 (12%) DK 2000 I 14 14 100% 2 (14%) R 1 1 100% 1(100%) S 395 395 100% 17 (4%) EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 71 country year PNSP Total SP Total SP Proportion tested isolates tested for erythro for erythro Nr I (%) Nr R (%) 2001 I 8 8 100% R 2 2 100% 1( 50%) S 317 317 100% 16 (5%) EE 2001 S 20 20 100% 1 (5%) ES 2000 I 126 121 96% 63 (52%) R 64 55 86% 1 (2%) 26(47%) S 394 368 93% 5 (1%) 25 (7%) 2001 I 167 162 97% 4 (2%) 96(59%) R 74 72 97% 2 (3%) 36(50%) S 408 389 95% 5 (1%) 50 (13%) FI 1999 I 8 8 100% 2 (25%) R 2 2 100% 1(50%) S 235 207 88% 4 (2%) 7 (3%) 2000 I 9 9 100% 5 (56%) S 167 167 100% 3 (2%) 6 (4%) 2001 I 27 26 96% 14(54%) R 2 2 100% 1(50%) S 320 320 100% 1 (0%) 28 (9%) FR 2001 not 693 693 100% 312 (45%) applicable non-susceptible HR 2001 I 3 3 100% S 17 17 100% 3 (18%) HU 2001 I 5 4 80% 3 (75%) R 3 2 67% S 28 25 89% 3 (12%) IE 1999 I 26 20 77% 3 (15%) R 4 3 75% 2(67%) S 127 98 77% 12 (12%) 2000 I 16 13 81% 3 (23%) R 10 7 70% 3(43%) S 176 129 73% 12 (9%) 2001 I 24 18 75% 2 (11%) R 6 3 50% 1 (33%) S 216 164 76% 20 (12%) 72 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY country year PNSP Total SP Total SP Proportion tested isolates tested for erythro for erythro Nr I (%) Nr R (%) IL 2001 I 59 53 90% 12 (23%) R 8 8 100% 2 (25%) S 102 90 88% 3 (3%) IS 1999 I 1 1 100% 1(100%) S 48 31 65% 2000 I 3 3 100% 3(100%) S 33 33 100% 1 (3%) 2001 I 3 3 100% 1 (33%) S 45 45 100% 3 (7%) IT 1999 I 21 21 100% 14(67%) R 3 3 100% 1 (33%) S 159 159 100% 1 (1%) 37 (23%) 2000 I 12 12 100% 5(42%) R 1 1 100% 1(100%) S 106 106 100% 28(26%) 2001 I 6 5 83% 4(80%) R 5 4 80% 3 (75%) S 110 91 83% 2 (2%) 30 (33%) LU 1999 I 1 1 100% 1(100%) R 1 1 100% 1(100%) S 7 7 100% 1 (14%) 2000 I 3 3 100% 3(100%) S 19 16 84% 2 (13%) 2001 I 2 2 100% 2(100%) R 3 2 67% 1(50%) 1(50%) S 36 35 97% 5 (14%) MT 2000 I 1 1 100% S 10 10 100% 4(40%) 2001 I 1 1 100% S 11 10 91% 2(20%) NL 1999 I 6 0 0% R 2 0 0% S 754 0 0% 2000 I 7 6 86% 2 (33%) R 3 3 100% S 729 675 93% 2 (0%) 25 (4%) EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 73 country year PNSP Total SP Total SP Proportion tested isolates tested for erythro for erythro Nr I (%) Nr R (%) 2001 I 5 3 60% 2(67%) R 2 2 100% 1(50%) S 707 570 81% 1 (0%) 26 (5%) NO 1999 S 28 0 0% 2000 I 7 0 0% R 2 0 0% S 379 0 0% PL 2001 R 1 1 100% 1(100%) S 7 6 86% PT 1999 I 20 20 100% 2(10%) 5 (25%) S 99 99 100% 4 (4%) 2000 I 28 28 100% 6 (21%) S 70 70 100% 5 (7%) 2001 I 40 0 0% S 122 0 0% SE 1999 I 11 8 73% 2 (25%) R 1 1 100% S 793 526 66% 12(2%) 17 (3%) 2000 I 16 15 94% 2 (13%) S 787 628 80% 3 (0%) 16 (3%) 2001 I 18 17 94% 1 (6%) 3 (18%) R 4 4 100% S 766 632 83% 26 (4%) SI 2000 I 9 5 56% 1(20%) S 31 20 65% 1 (5%) 1 (5%) 2001 I 31 25 81% 1 (4%) 12(48%) S 125 82 66% 6 (7%) SK 2001 S 6 5 83% 1(20%) UK 1999 I 8 8 100% 2 (25%) R 9 7 78% 2(29%) S 224 14 6% 4(29%) 2000 I 11 11 100% 3(27%) R 20 16 80% 5 (31%) S 472 227 48% 37 (16%) 74 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY country year PNSP Total SP Total SP Proportion tested isolates tested for erythro for erythro Nr I (%) Nr R (%) 2001 I 10 9 90% 3 (33%) R 15 13 87% 4 (31%) S 547 287 52% 33 (11%) Total 15288 11781 77% 2071 (18%) non-susceptible EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 75 References 1. Causes of annual deaths worldwide 1998. Geneva: World Health Organization, 1998. 2. Moellering RC. The continuing challenge of lower respiratory tract infections. Clin Infect Dis 34, Suppl: 1-3, 2002. 3. Appelbaum PC. Resistance among Streptococcus pneumoniae: Implications for Drug Selection. Clin Infect Dis 34:1613-20, 2002. 4. File TM. Appropriate use of antimicrobials for drug-resistant pneumonia: focus on the significance of beta- lactam-resistant Streptococcus pneumoniae. Clin Infect Dis 34, Suppl:17-26, 2002. 5. Hansman D, Andrews G. Hospital infection with pneumococci resistant to tetracycline. Med J Aust 11:498- 501, 1967. 6. Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med 343:1917, 2000. 7. The British Society for Antimicrobial Chemotherapy (BSAC) website. (1998). Standardized disc sensitivity testing method, The Newsletter of the British Society for Antimicrobial Chemotherapy, 1998. BSAC, Birmingham, UK. Update available online at: http://www.bsac.org.uk/discdiff/sensitivity2.pdf (21 June 2002, date last accessed). 8. Commissie Richtlijnen Gevoeligheidsbepalingen. (1996). Nederlands Tijdschrift voor Medische Microbiologie 4, 5. 9. MENSURA. (2000). Recomendaciones del grupo MENSURA para la seleccin de antimicrobianos en el estudio de la sensibilidad y criterios para la interpretacin del antibiograma. Revista Espaola Quimoterapia 13, 7386. 10. Socit Franaise de Microbiologie (1996). Report of the Comit de lAntibiogramme de la Socit Franaise de Microbiologie. Clinical Microbiology and Infection 2, Suppl.1, S149. 11. Cars, O. (Ed.) (1997). Antimicrobial susceptibility testing in Sweden. Scandinavian Journal of Infectious Diseases, Suppl. 1,105. 12. Deutsches Institut fr Normung. (1998). Methods for the Determination of Susceptibility of Pathogens (Except Mycobacteria) to Antimicrobial Agents. MIC Breakpoints of Antibacterial Agents, Suppl. 1, pp. 589404. DIN, Berlin. 13. Nielsen SV, Henrichson J. Incidence of invasive pneumococcal disease and distribution of capsular types of pneumococci in Denmark, 1989-4. Epidemiol Infect 1996;117:411-16. 14. New conjugate vaccine- helps prevent invasive pneumococcal disease in infants and young children (http://www.efpia.org/1_efpia/evm/pneuconfinal.htm) 15. World Health Organisation. Vaccines and Biologicals Pneumococcus. (http://www.who.int/vaccines/ intermediate/pneumococcus.htm) 76 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Chapter 6 A European study on the relationship of antimicrobial use and antimicrobial resistance S L A M Bronzwaer, O Cars, U Buchholz, S Mlstad, W Goettsch, I K Veldhuijzen, JL Kool, M J W Sprenger, J E Degener, and EARSS participants. Emerging Infectious Diseases 2002;8(3):278-82 Abstract In Europe, antimicrobial resistance has been monitored since 1998 by the European Antimicrobial Resistance Surveillance System (EARSS). We examined the relationship between penicillin nonsusceptibility of invasive isolates of Streptococcus pneumoniae and antibiotic sales. Information was collected on 1998-99 resistance data for invasive isolates of S. pneumoniae to penicillin, based on surveillance data from EARSS and on outpatient sales during 1997 for betalactam antibiotics and macrolides. Our results show that in Europe antimicrobial resistance of S. pneumoniae to penicillin is correlated with use of betalactam antibiotics and macrolides. Introduction Antimicrobial resistance is a growing problem worldwide, requiring international approaches. The World Health Organization (WHO) and the European Commission have recognized the importance of studying the emergence and determinants of resistance and the need for strategies for its control (1-3). In European countries, antimicrobial resistance has been monitored in selected bacteria from humans since 1998 through the European Antimicrobial Resistance Surveillance System (EARSS). Funded by the European Commission, EARSS is an international network of national surveillance systems intended to collect comparable and reliable resistance data. The purpose of EARSS is to document variations in antimicrobial resistance over time and place and to provide the basis for and assess the effectiveness of prevention programs and policy decisions. One of the indicator organisms in EARSS is Streptococcus pneumoniae. It was included for three reasons: it is of major clinical importance for pneumonia, bacterial meningitis, and otitis media; many countries have reported that its resistance to penicillin is increasing; and S. pneumoniae is representative of organisms that are transmitted in the community. A major risk factor for the development of resistance is thought to be inappropriate use of antimicrobial drugs. Most studies that have investigated the relationship of antimicrobial use and antimicrobial resistance have been undertaken in hospital, multicenter, or country settings (4-7). For infections with penicillin-non-susceptible S. pneumoniae (PNSP), studies have demonstrated that at the individual level, previous use of betalactam antibiotics such as penicillin is an important risk factor (8-10). Studies on carriage of PNSP in children have shown that sulfamethoxazole-trimethoprim (co- trimoxazole) and macrolides such as erythromycin have also been associated with selection of PNSP (11,12). Translated to the population level, sales of betalactam antibiotics, co-trimoxazole, or macrolides in a given geographic region may be proportional to microbial resistance to penicillin. If on the European level a relationship between antimicrobial resistance and antimicrobial use could be found (as in the case of S. pneumoniae and resistance to penicillin), efforts to control antimicrobial use and misuse could be stimulated and monitored in Europe. 78 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY We used an ecologic study design to examine the correlation between use of relevant antibiotics in the outpatient setting and the proportion of PNSP among invasive isolates of S. pneumoniae in 11 European countries. Methods Antimicrobial Resistance Data The estimated average coverage of the populations of countries participating in EARSS is 52% (range 10% to 90%) (13). Laboratories that participate in EARSS screen invasive S. pneumoniae isolates for oxacillin resistance (14). When an isolate is found to be non- susceptible, the EARSS protocol requests confirmation as intermediate- or high-level resistance to penicillin by determination of MICs. Laboratories perform microbiologic testing and interpret results according to their own standards. National guidelines in Europe differ; isolates of S. pneumoniae are considered non-susceptible to penicillin if the MIC is >0.06 (15-19) or >0.12 (20) mg/L. For this report, we use nonsusceptibility and intermediate resistance as synonyms; PNSP isolates are either intermediate or fully resistant to penicillin. Only the first invasive isolate per patient per quarter is reported. To assess the comparability of susceptibility test results, a quality assurance exercise was performed in September 2000 among 482 laboratories from 23 countries participating in EARSS. The concordance (agreement of reported results with intended results) for the detection of penicillin resistance in the three S. pneumoniae control strains was 91% (21). Laboratories send standardized data to the national EARSS data manager, who checks data contents and ensures conformity with the EARSS data format. In collaboration with WHO, an export module from the laboratory-based software WHONET was developed for EARSS (22). Every quarter, data are forwarded to the central database at the National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands, where the project is coordinated. Antimicrobial Use Data National outpatient sales data for antibiotics from 1997 were purchased from IMS Health Global Services, London, United Kingdom, for 13 of the 15 member states of the European Union. Corresponding data were obtained from the Danish Medicines Agency for Denmark and from the National Corporation of Swedish Pharmacies for Sweden (23). The IMS data were examined and adjusted according to the Anatomic Therapeutic Classification (ATC) system used by WHO (24). The amount in kilograms for an antimicrobial agent was converted to a number of defined daily doses (DDD). The DDD, which is based on the average daily dose used for the main indication of the drug, is appropriate for comparisons of drug use over time and in different geographic areas. For betalactam antibiotics, we combined ATC groups J01C (extended-and narrow-spectrum EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 79 penicillins) and J01D (cephalosporins); macrolides were classified under code J01F. No data were available for the combination of trimethoprim and sulphonamide. Nonadherence We considered nonadherence of patients to the physicians prescription in individual countries as a possible confounder of antimicrobial resistance. Branthwaite et al. reported nonadherence levels from a population-based survey in seven countries (25). Data from four of the seven countries (Spain, Belgium, the United Kingdom, and Italy) were also captured in EARSS. Statistical Analysis We calculated the proportion of PNSP among all invasive S. pneumoniae isolates from each country reported during 1998-99. Because probabilities allow only values between 0 and 1, we modeled the natural logarithm of the odds of PNSP resistance (logodds). Least-square linear regression analysis was used to assess correlation between antimicrobial use (of betalactam antibiotics and macrolides, expressed in DDD per 1,000 population per day) and the logodds of resistance. We correlated nonadherence levels with the logodds of resistance in the same way. We calculated the Spearman coefficient of determination (r-square) and its corresponding p value. For the calculation of the regression lines, we weighted the data points by the inverse of the variance of each data point. We used SAS software (SAS Institute Inc., Release 6.03., Cary, NC). Results Antimicrobial Resistance During 1998-99, 337 laboratories from 11 European Union member states (Belgium, Finland, Germany, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, and United Kingdom) and one nonmember state (Iceland) reported 4,872 invasive S. pneumoniae isolates to EARSS. The proportion of PNSP among isolates of invasive S. pneumoniae ranged from 1% to 34% (Table 6.1) (Figure 6.1). Southern European countries reported higher rates than northern European countries. Antimicrobial Use Data on outpatient sales of betalactam antibiotics and macrolides were available for 1997 from all 15 European Union member countries. Antimicrobial use varied widely between countries. Sales to outpatients ranged from 3.8 to 23.6 DDD per 1,000 inhabitants per day for betalactam antibiotics and from 0.97 to 5.98 DDD for macrolides. The three countries with the highest reported use were France, Spain, and Portugal for betalactam antibiotics 80 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY and France, Spain, and Italy for macrolides; the three countries with the lowest use were the Netherlands, Germany, and Austria for betalactam antibiotics and Sweden, the Netherlands, and Finland for macrolides. Correlation For 11 countries, information was available for both antimicrobial resistance and antimicrobial use. Linear regression of the correlation of use of betalactam antibiotics and the logodds of resistance showed an r-square of 0.80 (p=0.0002) (Figure 6.2). The equation for the regression is logodds of resistance =(-3.94)+(0.16xDDD). For the use of macrolides, we calculated an r-square of 0.46. Figure 6.3 shows the graph for nonadherence to antibiotics and the logodds of resistance. The r-square is 0.8 (p=0.2). Discussion We present for the first time Europewide, country-specific, representative data on antimicrobial resistance collected by EARSS. Using an ecologic study design, we demonstrate through the correlation with data on antimicrobial use one aspect of the usefulness of surveillance for antimicrobial resistance. The results from 11 European countries show a linear relationship between use of betalactam antibiotics and macrolides and the proportion of PNSP among all invasive S. pneumoniae isolates. EARSS data show that resistance for PNSP follows a north-south gradient. Southern European countries have higher proportions of PNSP than countries in northern Europe. A possible reason for this observation could be the difference in antimicrobial use, which also tends to be higher in southern European countries. If use of relevant antibiotics (betalactam antibiotics and macrolides) and the logodds of resistance are modeled through linear regression, a strong linear and statistically significant relationship is demonstrated. Our findings agree with those of Austin et al., who modeled the relationship between antimicrobial use and endemic resistance, based on population genetic methods and epidemiologic observations (26). The correlation in Figure 6.2 is consistent with the model developed by Austin et al. on theoretical grounds. We correlate antimicrobial sales data for 1997 with antimicrobial resistance data for 1998 and 1999. Others have observed that after a lag time of 1 or more years, changes in antimicrobial use may be followed by changes in antimicrobial resistance (27,28). Therefore, we believe that it is reasonable to correlate antimicrobial sales data in 1997 with antimicrobial resistance data from 1998-99. We address several limitations in our study. First, because it is an ecologic study, we can make no inferences on the individual level. Second, resistance rates in some countries (Table 6.1) are calculated from a relatively limited number of isolates. However, based on communications with EARSS country representatives, our data are EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 81 Table 6.1. Number of submitting laboratories, number of isolates of Streptococcus pneumoniae, number (#) and percent (%R) of penicillin nonsusceptible S. pneumoniae isolates, logodds of resistance (ln(%R/[1-%R]), and outpatient sales of betalactam antibiotics and macrolides Penicillin Outpatient sales of nonsusceptible antibiotics in DDD * / S. pneumoniae 1,000 inhabitants/day No. of S. No. of labo- pneumoniae %R ln Betalactam Country ratories isolates No. (95% CI) (%R/[1-%R]) antibiotics Macrolides Austria - - - - - 6 3.7 Belgium 96 940 131 14 (12-16) -1.82 14 4.1 Denmark - - - - - 7 2 Finland 11 211 8 4 (2-8) -3.18 8 1.9 France - - - - - 24 6.0 Germany 15 222 4 2 (1-5) -3.89 5 2.5 Iceland 2 54 1 2 (0-11) -3.89 N.a. N.a. Ireland 12 157 30 19(13-26) -1.45 11 2.5 Italy 46 194 26 13 (9-19) -1.87 15 5.1 Luxembourg 1 11 2 18 (3-52) -1.52 14 4.7 Netherlands 20 760 8 1 (0-2) -4.6 4 1.2 Portugal 12 134 25 19 (13-27) -1.45 16 3.7 Spain 76 1,240 418 34 (31-36) -0.66 21 5.9 Sweden 24 706 21 3 (2-5) -3.48 8 1 United Kingdom 22 243 21 9 (6-13) -2.31 9 3.2 N.a.= not available; DDD* = defined daily doses; CI = confidence interval. consistent with antimicrobial resistance levels derived from other sources (29). Third, an explanation for the differences in antimicrobial resistance could be sampling bias: clinicians in northern European countries may request blood cultures more frequently than their southern European colleagues, who may sample only in case of empirical treatment failure. Fourth, we have not addressed other, potentially important contributing factors for the development of antimicrobial resistance of organisms that are transmitted in the community, particularly nonadherence and over-the-counter sales of antimicrobial agents. Both these factors are difficult to measure. However, in 1993 nonadherence to prescribed antimicrobial agents was assessed in a survey in six European countries (25). Although the 82 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 83 Figure 6.1. Proportions of invasive isolates of Streptococcus pneumoniae resistant to penicillin (PNSP) among 12 European countries, 199899. < 3 %PNSP (countries) (4) (3) (3) (5) (2) no data 3 9 10 30 > 30 LU DDD betalactam antibiotics/1000 UK BE IT LU IE FI SE DE NL ES PT 0 5 10 15 20 25 1 0 -1 -2 -5 -3 -4 l n
( R / ( 1 - R ) ) Figure 6.2. The logodds of resistance to penicillin among invasive isolates of Streptoccus pneumoniae (PNSP; ln(R/[1-R])) is regressed against outpatient sales of betalactam antibiotics in 11 European countries; antimicrobial resistance data are from 1998 to 1999 and antibiotic sales data are from 1997. DDD = defined daily dose; BE = Belgium; DE = Germany; FI = Finland; IE = Ireland; IT = Italy; LU = Luxembourg; NL = the Netherlands; PT = Portugal; ES = Spain; SE = Sweden; UK = United Kingdom. number of data points is limited, Figure 6.2 suggests a direct relationship between non- adherence rates and logodds of resistance. Thus, if nonadherence is also related to sales of antimicrobial agents, it could potentially confound the relationship between use and resistance. Data on the degree of over-the-counter use among European countries are not widely available; we know of one Spanish and one Greek study reporting an estimate of over-the-counter use (30,31). The influence of these and other parameters on the level of resistance should be quantified and understood. Finally, because children are the main reservoir of carriage of S. pneumoniae, an age-stratified analysis would be desirable, i.e., a correlation of resistance with antimicrobial use among children. However, this analysis would require more detailed use data, for example, of liquid formulations of antibiotics. At least two studies in northern Europe have demonstrated that PNSP rates can be halted or even reversed when physicians avoid the inappropriate prescription of antimicrobial agents (32,33). Our study is timely because it shows that even at the European level a correlation can be observed between antimicrobial resistance (of S. pneumoniae to penicillin) and antimicrobial use. In several European countries, national action plans for the appropriate use of antimicrobial agents are being planned or implemented; their effectiveness should be monitored through prospective and continuous surveillance of antimicrobial resistance and antimicrobial sales data (34-38). 84 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Non-adherence (% of interviewees) UK BE IT ES 0 5 10 15 20 25 30 35 40 45 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 l n
( R / ( 1 - R ) ) Figure 6.3. The logodds of resistance of invasive isolates of Streptococcus pneumoniae to penicillin (PNSP; ln(R/(1-R))) is regressed against nonadherence rates to antibiotic therapy in four European countries. Nonadherence rates are from 1993; PNSP data are from 1998-99. UK = United Kingdom; BE = Belgium; IT = Italy; ES = Spain. Acknowledgements We thank all the dedicated laboratories that contributed data. We specifically thank all the national data managers and representatives of the countries participating in EARSS for their hard work in collecting and processing the data, Karl Kristinsson for highly relevant and constructive comments, John Stelling for help with software development, Nico Nagelkerke for significant statistical help, Marc-Alain Widdowson for thoughtful comments, and Jos van de Velde for helping to keep EARSS running. 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Deeks SL, Palacio R, Ruvinsky R, Kertesz DA, Hortal M, Rossi A, et al. Risk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae. The Streptococcus pneumoniae Working Group. Pediatrics 1999;103:409-13. 11. Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Molstad S, Gudmundsson S. Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross sectional prevalence study. BMJ 1996;313:387-91. 12. Melander E, Mlstad S, Alsterlund R, Ekdahl K, Jnsson G. Macrolides and broad-spectrum antibiotics are risk-factors for spread of pneumococci with reduced sensitivity to penicillin. Pediatr Infect Dis J 2000;19:1172-7. 13. European antimicrobial resistance surveillance system. Report on feasibility phase, p. 56. Available at URL: http://www.earss.rivm.nl Accessed September 26, 2000. 14. Goettsch W, Bronzwaer SLAM, Neeling de AJ, Wale MCJ, Aubry-Damon H, Olsson-Liljequist B, et al. Standardisation and quality assurance for antimicrobial resistance of Streptococcus pneumoniae and Staphylococcus aureus within the European Antimicrobial Resistance Surveillance System (EARSS). Clin Microbiol Infect 2000;6:59-63. 15. Commissie Richtlijnen Gevoeligheidsbepalingen. Nederlands Tijdschrift voor Medische Microbiologie 1996;4:5. 16. The National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; eight informational supplements. Vol 18, no 1. ISBN 1-56238-337-X. Wayne (PA): The Committee; 1998. 17. Cars O. Antimicrobial susceptibility testing in Sweden. Available at URL: http://www.ltkronoberg.se/ext/raf/raf.htm Accessed December 21, 2001. 18. Report of the Comit de lAntibiogramme de la Socit Franaise de Microbiologie. Clin Microbiol Infect 1996;2 Suppl 1: S1-S49. 19. British Society for Antimicrobial Chemotherapy. BSAC standardized disc sensitivity testing method. Birmingham (UK): Newsletter of the British Society for Antimicrobial Chemotherapy; 1998. 20. Deutsches Institut fr Normung. Methods for the determination of susceptibility of pathogens (except mycobacteria) to antimicrobial agents. MIC breakpoints of antibacterial agents. Berlin: DIN; 1998. Suppl 1:58940-4. 21. Buchholz U, Bronzwaer S, Snell J, Courvalin P, Cornaglia G, de Neeling J, et al. Comparability of microbiological susceptibility test results from 23 European countries and Israel: the European Antimicrobial Resistance Surveillance System (EARSS)/NEQAS study. Clin Microbiol Infect 2001;7 Suppl 1:25. 22. World Health Organization, Communicable Disease Surveillance and Response. WHONET 5 software. Available at URL: http://www.who.int/emc/WHONET/WHONET.html. Accessed September 28, 2000. 23. Cars O, Mlstad S, Melander A. Variation in antibiotic use in the European Union. Lancet 2001;357:1851-3. 24. ATC index with DDDs. Oslo: WHO Collaborating Centre for Drug Statistics Methodology; 1999. 86 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 25. Branthwaite A, Pechre J-C. Pan-European survey on patients attitudes to antibiotics and antibiotic use. J Int Med Res 1996;24:229-38. 26. Austin DJ, Kristinsson KG, Anderson RM. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc Natl Acad Sci U S A 1999;96:1152-6. 27. Seppala H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, Lager K, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med 1997;337:441-6. 28. Stephenson J. Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria [news]. JAMA 1996;275:175. 29. European antimicrobial resistance surveillance system. Annual report EARSS 2000. Available at URL: http://www.earss.rivm.nl Accessed 17 June, 2001. 30. Gonzlez J, Orero A. Consumo de antibiticos en Espaa. Revista Espaola de Quimicoterapia 1996;9 Suppl 4:155. 31. Contopoulos-Ionnides DG, Koliofoti ID, Koutroumpa IC, Giannakakis IA, Ioannides JPA. Pathways for inappropriate dispensing of antibiotics for rhinosinusitis: a randomized trial. Clin Infect Dis 2001;33:76-82. 32. Mlstad S, Cars O. Major change in the use of antibiotics following a national Programme: Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA). Scand J Infect Dis 1999;31:191-5. 33. Kristinsson KG. Modification of prescribers behaviour: the Icelandic approach. Clin Microbiol Infect 1999;5 (Suppl 4):S43-7. 34. Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP). Consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark, July 1999. Available at URL: http://www.svs.dk/ Accessed October 27, 2000. 35. Institute de Veille Sanitaire, Paris: Propositions pour un plan national dactions pour la matrise de la rsistance aux antibiotiques, January 1999 (English version: Proposals for a national action plan to control antibiotic resistance in France July 1999). 36. Ministries of Health and Agriculture, Ireland. A draft strategy document for control of Antimicrobial Resistance in Ireland - (SARI), 2000. Available at URL: http://www.ndsc.ie/ Accessed October 27, 2000. 37. National Board of Health and Welfare, Sweden. National plan against antibiotic resistance, 2000. Available at URL: http://www.sos.se/ (Swedish). Accessed October 27, 2000. 38. United Kingdom Department of Health. UK antimicrobial resistance strategy and action plan. Available at URL: http://www.doh.gov.uk/arbstrat.htm Accessed October 27, 2000. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 87 Chapter 7 Staphylococcus aureus susceptibility data in Europe Introduction Of the pathogens causing nosocomial infections, Staphylococcus aureus most rapidly spreads within hospitals and is now a difficult to control problem in many European countries. S. aureus is a Gram-positive micro-organism that is traditionally treated with penicillinase-stable betalactams. Immuno-compromised patients are at highest risk for S. aureus infection. Other risk factors for contracting S. aureus infections are impaired cellular immunity (e.g., patients with diabetes mellitus or impaired function of white blood cells), and, because S. aureus can contribute to the formation of biofilms on artificial devices, use of catheters or other invasive devices and presence of artificial grafts. S. aureus can cause a variety of infections, such as wound infections, septicemia, osteomyelitis, pneumonia, and urinary tract infection. Invasive infections resulting in bacteremia, endocarditis, metastatic infections (e.g., in respiratory system), sepsis and the toxic shock syndrome can lead to death [1]. However, in most humans S. aureus does not cause infections. In fact, S. aureus colonises the nasal cavities of about 30% of healthy humans without causing any symptoms of infection. Shortly after the introduction of methicillin - the first available betalactam stable penicillin - reports of resistance of S. aureus to methicillin appeared [2]. The emergence and spread of MRSA is favoured by the absence of hygienic measures to prevent the spread of the micro- organisms in hospital settings, probably in combination with high use of antibiotics [3-5]. MRSA strains are usually no more virulent than methicillin susceptible S. aureus (MSSA), but are often resistant to multiple drugs. Moreover, the antimicrobial agent of choice for treating an MRSA infection is vancomycin [1], which is more toxic and less efficient than betalactam antibiotics are. Possibly therefore, MRSA was associated with a higher case fatality rate in some studies [6, 7]. Thus, control of the spread of MRSA is important. Information on exactly which countries, hospitals and specific wards are most prone to harbouring MRSA will help policy makers take measures aimed at MRSA control and infection prevention. S. aureus was chosen as one of the two pathogens to start EARSS data collection with, because it meets the WHO criteria for public health relevance of bacterial pathogens, being a proven pathogen which is clinically relevant on hospital population level, having a high probability to spread in hospital settings and being able to develop resistance against currently used and recommended antibiotics (i.e. betalactams). In this chapter, we discuss S. aureus susceptibility data collected through EARSS over the period 1999 to 2001 and in greater detail data from 2001. As presented in earlier EARSS reports, MRSA proportions vary greatly among the European countries [8]. 90 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Methods EARSS protocol for Staphylococcus aureus testing Antimicrobial susceptibility test (AST) results of the first S. aureus blood isolate per patient per quarter are reported to EARSS. The EARSS protocol for S. aureus, requests the laboratories to report oxacillin susceptibility, preferably determined by an oxacillin screen plate (6 mg/l) or, alternatively, by an oxacillin disk test (1 g or 5 g). For isolates that are found to be oxacillin non-susceptible, the minimum inhibitory concentration (MIC) of oxacillin and vancomycin should be determined. The protocol accepts determination of the mecA gene by PCR for confirmation of MRSA. Apart from these protocol antibiotics, other antibiotics can optionally be reported to EARSS (i.e., ciprofloxacin, erythromycin, gentamicin, rifampin, streptomycin and tetracyclin). EARSS collects routinely generated data and as such accepts the interpretations, sensitive (S), intermediate (I) and resistant (R) of the laboratories. Antimicrobial susceptibility breakpoints All laboratories perform antimicrobial susceptibility tests and interpret their results according to their own guidelines. Most national guidelines in Europe as well as the NCCLS guideline consider isolates of S. aureus non-susceptible to oxacillin if the MIC is >2 mg/L [9-12]. The German guideline consider isolates non-susceptible to oxacillin if the MIC is >1 mg/L [13]. According to most guidelines, a MIC of 4 mg/L should be classified as resistant to oxacillin, but the German and Swedish [14] consider a MIC of 2 mg/L as resistant. Data processing and validation Laboratories send their data to the national EARSS data manager, who checks and forwards the data to the Dutch National Institute of Public Health and the Environment (RIVM). National data managers receive standard feedback reports for approval. The national data is then appended to the EARSS database and are accessible at the interactive EARSS web site, and are made available for statistical analysis using the SAS software. Data lacking mandatory information (i.e., laboratory code, date of sample collection, patient identifier or month and year of birth, pathogen code, antibiotic code, and test result (S or R) were rejected, as were observations with intermediate methicillin resistance test results. Data were de-duplicated to only the first invasive isolate per patient per year, and analysed by country. To test whether the MRSA proportions changed over the years, we performed the Cochran-Armitage test for trend by taking the MRSA prevalence per country per year; only countries reporting S. aureus AST results for all three years were considered. We also analysed data at the hospital level, only taking into account hospitals EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 91 that sent in more than 10 isolates in each of the 3 years (51 hospitals in eight countries). In addition, multidrug resistance was analysed, defined as resistance to three or more antibiotics of different classes [15]. A quality assurance exercise was performed in September 2000 by 471 laboratories of 23 countries participating in EARSS to assess the comparability of susceptibility test results (chapter 4). All laboratories detected correctly the homogeneously methicillin-resistant S. aureus (MRSA) strain (concordance rate 100%), but the concordance rate was much lower (77%) for the heterogeneously resistant MRSA strain. For tests of vancomycin susceptibility, the concordance rates were 98% and 100%. For the optional antibiotics tested (gentamicin and erythromycin), concordance rates of susceptibility results were between 98% and 100%. Results In 2001, results for 14723 isolates originating from 764 hospitals in 26 countries were reported. Over the period 1999-2001, 26 countries reported AST data for 32942 isolates. Total adherence to the EARSS protocol was 65.5% during the period 1999 2001. Non- susceptibility of S. aureus was confirmed either by determining the oxacillin/methicillin 92 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Figure 7.1. Mean proportion of methicillin resistant Staphylococcus aureus (MRSA) in blood isolates over the period 1999-2001. < 3 % R Missing 3 9 10 30 > 30 LU MT MIC or by the mecA PCR for 71.8% of the MRSA isolates. Vancomycin MIC was obtained from 66.4% of the MRSA isolates. The mean proportion of MRSA blood isolates per country over the years 1999-2001 is shown in Figure 7.1. Nordic countries and the Netherlands have the lowest level of resistance, whereas the percentages in most southern European countries, the United Kingdom, Ireland, and Israel, are much higher and even exceed 40% in some countries (Figure 7.2). Figure 7.2 gives the MRSA percentages in 2001 by country, ordered by relative frequency, indicating also the number of isolates that have been reported. More detailed information on the proportion of MRSA by country and year can be found in Appendix 7.1. Time trend Figure 7.3 shows the prevalence of MRSA per year per country for the 3 years of MRSA surveillance through EARSS. Only countries with data over the complete period are included in this Figure (the total number of isolates is 25 442). In most countries the proportion of MRSA seems to be relatively stable, whereas in others, it has increased EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 93 Figure 7.2. Staphylococcus aureus methicillin resistance (MRSA) in blood isolates per country in 2001 (number of isolates between brackets). For country codes, see appendix 7.0. 0 p r o p o r t i o n
o f
i M R S A
s o l a t e s
( % ) country code (number of isolates) 50 40 54.2 45.4 30 20 10 60 M T
( 8 3 ) U K
( 1 4 8 8 ) I E
( 7 9 8 ) I T
( 8 3 9 ) G R
( 3 5 6 ) I L
( 3 8 1 ) F R
( 1 7 4 1 ) P T
( 5 2 1 ) H R
( 1 4 9 ) B G
( 1 0 3 ) E S
( 1 0 1 1 ) B E
( 1 9 4 ) L U
( 8 5 ) S I
( 2 7 0 ) D E
( 7 8 3 ) P L
( 1 5 1 ) A T
( 2 7 7 ) C Z
( 1 0 7 4 ) S K
( 3 7 ) E E
( 7 9 ) H U
( 3 0 1 ) S E
( 1 6 3 2 ) D K
( 5 2 0 ) N L
( 1 2 9 2 ) F I
( 5 2 2 ) I S
( 6 3 ) 41.7 41.0 39.3 38.6 32.9 31.9 31.5 27.2 23.1 21.6 20.0 7.6 19.6 17.5 15.2 5.9 5.4 5.1 4.7 0.9 0.8 0.5 0.4 0.0 during the past three years (see Figure 7.3). MRSA proportions are increasing by about 1.6% per year (R 2 =0.96; p< 0.0001). We found a linear increase in MRSA proportions of almost 6% per year in the United Kingdom (from 33% in 1999 to 45% in 2001; R 2 =0.99; p< 0.0001). Similarly, in Germany, MRSA proportions increased by almost 4% per year from 10% in 1999 to 17% in 2001 (R 2 =0.99; p< 0.0001). MRSA in hospitals We restricted the analyses to hospitals with data on more than 10 isolates each year (1999-2001), the analyses included 9 454 isolates from 66 hospitals in 7 countries (Belgium, Denmark, Ireland, Italy, the Netherlands, Sweden and the United Kingdom). The number of isolates per hospital per year varied and was mostly below 30, which hinders proper statistical analysis. Generally, there was no large variation in hospitals within countries with the highest (e.g., Ireland, Italy and the United Kingdom) or the lowest MRSA proportions (e.g., Denmark, the Netherlands and Sweden). Although MRSA proportions differed among hospitals within countries, these differences were generally small (data not shown). It may be that university hospitals are over-represented in this selection. 94 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Figure 7.3. Staphylococcus aureus methicillin resistance (MRSA) in blood isolates from 1999 to 2001 (number of isolates between brackets). Only countries reporting to EARSS for all three years of surveillance are presented. 0 50 40 30 20 10 60 p r o p o r t i o n
o f
i s o l a t e s
w i t h
M R S A
( % ) year of sample collection IE (647) UK (1212) GR (301) LU (59) 1999 2000 2001 IT (818) BE (431) DE (862) FI (400) IS (45) NL (1303) PT (347) SE (1477) DK (580) country code (mean sample-size per year) Demographic data Demographic data (age, sex and type of patient (i.e., in or outpatient)) were available for 95% of the isolates. Eighty-six percent of the isolates were those of inpatients. Table 7.1 shows that in 2001 there were more isolates from males than from females (61% vs. 32%, p< 0.0001), and MRSA isolates were also more frequent among males. MRSA proportions were the highest among isolates for which the gender of the source patient was not known. Patients with an MRSA infection were on average older than patients with MSSA infections (Table 7.1). MRSA proportions were much higher among hospital patients than among outpatients. With respect to hospital wards, only about 13% of all isolates were isolated from patients being nursed at ICUs. Almost half of the isolates came from internal medicine departments, but MRSA isolates more frequently originated from intensive care units than from other wards. The hospital department where the isolate originated was unknown for 13% of the isolates, which were significantly more often identified as methicillin (oxacillin) susceptible isolates (Table 7.1). In 8 of 26 countries, the reported prevalence of MRSA was higher in isolates from surgery than from intensive care units. In some countries, the place of isolate sampling was reported for almost all isolates (>98%; Germany, France, Croatia, Portugal and Sweden), whereas origin was known for only 29% of isolates from Iceland and for 37% and 39% of the isolates reported from the Netherlands and Finland, respectively. Non-susceptibility to non-protocol antibiotics Table 7.2 shows all optionally reported antibiotics that were relatively frequently reported to EARSS. Of the non-protocol antibiotics that can be reported to EARSS for MRSA isolates, erythromycin, gentamicin and vancomycin were reported for at least half of the MRSA isolates. Isolates were most frequently tested for susceptibility to vancomycin. The EARSS protocol requires testing for vancomycin susceptibility of MRSA strains. In general, MSSA isolates were less likely to be tested for susceptibility to non-protocol antibiotics than MRSA isolates (with the exception of rifampicin). MRSA isolates were more often resistant to other drugs than MSSA isolates. Almost all MRSA isolates were also non-susceptible to ciprofloxacin (91%), whereas ciprofloxacin resistance occurred in only 6% of the MSSA isolates. Vancomycin intermediate S. aureus (VISA) was confirmed in two MRSA isolates from France. Confirmed MICs of vancomycin were respectively 6 and 12 mg/L. Multidrug resistance Multidrug resistance (i.e., resistance against at least three antibiotics of different classes) occurred in 1210 (11.5%) of the 10527 isolates that were tested for at least three classes of antibiotics. Resistance to betalactams most frequently occurred in combination with resistance to quinolones and macrolides, sometimes in combination with aminoglycoside resistance. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 95 Multidrug resistance was more common among men than among women (12.5% and 8.6% respectively, p<0.0001). Patients with multidrug resistance were older (65.1 18.3 years) than patients whose isolates were resistant to at most two different antibiotics (58.5 23.5 years). The proportion of multidrug resistance was highest in the isolates from ICUs (21.4%), followed by those from surgery (14.4%) and lowest (3.7%) in the isolates of which the ward of origin was not reported. Discussion We found that methicillin resistant Staphylococcus aureus (MRSA) proportions vary importantly within Europe. Southern European countries, the United Kingdom and Ireland reported the highest proportions, whereas northern European countries had proportions below 1%. These figures are consistent with those obtained through other surveillance systems [16-19]. MRSA proportions vary more than 100-fold among the European countries. A similar variation in proportions was previously reported [20] and probably is mainly due to differences in hygiene policy [21] and may also in part be caused by the large variation in the use of antimicrobial drugs [4, 5]. Increased awareness of health professionals is essential to enable strict hygienic measures to be taken and to optimise antimicrobial use in hospitals. Further research is needed to quantify the 96 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Table 7.1. Staphylococcus aureus: demographic data of patients of whom isolates originated in 2001. Characteristic MSSA MRSA Total Percentage (n=11 589) (n=3 134) (n=14 723) of MRSA Sex of patient Male 6 730 1 903 8 633 22.0 * Female 4 332 1 018 5 350 19.0 Unknown 527 213 740 28.8 Age of patient, mean SD 58.2 23.5 64.8 19.4 *, Patient admitted to ICU 1 228 652 1 880 34.7* Internal medicine 4 416 1 126 5 542 20.3 Surgery 1 420 527 1 947 27.1 Other wards 2 753 634 3 387 18.7 Unknown 1 772 195 1 967 9.9 * statistically significant difference, i.e. p<0.05, as determined by Chi-square test. age of the patient of which the isolate originated was missing in 374 (MSSA), respectively 235 (MRSA) instances. determinants for this high level of variation, and may provide additional clues for intervention. MRSA proportions increased during the 1990s [18], and our data show strong indications for a rapid increase in the prevalence of methicillin/oxacillin resistance in the United Kingdom (almost 6% increase per year) and in Germany (almost 4% increase per year). Especially in the United Kingdom, MRSA is a serious resistance problem, as its prevalence has risen up to 45% by 2001. However, it should be mentioned that the follow-up period of three years is still relatively short. Moreover, data from some countries (Portugal and Greece) fluctuate over the years and some countries reported a low number of isolates. Therefore, although specific trends seem to be present in some countries, no firm conclusions about time trends overall can be drawn yet. Generally, we found only small differences in MRSA proportions among hospitals of the same country, indicating the importance of national policies and practices. However, to increase our understanding of determinants of the spread among and persistence within hospitals, it is important to collect more information about the MRSA-problem at hospital level. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 97 Table 7.2. Resistance of Staphylococcus aureus strains from invasive isolates to non-protocol antibiotics, by methicillin susceptibility. MSSA (n=11 589) MRSA (n=3 134) Antibiotic % of isolates % of non- % of isolates % of non- tested susceptibility (I+R) tested susceptibility (I+R) Ciprofloxacin 43.1 6.0 61.9 91.1 Erythromycin 57.3 13.2 67.9 77.3 Gentamicin 57.2 2.0 71.9 37.6 Rifampicin 50.8 0.49 39.3 19.0 Vancomycin 82.6 0 95.0 0.07 * Tetracycline 21.3 6.1 34.4 45.9 * two confirmed VISA strains from France More S. aureus isolates originated from males than from females, and the proportion being methicillin resistant was also higher among males. These proportions may have been higher because intensive care units, reporting more invasive infections and the highest MRSA proportions, count more men than women [5]. There is a marked difference between the resistance profiles of methicillin susceptible compared to methicillin resistant S. aureus isolates. Almost all MRSA isolates were non- susceptible to ciprofloxacin, whereas ciprofloxacin resistance occurred in only a small percentage of the MSSA isolates. The two antimicrobial drugs that are most likely to still be active against MRSA were rifampicin and vancomycin. Methicillin resistance indeed seems to be synonymous with, or at least indicative of multidrug resistance. This "co- evolution" of resistance is of concern as treatment options for multidrug resistant infections are limited. So far, two confirmed VISA strains have been reported to EARSS. The potential emergence of VISA strains needs to be carefully monitored. Consensus on how to define and detect VISA is imperative at national and at European level and testing and reporting of VISA through EARSS needs to be improved. In fact, EARSS recently issued a technical guide for the screening of VISA/VRSA, providing a stepwise procedure for screening, testing and reporting within EARSS. 98 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Appendix 7.0. EARSS country codes Austria AT Italy IT Belgium BE Luxembourg LU Bulgaria BG Malta MT Croatia HR Netherlands NL Czech Republic CZ Norway NO Denmark DK Poland PL Estonia EE Portugal PT Finland FI Rumania RO France FR Russia RU Germany DE Slovakia SK Greece GR Slovenia SI Hungary HU Spain ES Iceland IS Sweden SE Ireland IE Switzerland CH Israel IL United Kingdom UK EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 99 Appendix 7.1. Methicillin resistant Staphylococcus aureus (MRSA) blood isolates reported to EARSS in the period 1999-2001 per country per year. Total nr of country year Nr of Labs S. aureus isolates Nr MRSA % MRSA AT 2000 9 156 8 5.1% 2001 9 277 21 7.6% BE 1999 47 442 102 23.1% 2000 42 657 137 20.9% 2001 35 194 42 21.6% BG 2000 16 111 41 36.9% 2001 17 103 28 27.2% CZ 2000 31 515 22 4.3% 2001 39 1074 63 5.9% DE 1999 12 1063 102 9.6% 2000 10 741 107 14.4% 2001 9 783 137 17.5% DK 1999 5 718 2 0.3% 2000 4 501 1 0.2% 2001 4 520 4 0.8% EE 2001 6 79 4 5.1% ES 2000 31 836 235 28.1% 2001 37 1011 234 23.1% FI 1999 13 316 3 0.9% 2000 12 362 5 1.4% 2001 9 522 2 0.4% FR 2000 1 22 9 40.9% 2001 21 1714 572 33.4% GR 1999 19 192 60 31.3% 2000 15 354 179 50.6% 2001 25 356 140 39.3% HR 2001 14 149 47 31.5% HU 2001 18 301 14 4.7% IE 1999 11 511 200 39.1% 2000 18 632 248 39.2% 2001 19 798 333 41.7% IL 2001 5 381 147 38.6% 100 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Total nr of country year Nr of Labs S. aureus isolates Nr MRSA % MRSA IS 1999 2 32 0 0.0% 2000 2 40 1 2.5% 2001 3 63 0 0.0% IT 1999 56 1158 473 40.8% 2000 48 456 200 43.9% 2001 53 839 344 41.0% LU 1999 1 25 4 16.0% 2000 4 67 12 17.9% 2001 8 85 17 20.0% MT 2000 1 76 27 35.5% 2001 1 83 45 54.2% NL 1999 20 1224 4 0.3% 2000 24 1392 5 0.4% 2001 22 1292 7 0.5% PL 2001 19 151 23 15.2% PT 1999 13 369 136 36.9% 2000 8 150 38 25.3% 2001 16 521 166 31.9% SE 1999 24 1320 13 1.0% 2000 19 1478 9 0.6% 2001 21 1632 14 0.9% SI 2000 10 154 33 21.4% 2001 10 270 53 19.6% 2001 7 37 2 5.4% UK 1999 23 655 219 33.4% 2000 27 1494 591 39.6% 2001 25 1488 675 45.4% 26 countries Total 32942 6360 19.3% EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 101 References 1. 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EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 103 Chapter 8 The Community Strategy against Antimicrobial Resistance concerning human medicine Bronzwaer S, Lnnroth A, Haigh R. Submitted to the European Journal of Public Health. Abstract In 2001 the European Commission agreed a Communication to the European Parliament and the Council outlining the Community strategy against Antimicrobial Resistance. One important part of that Community strategy is the 'Council Recommendation on the prudent use of antimicrobial agents in human medicine', recommending Member States to ensure that specific strategies to contain antimicrobial resistance are implemented at national level. The Community strategy consists of fifteen actions in four key areas: surveillance, prevention, research and product development, and international co- operation. Of these fifteen actions comprising the strategy, this paper discusses eleven points of action that are directly related to human medicine, and presents relevant Community activities. The European Commission has initiated, through its various services, a wide range of activities. In past years the problem of antimicrobial resistance was addressed through an increasing number of isolated measures, but through the Community strategy the Commission has set a comprehensive and pro-active approach. Under the new public health programme as well as under the Commissions research programmes, antimicrobial resistance is of key priority, and specific priorities within the area of antimicrobial resistance are presented. Introduction In recent years the problem of antimicrobial resistance has received increasing attention and many activities have been started in parallel. Member States of the European Union (EU) are progressively taking initiatives to contain antimicrobial resistance by, for example, implementing national surveillance systems, training health professionals, providing information to the public, etc. With many initiatives on-going there is added value in sharing experiences and need for co-ordinating control efforts. At level of the European Community (hereinafter referred to as Community) the problem of antimicrobial resistance has been recognised as a public health priority and addressed since several years. The Treaty of Amsterdam (1997) makes provisions for action directed towards improving public health, preventing human illness and diseases, placing the responsibility on Community Institutions (Commission and Council) and on the Member States. At the EU conference The Microbial Threat, held in Copenhagen in September 1998, the participants unanimously agreed that antimicrobial resistance was no longer a national problem, but a major international issue requiring a common strategy at European level. 1 In May 1999 a Commissions committee of independent scientists (Scientific Steering Committee) delivered its opinion on antimicrobial resistance with recommendations for 106 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY action. 2 It emphasised that antibiotics are of utmost importance to treat and contain communicable diseases, but that increasing prevalence of antimicrobial resistance calls for immediate action to limit their use to diseases with strict indications. The overall use of antibiotics should be reduced in a balanced way in all areas: human medicine, veterinary medicine, animal production and plant protection. In its advice, the Committee pointed out the possible need to introduce effective legislation and regulation to support the achievement of its recommendations. For example, Europe took action to phase out the use of antibiotics as growth promoters in farm animals, and is now adopting a Directive to this effect. Also in the fields of plant protection and veterinary medicine many measures are in place and more legislative acts are being agreed to limit the use of antibiotics. Prudent use of antimicrobials in man is an important part of a comprehensive strategy on the overall use of these agents, and this paper limits itself to discussing the problem in the area of human medicine. In June 1999, the Council, drawing on recommendations of the 'Microbial Threat conference', adopted a Resolution on antibiotic resistance 'A strategy against the microbial threat', considering that preservation of the effectiveness of antibiotics for the treatment of infection cannot be achieved by national initiatives alone, but requires a common strategy and co-ordinated action at Community level. 3 To follow-up on the recommendations from the Microbial Threat conference in Copenhagen, an invitational EU conference on antimicrobial resistance was held in June 2001, in Visby, Sweden. Also, in June 2001 the Commission approved a Communication to the European Parliament and the Council outlining the Community strategy against Antimicrobial Resistance (hereinafter referred to as Community strategy). 4 A few months later during the EU conference on Antibiotic Use in Europe, held in November 2001 in Brussels, the Council Recommendation on the prudent use of antimicrobial agents in human medicine was launched (hereinafter referred to as Council Recommendation). 5,6,7 This Council Recommendation constitutes an important part of the Community strategy. It recommends that Member States ensure that specific strategies to contain antimicrobial resistance exist and are implemented at national level. Member States are recommended to encourage a more prudent use of antimicrobial agents and to take measures related to surveillance, education, information, prevention and control, and research in co-operation with the Commission. The Council Recommendation charges the Commission with the task of supporting Member States efforts through the Community Network on the epidemiological surveillance and control of communicable diseases (hereinafter referred to as Community Network). 8 This paper aims to present the Community strategy against antimicrobial resistance in EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 107 the area of human medicine, including the Council Recommendation that forms an integral part of it, and to present related Community activities funded under the public health programmes and under the framework programmes for research. Community strategy against antimicrobial resistance In past years the problem of antimicrobial resistance was addressed through an increasing number of isolated measures. In its Communication of July 2001 the Commission proposed one comprehensive Community strategy against antimicrobial resistance, consisting of fifteen actions in four key areas: surveillance, prevention, research and product development, and international co-operation (Table 8.1). Of these fifteen actions comprising the Community strategy, we describe the eleven points of action that are directly related to practices in human medicine. Surveillance Action 1 of the Community strategy concerns surveillance and requires the development of surveillance networks at the European level, encouraging the participation also of non- EU countries. At EU level this is undertaken through the Community Network that came into place in 1998, with antimicrobial resistance as one of its priorities. The two main pillars of this Community Network are epidemiological surveillance of communicable diseases and an early warning and response system. One of the surveillance networks funded within this Community Network is dedicated to antimicrobial resistance surveillance. This large European Antimicrobial Resistance Surveillance System (EARSS) is a network of national surveillance systems and currently comprises about 800 laboratories from 28 countries. 9 Laboratories follow a standardised EARSS protocol and submit quarterly susceptibility data of invasive isolates of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, Enterococcus faecium and Enterococcus faecalis. The main function of EARSS is to monitor variations in resistance of indicator pathogens of main public health relevance for targeting interventions and assessing effectiveness of national intervention programmes. Also a number of other surveillance networks falling under the Community Network look into the susceptibility of the pathogens under surveillance. For instance, the Enter-net network performs surveillance of Salmonella and verotoxin-producing E. coli (VTEC) infections including the susceptibility to antibiotics whilst EuroTB performs surveillance of tuberculosis including (multi) drug resistance. Monitoring of susceptibility of meningococci, gonococci and syphilis has also begun in the context of other surveillance networks. Table 8.2 provides an overview and specifies web site addresses of antimicrobial resistance related projects funded under the (1996-2002) Community action programme on public health (hereinafter referred to as PHP). In addition, through the European Commissions Fifth Framework Programme 108 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY (hereinafter referred to as FP5) for Research and Technological Development (1998- 2002) 10 , funding is provided for the development of improved technologies for surveillance of antimicrobial resistance in tuberculosis, Pseudomonas aeruginosa, meningococcal disease and salmonellosis as well as for research addressing the risk of transmission between food animals and humans. Also, as part of the Community strategy, the Council Recommendation calls on Member States to establish or strengthen sustainable antimicrobial resistance surveillance systems building upon existing national and international systems using, wherever possible, internationally recognised classification systems and comparable methods. The same recommendation holds for the monitoring of the use of antimicrobial agents that in fact constitutes the second point of action. Action 2 of the Community strategy sets out to put in place and improve the collection of data on consumption of antimicrobial agents in all sectors. Sound data on the consumption of antimicrobial agents are needed for developing intervention strategies. Such data already exist in many Member States but they are scattered, heterogeneous, and in many instances not easily accessible. The Council Recommendation asks the Member States to co-operate with the Commission to develop indicators to monitor prescribing practices. The Commission is funding, through the PHP, the European Surveillance of Antimicrobial Consumption in humans (ESAC) project that started in November 2001 with first results of the retrospective data collection presented at the 13 th ECCMID conference in Glasgow. Through this network about 30 participating countries deliver comprehensive national data on cost and volume of antimicrobial consumption in ambulatory and hospital care. Prospective and standardised data collection starts as of 2003 and indicators for the evaluation of the appropriateness of antimicrobial use will be developed. FP5 supports a project to implement the defined methodologies of EARSS and ESAC in the Mediterranean region, starting in 2003. In this Antimicrobial Resistance in the Mediterranean (ARMed) project at present seven Mediterranean countries participate (Malta, Cyprus, Turkey, Egypt, Tunisia, Morocco and Jordan). To guide intervention it is critical to understand the relation between antimicrobial resistance and use. A recent study using EARSS data showed that in the EU antimicrobial resistance of S. pneumoniae to penicillin is correlated with use of beta-lactam antibiotics and macrolides at country level. 11 To study and monitor further the link between antimicrobial resistance data and antimicrobial use EARSS and ESAC linked their respective databases. Prevention Actions in this key area of the Community strategy aim to stimulate work on the EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 109 prevention of communicable diseases, and infection control to reduce the need for antimicrobial agents. Action 3 of the Community strategy aims to increase the importance of antimicrobial resistance information for the market authorisation process. Concerns have been expressed by regulators in various European authorities that different indications, doses, dose regimens (duration of treatment) and different pharmacodynamic information exist for the same and similar products already licensed in the EU. National competent authorities in consultation with the European Agency for the Evaluation of Medicinal products (EMEA) are currently considering the issue of divergent product information, and Member States are asked through the Council Recommendation to initiate activities to evaluate, and as necessary, update and harmonise the summary of product characteristics (SPC). The EMEA has published a discussion paper on antimicrobial resistance outlining its activities and pointing out the need to find ways to promote new effective antibiotics. 12 Criteria for market authorisation of new antibacterial medicinal products are outlined in three EU guideline documents. 13,14,15 Action 4 of the Community strategy sets out to support, at Community level, educational campaigns directed at professionals and the general public to avoid overuse and misuse of antimicrobial agents. An FP5 supported research project, the European Resistance Intervention Study (EURIS), evaluates different approaches to reduce the prevalence of resistant pneumococci among children in European day-care centres. These interventions include reduced use of antibiotics through education of doctors, day-care staff, parents and children, optimised dosing, improved hygiene, notification of resistant strains and isolation of carriers. Another FP5 project, the Antibiotic Resistance Prevention And Control (ARPAC), aims at identifying hospital policies and prescription patterns which are associated with lower resistance rates. The objective of ARPAC is to evaluate and harmonise strategies for prevention and control of antibiotic resistance in hospitals. Results are to be expected in 2004. In addition, the Council Recommendation encourages Member States to promote education and training of health professionals on the problem of antimicrobial resistance in undergraduate and postgraduate training. Member States should also promote training on hygiene and infection control standards and on immunisation programmes in order to reduce the spread of micro-organisms. Also the general public should be informed on the importance of prudent antimicrobial use by raising awareness of the problem of antimicrobial resistance, proper prescription, good patient adherence, the value of hygiene, and the impact of vaccination. The Commission is taking this forward in part by funding (under the PHP) a Swedish Film 110 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY and Television company to produce in 2003 a TV-documentary on the battle against resistant bacteria to be used as an educational tool to promote appropriate antimicrobial use. This film should be followed up at national level by TV talk shows, newspaper articles and school discussions. Action 5 of the Community strategy sets out to fully apply the principle that antibacterial substances are available in human and veterinary medicine by prescription only. Antimicrobial agents for systemic use in human medicine are by law prescription-only medicines in all Member States, but enforcement of this regulation varies. Under the PHP a Self-medication with Antibiotics and Resistance levels in Europe (SAR) project is funded that aims to quantify the consumption of antibiotics sold over-the-counter (without prescription) and of leftover (prescribed) antibiotics hoarded at home. Building on the EARSS and ESAC networks, this project will also investigate the possible impact of non- prescribed consumption on the development of resistance. Action 6 of the Community strategy aims to reinforce and promote prevention programmes of infections in human and veterinary medicine, and in particular immunisation programmes. In the frame of the Community network on communicable diseases, surveillance networks have been started on vaccine preventable diseases like measles, pertussis, and rubella. The development of vaccination registers was started to evaluate best results in terms of vaccination coverage in Member States. The pneumococcal disease in Europe (PNC-Euro) project, funded in FP5, studies the epidemiology of S. pneumoniae in a variety of European countries prior to the introduction of new conjugate vaccines. The study will produce information to design cost-effective prevention strategies against pneumococcal infection. Containment of antimicrobial resistance is intrinsically linked to infection control practices. Hospitals in Europe Link for Infection Control and Surveillance (HELICS) is a Commission funded project (PHP) to monitor hospital acquired infections developing protocols for databases on surgical and intensive care unit infections, and to setup evidence-based infection control standards and recommendations. Member States are asked by the Council Recommendation to implement preventive and control measures by developing evidence-based principles and guidelines on good practice for the management of communicable diseases, and controlling good practice of marketing of antimicrobial agents. Member States should ensure proper implementation of hygiene and infection control standards in health care facilities and in the community and encourage national immunisation programmes. Actions 7 to 10 refer to preventive action in the fields of growth promoters, food, and environment and although very relevant to public health do not fall within the scope of this paper. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 111 Research and product development Antimicrobial resistance has been for a long time part of the Community research priorities. Already under the Fourth Framework Programme for Research and Technological Development (1994-1998), some actions addressing antimicrobial resistance were initiated. Along with the Commissions increasing efforts to contain resistance, research efforts were significantly intensified during FP5. The programme is currently funding about 80 projects related to antimicrobial resistance at a total Commission contribution of over 100 million. This project portfolio addresses anti- bacterial, anti-fungal, anti-viral and anti-protozoan resistance through various approaches, ranging from basic mechanisms of emergence and transmission of resistance, through development of new drugs and diagnostic tests to epidemiological and public health research. A comprehensive overview of all these projects is available at: http://www.cordis.lu/lifescihealth/major/drugs.htm Action 11 of the Community strategy promotes the development of new antimicrobial agents. About one third of the antimicrobial resistance portfolio of FP5 is devoted to the development of new classes of anti-infectives. Some of these projects focus on microbial functional genomic approaches, in particular against tuberculosis and S. aureus. Other projects investigate novel potential molecular targets, such as the bacterial ribosome, protein replication initiation, or secretion and adhesion mechanisms. Yet other projects focus on the development of new concepts for antimicrobial drugs through the exploitation of antibiotics-producing organisms. Action 12 of the Community strategy encourages the development of alternative treatments and vaccines. Current FP5 research includes the development of resistance inhibitors, such as beta-lactam inhibitors for combination treatment, bacterial conjugation inhibitors and inhibitors of bacterial adhesion at mucosal surfaces. Lactic acid bacteria, already widely used as probiotics for human consumption, are now subject to a rigorous biosafety evaluation study in the scope of an FP5 project. Vaccine development is a major priority in FP5 and several research projects are currently on- going. Special emphasis is given to tuberculosis, malaria, HIV/AIDS, and Hepatitis C virus through multiple approaches, but also influenza, respiratory syncytical virus, shigellosis and Neisseria meningitidis serogroup B are being addressed. Efforts are also devoted to the development of novel vaccine delivery systems and formula. In addition, under Article 169 of the Treaty of Amsterdam, a unique effort has been launched in Europe to provide an infrastructure for clinical trials of vaccines against tuberculosis, malaria and HIV/AIDS. This European and Developing Countries Clinical Trials Partnership (EDCTP) has been set up through a joint collaborative initiative among Member States and developing countries with the Commission as supporting partner. The main goal is to 112 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY support phase II and phase III clinical trials of promising new clinical interventions against HIV/AIDS, malaria and tuberculosis in, with, and for, developing countries. Action 13 of the Community strategy sets out to support the development of rapid and reliable diagnostic and susceptibility tests. In order to achieve a long-term sustainable prudent use of antimicrobials, improved access to rapid read-out, reliable and inexpensive diagnostic tests is essential. Currently funded FP5 projects include the development of sensors for multi-drug resistant strains of tuberculosis, a DNA chip based diagnostic test for P. aeruginosa, nucleic acid based amplification methods for the detection of respiratory pathogens in community acquired pneumonia and a network for automated bacterial strain fingerprinting. International co-operation An effective Community strategy requires close co-operation and consultation between the Commission, the Member States and other involved parties. Action 14 of the Community strategy encourages the development of co-operation, co-ordination and partnership at international level, in particular via existing international organisations. The Commission and the World Health Organisation (WHO) have signed a Memorandum of Understanding reconfirming their common interest in health. Antimicrobial resistance is among the agreed priorities and close co-operation with WHO has been ensured for all antimicrobial resistance related networks. The Commission is developing a programme with WHO on strengthening pharmaceutical policies, including rational use of drugs and particularly supporting national programmes to contain antimicrobial resistance, through the expansion of projects that link surveillance data to rational prescribing programmes. The Commission is invited to take a leading role in the implementation of the Northern Dimension Action Plan that includes actions on antimicrobial resistance, particularly through the Baltic Sea States Task Force on communicable diseases control. Out of the FP5 research portfolio on antimicrobial resistance, seven projects are specifically focused on international issues, covering a broad spectrum of issues that range from the control of use of antibiotics and resistance in Latin America to the problem of drug resistance in Asian aquacultural environments. Action 15 of the Community strategy attributes special attention to applicant and developing countries by helping putting in place the appropriate structures. The participation of non-member countries is foreseen in the Community Network and most applicant countries already participate in antimicrobial resistance surveillance networks and projects funded under the PHP. Active participation of applicant countries in projects under the framework programmes for research is also encouraged. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 113 Discussion The public health problem of antimicrobial resistance is receiving more and more the attention it requires, and over the years the Commission has given due priority to the matter. As presented here for human medicine, various Commission services have initiated wide-ranging activities and through a number of legal acts, recommendations for action are made to the Member States. 7,8,16 On 23 September 2002, the European Parliament and the Council adopted a Decision establishing a new programme of Community action in the field of public health (2003- 2008). 17 This programme modernises and combines into one framework the former eight Community action programmes on public health carried out from 1996 to 2002. The new programme provides the framework for an annual public health workplan and a funding mechanism for projects addressing Community priorities. In the workplan 2003, antimicrobial resistance and guidelines for best practice on prudent antimicrobial use are defined as key priorities, and the Commission is calling for proposals in this area. 18 The Council invites the Commission to propose, where appropriate, common methodology, case definitions, and nature and type of data to be collected for surveillance of antimicrobial resistance and antimicrobial use. Surveillance networks now face problems in comparability of susceptibility data because of differences in methodology and guidelines for susceptibility testing. The Commission has therefore defined as priority in its public health workplan 2003 to stimulate activities that propose a common or harmonised methodology and possibly common criteria for defining resistance. Other Community challenges in the field of antimicrobial resistance that have priority in the workplan 2003 are to support information exchange and co-ordination of education and intervention programmes aimed at hospitals and the open population. Recent reports about the MRSA problem in the UK illustrate the importance of hospital infection control to contain the spread of antimicrobial resistance. 19 To build further on results of existing projects, the Commission also calls for developing a permanent system for information connecting interested parties such as prescribers, pharmacists, consumers, health insurance, etc. on consumption of antimicrobials and related trends in resistance. Applications for activities to update product information where necessary are also called for. An increasing number of countries are implementing a system for laboratory-reporting in addition to the statutory notification of communicable diseases through physicians. These systems offer additional benefit but need to meet basic requirements such as good quality and comparable data from participating labs. As many countries are only just beginning, there is added value if the Commission could bring together national groups to exchange information and harmonise issues like: minimum data set, un-duplication, 114 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY external quality control of laboratories, confidentiality and access to data, algorithms for early warning, etc. Through the new PHP, under the frame of the Community Network, the Commission will support actions aimed at networking and co-operation between European laboratories, with the aim to foster communication, to enhance quality assurance and harmonisation of laboratory methods in order to ensure comparability of data. Furthermore, the Commission recently launched the Sixth Framework Programme (FP6) for Research and Technological Development (2002-2006). 20 This programme is supported by a set of new instruments designed to ensure a more effective way of carrying out research in Europe. These instruments are 'Networks of Excellence', which aim to structure, integrate and co-ordinate research resources and activities around a given topic and Integrated Projects, which bring together complementary expertise to tackle specific ambitious research objectives in a co-ordinated fashion. Research on antimicrobial resistance has been selected as one of the priority areas and will thus receive a further boost in FP6. The new instruments will be used to channel microbial and human genomic research towards applications into new molecular drug targets, alternative therapeutic and preventive strategies, new diagnostic and susceptibility tests, epidemiological approaches and improved knowledge of molecular mechanisms behind resistance. Furthermore, measures to provide scientific support to antimicrobial resistance in the context of the Community Network are placed high on the FP6 agenda under policy- oriented research. These new initiatives aim to further complement the Commissions contribution to the Community strategy. Accurate information regarding antimicrobial resistance and antimicrobial use is needed to target interventions. Hence, each Member State should have an appropriate framework in place to monitor accurately antimicrobial use and antimicrobial resistance. Effective implementation requires a number of key features, including a clear action plan, delegation of authority and power to act, resources and sound mechanisms to assess the effectiveness of interventions, allowing feedback of results to influence future strategies. Therefore the Council Recommendation asks Member States to put in place an intersectoral mechanism for implementing relevant measures and for effective co- ordination with other Member States and the Commission. No specific recommendations are made to the nature of this mechanism, but one might assume that in this body, local, regional and national health authorities, the legislator, professionals of the different disciplines concerned, and consumers, would be represented. This national mechanism should co-ordinate reporting structures at local and hospital level, prioritise the action needed, and recommend the health authorities responsible for taking action. The Commission created a working group of representatives of the different national EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 115 intersectoral mechanisms under the auspices of the Community Network to assist in evaluating the implementation of the Council Recommendation. Member States are to report to the Commission on the implementation of the Council Recommendation within two years of its adoption. The Commission monitors this implementation closely and has recently sent out a template for reporting to facilitate and structure the reports from Member States. The Commission intends to follow-up on these reports including other relevant actions under the Community strategy. In conclusion, in past years the problem of antimicrobial resistance was addressed through an increasing number of individual measures, but through the Community strategy the Commission has set a comprehensive and pro-active approach, giving special attention to applicant countries. Under the new public health programme as well as under the Commissions research programmes, antimicrobial resistance is of key priority. 116 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Table 8.1: The four key areas and fifteen priority actions of the Community strategy against antimicrobial resistance Key area Action Surveillance 1. Develop co-ordinated and coherent surveillance networks at the European level. Encourage the participation of non-EU countries and the links between already established surveillance networks in human and veterinary medicines 2. Put in place and improve the collection of data on consumption of antimicrobial agents in all sectors Prevention 3. Increase the importance of antimicrobial resistance information for the market authorisation process in human medicine, veterinary medicine and agriculture 4. Support, at Community level, educational campaigns directed at professionals (clinicians, veterinarians, farmers) and the general public to avoid overuse and misuse of antimicrobial agents 5. Fully apply the principle that antibacterial substances are available in human and veterinary medicine by prescription only and distributed in a controlled way in agriculture, and evaluate whether the prescription-only rule should be applied to all antimicrobial agents as a precaution 6. Reinforce and promote prevention programmes of infections in human and veterinary medicine, in particular immunisation programmes 7. Reinforce the residue monitoring system in food as regards methods of analysis, sanctions and reporting system 8. Phase out and replace antimicrobial agents used as growth promoters in feed 9. Review the use of the two authorised antimicrobial agents in food 10. Ensure that GMOs which contain genes expressing resistance to antibiotics in use for medical or veterinary treatment are taken into particular consideration when carrying out an environmental risk assessment, with a view to identifying and phasing out antibiotic resistance markers in GMOs which may have adverse effects on human health and the environment Research and product development 11. Encourage the development of new antimicrobial agents 12. Encourage the development of alternative treatments and vaccines 13. Support the development of rapid and reliable diagnostic and susceptibility tests International co-operation 14. Encourage strongly the development of co-operation, co-ordination and partnership at international level in particular via the existing international organisations 15. Pay special attention to candidate and developing countries by helping them putting in place the appropriate structures EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 117 Table 8.2. Projects funded under the public health programme related to antimicrobial resistance Acronym Full title Focus Co-ordinated by Web site EARSS European Antimicrobial resistance RIVM, Bilthoven, www.earss.rivm.nl/ Antimicrobial of invasive isolates Netherlands Resistance of S. pneumoniae, Surveillance S. aureus, E. coli, System E. faecium / faecalis ESAC European Scientific Evaluation on University of www.uia.ac.be/esac Surveillance the Use of Antimicrobial Antwerp, Belgium Antibiotic Agents in Human Therapy Consumption EU-IBIS European Union Invasive Haemophilus PHLS, London, UK www.phls.org.uk/ Invasive Bacterial influenzae and inter/eu_ibis/ Infections Neisseria meningitidis aims.htm Surveillance disease Enter-net International Salmonella, infection PHLS, London, UK www.phls.co.uk/ surveillance with E. coli O157 inter/enter-net/ network for the menu.htm enteric infections EuroTB Surveillance of Tuberculosis including InVS, Paris, France www.eurotb.org/ tuberculosis in multi-drug resistance Europe HELICS Hospitals in Nosocomial infections Universit Claude http://helics.univ- Europe Link for Bernard, Lyon, lyon1.fr Infection Control France through Surveillance SAR Self-medication Quantification of levels University of none with antibiotics and of self-medication Groningen, resistance levels (OTC and use of Netherlands in Europe leftovers of antibiotics) in different European countries TV-film The battle against Production of a television Meter-film, none antibiotic resistant film on antibiotic Stockholm, bacteria resistance aiming to raise Sweden awareness of this problem in the general public 118 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY References 1 State Serum Institute and Danish Veterinary Laboratory, eds. The Copenhagen recommendations on the microbial threat. Ministry of Health, Ministry of Food, Agriculture and Fisheries, 1998. 2 Opinion of the Scientific Steering Committee on Antimicrobial Resistance - 28 May 1999. Available at: http://europa.eu.int/comm/food/fs/sc/ssc/out50_en.html. Accessed 18 February 2003. 3 OJ C 195, 13.07.1999, p.1. Council Resolution of 8 June 1999 on antibiotic resistance "A strategy against the microbial threat". 4 Com (2001) 333 final 20.06.2001. Commission of the European Communities. Communication from the commission on a community strategy against antimicrobial resistance. Available at: http://europa.eu.int/comm/health/ph/others/antimicrob_resist/am_02_en.pdf. Accessed 11 December 2002. 5 Midday Express. European conference on antibiotic use in Europe, 14 November 2001. Available at: http://europa.eu.int/comm/dgs/health_consumer/library/press/press206_en.pdf. Accessed 11 December 2002. 6 Byrne D. European Commissioner for Health and Consumer Protection. The EU strategy on antimicrobial resistance in humans. European Conference on Antibiotic Use in Europe Brussels, 15 November 2001. Available at: http://europa.eu.int/rapid/start/cgi/guesten.ksh?p_action.gettxt=gt&doc=SPEECH/ 01/542|0|RAPID&lg=EN. Accessed 11 December 2002. 7 OJ L34 of 5.2.2002, p.13. Council Recommendation of 15 November 2001 on the prudent use of antimicrobial agents in human medicine (2002/77/EC). Available at: http://europa.eu.int/eur- lex/pri/en/oj/dat/2002/l_034/l_03420020205en00130016.pdf. Accessed 11 December 2002. 8 OJ L 268. 3.10.98, p.1. Decision no. 2119/98/EC of the European Parliament and of the Council of 24 September 1998 setting up a network for the epidemiological surveillance and control of communicable diseases in the Community. Available at: http://europa.eu.int/eurlex/pri/en/oj/dat/1998/l_268/ l_26819981003en00010006.pdf. Accessed 11 December 2002. 9 EARSS management team, advisory board and national representatives. EARSS Annual Report 2001. Bilthoven, the Netherlands, July 2002. Pages 95. ISBN-number: 90-6960-098-6. Downloadable from EARSS official web-site: www.earss.rivm.nl. Accessed 24 February 2002. 10 OJ L26, 1.2.1999, p.1. Decision of the European Parliament and of the Council, of 22 December 1998, concerning the Fifth Framework Programme of the European Community for research, technological development and demonstration (RTD) activities (1998-2002). 11 Bronzwaer S, Cars O, Buchholz U, Mlstad S, Goettsch W, Veldhuijzen I, Kool J, Sprenger M, Degener J, and EARSS participants. A European Study on the Relationship between Antimicrobial Use and Antimicrobial Resistance. Emerg Inf Dis 2002;8(3):278-82. 12 EMEA/9880/99. EMEA discussion paper on antimicrobial resistance. Available at: http://www.emea.eu.int/pdfs/human/regaffair/988099en.pdf. Accessed 11 December. 13 EMEA document CPMP/EWP/558/95. Note for guidance on evaluation of new antibacterial medicinal products. Available at: http://www.emea.eu.int/pdfs/human/ewp/055895en.pdf. Accessed 11 December 2002. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 119 14 EMEA document CPMP/EWP/520/96. Note for guidance on the pharmacodynamic section of the SPC for antibacterial medicinal products. Available at: http://www.emea.eu.int/pdfs/human/ewp/052096en.pdf. Accessed 11 December 2002. 15 EMEA document CPMP/EWP/2655/99. Points to consider on pharmacokinetics and pharmacodynamics in the development of antibacterial medicinal products. Available at: http://www.emea.eu.int/pdfs/human/ ewp/265599en.pdf. Accessed 11 December 2002. 16 OJ L 244, 30.09.1993, p.35. Council Directive 92/117/EEC of 17 December 1992 concerning measures for protection against specified zoonoses and specified zoonotic agents in animals and products of animal origin in order to prevent outbreaks of food-borne infections and intoxications. 17 OJ L 271, 09.10.2002, p.1. Decision No 1786/2002/EC of the European Parliament and of the Council of 23 September 2002 adopting a programme of Community action in the field of public health (2003-2008). Work Plan 2003 for the implementation of the Public Health Programme (2003-2008). Documents regarding the call for proposals are downloadable from: http://europa.eu.int/comm/health/index_en.html. Accessed 27 March 2003. 18 Public Health Laboratory Service. Report for the Department of Health into rates of hospital infections caused by methicillin-resistant Staphylococcus aureus (MRSA). February 2002. 19 OJ L232, 29.8.2002, p.1. Decision No 1513/2002/EC of the European Parliament and of the Council, of 27 June 2002, concerning the Sixth Framework Programme of the European Community for research, technological development and demonstration activities contributing to the creation of the European Research Area and to innovation (2002 to 2006). Available at http://www.cordis.lu/fp6/find-doc.htm 120 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Chapter 9 General Discussion Surveillance as a tool for action To gain control over antimicrobial resistance it is essential to undertake appropriate surveillance. Many different initiatives are in place to monitor antimicrobial resistance and to understand the problem. In a review by Monnet et al. more than 20 different multinational multicentre surveillance or research projects were identified that produce data on antimicrobial resistance in Europe (1). Each of these surveillance components plays a valuable part in a comprehensive programme, but no single part can provide all the answers. In fact, various approaches are needed to answer different questions at the basis of the resistance problem. Surveillance entails data collection to come to action. The actions taken on basis of the data will differ depending on the level at which the data are being collected and analysed. Thus, local surveillance data should be used to guide clinical management, to update treatment guidelines, educate prescribers and guide infection control policies, and to promote improvements in quality and in communications. Nationally collected surveillance data should be used to inform policy decisions, update national formularies or lists of essential drugs and standard treatment guidelines and evaluate cost-effectiveness of interventions (2). With travel and trade increasing over the years, the risk of dissemination of (resistant) pathogens grows. Certain strains have been shown to spread between European countries (3). There is a clear need to coordinate international surveillance, as resistance rates found in different surveys cannot easily be compared due to differences in study design, study population, and time period. From a public health standpoint, it would be relevant to detect the incidence of infections caused by resistant organisms among the total number of infections in a population (4). Because it is difficult to relate the number of infections to a denominator (the catchment population), results of surveillance are mostly given as the proportion of resistant organisms among all organisms tested (prevalence of resistance, often called resistance rate). Important parameters to study the relevance of the resistance problem are the clinical diagnosis and patient outcome. In most surveillance systems, unfortunately, these parameters are not collected because they are mostly not included in Laboratory Information Systems (5). It requires active surveillance where the microbiologist contacts treating physicians to collect clinical information. This is often not done because of time- and cost-constraints. It is essential however that the burden of antimicrobial resistance on morbidity and mortality is better understood and quantified, possibly through special studies as referred to in the Introduction of this thesis. Notwithstanding these difficulties surveillance of resistance rates is fundamental to understand trends in resistance, to target areas for interventions, and to assess the effectiveness of the intervention. 122 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY In chapter 2 EARSS is defined as an international network of national surveillance systems collecting antimicrobial resistance data aiming to assist in the control of antimicrobial resistance. EARSS opted from the beginning to build on national surveillance systems and to collate data first at national level before entering them into the central database. In this way EARSS helped to standardise antimicrobial resistance surveillance at national level and in some countries it even initiated the process of collection of susceptibility data. This is important because the responsibility for taking action to control antimicrobial resistance lies foremost at national level. The national representatives whom are formally recognised by their national authorities collect samples of isolates by either total or representative coverage allowing to produce official national resistance data that constitute a basis for policy decisions. EARSS monitors trends of antimicrobial resistance, which enables to target problem areas and monitor the effect of interventions. The results of the EARSS project are brought to the attention of a broad public through Newsletters, publications and annual reports. Latest results are always freely accessible on-line at www.earss.rivm.nl. Routine surveillance Surveillance of routine susceptibility tests means that susceptibility tests performed in the course of routine clinical care are captured and analysed. The output of the analyses can consist of aggregated summaries or detailed stratified reports. A major advantage of routine surveillance is that it is principally a matter of data management rather than performing extra tests with consequent costs. With the advances in the information technology domain we witness in many European countries that next to notification of physicians of infectious diseases more and more use is made of laboratory notification (6). Routine surveillance is very much in line with this development. Advantages and disadvantages are summarised below: Advantages of routine surveillance Disadvantages of routine surveillance geographically and demographically routinely available specimens representative little clinical information broad range of questions can be no specimens for common clinical addressed, both prospectively scenarios where most treatment and retrospectively is empirical follow baseline trends routine quality identification of new and unexpected often a limited number of antibiotics problems often only qualitative data relatively inexpensive wide variety of laboratory permits evaluation of the quality information systems of routine data EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 123 From the start of EARSS it was decided that the system uses routinely generated data from laboratories so that no changes to the primary diagnostic process are needed. As discussed above, this approach has several limitations because not all participants use the same method and quantitative data are limited, but it allowed to build up an enormous large network with presently 800 laboratories in 28 countries reporting. In chapter 3 we described how these limitations are addressed. S. pneumoniae and S. aureus were chosen as indicator pathogens because these pathogens are routinely tested and breakpoints for the most relevant antibiotics for these pathogens do not differ significantly among the different national breakpoint committees. The EARSS protocol for susceptibility testing is designed in order to standardise data collection allowing for collation of data among participants. A limitation within EARSS is the problem of sampling bias, where clinicians in some countries may request blood cultures more frequently than their colleagues in other countries, who may sample only in case of empirical treatment failure. Attempts have been made within EARSS to quantify blood culture request habits in different European countries but without satisfactory results so far. Bacteria readily exchange information, so should we Surveillance data are essential to target and monitor interventions and above we discussed that there is not one golden method to perform surveillance. Instead data from a variety of sources are available, and should be used to target and monitor interventions. The objective of establishing surveillance systems on antimicrobial resistance (and on the consumption of antibiotics) is a public health function, what implies that this information has to be in the public domain. The more so because in intervention strategies many parties are involved. For this reason anonymised surveillance data should be freely available for public health purposes. Moreover, it can be argued that data which are routinely generated in public laboratories is publicly funded and therefore should be considered to be publicly owned (7). However, in any organised control strategy the issue of data ownership and accessibility should be explicitly addressed and agreed among participants. In this respect we could and should learn from micro-organisms who survive thanks to their ability and practise to exchange resistance information (genes!) rapidly. Bacteria readily exchange information, so should we ... Quality assurance Antimicrobial resistance surveillance also can provide an opportunity to improve the quality of susceptibility testing among those taking part in the surveillance (8). Chapter 4 describes an external quality exercise (EQA) of antibiotic susceptibility testing for laboratories participating in EARSS in order to assess the comparability of susceptibility test results across countries and guidelines. This European-wide QA-exercise was characterised by an excellent response rate with 433 (92%) of 471 laboratories from 23 countries reporting back. 124 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY It confirmed that an exercise of this dimension is feasible and demonstrated the commitment of EARSS participants to quality. Strains were correctly identified at the genus and species level, and the average concordances over all control strains were high. We distributed control strains that tested the laboratories capability to identify the most clinically relevant resistances (penicillin G in S. pneumoniae, methicillin in S. aureus and glycopeptide in staphylococci) and feel reassured to continue using surveillance data generated by the participating national surveillance systems. For continuous external quality assessment we recommend that laboratories participate in national and international schemes with frequent distributions of control strains. EQA gives credibility to the laboratory as a responsible approach to quality can be demonstrated, it may identify deficiencies to be rectified, and it is a stimulus for education of staff. International EQA exercises have the additional benefits of strengthening collaboration between national groups and possibly highlighting limitations of particular national methods (8). Building on the EARSS experience and network, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) is currently planning a more structural EQA approach with a central European strain collection that could be used by different national and international schemes. The quality assurance exercise also provided a good overview of the guidelines being followed in Europe, showing that the NCCLS guideline are widely used. It should be noted that for many antibiotics the breakpoints defining susceptibility or resistance of bacteria to antimicrobial agents do not differ greatly between guidelines used in Europe. In our experience EARSS adds to the process of harmonising breakpoints in Europe as is brought forward by the EUCAST. The EUCAST has taken initiatives to propose an international reference method and agreement on epidemiological MIC breakpoints to which all other methods can relate. Surveillance of resistance of S. pneumoniae and S. aureus Several striking differences in the proportions of antimicrobial resistance for the two indicator pathogens (S. pneumoniae, S. aureus) under surveillance by EARSS exist among European countries (chapters 5 and 7). The consistency of data over the years and the consistency with results of other antibiotic resistance surveillance projects confirm the reliability of the data. It is clear that there is a problem with resistance in many European countries and it seems that this problem is on the rise in hospital settings. In order to target and monitor interventions EARSS monitors resistance over time and place. In doing so it is important to distinguish community-acquired infections from hospital- acquired infections that each have specific driving mechanisms. EARSS deliberately started with the two mentioned indicator-pathogens, with S. pneumoniae as representative of a pathogen that is community-acquired and S. aureus as an indicator of hospital-acquired infections. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 125 Community-acquired infections Considerable increases in penicillin-resistant S. pneumoniae (PNSP) have been noted over the past decade. (9, 10) EARSS data show there is a clear north-south gradient for the proportion of invasive PNSP (chapter 5). The prevalence of invasive and penicillin non- susceptible (20%) S. pneumoniae is highest in children 4 years and younger. This emphasises the importance of physician and parent education about the prudent use of antimicrobial agents, as well as the importance of new conjugate vaccines from which children could benefit. This vaccine is currently introduced in a number of Member States and hopefully EARSS may document a decrease in S. pneumoniae prevalence and PNSP proportions in the coming years. In many countries the proportion of macrolide resistant S. pneumoniae is high. It is apparent from chapter 5 that penicillin and macrolide resistance is often associated. Thus in situations where penicillin and erythromycin resistance is common, the empirical use of macrolides should be discouraged. There are large differences between countries in the resistance proportions of PNSP for 3 rd generation cephalosporins and fluoroquinolones. The development of new drugs cannot be relied on to contain antimicrobial resistance. One important driver of antimicrobial resistance is high levels of antimicrobial use (chapter 6). Other important determinants are inappropriate use of antibiotics dependent on drug-seeking behaviour of patients, prescription behaviour, compliance of patients, and over the counter availability of antimicrobials (11, 12, 13). Hence, data needed to come to intervention are resistance rates and antibiotic usage data in the community. Furthermore, patients and doctors attitudes as well as over the counter availability of antimicrobials need to be studied. In chapter 6, proportions of resistance for invasive S. pneumoniae isolates from EARSS were related to data on the usage of antibiotics. It provided evidence of a strong correlation of penicillin resistance in S. pneumoniae, and the use of beta-lactam antibiotics and macrolides at country level. Building on the EARSS network, ESAC (European Surveillance of Antimicrobial Consumption) collects comprehensive national data on cost and volume of antimicrobial consumption in ambulatory and hospital care from about 30 participating countries. The prospective and standardised data collection is starting as of 2003 and definitions of indicators for antimicrobial use will be developed. EARSS and ESAC co-operate closely, aiming at linking antibiotic resistance and antibiotic usage data not only at country level, but possibly at regional / local level. Self-medication with antibiotics may be an important component of the use of antibiotics in some European countries, but little data is available yet. Chapter 6 also suggests a direct relationship between non-adherence rates and antimicrobial resistance. If non-adherence is also related to sales of antimicrobial agents, it could potentially confound the relationship between use and resistance. The influence of this parameter should be quantified and understood. Therefore, a self-medication study will start in 2003. EARSS will also co- 126 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY operate with ESAC and the Antibiotic Resistance Prevention and Control (ARPAC) survey to study the correlation between resistance, antibiotic usage and the policy regarding guidelines and infection control. In some Member States it has proved possible to bring about a change in the level of resistance by restricting the use of antibiotics (14, 15). Such action is needed at all levels: in hospitals, and at national and international level (16). Hospital-acquired (nosocomial) infections Methicillin-resistant Staphylococcus aureus is common in many centres. Among European countries an overview is given in chapter 7, showing that southern European countries, the United Kingdom and Ireland reported the highest proportions, whereas northern European countries had proportions of MRSA in bacteraemia patients below 1%. The uncompromising "search-and-destroy" policy in the Netherlands and in Nordic countries appears to be effective in controlling the emergence of MRSA. There are strong indications for a rapid increase in the prevalence of MRSA in the UK (with 6% increase per year) and in Germany (almost 4% increase per year). Numerous factors responsible for antimicrobial resistance in hospitals have been identified and can broadly be classified in four categories (17): 1. antimicrobial use issues such as overuse, misuse and co-usage of antibiotics, 2. infection control issues such as compliance to barrier precautions, workload, existence of outbreaks, reservoirs and patient transfers, 3. patient issues such as severity of illness and utilisation of medical devices, and 4. community issues including prevalence of resistance in the primary health care sector and in animals. Models for the interpretation of the results of concomitant surveillance of antimicrobial resistance and antimicrobial use in hospitals have been proposed but should be further validated (18, 19). There is no consensus yet on the level of stratification of results. Antimicrobial resistance levels and antibiotic consumption are generally calculated for an entire hospital; however, large differences can be observed among units within one hospital (20, 21). Consequently, analyses of data from surveillance systems should probably be stratified at the unit level or at least by type of unit. EARSS data indicate which countries face a problem with MRSA (as an indicator of hospital-acquired infections) and is a clear stimulus for national authorities to enforce strict hospital infection control guidelines and programs. Community strategy In chapter 8 we discussed how EARSS fits into the overall Community strategy against antimicrobial resistance. EARSS (and ESAC) are explicitly mentioned in the recitals of the Council Recommendation on the prudent use of antimicrobial agents in humans as EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 127 European Surveillance systems. Various Commission services have initiated a wide range of activities. Community action is not only taken in the area of surveillance but also on prevention, education, research, and product development. In past years the problem of antimicrobial resistance was addressed through an increasing number of isolated measures, but through its Communication the Commission has taken a very pro-active approach outlining one comprehensive Community Strategy against Antimicrobial Resistance. Accurate information regarding antimicrobial resistance and antimicrobial use is at the basis to target interventions. Hence, each Member State should have an appropriate framework in place to monitor accurately antimicrobial use and antimicrobial resistance. EARSS collects routinely generated laboratory data allowing comparison of susceptibility data among countries. However, national action plans to contain antimicrobial resistance should incorporate aspects of different surveillance strategies, for example the addition of intermittent national surveys to answer specific questions. Effective implementation requires a number of key features, including a clear action plan, delegation of authority and power to act, resources and sound mechanisms to assess the effectiveness of interventions, allowing feedback of results to influence future strategies. Therefore the Council Recommendation asks Member States to put in place an intersectoral mechanism. In this body, local, regional and national health authorities, the legislator, professionals of the different disciplines concerned, and consumers, should possibly be represented. Differences in prevalence, health care systems and problem diseases may all influence the national approach taken to contain antimicrobial resistance. These intersectoral mechanisms should play an important role co-ordinate reporting structures at local and hospital level, prioritise the action needed, and recommend the health authorities responsible for taking action. References 1. Monnet DL. Characteristics of multicenter surveillance and research projects on antimicrobial resistance in Europe and the United States. Copenhagen, Denmark: Division of Microbiology, Statens Serum Institut; 1998. 2. Kim T, Oh PI, Simor AE. The economic impact of methicillin-resistant Staphylococcus aureus in Canadian hospitals. Infect Control Hosp Epidemiol. 2001 Feb;22(2):99-104. 3. Mato R, Santos Sanches I, Venditti M, Platt DJ, Brown A, Chung M, de Lencastre H. Spread of the multiresistant Iberian clone of methicillin-resistant Staphylococcus aureus (MRSA) to Italy and Scotland. Microb Drug Resist 1998; 4: 107-12. 4. Williams RJ, Ryan MJ. Surveillance of antimicrobial resistance an international perspective. BMJ 1998;317:651. 5. GAO, Report to Congressional Requesters. Antimicrobial Resistance, Data to assess public health threat from resistant bacteria are limited. Available at: http://www.cdc.gov/. Accessed May 20, 2002. 128 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 6. Hedlund J, Olsson-Liljequist B. Control programme for antibiotic-resistant pneumococci; mandatory notification sometimes neglected by physicians. Lkartidningen 1997; 94:4914-18. 7. Bronzwaer SLAM, Buchholz U, Kool J. International surveillance of antimicrobial resistance in Europe: now we also need to monitor antibiotic use. Eurosurveillance 2001;6;1:1-2. 8. Kahlmeter G, Brown D. Resistance surveillance studies comparability of results and quality assurance of methods. J. Antimicrob. Chemother. 2002 50: 775-7. 9. Appelbaum PC. Antimicrobial Resistance in Streptococcus pneumoniae: An overview. Clin Infect Dis 1992; 15, 77-81. 10. Baquero F. Pneumococcal resistance to beta-lactam antibiotics: A global geographical overview. Microb Drug Resist. 1995; 1, 115-20. 11. Stephenson J. Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria [news]. JAMA 1996;275:175. 12. Mainous AG. An evaluation of statewide strategies to reduce antibiotic overuse; 2000. Family Medicine. 13. Branthwaite A. Pan-European survey of patients attitudes to antibiotics and antibiotic use; 1996, The J of Intern Med Research. 14. Mlstad S, Cars O. Major change in the use of antibiotics following a national programme: Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA). Scand J Infect Dis 1999; 31(2): 191-5. 15. Stephenson J. Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria [news]. JAMA 1996; 275: 175. 16. Williams R, Ryan M. Surveillance of antimicrobial resistance an international perspective. BMJ 1998; 317; 651. 17. Monnet D. Toward multinational antimicrobial resistance surveillance systems in Europe. Int J Antimicrob Agents. 2000 Jul;15(2):91-101. 18. Monnet DL, Archibald LK, Phillips L, et al. Antimicrobial use and resistance in eight US hospitals: complexities of analysis and modeling. Infect Control Hosp Epidemiol 1998;19:388-94. 19. Ballow CH, Schentag JJ. Trends in antibiotic utilization and bacterial resistance. Report of the National Nosocomial Resistance Surveillance Group. Diagn Microbiol Infect Dis1992;15:37S-42S. 20. Pierson CL, Friedman BA. Comparison of susceptibility to beta-lactam antimicrobial agents among bacteria isolated from intensive care units. Diagn Microbiol Infect Dis 1992;15(2 Suppl):19S-30S. 21. Stratton CW 4th, Ratner H, Johnston PE, Schaffner W. Focused microbiologic surveillance by specific hospital unit: practical application and clinical utility. Clin Ther 1993;15(Suppl A):12-20. EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 129 Summary The emergence of resistance is to some extent an inevitable result of the therapeutic use of antibiotics. Killing or suppressing the micro-organisms that are sensitive to antimicrobials allows for naturally drug-resistant ones to emerge. Antimicrobial resistance makes infections more difficult to treat, and may increase the length and severity of illness. Some 60 years after the introduction of penicillin in clinical practice, antimicrobial resistance has become a worldwide public health concern, requiring international strategies for its control. The problem can not be overcome by continuously developing new drugs. An important complementary step is to avoid further increases in resistance by reducing unnecessary and inappropriate use of antibiotics. Measures are needed to slow the emergence of resistance and to limit its spread. Surveillance of antimicrobial resistance is a first step towards containment of the problem and serves to assess the scale of the resistance problem, to monitor changes in resistance rates, and to provide a measure of the effectiveness of interventions aimed at reducing resistance. This thesis describes the set up of a European antimicrobial resistance surveillance system (EARSS) and its contribution to the Community strategy against antimicrobial resistance. EARSS is set up as an international network of national surveillance systems, collecting comparable and validated antimicrobial resistance data for public health purposes. The objectives, infrastructure and data management aspects of the surveillance system were defined by consensus of leading microbiologists and epidemiologists in Europe. At the kick-off meeting the community-acquired pathogen S. pneumoniae and the hospital- acquired pathogen S. aureus were chosen as most relevant pathogens to start surveillance for in EARSS. During the same meeting the EARSS protocol for susceptibility testing was developed, aiming to standardise data collection to allow for comparison of susceptibility data among participants. To minimise sample bias, it was decided to report only the first isolate of S. pneumoniae from blood and cerebrospinal fluid and the first S. aureus isolate from blood. This European initiative acted as a catalyst for national surveillance systems. To assess the comparability of susceptibility test results across countries and guidelines, an external quality assurance exercise of antibiotic susceptibility testing for laboratories participating in EARSS was organised. Overall, 433 (92%) of 471 laboratories from 23 countries reported back. Of the 8685 tests that were assessed, 8322 (96%) were interpreted correctly by the participants. Concordance for detection of penicillin resistance in the three S. pneumoniae control strains was 96%, 90% and 87%, respectively. Laboratories performed extremely well in detecting oxacillin resistance in the homogeneously methicillin-resistant S. aureus (MRSA) strain, but the concordance rate dropped from 100% to 77% in the heterogeneously resistant MRSA strain. The NCCLS 132 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY guideline was the most frequently followed, by 61% of laboratories from 19 countries. It was concluded from this exercise that the comparability of susceptibility data for penicillin resistance in S. pneumoniae and for homogeneous methicillin resistance in S. aureus is satisfactory among European countries and across guidelines. Over 1999, 2000, and 2001 EARSS collected susceptibility data from 15.288 S. pneumoniae isolates from 26 European countries. Southern European countries reported higher proportions of penicillin non-susceptible S. pneumoniae (PNSP) than countries in northern Europe. Prevalence of invasive S. pneumoniae was seasonal with clear peaks during winter, but the prevalence of PNSP showed no seasonality. The proportion of invasive S. pneumoniae isolates being non-susceptible was highest in children 4 years and younger, underlining the importance of prudent antimicrobial use and vaccination in this age group. In an ecological study the relationship between penicillin non-susceptibility of invasive isolates of S. pneumoniae and antibiotic sales was examined. Information was collected on 1998-99 resistance data for PNSP through EARSS and on outpatient sales during 1997 for beta-lactam antibiotics and macrolides. The study showed that in Europe antimicrobial resistance of S. pneumoniae to penicillin is correlated with use of beta- lactam antibiotics and macrolides at country level, demonstrating one aspect of the applicability of antimicrobial resistance data. Susceptibility data from 32.942 invasive S. aureus isolates from 26 European countries have been collected by EARSS over the period from 1999 - 2001. Methicillin-resistant Staphylococcus aureus (MRSA) is common in many centres and high proportions of MRSA are found in several European countries. Southern European countries, the United Kingdom and Ireland reported the highest proportions (over 30%), whereas northern European countries had proportions of MRSA in bacteraemia patients below 1%. The uncompromising search-and-destroy policy in the Netherlands and in Nordic countries appears to be effective in controlling the emergence of MRSA. In many countries the proportion of MRSA seems to be relatively stable over 1999 - 2001. However, EARSS data show an overall increase in the prevalence of MRSA by about 1.6% per year, with a particular rapid increase in the UK (6% increase per year) and in Germany (almost 4% increase per year). EARSS is part of the broader Community strategy against antimicrobial resistance. This strategy defines necessary action at Community level to contain the emergence and spread of antimicrobial resistance. Community action is not only taken in the area of surveillance but also on prevention, education, research, and product development. In past years the problem of antimicrobial resistance was addressed through an increasing EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 133 number of individual measures, but through its Communication the European Commission has taken a pro-active approach outlining one comprehensive Community strategy. Accurate information regarding antimicrobial resistance is at the basis to target interventions. Hence, each Member State should have an appropriate framework in place to monitor accurately antimicrobial resistance and use. National intersectoral mechanisms have an important role to co-ordinate reporting structures at local and hospital level, prioritise the action needed, and recommend the national health authorities responsible for taking action. EARSS is built on national surveillance systems through which routinely generated data are collated first at national level, helping to standardise antimicrobial resistance surveillance and in some countries even initiating the process of collection of susceptibility data. The national representatives whom are formally recognised by their national authorities collect samples of isolates by either total or representative coverage producing official national resistance data that constitute a basis for policy decisions. Quality assurance exercises show that susceptibility data generated by these national surveillance systems are valid and comparable. Through EARSS, European data are collected and analysed, and feedback is provided through Newsletters, publications and annual reports. Latest results are always freely accessible on-line at www.earss.rivm.nl. An enormous large network has been built up with presently 800 laboratories in 28 countries reporting. EARSS monitors trends of antimicrobial resistance enabling to target problem areas and monitoring the effect of interventions. Finally, our studies in the framework of EARSS have shown that the level of antimicrobial resistance varies markedly among countries. This is most likely the result of differences in antimicrobial consumption and hospital infection control. As a consequence, policies to contain resistance should be tailored to national (and local) need. In order to better understand and quantify the impact of different determinants of antimicrobial resistance several initiatives have been started through or in close collaboration with the EARSS network. 134 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Nederlandse Samenvatting Europese antimicrobile resistentie surveillance, onderdeel van een Communautaire strategie Het ontstaan en de verspreiding van resistentie is in zekere zin een onvermijdelijk resultaat van het therapeutisch gebruik van antibiotica. Het elimineren of onderdrukken van micro-organismen die gevoelig zijn voor antibiotica staat de natuurlijk ongevoelige bacterin toe om te groeien. Antimicrobile resistentie maakt infecties moeilijker behandelbaar, en kan de duur en ernst van de ziekte verergeren. Inmiddels, zo'n 60 jaar na de introductie van penicilline in de klinische praktijk, is antimicrobile resistentie een volksgezondheidsprobleem van wereldwijde omvang geworden, en vereist internationale controle maatregelen. Het probleem kan niet worden opgelost door steeds maar nieuwe antibiotica te ontwikkelen. Maatregelen zijn nodig om het opkomen van resistentie en de verspreiding ervan tegen te gaan, bijvoorbeeld door onnodig en oneigenlijk gebruik van antibiotica tegen te gaan. Surveillance van antimicrobile resistentie is een eerste stap in de richting om het probleem te beheersen en dient om de omvang van het probleem te begrijpen, om veranderingen in resistentie percentages te monitoren, en om een maatstaf te bieden voor de effectiviteit van resistentie-verlagende interventies. Dit proefschrift beschrijft het opzetten van het 'European Antimicrobial Resistance Surveillance System' (EARSS) en de bijdrage hiervan aan de 'Communautaire strategie tegen antimicrobile resistentie'. EARSS is opgezet als internationaal netwerk van nationale surveillance systemen, en verzamelt vergelijkbare en gevalideerde antimicrobile resistentie data voor volksgezondheidsdoeleinden. De doelstellingen, infrastructuur en data management aspecten van het surveillance systeem werden op basis van consensus vastgesteld door Europese experts op het gebied van de medische microbiologie en de epidemiologie van infectieziekten. Tijdens de eerste bijeenkomst werden de 'open-populatie-verworven' Streptococcus pneumoniae en de 'ziekenhuis-verworven' Staphylococcus aureus gekozen als meest relevante ziektekiemen om te surveilleren. Tijdens dezelfde ontmoeting werd het EARSS protocol ontwikkeld om de gegevens verzameling te standaardiseren met als doel om gevoeligheidsgegevens tussen deelnemers te kunnen vergelijken. Om selectie bias te minimaliseren werd besloten om enkel de eerste S. pneumoniae stam uit bloed en hersen- liquor en de eerste S. aureus stam uit bloed te rapporteren. Dit Europese initiatief diende als katalysator voor nationale surveillance systemen. Om de vergelijkbaarheid van gevoeligheidsresultaten te testen tussen landen en richtlijnen voor gevoeligheidsbepalingen werd een externe kwaliteit controle georganiseerd voor deelnemende laboratoria in EARSS. 433 van de 471 deelnemende laboratoria (92%) uit 23 landen rapporteerde terug. Van de 8685 testen die werden beoordeeld zijn er 8322 (96%) correct genterpreteerd door de deelnemers. Correcte detectie van de penicilline resistentie in de drie S. pneumoniae controle stammen was 136 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY respectievelijk 96%, 90% en 87%. Laboratoria presteerden uitzonderlijk goed in de detectie van oxacilline resistentie in de homogeen methicilline resistente S. aureus (MRSA) stam, maar de proportie correct detecterende laboratoria zakte van 100% naar 77% voor de heterogeen resistente MRSA stam. De Amerikaanse NCCLS richtlijn was de meest gevolgde richtlijn door 61% van de laboratoria in 19 landen. Uit de resultaten van de studie kan de conclusie worden getrokken dat de vergelijkbaarheid van gevoeligheidsdata voor penicilline resistentie in S. pneumoniae en voor homogene methicilline resistentie in S. aureus bevredigend is tussen Europese landen en tussen richtlijnen. Over de jaren 1999, 2000, en 2001 verzamelde EARSS gevoeligheidsdata van 15.288 S. pneumoniae stammen uit 26 landen. Zuidelijke landen rapporteerden hogere proporties van penicilline niet-gevoelige S. pneumoniae (PNSP) dan landen uit Noord-Europa. Prevalentie van invasieve S. pneumoniae was seizoensafhankelijk, met duidelijke pieken in de winter. De prevalentie van PNSP vertoonde echter geen seizoensvariatie. De proportie van invasieve S. pneumoniae stammen die niet gevoelig waren voor penicilline was het hoogst in kinderen jonger dan 4 jaar, wat het belang van verstandig antibiotica gebruik en vaccinatie in deze leeftijdsgroep benadrukt. In een andere studie werd de relatie tussen penicilline ongevoeligheid van invasieve S. pneumoniae en antibioticumgebruik bestudeerd. EARSS resistentie data uit 1998-99 voor PNSP werd bestudeerd in relatie tot de verkoopcijfers in de open-populatie voor betalactam antibiotica en macroliden. De studie toonde aan dat in Europa antimicrobile resistentie van S. pneumoniae voor penicilline is gecorreleerd met het gebruik van betalactam antibiotica en macroliden op landsniveau. Dit demonstreert n aspect van het nut van gegevens over antimicrobile resistentie en gebruik. Gevoeligheidsdata van 32.942 invasieve S. aureus stammen uit 26 Europese landen werden verzameld door EARSS over de periode 1999-2001. MRSA is endemisch in veel ziekenhuizen en hoge MRSA proporties werden gevonden in verschillende Europese landen. Zuidelijke Europese landen, het Verenigd Koninkrijk en Ierland rapporteerden de hoogste proporties (>30%), terwijl noordelijke Europese landen MRSA proporties in sepsis patinten rapporteerden lager dan 1%. Het 'search-and-destroy' beleid in Nederland en in de Noordelijke landen lijkt effectief om het opkomen van MRSA te controleren. In veel landen lijkt de MRSA prevalentie relatief stabiel over 1999-2001. Maar EARSS data laat over het geheel genomen toch een stijging in de MRSA prevalentie zien van ongeveer 1.6% per jaar, met een bijzonder snelle stijging in het Verenigd Koninkrijk (6% stijging / jaar) en in Duitsland (bijna 4% stijging / jaar). EARSS is deel van een brede 'Communautaire strategie tegen antimicrobile resistentie'. Deze strategie definieert de noodzakelijke maatregelen op Gemeenschapsniveau om het EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 137 opkomen en verspreiden van antimicrobile resistentie te controleren. Niet alleen voor surveillance wordt Communautaire actie ondernomen maar ook op de gebieden van preventie, voorlichting, onderzoek, en productontwikkeling. Gedurende de laatste jaren werd het probleem van antimicrobile resistentie bestreden door een toenemend aantal losstaande maatregelen, maar in dit Communiqu stelt de Europese Commissie een actieve aanpak en een veelomvattende Communautaire strategie voor. Exacte informatie over antimicrobile resistentie ligt ten basis aan het bepalen van toegespitste interventies. Iedere lidstaat moet dus in staat zijn om antimicrobile resistentie en gebruik nauwgezet te kunnen monitoren. Nationale multidisciplinaire werkgroepen hebben een belangrijke rol om rapportages uit lokaal en ziekenhuis niveau te cordineren, initiatieven te prioritiseren en om aanbevelingen te doen aan nationale autoriteiten die verantwoordelijk zijn voor actie. EARSS stoelt op nationale surveillance systemen die allereerst op nationaal niveau routine laboratoria data verzamelen. EARSS helpt hiermee een standaardisatie van antimicrobile resistentie surveillance in de hand en in sommige landen heeft het zelfs het verzamelen van gevoeligheidsdata op nationaal niveau genitieerd. De nationale vertegenwoordigers, die formeel worden erkend door nationale autoriteiten, verzamelen gegevens over stammen door een surveillance systeem ofwel met totale maar in ieder geval met representatieve dekking. Dit is nodig om officile nationale resistentie data te produceren die aan de basis liggen voor beleidsbeslissingen. Kwaliteit controle laat zien dat de gevoeligheidsdata die door deze nationale surveillance systemen worden geproduceerd vergelijkbaar en betrouwbaar zijn. Door EARSS worden Europese data verzameld en geanalyseerd, en feedback wordt verzorgd in de vorm van Newsletters, publicaties en jaarrapporten. De laatste resultaten zijn altijd vrij toegankelijk on-line via www.earss.rivm.nl. Een enorm breed netwerk is opgebouwd waarin momenteel 800 laboratoria uit 28 landen rapporteren. EARSS volgt ontwikkelingen in antimicrobile resistentie om probleem gebieden te detecteren en het effect van interventies te monitoren. Tenslotte, onze studies binnen het EARSS netwerk hebben laten zien dat het niveau van antimicrobile resistentie aanmerkelijk verschilt tussen landen. Dit is waarschijnlijk vooral het gevolg van verschillen in antimicrobieel gebruik en ziekenhuisinfectie controle. Dientengevolge moet het beleid om resistentie te beperken aangepast zijn aan nationaal (en lokaal) niveau. Om beter de invloed van verschillende determinanten van antimicrobile resistentie te begrijpen en te kwantificeren zijn er verschillende initiatieven gestart door of in nauwe samenwerking met EARSS. 138 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Acknowledgements An important part of any thesis is acknowledging the many persons that have contributed. I would like to thank all the people I have been working with in these past years, as well as family, friends, and focolare. I would like to thank explicitly the many EARSS national representatives and data managers (see table) with whom I have enjoyed working closely for almost 4 years. I express my gratitude for your time, dedication, and confidence in building up of what has become a largely extended and well functioning network. Indeed, EARSS is a peoples network. We witnessed that this model of European collaboration inspired more and more countries to participate as well as that it provided an ideal platform for related activities. I am convinced that in bringing EARSS further successfully your endeavor will continue to contribute to the containment over the problem of antimicrobial resistance. I also thank the more than 800 laboratories for their essential efforts in providing so constantly their input. Well-appreciated occasions to meet with collaborators in EARSS were the regular meetings of the 'EARSS Advisory Board' and 'EARSS Quality Assurance Committee'. These meetings really set out the way to bring EARSS forward and I learned a lot from all participants. In particular I would like to mention the close collaboration with the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the European Committee on Antimicrobial Susceptibility Testing (EUCAST), with the Centre national de Rfrence des AntiBiotiques (CRAB), and with the UK National External Quality Assurance Scheme (NEQAS), in particular with Jerry Snell. The collaboration with WHO has been very valuable through the persons of Rosamund Williams and John Stelling whose positive support was and is and ever shall be appreciated. Good collaboration is built on professionalism and trust and these ingredients have been present from the beginning in the collaboration with Herman Goossens and Monique Elzeviers from the European Surveillance on Antimicrobial Consumption project (ESAC), and with Floor Haaijer-Ruskamp from the Self-medication with antibiotics and resistance levels in Europe project (SAR). I have also appreciated the collaboration with other Commission funded surveillance projects under the umbrella of the EU Network on Communicable disease surveillance and control. Acknowledgement for the financial support is done elsewhere but here I would like to thank the collegial support of staff members of the European Commission. Thanks are due also to the Dutch Ministry of Health (in particular Marja Esveld and Trudy van Dijk) as well as to management at RIVM (special thanks to Marc Sprenger, who is actually at the basis of EARSS and this thesis, Jacob Kool, and Marina Conyn, as 140 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY subsequent Heads of the unit infectious disease epidemiology). I thank also Daan Kromhout for supporting me in doing my Masters of Public Health where I appreciated working together with Niek Klazinga. I thank the Netherlands School of Public Health and Johan Mackenbach who triggered the idea for performing the ecological study in Chapter 6. During these years I have received much professional satisfaction and enjoyed day-by-day work together with the EARSS Management Team (Nienke Bruinsma, Jos Monen, Han de Neeling, Carola Schinkel, Paul Schrijnemakers, Edine Tiemersma, Jose van de Velde, and in earlier days also Peter Bootsma, Udo Buchholz, Sandra van Dissel, Wim Goettsch, Mireille Greijmans, and Irene Veldhuijzen). Since I moved to Luxembourg I was happy to see Paul and others manage EARSS so successfully and I most warmheartedly welcome Hajo Grundmann who embodies the perfect profile of an EARSS project leader. A very special thank you goes to my 'Paranimphen'. Udo, in a relatively short period you have achieved more than could be expected and in particular I thank you for your work on Chapter 6. Paul, I have great respect for your management skills, your critically positive spirit and your sense for team-work and loyalty. I also thank all my other colleagues from the infectious diseases epidemiology unit who form a great team of young and enthusiastic professionals and in particular I thank the support of Eric Elbers, Yves van de Berg, and the persons I shared office with: Liesbeth van Eerden and Jacco Wallinga. Appreciation also for the work of the RIVM-studio. Finally, I thank John Degener for the many times he has freed himself from his many duties to provide essential support in keeping EARSS going. It was always a pleasure to work with and learn from you. Last but certainly not least I thank Pa, to whom I dedicated this thesis, and Ma for their endless energy, love, and trust invested in my person. I thank my 4 'big' brothers for the wonderful family they are and for keeping me alive To conclude in supremo I think I owe the biggest grazie to my wife Karin for the infinite support and for delivering the most important output of these years: Angelique, Laura, and Nikita. Karin it has been a wonderful 5 years; I look forward to many more EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 141 National representatives and data managers in EARSS over 1998-2002 Austria Belgium Bulgaria Croatia W. Koller H. Goossens B. Markova S. Kalenic S. Metz E. Hendrickx H. Velinov A. Tambic-Andrasevic H. Mittermayer F. van Loock M. Struelens J. Verhaegen Czech Republic Denmark Estonia France V. Jakubu T.L. Soerensen P. Naaber H. Aubry-Damon P. Urbaskova D. Monnet P. Courvalin A. De Benoist Finland Germany Greece Hungary P. Huovinen T. Breuer N. Legakis M. Fzi O. Lyytikinen U. Buchholz J. Papaparaskevas M. Konkoly-Thege T. Mttnen F. Tiemann A. Vatopoulos Z. Vgh W. Witte Iceland Ireland Israel Italy H. Briem S. Murchan H. Edelstein D. Boccia K. Kristinsson O. Murphy R. Raz G. Cornaglia S. Vilhemsson D. O'Flanagan F. D'Ancona D. Whyte M.L. Moro Luxembourg Malta the Netherlands Norway O. Courteille M. Borg W. Goettsch E. Bjorlow R. Hemmer E. Scicluna A.J. de Neeling E. Hoiby E. Tiemersma D. Katzenelson 142 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY Poland Portugal Rumania Russia P. Grzesiowski M. Cania C. Balotescu R. Kozlov W. Hryniewicz P. Lavado I. Codita L. Stratchounski M. Paixao Slovakia Slovenia Spain Sweden L. Langsadl M. Gubina F. Baquero O. Cars J. Kolman J. Campos K. Ekdahl S. Cruchaga L. Gezelius J. Iglesias G. Kahlmeter B. Olsson-Liljequist UK S. Cavendish A. Johnson D. Livermore A. Noone M.C.J. Wale EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY 143 Curriculum vitae Stef Bronzwaer was born on 28 April 1967 in Heerlen, the Netherlands. He passed his secondary school (Lyceum) exams at the Bisschoppelijk College in Weert in 1986. He went to the University of Amsterdam where he graduated from College of Medicine in 1992 and took his Board Exam in 1995. In 2001 he completed his Master of Public Health degree at the Netherlands School of Public Health in Utrecht, the Netherlands. As a medical doctor he worked shortly at the Social Medical Centre Bukas Palad in a slum-area outside Tagaytay City, and as resident at the department of paediatrics at De La Salle University Medical Center near Manila, the Philippines. Here he studied risk factors for a complicated disease course in children with measles. He then moved to the Infectious disease unit of the Istituto Superiore di Sanit in Rome, Italy, where he worked as project manager of an EU-project making an inventory of resources and means for controlling communicable diseases. From 1998 to 2002 he worked in the Department of Infectious Disease Epidemiology of the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, where he helped establish the European Antimicrobial Resistance Surveillance System (EARSS), for which he served as project leader. The work described in this thesis was realised within this network. Since 2002 he works at the Communicable, rare, and emerging diseases unit of the Directorate Public Health (DG Health and Consumer protection) at the European Commission in Luxembourg. He holds responsibility for the proper functioning and coherence of a number of European surveillance networks on communicable diseases and follows the implementation of the Community strategy against antimicrobial resistance. 146 EUROPEAN ANTIMICROBIAL RESISTANCE SURVEILLANCE AS PART OF A COMMUNITY STRATEGY