The Current Status of Antimicrobial Resistance Surveillance in Europe: Report of a WHO Workshop held in Collaboration with the Italian Associazione Culturale Microbiologia Medica.
Verona, Italy, 12 December 1997
World Health Organization
Emerging and other Communicable Diseases, Surveillance and Control
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Acknowledgements:
The Division of Emerging and other Communicable Diseases Surveillance and Control would like to express their thanks to the University of Verona and the WHO Regional Office for Europe, Cøpenhagen, Denmark for their contribution in the organization of the Workshop.
Table of Contents
Page
1. SUMMARY . . . 1
2. INTRODUCTION . . . 2
3. EXAMPLES OF NATIONAL ANTIMICROBIAL RESISTANCE PROGRAMMES . . . . 2
3.1 The Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA) . . . 2
3.2 The Organization of the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) . . . 4
3.3 Resistance Surveillance in the Czech Republic . . . 5
3.4 The Italian Surveillance Group for Antimicrobial Resistance (ISGAR) and the Veneto Region Resistance Surveillance System . . . 7
3.5 British Society for Antimicrobial Chemotherapy/PHLS Surveillance Initiative . . . 8
3.6 Surveillance of Antibiotic Resistance in France . . . 9
3.7 Surveillance of Antibiotic Resistance in Spain . . . 10
3.8 Surveillance of Antibiotic Resistance in Greece . . . 11
4. EXAMPLES OF REGIONAL AND INTERNATIONAL ANTIMICROBIAL RESISTANCE PROGRAMMES . . . 13
4.1 Surveillance and Molecular Epidemiology of Antimicrobial Resistance in the European Network of Antimicrobial Resistance and Epidemiology (ENARE) . . . 13
4.2 European Antimicrobial Resistance Surveillance System (EARSS) . . . 14
4.3 The WHO Antimicrobial Resistance Monitoring programme . . . 16
5. PANEL DISCUSSIONS . . . 17
5.1 Panel Discussion: Sample and Isolate Selection for Resistance Monitoring 5.1.1 Introduction . . . 17
5.1.2 Sample and Isolate Selection for Resistance Monitoring in Poland . . . 18
5.1.3 Sample and Isolate Selection for Resistance Monitoring in Portugal . . . 18
5.1.4 Sample and Isolate Selection for Resistance Monitoring in Norway . . . 19
5.1.5 Sample and Isolate Selection for Resistance Monitoring in Hungary . . . 20
5.1.6 Sample and Isolate Selection for Resistance Monitoring in Bulgaria . . . 21
5.2 Panel Discussion: Susceptibility Test Methods for Resistance Monitoring 5.2.1 Introduction . . . 22
5.2.2 Susceptibility Test Methods for Resistance Monitoring in Russian Federation 22 5.2.3 Susceptibility Test Methods for Resistance Monitoring in Belgium . . . 23
5.2.4 Susceptibility Test Methods for Resistance Monitoring in Finland . . . 24
6. CONCLUDING REMARKS . . . 26
ANNEX 1: WHO QUESTIONNAIRE ON ANTIMICROBIAL RESISTANCE MONITORING NETWORKS IN EUROPE 1.1 Summary . . . 28
1.2 Tables . . . 30 1.3 Surveys . . . 31-77 ANNEX 2: LIST OF PARTICIPANTS . . . 78-80
The emergence and spread of antimicrobial resistance is a significant problem to all people in all countries, both developed and developing. It impacts both patients with infections and clinicians facing growing limitations on their efficacious use of antimicrobials. It influences a health care system’s ability to implement rational drug use policies and efficiently allocate resources. Because the emergence of antimicrobial resistance is a global problem that affects us all, national and international efforts are needed to address the problem. Information and experience, must be shared so that all can learn and benefit. This WHO workshop was designed to act as a forum for the sharing of information and ideas between interested parties in Europe on the surveillance of antimicrobial resistance.
Key findings of the workshop were:
C The communication chain between antimicrobial resistance surveillance networks and national and regional decision makers must be strengthened and used. Much useful information is already being generated in Europe on antimicrobial resistance.
This information, however, is not consistently reaching persons responsible for developing and implementing national antimicrobial use and other health care policies.
C A key element in a good antimicrobial resistance surveillance programme is the emphasis placed on well-defined and strictly-adhered-to quality assurances to ensure the validity, quality and comparability of the data generated. There is a need to harmonize quality assurance standards throughout Europe.
C Adequate support for microbiology and epidemiology training programmes, for laboratory infrastructure, and for data analysis and communication, is required.
Progress can be made by utilizing the talents and capacities already existing in Europe and by strengthening that capacity through training and the development of regional partnerships providing adequate funding is available.
C The emergence and growth of antimicrobial resistance cannot be addressed effectively by any one country or group working in isolation. Europe-wide coordination and cooperation are critical elements for any effective approach.
Further discussions are necessary, to develop collaboration between existing antimicrobial resistance surveillance programmes.
2. INTRODUCTION
A workshop on the current status of antimicrobial resistance surveillance in Europe was held on 12 December, 1997 in Verona, Italy. It was organized jointly by the Antimicrobial Resistance Monitoring programme, Division of Emerging and other Communicable Diseases Surveillance and Control, WHO, the WHO Regional Office for Europe and the Italian Associazione Culturale Microbiologia Medica. The objectives were to provide descriptions of how some European countries are approaching the issue of antimicrobial resistance surveillance, to provide a venue for discussing common features of successful programmes, and to identify and discuss any unique attributes which could be applicable to other programmes in the region. Participants were invited based on their familiarity with national, regional or multi-centre antibiotic resistance surveillance schemes, and their knowledge of the various methods presently used for resistance monitoring and analysis.
The abstracts below summarize the formal workshop presentations. In addition, informal discussions were encouraged to foster dialogue and collaborations between participants as a means of sharing expertise and encouraging optimal use of resources within the Region.
3. EXAMPLES OF NATIONAL ANTIMICROBIAL RESISTANCE PROGRAMMES.
3.1 The Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA) O. Cars
Between 1983 and 1993, antibiotic sales increased yearly in Sweden, with more than 90% of antibiotics being prescribed to out-patients, and 60% of these being prescribed for respiratory tract infections. This trend, together with the increasing numbers of penicillin- resistant Streptococcus pneumoniae infections (up to 10% in some parts of the country), encouraged the formation in 1994 of a national network, STRAMA (Swedish Strategic Programme for The Rational Use of Antimicrobial Agents and Surveillance of Resistance) for addressing the growing problem of antimicrobial resistance in the country. STRAMA was formed by specialists in infectious diseases, microbiology, general practice, otolaryngology, paediatrics, and representatives from the Swedish Medical Products Agency,
antibiotics and lower the level of detected antimicrobial resistance in both community-acquired infections (primarily Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, urinary tract pathogens) and in nosocomial infections (primarily Staphylococcus aureus, enterococci). Under the project, as a means of promoting the rational treatment of respiratory tract infections where the use of antibiotics might not be indicated, a programme was instituted to offer patients with respiratory tract infections a free return visit to their physicians if they were willing to forego receiving antibiotic prescriptions during their initial visit. This was coupled with the distribution of educational materials produced by STRAMA and containing information on the rational treatment of respiratory tract infections.
Since the implementation of the STRAMA project, the level of antibiotic sales in Sweden has decreased by 10% each year, with reductions in antibiotic use being most pronounced in children aged 0-6 years of age. It is believed that the most important factor for achieving the decrease has been the adoption by many practising physicians of a more considered approach towards prescription practices due to their exposure to and cooperation with the county-based STRAMA groups.
In addition to the STRAMA project, the Swedish Reference Group for Antibiotics (SRGA) began standardizing the methods of antimicrobial susceptibility testing in Sweden.
Efforts began 20 years ago and the resulting SRGA recommendations for susceptibility testing have been accepted by all (approx. 30) Swedish laboratories doing resistance monitoring. The standards currently call for the use of a set of species-related zone diameter breakpoints for the routine detection of resistance by disk diffusion. Internal laboratory quality control assessments are conducted through control-strain testing and reference- histogram comparisons. Educational programmes for personnel are also conducted in the laboratories.
In addition, an external quality control programme for laboratories is in place. This programme calls for the reporting of susceptibility zone diameters for 100 consecutive routine clinical isolates of specified bacteria and antibiotics. By choosing species/antibiotic combinations which have both methodological and epidemiological interest in Sweden, this programme fulfills an antimicrobial resistance surveillance role. A yearly survey of approximately 3000 strains of S. pyogenes, H. influenzae and S. pneumoniae against a number of commonly used antibiotics is accomplished. In addition, special surveys are conducted at regular intervals in order to detect antimicrobial resistance in Gram-negative isolates from hospitals generally, urinary tract pathogens from primary care facilities, and pathogens isolated from patients in intensive care units. In 1998 the surveillance programme will be expanded to include the computerized delivery of zone histograms from laboratories to the STRAMA project.
3.2 The Organization of the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP)
T. Sørensen
In the light of the world wide trend towards increasing rates of antimicrobial resistance, and in particular, the emergence of vancomycin resistance in human isolates of enterococci possibly associated with the increasing use of avoparcin in the Danish food- animal production industry, the Danish Ministry of Health and Ministry of Food, Agriculture and Fisheries initiated a national surveillance and research programme in 1995 to monitor the overall development and spread of antimicrobial resistance in Denmark. The programme identifies and evaluates antibiotic usage patterns or other risk factors which contribute to antimicrobial resistances in humans, food animals and foods as a result of the use of antibiotics for food-animal growth promotion and as a result of therapeutic interventions in both humans and animals.
The main partners in this Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) are the Danish Veterinary Laboratory (DVL), the National Food Agency of Denmark (NFA) and the national reference laboratory, the Statens Serum Institut (SSI), which receives samples from all 15 county clinical microbiological laboratories in Denmark. DANMAP receives funding from both the Ministry of Health and the Ministry of Food, Agriculture and Fisheries. The Danish Plant Directorate (responsible for monitoring the use of growth promoters and other therapeutic agents as feed additives), and the Danish Medicines Agency (responsible for monitoring the human and veterinarian consumption of antimicrobials for therapy) are also active partners in the Programme.
National surveillance activities under DANMAP are coordinated by its Steering Committee. The Committee is composed of two senior and administrating scientists from each of the participating institutions. The Steering Committee also coordinates specific research projects undertaken by participating institutions. It meets six times a year to discuss various project results and plan for future or continuing Programme activities. The Committee maintains several subgroups which periodically meet to discuss and co-ordinate programme activities requiring specific expertise. These include evaluations of methods for susceptibility testing, the epidemiology of antibiotic consumption, and studies on resistance phenotypes and genotypes. Cooperation between all the different parties is considered necessary for the success of the overall Programme.
Under DANMAP, reports are generated yearly, to help facilitate the monitoring of antimicrobial-use trends in food animals and humans. They focus on selected bacterial species from both healthy humans and animals; enterococci, coagulase negative staphylococci and Escherichia coli and human and animal associated pathogens as well as major zoonotic species, and report on detected changes in antimicrobial resistance patterns and on possible relationships between the levels of resistance noted and the levels of antibiotic consumption by humans and the levels used in animals and in food production.
The reports also include recommendations for further activities.
DANMAP activities are expected to result in the provision of useful information about the epidemiology of human and animal antimicrobial resistance. This information will serve as a basis for refining existing recommendations on the rational use of antimicrobials in human medicine, and as growth promoters and therapeutic agents in food animals.
Conclusions based on the most recent DANMAP report are that while the levels of antimicrobial resistance currently in Denmark do not give rise to immediate concern, there is good agreement between the levels of resistance observed in human and animal isolates and the use of antimicrobials. This observation has stimulated a call for further investigation of the question.
3.3 Resistance Surveillance in the Czech Republic J. Schindler
Antimicrobial resistance surveillance in the Czech Republic was initiated in 1974 at the Charles University Teaching Hospital in Prague, but before 1984 there was no real quality control aspect to the resistance monitoring activities. Beginning in 1984, a pilot project expanded surveillance to15 hospital laboratories around the country, with qualitative data (inhibition zone, susceptible/resistant) being collected on punch cards and floppy disks for registry into a main computer in Prague. This national project was evaluated in 1989, and at that time several improvements were suggested. These included: the limiting of specimens to be monitored to the first isolate of one species from a patient, the introduction of MIC dilution micro methods, the use of NCCLS interpretation criteria, the use of standardized data coding, and the introduction of data processing software. The National Reference Laboratory annually issued national surveillance reports as a part of a research grant from the Ministry of Health. By 1995, however, it was evident that several problems remained. Diverse clinical laboratory information systems were still in use by the various participating laboratories, as were different test coding systems. This made a meaningful comparison of submitted data at the national level impossible. Also, the simple transfer of data between laboratories and into the project office was not always possible. A chronic problem for the project was insufficient funding.
A re-evaluation of the situation in 1997 concluded that project quality control activities were still needed and desirable, and that activities for the uniform generation and reporting of data needed strengthening. Recommendations included the general adoption of quantitative test readings (such as MIC and zone diameter readings), a change from user- developed or adapted data formats and coding systems to more uniform and standardized ones for national use, and the limiting of the number of isolates reported to those from blood, CSF and catheter samples, and gram-negative rod urinary tract samples (isolates from the upper respiratory tract were excluded). The new system emphasised surveillance for the more relevant and problematic bacterial species in the Czech Republic. Adequate funding for data capture and processing activities, the generation of annual reports and Internet publishing, however, remain a problem.
Currently, laboratory participation in the project is on a voluntary basis. This is necessary because of limited funding. To help overcome this problem, a continuation and further development of the Czech national resistance surveillance project will need to rely heavily on participants understanding the importance of the system, and on their enthusiasm and interest in this volunteer project.
Since 1990, the trends in antimicrobial resistance noted have been influenced, by and large, by the changes in the economic and political conditions in the country. Pockets of antimicrobial resistance are thought to have always existed in the Czech Republic, but in general, the overall rate of resistance has been considered low. This has been attributed to a relative unavailability and restricted access to antibiotics before 1990. Even now it is thought that the rate of antimicrobial resistance is lower than in some areas of Europe. (For example, penicillin resistance of pneumococci averages about 3%.) With increasing economic development and greater access to antibiotics, however, the situation is in flux and increasing levels of antimicrobial resistance are expected.
Therefore, the present goal is to further develop and improve the national surveillance programme which will, in turn, call more attention to the problem of antimicrobial resistance in the Republic. It will help the medical community adhere more strictly to national antibiotic use policies before the levels of antimicrobial resistance become difficult to manage.
3.4 The Italian Surveillance Group for Antimicrobial Resistance (ISGAR) and the Veneto Region Resistance Surveillance System
G. Cornaglia
Antimicrobial resistance surveillance in Italy is not yet under a comprehensive national or government-sponsored programme. The Italian Surveillance Group for Antimicrobial Resistance (ISGAR) headquartered in Verona, however, has been working on the foundations of such a network for the last five years by organizing and supporting a project for the nation-wide collection and analysis of antimicrobial resistance data. At present there are about 30 laboratories participating in the project, mostly from the northern part of Italy (where the majority of laboratories in Italy are located). Plans are underway to expand project capability to other regions.
Under this project, hospital-associated laboratories are encouraged to submit data on all susceptibility tests conducted irrespective of the microorganism isolated and its source and collection location (hospital, ward, community etc.). Susceptibility testing methodology must conform with established ISGAR standards, however. It is recommended that either the Kirby-Bauer technique or automated reading techniques such as ATB (bioMérieux), Microscan (Dade-Behring), Sceptor (Becton Dickinson), Semedia (Oxoid), Videobact (Biokit) or Vitek (bioMérieux) be used. Participating laboratories are expected to send their antimicrobial susceptibility test results electronically to ISGAR four times a year. The testing methods practised under the project are expected to conform with UK NEQAS, WHO and CDC quality control recommendations.
ISGAR collects the data and analyses it to identify general trends in antimicrobial resistance patterns nationally. The data are also used to facilitate in-depth quantitative analyses for presentation at ISGAR annual meetings. The collected data are also made available to interested parties through scientific papers, on the ISGAR Web site, and in the future in periodically printed ISGAR reports.
In addition to the above, a Veneto Region Task Force, officially sponsored by the Veneto Regional Government, uses the ISGAR data for drawing attention to the significance of available data on antibiotic consumption rates in the region. To help disseminate information on the connection between antibiotic consumption and antimicrobial resistance development, the Task Force has been holding annual regional meetings for local medical associations. In 1998, it is supplementing this meeting with a published bulletin on antimicrobial resistance and antibiotic consumption trends in the region. The Task Force is headed by a microbiologist, and includes specialists in infectious diseases, epidemiology and paediatric and general medicine.
3.5 British Society for Antimicrobial Chemotherapy/PHLS Surveillance Initiative
R. Wise
A recent survey of methods of susceptibility testing used in the UK found that 97%
of the laboratories use the Stokes’ method, 26% use a combination of the disc method and a breakpoint method, but no laboratory uses the breakpoint method alone. 17% use the E test, mainly for confirmation purposes, often of penicillin-resistant pneumococci. The media employed in the UK is in the main Iso-Sensitest agar and DST agar (approxmately 50% of laboratories surveyed using one or the other). A few laboratories use Mueller-Hinton for detecting methicillin resistance.
In order to obtain meaningful data on bacterial resistance in the UK overall, it was decided three years ago to initiate the use of a standardized method for susceptibility testing.
Although this has some similarities with the NCCLS method, the medium chosen for use will be Iso-Sensitest and the inoculum will be semi-confluent growth. This means that zone sizes obtained by the UK standardised method will, other factors being the same, be different from those obtained by the NCCLS.
The British Society of Antimicrobial Chemotherapy, in conjunction with the Public Health Laboratory Service, is exploring ways in which meaningful surveillance data can be obtained in the UK. As mentioned above, standardization of methodology is being addressed. Another matter to be resolved is the particularly difficult one of obtaining accurate denominator data for different clinical situations.
3.6 Surveillance of Antibiotic Resistance in France P. Courvalin
In 1980, the French National Committee for Breakpoints (Comité de l'Antibiogramme de la Societé Française de Microbiologie, CA-SFM) was created by the National Reference Centre for Antibiotics, Pasteur Institute, to issue yearly recommendations on the clinical categorization of human pathogens with respect to antimicrobial resistance. Even though this activity is continuing, and there is much antimicrobial resistance monitoring throughout France, a single nation-wide antimicrobial resistance surveillance system or programme does not exist. Rather, many networks and independent laboratories are doing this work.
At the national level, the Collège de Bactériologie Virologie Hygiéne des Hôpitaux, Réussir - France, Hôpitaux des Armées, AFORCOPI - BIO, EPIVILLE and RESABO are among the larger networks with over 100 participating laboratories each. Regionally, surveillance networks include C-CLIN Est, C-CLIN Paris-Nord, C-CLIN Sud-Ouest, Département de Microbiologie de Paris, Groupe des Microbiologistes d’Ile-de-France, and Réseau Franc-Comtois LIN. Not all regions are covered by a regional network.
There is also the Centre National de Référence des Antibiotiques (CRAB). It will be part of the European Antimicrobial Resistance Surveillance System (EARSS, see page 14) and also belongs to the International Nosocomial Surveillance Programme for Emerging Antimicrobial Resistance (INSPEAR) and the Antibiotic Resistance in Bacteria from Animals Concerted Action. CRAB strives for a multi-centre approach to antimicrobial resistance surveillance. Also existing is the Centre de Référence des Haemophilus and the Centre de Référence des Pneumocoques.
Attempts are underway to generate a single national network composed of the different local and regional networks and independent laboratories. Under such a system, common quality control standards between the various laboratories could be established which would include the use of two sets of strains (one composed of susceptible strains to study the variability of the results within and between the laboratories. The second composed of isogenic pairs of strains, susceptible and resistant, harbouring a single resistance mechanism genetically and biochemically characterized, to study the ability of the various laboratories to detect resistance.) Such a national network would promote the use of common sets of antibiotics for detecting resistance mechanisms. It would also serve to identify common questions in order to generate comparable answers between laboratories.
In addition, it could initiate a European Web site to facilitate the exchange of information.
3.7 Surveillance of Antibiotic Resistance in Spain F. Baquero
The National Institute of Public Health (Madrid) at the Instituto Carlos III is the central national microbiology laboratory of Spain. It performs serotyping of selected, invasive bacterial strains such as Streptococcus pneumoniae, Neisseria meningitidis, and Salmonella spp. that are submitted by different microbiology laboratories from around the country. The National Institute also monitors antimicrobial resistance in these selected strains. As a forerunner of the above, there was a voluntary reporting system conducted by the National Institute of Epidemiology which monitored for antimicrobial resistance in nosocomial pathogens. This earlier system was discontinued due to difficulties in harmonizing the various reporting systems used among the participating laboratories and because of problems with data quality.
Programmes for antimicrobial resistance surveillance are being organized through the MITRA Network. MITRA will allow the mapping of trends in antimicrobial resistance throughout the country. Currently it is composed of approximately 70 hospital-based and out-patient based microbiological laboratories which use PASCO type equipment, and which transfer data two to three times a year by an automated system to the central data base MENSURA (Spanish Table for Normalization of Susceptibility and Resistance to Antibiotics). The data submitted is generated by using micro dilution (MIC) methodology, using a standardized panel of antibiotics. MENSURA, through the Spanish Society for Chemotherapy and the Spanish Society for Clinical Microbiology and Infectious Diseases (SEIMC) analyses the data and recirculates it back to participating laboratories.
In addition to MITRA, there is a Microb.Net. organized by the Madrid Society for Microbiology. This network is composed of the 13 leading hospital laboratories in Madrid.
Each laboratory produces a qualitative report on bacterial isolations and susceptibility testing, along with such epidemiologic information as resistance rates relative to the numbers of patients sampled, hospital size, average work load for the laboratory, and percent of positive cultures. The reports are sent to Micro.Net. where they are analysed and posted on a WEB site for public viewing.
A more pathogen oriented, but geographically broader, independent surveillance project in Spain is the SEIMC Working Group for Staphylococcus, which periodically evaluates epidemiologic factors for staphylococcal infections in 125 hospitals. Other current studies include one by the Development of Resistance Study Group (Hoechst Marion Roussel) which covers 20 hospitals and conducts one-week resistance prevalence studies on a yearly basis, the Spanish Alexander Project (SmithKline Beecham) with 15 hospitals participating in monitoring resistance on respiratory pathogens, the Surveillance Network for Resistance in Animals which is a network of veterinary laboratories using the Veterinary Faculty at the University of Madrid as a central reference laboratory, and a University of La Rioja project on resistance in lactic-acid bacteria. Finally there is a National Prevalence Study of Nosocomial Infections (EPINE) which collects data on antibiotic consumption in hospitals.
In the future, it is hoped that surveillance will expand to include the collection of information on the clonal characteristics of selected bacteria in order to gain a better understanding of the pattern of antimicrobial resistance detected in these organisms.
3.8 Surveillance of Antibiotic Resistance in Greece A.Vatopoulos
Antimicrobial resistance has become a very serious public health issue in Greece.
The Greek Ministry of Health has attempted to address it by initiating an antibiotic prescription audit process to restrict the hospital use of such antibiotics as third generation cephalosporins, aztreonam, imipenem and quinolones. Although this policy has been generally successful in reducing the frequency of prescriptions for these newer antibiotics, its success in reducing overall antimicrobial resistance has not be satisfactorily assessed.
This is partly due to the lack of an efficient and valid surveillance system. To overcome this, during the last three years, a project has been launched for establishing a national network to continuously monitor for resistance.
The project is based on the tenet that daily, routine antibiotic sensitivity testing can be used to generate accurate epidemiologic descriptions of antibiotic resistance. This requires that test results be generated through quality-controlled methodology, that they reflect all or a valid representative sample of all infections, and that they are coupled with essential demographic and other pertinent source data such as the geographic origins of samples, and hospital or ward identification.
Seventeen hospitals are involved currently in the network. The WHONET software is used to collect and analyse sensitivity test results. Analyses and data quality assessments are done in parallel through the use of the WHO External Quality Control and Proficiency Test Scheme. The data are used to assess the antimicrobial resistance problem at the local hospital level; compare any differences in results between hospitals in order to set priorities for more intensive study; identify the development of "subclinical" resistance by studying zone diameter distributions or MICs in order to observe possible differences in microbiological break points; identify important resistance phenotypes and the appearance of "new" resistance traits; and identify mechanisms of resistance through interpretative readings of antibiograms. Molecular studies for the further elucidation of mechanisms and modes of antimicrobial resistance spread are often initiated as a result of the data generated from the above activities.
Data reports and study findings are produced and distributed within each hospital every 6 months. Multi-centre reports are also developed, and are published on a Web site.
They are also reported in the Archives of Hellenic Medicine, the official Journal of the Athens Medical Society.
Since January 1998, the Greek Network is supported in part by a grant from the Division of Public Health, Greek Ministry of Health and Welfare.
4. EXAMPLES OF REGIONAL AND INTERNATIONAL ANTIMICROBIAL RESISTANCE SURVEILLANCE PROGRAMMES
4.1 Surveillance and Molecular Epidemiology of Antimicrobial Resistance in the European Network of Antimicrobial Resistance and Epidemiology (ENARE)
J. Verhoef
At the beginning of 1996, the European Network for Antimicrobial Resistance and Epidemiology (ENARE) was established to survey multi-drug resistant bacteria within European hospitals, and to determine and analyse the factors influencing the spread of these micro-organisms including the level of antibiotic consumption and hospital infection-control practices. ENARE received funding from the European Union (EU). Currently, ENARE is coordinated through the Eijkman-Winkler Institute, University Hospital, Utrecht, Netherlands, and compares antibiotic consumption rates and practices in various EU hospitals, reviews hospital infection control practices, and investigates the existence of other epidemiological factors which correlate with the presence of multi-drug-resistant bacterial phenotypes. ENARE also determines the distribution of specific genetic determinants of bacterial resistance as part of its multi-hospital evaluations and comparisons.
ENARE includes some 26 participating hospitals in 14 different European countries.
Effective communication is maintained between each hospital and ENARE through the ENARE WEB site and through the ENARE.
ENARE is the European component of Sentry, a global antimicrobial resistance surveillance network sponsored by the Bristol Myers Squibb Pharmaceutical Group in collaboration with the University of Iowa, USA. The goals of the Sentry network are to augment the understanding of bacterial resistance trends and mechanisms, to enable the formulation of guidelines encouraging more effective infection-control measures within hospitals, and to promote better antimicrobial prescribing practices in all geographic areas of the world. The Sentry network was designed to accurately monitor nosocomial and selected community acquired infections over a five-year study period, to facilitate the development of trend assessments for nosocomial pathogen distributions and antimicrobial resistances, and offer the capability to perform modular analyses of antimicrobial resistance factors applicable to several locations throughout the world. The microbiological methods used in participating Sentry hospitals undergo validation procedures for quality control. A central bacterial isolates bank is planned which will be used for susceptibility testing of new and old antimicrobial agents and standardised selective epidemiological typing of persistent isolates and clones of resistant phenotypes. The bank will be located at the University of Iowa and at regional co-ordinating centres such as the University Hospital Utrecht.
4.2 European Antimicrobial Resistance Surveillance System (EARSS) M. Sprenger
In several countries of the EU an increased resistance of micro-organisms to different antimicrobial agents is reported. Currently however, from an epidemiological and methodological standpoint, a comparison of antimicrobial resistance levels from across Europe is extremely difficult to obtain because there are no uniformly accepted methods for antimicrobial resistance surveillance. There are no commonly agreed to criteria for sampling practices, no agreement on which organisms to monitor, no consistency on which antimicrobial agents to test, and no commonly agreed to breakpoints for use in antimicrobial susceptibility readings. Furthermore, the problem is compounded by a tendency to use data from point prevalence studies to make longitudinal comparisons despite major differences in study conditions and methodology.
In order to help overcome this confusing situation, in 1997, a feasibility project was proposed to the EU for developing a new European Antimicrobial Resistance Surveillance System (EARSS) for antimicrobial resistance monitoring. EARSS was envisioned as an organizational network to accumulate antimicrobial resistance surveillance data from the various EU Member-State National Reference Laboratories. This information on local and European-wide changes in resistance patterns would be used to promote the rational use of antibiotics and improve hospital hygiene practices. Through the EARSS project, national and EU authorities would be provided with pertinent information upon which to base their antibiotic usage policies. Physicians would be encouraged to refine their antibiotic prescription practices, and collected data would be used to detect regional difference in antimicrobial resistance, which in turn, would be used to identify risk factors influencing the development of resistance.
The long term objective of EARSS is the reduction of antimicrobial resistance levels in the EU. In the short term, its objective is to establish an initial but permanent facilitating and co-ordinating structure for antimicrobial resistance surveillance. This would include an
‘early warning system’ for antimicrobial resistance development and trends analysis, and would permit a comprehensive evaluation of currently active national and international antimicrobial surveillance systems. Another objective is the generation of standard recommendations for improving and validating antimicrobial susceptibility testing methods and identifying risk factors for their development and spread of resistance. To achieve this, several evaluative and methodologic criteria for antimicrobial resistance monitoring,
EARSS has been designed to fit into the WHO network-of-networks system. As such, links with programmes outside Europe are possible. Also, EARRS has the capacity to maintain links with other organizations, including the Interchange of Data between Administrations (IDA), the European Feed Additive Antibacterials “Surveillance” system (as proposed by the Scientific Committee for Animal Nutrition), the European Federation of Animal Feed Additive Manufacturers (FEFANA ), the HELICS European Group on nosocomial infections, the ESCMID Study group on Hospital Infections, SALMNET/ENTERNET, the EWGLI scheme for Legionella infections, the Tuberculosis Network, the European Zoonotic Antibiotic Resistance Monitoring (EZARM) project, the European Network for Antimicrobial Resistance and Epidemiology (ENARE), and the European Agency for the Evaluation of Medicinal Products (EMEA).
It is envisaged that the exchange and dissemination of information generated by EARSS will take place through the monthly EuroSurveillance bulletin and the IDA-network.
To accomplish this, data will be transmitted electronically to EARSS on a quarterly basis from the national reference laboratories using a standardized format. Data will then be validated, processed and aggregated centrally and presented on a Web site. In addition, EARSS will feedback resistance data on a regular basis to the member National Reference laboratories using a restricted Internet application. The Internet will also be used by the different laboratories in the EU Member States to report promptly any detected sudden or unexpected changes in antimicrobial resistance levels.
4.3 The WHO Antimicrobial Resistance Monitoring programme J. Stelling
The World Health Organization established the WHO Antimicrobial Resistance Monitoring (ARM) programme with the long-term goal of reducing the emergence and spread of antimicrobial resistance and ensuring the use and availability of appropriate therapies for treating resistant infections. The focus of ARM programme activities is to assist institutions and countries to establish their own comprehensive programmes for managing the emergence and growth of antimicrobial resistance. Such programmes are designed to encompass approaches for antimicrobial resistance surveillance, the development and use of rational drug usage policies, and the evaluation and utilization of methods for controlling the spread of antimicrobial resistant organisms in hospital as well as in community settings.
To these ends, ARM programme activities include a WHO pilot External Quality Assurance Programme in Antimicrobial Susceptibility Testing (a collaboration with the Centers for Disease Control and Prevention, USA), WHO Laboratory Training Courses in Antimicrobial Susceptibility Testing and Resistance Monitoring, and WHO National Policy Workshops on Rational Antimicrobial Usage and Resistance Management. The policy workshops bring together individuals involved in the use of antimicrobials and/or in the management of resistant microorganisms for the purpose of initiating dialogues and drafting plans of action for national programmes. Participants in the policy workshops include microbiologists, clinicians, pharmacists, infection control specialists, national regulatory authorities, and other interested parties such as local representatives of pharmaceutical or diagnostic companies.
WHO has also promoted international collaborations between microbiologists, epidemiologists, public health agencies, national authorities and industry representatives through the sponsorship of such meetings as this workshop and the recent meeting in Berlin entitled The Medical Impact of the Use of Antimicrobials in Food Animals.
5 PANEL DISCUSSIONS
Two panel discussions were conducted during the workshop to encourage focused discussion and debate on two topics: sample and isolate selection, and susceptibility test methods. Panel members were invited to present their thoughts on these topics through the perspective of their national programmes and experiences, then lead audience discussions which explored the diversity of the approaches described. The discussions also focused on how a more harmonized, pan-European approach might be formulated.
5.1 Panel Discussion: Sample and Isolate Selection for Resistance Monitoring
5.1.1 Introduction W. Hryniewicz
In general, the problems inherent in antimicrobial resistance monitoring in Europe are complex. Contributing to this complexity is the fact that resistance monitoring practices are quite variable throughout the region. Sampling selections may come from different patient populations, from either hospitals or communities, or from different patient sampling sites such as urinary tract infections or surgical wounds. Often the selection of samples is based on the particular types of problems identified as having particular significance in a hospital or country. In some countries an overall scarcity of available funding also contributes to the development of non-uniform and perhaps sporadic levels of monitoring.
The frequencies of national or local surveys also vary. Some surveys are continuous, some periodic, and some sporadic. As a result, comparable, statistically significant numbers of samples with which to adequately assess resistance levels in affected populations are not being generated. Without sufficient numbers of properly defined samples, accurate interpretations of prevalence and antimicrobial resistance rates for Europe cannot be developed.
5.1.2 Sample and Isolate Selection for Resistance Monitoring in Poland
W. Hryniewicz
In Poland, the National Reference Centre for Antibiotic Susceptibility Testing (SVCRL) conducts a national surveillance system through several single species networks.
These include national surveillance networks for Enterococcus spp., Neisseria meningitidis, Pseudomonas aeruginosa, Staphylococcus aureus and coagulase negative staphylococci from blood, Streptococcus pyogenes, and penicillin-resistant Streptococcus pneumoniae.
The Centre uses several very sophisticated molecular techniques for tracking resistant clones. These networks collect data on patient demographics, specimen type, species tested and test and quality control results. Most of the networks do not record results from replicate samples. Data entry is done by the Centre as the coordinating laboratory and is used for publications distributed to participating institutions, governmental agencies, clinicians, microbiologists and other international recipients.
The SVCRL is also involved in many international networks for resistance monitoring such as the Alexander Project, Sentry, and CEM/Net, etc.. Under the Alexander Project, selected species surveillance is conducted for Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and Staphylococcus aureus.
5.1.3 Sample and Isolate Selection for Resistance Monitoring in Portugal
H. de Lencastre
Currently there is an ongoing five year surveillance study on multi-drug resistant Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and other respiratory pathogens. This study, through the participation of 15 hospitals, is focusing on identifying antibiotic use patterns in children who visit day care centres in Lisbon, and on hygiene and bacterial transmission problems at these institutions. The overall aim of the study is to demonstrate the need for lowering the level of antibiotic consumption by tracing which antibiotics have been administered to children and the associated bacterial resistance rates. It is hoped that this will lead to improved antibiotic prescription practices by paediatricians and other health care providers. This study is a joint endeavour by the Ministry of Education and the Centro de Epidemiologia Molecular and Network for Epidemiological Tracking of Antibiotic-Resistant Pathogens (CEM/NET).
CEM/NET is composed of two microbiology laboratories, Molecular Genetics Unit, Universidade Nova de Lisboa (ITQB) and Instituto de Biologia Experimental e Tecnológica (IBET) Oeiras, Portugal, which work in collaboration with the Rockefeller University, USA.
Its purpose is to support collaborative projects between the core laboratories and clinical microbiologists and infectious diseases experts from both Portugal and around the world with the ultimate aim of building an international network of independent and high quality centres for surveillance and epidemiologic studies based on the molecular fingerprinting of microbial isolates. The two core laboratories serve as the quality control and centralized information storage centres for the network.
5.1.4 Sample and Isolate Selection for Resistance Monitoring in Norway
M. Steinbakk
A national antimicrobial resistance surveillance programme is currently in the planning stage in Norway. There is already a national registry for the mandatory reporting of infections with multi-drug resistant Staphylococcus aureus, vancomycin-resistant enterococci, penicillin-resistant pneumococci, systemic fungal isolates and Mycobacterium species, but the detection of other antimicrobial-resistant organisms is primarily limited to sporadic reports generated from various local or regional projects.
A prime goal of a national programme will be to have the participation of all private, community and hospital-based laboratories in Norway. Data from veterinary, and perhaps food industry microbiology laboratories will also be sought. Routine surveillance will be periodic, restricted to selected organisms, and be limited to specifically defined origins such as blood culture, urine, enteropathogens, etc. Resistance monitoring will be standardized by employing only disk diffusion (inhibition zone) methodology. Quality control exercises will be selective and periodic, using dilution/E-test methodology.
The developed data base will be electronic, using a well defined and strictly adhered to reporting format. How the programme is to be funded, who will have access to the data base, and who will be responsible for its overall management, still remains to be determined.
5.1.5 Sample and Isolate Selection for Resistance Monitoring in Hungary
M. Konkoly-Thege
The antibiotic resistance surveillance system in Hungary has a relatively long history.
Beginning in the late 1960s, even though the availability of antibiotics in Hungary was generally limited when compared to that in other countries, it was recognized that an urgent need existed for generating accurate information about antimicrobial susceptibility/resistance patterns of the more important pathogenic bacteria in the country. As a result, by the early 1970s, a nation-wide initiative to define the antimicrobial resistance problem in Hungary was started. This occurred in parallel with the introduction of a standardized sensitivity testing method in the bacteriology laboratories.
Under this initiative, 22 public health laboratories were selected to generate antibiotic sensitivity/resistance data on all submitted isolates. These laboratories were already processing 100% of the faecal specimens and about 60% of other kinds of clinical specimens collected in Hungary, and were practising standardized laboratory methods and participating in proficiency testing programmes.
Initially, the laboratories submitted their collected data on printed report forms which were summarized manually at the Department of Bacteriology, National Institute of Hygiene in Budapest. In 1974, the reporting system was computerized for more efficient statistical analysis. By 1987, with the introduction of new computer software capabilities, the information collected and processed was expanded to include patients’ demographic data, along with culture and antibiotic sensitivity/resistance results. Today, this software is used uniformly by all 22 public health laboratories as well as by 36 of the 94 hospital and university bacteriology laboratories in Hungary. Future plans call for the use of this computerized system in all 94 laboratories. This will enable these laboratories to monitor antimicrobial resistance at the local level, and will allow for the direct reporting of results to practising clinicians. Since 1996, the participating laboratories have been able to send their data on floppy discs to the central coordinating laboratory at the Department of Bacteriology, National Institute of Hygiene, for data analysis. This central laboratory evaluates the submitted data and gives written feedback to the local laboratories on data quality and content. The central laboratory also summarizes and publishes the summarized data, and makes it available to microbiologists, clinicians, governmental bodies and pharmaceutical companies so it can be used for educational and training purposes.
5.1.6 Sample and Isolate Selection for Resistance Monitoring in Bulgaria
B. Markova
In Bulgaria, some antimicrobial resistance monitoring activities were begun in 1993, but no national surveillance system has been developed. Currently there are less than 10 established hospital-based programmes. Because of an overall lack of funding for training and supplies, most past efforts to introduce programmes for rational antimicrobial usage (which would include the periodic cycling of antibiotic usage and the grouping of antibiotics for their more effective use in high risk situations such as intensive care units) have not been successful.
Antimicrobial resistance is, however, recognized as one of the major problems facing Bulgaria. A three-fold rise in penicillin-resistant pneumonias has been detected since 1993.
Also noted are increases in methicillin-resistant Staphylococcus aureus, high-level gentamicin-resistant Enterococcus faecalis, and vancomycin-resistant enterococci infections.
An increasing antimicrobial resistance in gram negative bacteria is also being observed.
Recognizing the constraints facing Bulgaria, and the pressing problem of an increasing rate of antimicrobial resistance, two approaches are being considered to help improve the situation. One suggestion has been made that antimicrobial resistance monitoring should be limited by body-site specific parameters, for example the analysis of blood cultures only. Even though this could lead to the introduction of a significant sampling bias, it would help provide a gross indication of the nature and extent of antimicrobial resistance occurring in Bulgarian hospitals. A second approach would be to limit monitoring to specifically designated bacterial species, for example, nosocomial gram- negative bacteria such as Escherichia coli, Klebsiella, Enterobacter or Serratia, or to nosocomial gram-positive organisms, or respiratory tract pathogens, or anaerobes like Bacteroides fragilis. In this way, available resources could be channelled into tackling discrete more manageable segments of the antimicrobial resistance problem facing the country.
5.2 Panel Discussion: Susceptibility Test Methods for Resistance Monitoring 5.2.1 Introduction
I. Phillips
In Europe a variety of susceptibility test methods are currently in use. This may reflect differences in the ultimate purpose of the testing being performed by the different laboratories. Certainly, there is no one correct method usable under all conditions for all situations. Some flexibility is needed so that appropriate questions can be answered by the most appropriate methods.
5.2.2 Susceptibility Test Methods for Resistance Monitoring in the Russian Federation
L. Stratchounsky
There are several identifiable problems associated with antimicrobial resistance monitoring and surveillance at the local laboratory and national levels in the Russian Federation. To begin, as a generality, not all clinical microbiologists in Russia are familiar with what in Western Europe may be considered basic or standard techniques and procedures for antimicrobial resistance monitoring. This problem is compounded by limited funding available to most Russian laboratories for training and supplies, and the need to use dated national criteria for antimicrobial susceptibility testing which are not applicable for many of the newer antimicrobial agents. The national standards also do not address criteria for fastidious microorganisms. Also problematic is the fact that the test medium currently most widely used in Russia is not suitable for the determination of susceptibility of Pseudomonas aeruginosa to aminoglycosides, or Haemophilus influenzae or Neisseria gonorrhoeae to trimethoprim and sulfonamides.
Two years ago the Ministry of Health introduced a national quality control scheme for microbiology laboratories, but not all laboratories are participating in this scheme. This introduction is supplemented by the activities of international scientific societies: European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Alliance for the Prudent Use of Antibiotics (APUA), American Society of Microbiologists, and the ISC/ESC, which are conducting various courses and seminars on antimicrobial resistance monitoring.
Some pharmaceutical companies such as Merck Sharp & Dohme, Bristol-Myers Squibb, Hoechst Marion Roussel, KRKA, Lek, Pfizer and SmithKline Beecham are also supporting
To address this situation, the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (IACMAC) was founded in 1997. IACMAC has two main objectives. First, to bring together all parties interested in clinical microbiology and antimicrobial chemotherapy in Russia. Second, to enhance the knowledge and practical skills of physicians and bacteriologists for the prudent use of antimicrobials. IACMAC has branches in Moscow, St Petersburg, Krasnodar, Novosibirsk, Rjazan, Smolensk, Tatarstan and Tomsk, and collaborates with different national and international institutions. IACMAC intends to conduct educational programmes on basic antimicrobial resistance monitoring methodology in its participating laboratories and to investigate the possible use of domestically produced medium (AGV) for a broader range of bacteria and antimicrobials.
Laboratory participation in a national quality control programme is also being encouraged.
In addition, IACMAC has identified inclusion priorities for new national standards. They include the detection of penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase production in gram-negative bacteria. Finally, the resistance monitoring network ROSNet has been established, linking 30 centres in different parts of Russia, including the Urals, Siberia and the Far East, and uses the NCCLS guidelines and WHONET technology as its base. It is anticipated that the WHO External Quality Control and Proficiency Test Scheme will be adopted as its quality control scheme. The Smolensk State Medical Academy is the central laboratory for ROSNet.
5.2.3 Susceptibility Test Methods for Resistance Monitoring in Belgium
M. Struelens
A national uniform system for antimicrobial resistance surveillance will be difficult to achieve in Belgium, since no specific national committee for standards currently exists, and individual laboratories are using different techniques for susceptibility testing and internal quality control assessments based generally on NCCLS guidelines but modified by other countries to fit their standards. There is, however, a national External Quality Assessment system under the Ministry of Social Affairs and Public Health, which together with interested national scientific societies is encouraging the optimization of accurate susceptibility testing. Surveys on the effect of this encouragement have suggested that Belgian laboratories have good overall performance with respect to antimicrobial resistance surveillance. Given this situation, and considering the situation for Europe as a whole, an end-result performance standard for antimicrobial susceptibility testing might be a more achievable goal than the adoption by all laboratories of one ‘ideal’ methodology for resistance surveillance. If quality performance standards can be agreed upon, a realistic
‘uniformity’ of procedural methodology will naturally follow.
In Belgium there are also several voluntary surveillance networks organized by scientific societies and/or the federal "Institut Scientifique de la Santé" for monitoring antimicrobial resistance rates. They also monitor the incidence of associated disease, and in some schemes (such as for multi-drug resistant Staphylococcus aureus, glycopeptide-resistant enterococci and penicillin-resistant pneumococci), for the spread of resistant clones through the use of molecular epidemiology. The potential exists for linking these Belgian networks with similar ones organized in other European countries.
5.2.4 Susceptibility Test Methods for Resistance Monitoring in Finland
P. Huovinen
The standardization of susceptibility test methods in Finland is carried out by the Finnish Study Group for Antimicrobial Resistance (FiRe). FiRe is a network of 22 to 30 laboratories (90% of all Finnish labs are participating), representing some of the largest clinical microbiology laboratories in the country. Its leadership, a five-member board, is elected yearly. Participation in FiRe is voluntary and is fluid depending on the nature of different FiRe scientific studies and programmes.
Under FiRe antimicrobial resistance monitoring is carried out through two mechanisms. In the first, collected clinical strains, e.g. group A streptococci, gonococci, pneumococci, Haemophilus influenzae, and Moraxella catarrhalis, are MIC-evaluated by the National Public Health Institute. In the second, routine disk diffusion test data are collected by FiRe and evaluated for any needed changes in recommended disk diffusion techniques.
Quality control is regularly done in all FiRe-laboratories by the FiRe-network itself, and through collaborations with Labquality, Co. In addition, some participating laboratories also take part in the National External Qualtiy Assurance Scheme (NEQAS) run by PHLS, UK. Further quality control evaluations have been conducted using WHO control strains.
A problem addressed by FiRe has been the variety of different susceptibility test methods in use in Finland over the years. In 1995, for example, there were 14 different disk diffusion test methods used by various major Finnish clinical microbiology laboratories. To foster more uniformity and therefore more comparability, FiRe-laboratories began adopting more standardized testing methods as recommended by FiRe. Previously used susceptibility tablets have been exchanged for disk diffusion systems and routinely used test media have been limited to two standard types, Mueller-Hinton agar and Iso-Sensitest agar.
Interpretation of test results has been standardized to fit NCCLS guidelines, but slight modifications to the guidelines have been made to assure compatibility with the Finnish national antibiotic policy.
Another problem identified in Finland is that some clinical microbiologists are still unfamiliar with current computerized data processing systems. Despite this limitation, the WHONET analysis programme has been widely accepted in Finland, as have other hospital computer programmes.
In 1998, the MIKSTRA-project (Strategies for Antimicrobial Use in Finland), will begin a nation-wide five year endeavour to develop national recommendations on uniform diagnostic and antimicrobial treatment practices for outpatient infections. This will supplement ongoing FiRe activities. MIKSTRA will also concentrate on developing a cost- analysis report for outpatient infections.
6. CONCLUDING REMARKS I. Phillips
Antimicrobial resistance surveillance begins with the dilemma of choice. Should hospitalized patients with identified sites of infection be the source of microbial isolates for surveillance, or should the source be apparently healthy individuals in institutions such as nursing homes or day-care centres, or should the source be persons from the community in general? Should samples come from the inanimate environment, from food, from animals?
It may be decided that the samples should come from all clinical samples submitted to a laboratory. It may be decided, however, that samples should be restricted to those from a defined sampling site, such as the blood or the urinary tract. Clearly resistance rates will vary depending on which particular definition and choice of sample types or denominators are used. There will also be variations in the actual samples or numerators submitted for surveillance. An individual physician’s clinical evaluations and decisions will also greatly influence which samples are included in the numerators. Improperly identified or duplicate samples may be included. Such sampling biases will limit the validity and interpretability of any so-called national, or even institutional, determination of resistance rates.
The decision on which bacterial species to study presents the next opportunity for choice. What inclusion or exclusion criteria will be used? Some programmes attempt surveillance on all bacterial species, while others concentrate on particular ones, or even on selected species isolated from specific settings such as intensive care units, or from specific sites of infection such as the respiratory tract. Certainly, the cost of processing the samples and the overall resources available for the surveillance system are limiting factors which must be considered when deciding which and how many bacterial species to include.
To compound the above opportunities for choice in study parameters, there is also considerable diversity in the laboratory methodologies used for antimicrobial susceptibility testing. This severely limits the confidence one can place in the comparability of results from different studies. For example, the disc-diffusion method is very popular in Europe.
But, even among its users, there are variations in the media used, the size of inocula, and the antibiotic content of discs. Testing methodology tends to be less varied for dilution tests, but in some countries automation is common, in others, it is almost non-existent. The introduction of molecular detection methods offers great hope for uniformity in methodology between laboratories, but even with a resulting convergence in methodologies, there still remains differences in interpretation; that is, criteria for breakpoints.
Therefore, while it is acknowledged that it would be ideal if all laboratories and networks used the same methods and criteria for antimicrobial resistance surveillance, there is no agreement on which methods and criteria should be used. A willingness exists to investigate the use of common reference methods (as suggested in the International Collaborative Study of 1971), and to attempt to reach consensus on interpretation, but a universal consensus on these choices has not yet been achieved.
At present, many groups are attempting to harmonize local, national and international antimicrobial resistance surveillance methodologies. These attempts are not necessarily coordinated with one another, however, and there is a growing perception, reinforced by discussions held during this workshop, that a positive role could be played by a pan- European co-ordinating group. Such a group could reflect the various national and European-wide interests in antimicrobial resistance surveillance. It could be initiated as a study group of the European Society of Clinical Microbiology and Infectious Diseases and focus on actively promoting the performance of good-quality local studies which generate internationally comparable data. Such data could in turn, be used to facilitate the accurate interpretation of results between studies and generate information on the extent of antimicrobial resistance in Europe. An essential component of any group’s success, of course, will be adequate funding.
Finally, there is the question of what should be the ultimate use of the antimicrobial resistance information collected. Certainly the objectives of WHO, to educate, to influence policy, to guide research and to improve public health, suggest laudable applications for the information. Could not the information gained by a concerted European-wide effort in antimicrobial resistance surveillance be used by local, national and international decision and policy makers to actively prevent further resistance development, and perhaps, in some cases, even reverse it?
ANNEX 1 WHO QUESTIONNAIRE ON ANTIMICROBIAL RESISTANCE MONITORING NETWORKS IN EUROPE
1. SUMMARY
WHO ARM programme questionnaires entitled Antimicrobial Resistance Monitoring Networks in Europe were distributed to participants before the workshop. A total of 41 questionnaires, from 24 countries, were completed and returned. (See responses below.) Of these, 29 described current national-level surveillance activities or networks, with 17 having three or more years of operating experience. Five other returned questionnaires gave information on national-level surveillance activities to be initiated in the future. The networks ranged in size from those with less than 10 participating laboratories to those having more than 50 laboratories (Table 1). One questionnaire described a federated network-of-networks composed of 11 separate networks working in one country (ONERBA). Three others described international networks such as CEM/NET, ENARE/SENTRY, and INSPEAR. One described a network sponsored by the pharmaceutical industry (Alexander project) with participating laboratories in several countries.
Among the 29 national surveillance activities or networks described, approximately half targeted their surveillance to a single bacterial species. (A returned questionnaire describing a network for tuberculosis surveillance was not considered for this analysis.) Five of the networks used some degree of target species selection (Table 2), and the remaining performed non-selective surveillance on routine clinical isolates. Staphylococcus aureus and Streptococcus pneumoniae were the most often chosen species for surveillance in the networks. The number of isolates tested per year ranged from 100 to 1000 for single- species networks, to 2000 to 200,000 (average 60,000) for networks testing unselected isolates. Twenty-one networks included isolates from both hospitalized and community sources in their surveillance programmes. Seven networks restriced their isolates to those from hospitalized cases only, and one restricted the origin of its isolated to those from community sources. The frequency of surveillance ranged from continuous, which was the most often practised, to sporadic.
A wide variety of different antimicrobial susceptibility test methods were identified as being used by the respondents. In some networks, multiple test methods were in use simultaneously and a further breakdown and analysis of the responses was not attempted.
In the majority of networks, antimicrobial resistance testing was performed by participating laboratories, and confirmatory testing was performed by the central or coordinating laboratory. In 7 networks, however, testing was done entirely by participating laboratories, and in 4 other networks testing was conducted solely in the coordinating laboratory. The task of entering data into network data and information banks was performed about equally by the participating and the central or coordinating laboratories.
Twenty-seven of the 29 networks carry out routine internal quality control procedures. Twenty-three of these also participate in external quality assurance schemes at either the national or international level. One network not using an internal quality control system reported participation in an external quality assurance scheme. Seven respondents reported that their networks used quality assurance programmes specifically established for this surveillance.
All networks reported that they produced written reports of their surveillance findings. The Internet was used by seven networks as an additional tool to disseminate their surveillance results. The usual recipients of the reports were identified as laboratories participating in the network, clinicians and microbiologists. Sixteen of the 29 networks were forwarding their surveillance results to their relevant government agencies.
Finally, respondents identified the following obstacles faced in improving their programmes for resistance monitoring: lack of funding, (this was the most frequent obstacle identified), unavailability of a standardized susceptibility testing methodology, difficulty in performing accurate data analyses, insufficient government support for the network, insufficient numbers of trained professionals to perform surveillance work, and limited awareness by clinicians about the problem of antimicrobial resistance.
The information provided from the questionnaire is being registered in a global information bank on antimicrobial resistance monitoring developed by the WHO ARM programme.
2. TABLES
Table 1
SIZE OF NETWORKS
(based on the number of participating laboratories) Number of laboratories Number of networks
<10 8
10 - 19 8
20 - 49 5
> 50 3
not known/variable 5
Table 2
SELECTION OF SPECIES
Single Species* Semi-selected# Unselected# (circ. 5 species)
No. of networks 13 5 11
No. of isolates 100 - 1 000 2000 - 200 000
per year (One network17 000) (av. 60 000)
*Species (number of networks involved) Staphylococcus ssp. (5)+
Streptococcus pneumoniae (4)+ Enterococcus ssp. (1)
