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3.G Genomics for Infection Prevention

Project 1: EurSafety Health-net
Funding: EU
Project staff: dr. Artur Sabat, Biochemist, Senior researcher, John W. A. Rossen, PhD, Medical Molecular Microbiologist Senior Researcher,
Vikta Akkerboom (technician), Eric Bathoorn, Arts Microbioloog, Silvia Garcia-Cobos, PhD, Postdoctoral Scientist, Jan-Willem Dik, PhD student, prof. dr. Alex W. Friedrich
Cooperation: dr. Jan Arends, Arts Microbioloog, Xuewei Zhou,  AIOS Medical Microbiology, Dirk Borst, infection control practitioner

EurSafety Health-NetEuregional Dutch/German Network for Patient Safety and Infection Protection
European patient mobility and crossborder health care are of highest priority for Europe. The European commission’s directives and European High court’s decisions in the last years clearly outline healthcare service across the border. Since primary obstacles for crossborder healthcare, such as divergent social funding and insurance systems have been tried to overcome by mutual agreements, differences in quality of healthcare is nowadays one of the most important factors limiting regular crossborder health care. The principle goal of the EurSafety Health-net is assuring the highest good in medical healthcare, the patient safety (primum non nocere). Here, crossborder research is done and structural changes are initiated in order to understand infectious disease spread across the border and to establish prevention measures to protect patients and the population from infection. The project works alongside the whole Dutch-German-Belgium border. In this context especially the protection from infections by antibiotic-resistant microorganisms (ARM, e.g. MRSA, ESBL, VRE) stand in the main focus, because in Germany and Belgium MRSA are up to 20 times more frequent than in the Netherlands. On this basis 3 activity lines have been set up,

i.) euregional networks,
ii.) research workpackages and
iii.) communication and training

In the euregional network building it is the task to equalize quality of healthcare on both sides of the border, prevention of healthcare-associated infections and therefore patient safety need to be addressed in structured way by the synergic efforts of the actors of the healthcare systems on both sides of the border. The major is therefore the creation of a crossborder network of the healthcare services alongside the whole Dutch-German border euregions Maas-Rijn, Maas-Rijn-Noord, Rijn-Waal, Gronau-Enschede, Ems-Dollart, in order to protect patients seeking healthcare from infections.

The research focus lies on the pathogenicity of multi-resistant microorganisms (e.g. MRSA, ESBL, VRE), the (molecular) epidemiology, antibiotic consumption, intervention studies of prevention programs. Herewithin, applied and basic research lines are developed in order to better understand the crossborder transmission of infectious diseases and the effectiveness of prevention programs. Hereby, the molecular epidemiology and virulence potential of MRSA, ESBL and E. faecium is studied.

The communication and training activities assure the training of health care providers in infection prevention and inform regularly the public. Two academies in Oldenburg and Düsseldorf assure the training and continues education of staff. Furthermore, a network between the project participants is woven by a telematic platform which makes possible the coordinated collection and transfer of data necessary for patient safety and infection prevention in the Euregios. By means of cooperation and telematic exchange of all information within the EUREGIO, this project can help to decline the barrier for the free movement of patients and health care workers. The medical supply will be changed for the better by enhancing patient safety, strengthening quality of healthcare and the medium-term strategy guarantees an important advantage of location for the Dutch-German border-region facilitating at the same time European integration.

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Project 2: Zoonotic potential of microbes: From Shiga toxin-producing E. coli (STEC) to HUS-associated E. coli (HUSEC) – Virulence mosaic, risk assessment and infection prevention
Funding: EU
Project staff: John W. A. Rossen, PhD, Medical Molecular Microbiologist Senior Researcher, Mithila Ferdous, PhD student, prof. dr. Alex W. Friedrich

Escherichia coli (E. coli) are well-known inhabitants of the human and otherwise mammalian intestines. Many of them are commensals but some of these are pathogenic and can cause diarrhea (often by Shiga toxin-producing E. coli (STEC)), of which some even cause bloody diarrhea (therefore called Enterohemorrhagic E. coli (EHEC)) with possible, severe complications like Hemolytic Uremic Syndrome (HUS). This severe complication develops in 15% of the cases of an EHEC infection. HUS occurred by 800 patients during the major EHEC outbreak in Germany, summer 2011, at which approximately 4000 patients got infected by EHEC. 51 of these 800 HUS-patients died because of this complication and many others had to suffer from a longtime disease episode.

The problem with HUS is that it requires immediate medical treatment, for if untreated, there is a mortality of almost 95%. Because of this, good diagnostics are needed to assess an EHEC infection by an episode of bloody diarrhea, and in case there is an infection with EHEC, to assess the risk of development of HUS.

In 2002, Friedrich et al. in a retrospective study assessed for the first time that specific subtypes of Shiga toxins (Stx) produced by some of the STEC and EHEC, are associated with HUS, whereas other subtypes are not. With other words, some STEC/EHEC that produce a specific subtype of these Stx, are such virulent, that an infection with them gives a higher chance for the development of HUS. Other STEC/EHEC, which produce other (or a combination of other) subtypes of Stx, are not associated with HUS at all. There are up to now at least 8 stx-genotypes and some occur in specific combinations. There is however a pitfall in diagnostics of Stx, since they can also be produced be bacteriophages, which do not cause diarrhea or HUS by themselves and which can also occur in human stool and in our environment (groundwater, food), so that the diagnostics of Stx do not necessarily mean that STEC or EHEC are involved.

At the moment there is not a very good way and procedure to assess the risk of the development of HUS by an EHEC-infection. In case of co-infection with other microorganisms, the detection of stx-genes in faeces might be of less clinical importance. On the other side, is the unique detection of STEC in diarrhea patients not always followed by the severe HUS complication, as this is usually only the case in EHEC. In this case, it might lead to an overestimation and excessive precautions, with hospitalization and unnecessarily rigorous Public Health measures (e.g. prohibition to work). Correlation between the different microbiological findings and the clinical outcome is therefore necessary.

Currently, research is being done for improving the risk assessment in case of a STEC or EHEC infection. With a better risk assessment, patients that might develop HUS might be selected earlier, so that precautionary measures can be taken earlier, like intensive monitoring; in case of signs for complications like HUS, they will get earlier adequate therapy. This will lead to a decrease in morbidity and mortality, which will lead on its turn to less hospitalization.
The intention of this research line is to identify the prevalence of STEC, EHEC and HUSEC in the Euregio and the Netherlands and to set up a Dutch HUSEC-collection.


Project 3: Zoonotic potential of microbes
Funding: EU (SafeGuard 2009-2014)
Project staff: John W. A. Rossen, PhD, Medical Molecular Microbiologist Senior Researcher, dr. Artur Sabat, Biochemist, Senior researcher, Vika Akkerboom (technician), Silvia Garcia-Cobos, PhD, Postdoctoral Scientist, prof. dr. Alex W. Friedrich

In addition to human sources in recent years, zonotic potential of MRSA and ESBL has been a rising concern in the veterinary and agriculture sector as a new reservoir (eg in horses, pigs, cattle) has moved into the focus of MRSA epidemiology. In particular, data from the Netherlands and North Rhine-Westphalia showed that in up to 60% of the farms studied MRSA could be detected in healthy pigs. On the other hand, up to 23% of farmers and 10% of veterinarians are colonized with MRSA. This raises new issues of concern for the development of MRSA and necessary prevention strategies for solving the problem of MRSA in animals and humans.

Humans, animals and pathogens know no borders, not between species and not between countries. Because the MRSA problem remains of high importance for Europe, a cross-border cooperation is adapted by this project, being a workpackage within the SafeGuard project.

For this reason, human doctors, veterinarians and farmers/food industry work together in the border area of the Netherlands, North Rhine-Westphalia and Lower Saxony in roder to understand better the zoonotic potential of MRSA within humans, plants and animals. Studies on transmission of LA-MRSA and intervention-studies for the prevention of MRSA infections are one important goal of this study.

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Project 4: Euregio MRSA-net
Funding: EU (EurSafety Health-net)
Project staff: John W. A. Rossen, PhD, Medical Molecular Microbiologist Senior Researcher, prof. dr. Alex W. Friedrich

MRSA-NetStaphylococcus aureus (S. aureus) is one of the most important causes for hospital-acquired infections worldwide. Thereby infections are particularly susceptible to being caused by Methicillin-resistant Staphylococcus aureus (MRSA), for which there are only few, if any, possibilities of antibiotic therapy. It has been clearly demonstrated by various authors that Methicillin resistance is directly associated with increased mortality and morbidity with S. aureus infections. In the last 10 years an increase in the MRSA rate from 2% to approx. 25% was observed in Germany. In the Netherlands and Scandinavia a stable rate under 3% has been recorded for years. Particularly, for the Netherlands, adhering to a consequent "search and destroy" policy, MRSA felt off to very low rates and is now under control. In the Netherlands the main focus will be on isolating and controlling CA-MRSA, that are a possible danger for the open population outside hospitals. The main aim of the project is to understand the differences in prevention strategy between the Netherlands and Germany, the creation of a network of the major health care providers in the region and the achieving of a lower MRSA rate, a reduction of the number of MRSA infections and thus a shorter stay in hospital as a result. A basic requirement for this is the active education of the region's population by the EUREGIO network.

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Project 5: Network for Sequence-based typing of S. aureus
Project staff: John W. A. Rossen, PhD, Medical Molecular Microbiologist Senior Researcher, dr. Artur Sabat, Biochemist, Senior researcher,  Eleni Sibbald-Tsompanidou, researcher, Vika Akkerboom (technician), Ruud Deurenberg, researcher, prof. dr. Alex W. Friedrich
Cooperation: prof. dr. Hajo Grundmann is a scientific network of currently 50 laboratories from 27 European countries in order to establish a European network of excellence for sequence based typing of microbial pathogens. The principle goal of is to establish unambiguous, electronic, portable, easily comparable typing data for local infection control and national and European surveillance of sentinel micro-organisms. This will be achieved (1) by harmonization of sequencing methods for sequence based typing and building capacity for DNA sequencing in diagnostic microbiology, (2) by establishing quality control/quality assessment (QC/QA) for DNA sequencing in diagnostic microbiology, (3) by improving the general access to sequence based microbial typing results and the transfer of data at international level and (4) by dissemination of the projects results through a web-portal.

The initiative is a vivid European-wide network of laboratories for sequence based typing of microbial pathogens. It generates high quality typing data that are available "on the fly" to all participants and the public through the web-portal. Moreover, the typing data can already be used for molecular epidemiological trend analysis and early warning algorithms as well as for other research purposes. Other laboratories are welcome to join this initiative. If you are interested in joining, please contact the co-ordinators.

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Project 6: Co-project of the Dutch National SOM-study
Funding: ZonMW, Project leader: Medical Microbiology, VUE Amsterdam
Project staff: John W. A. Rossen, PhD, Medical Molecular Microbiologist Senior Researcher, dr. Greetje Kampinga, Arts Microbioloog, , Erwin Raags, technician
Cooperation: Greetje Kampinga, Medical Microbiologist, prof. dr. Alex W. Friedrich

In this project, Groningen is one of the major study centres. The goal of the study is the identification of clinical ESBL and using a cross-ove design the answer to the question whether ESBL patients need to be isolated in the hospital or not. Groningen is hereby part of the national study and collaborating intensively with the project coordinator (Marjolein Kluytmans, VUE)


Project 7: Efficacy of bacteriological monitoring of endoscope reprocessing
Project staff: prof. dr. Alex W. Friedrich
Cooperation: prof. dr. Henny van der Mei

Endoscopy is widely applied for diagnosis, intervention and therapy in diverse anatomical sites in the human body. The safety of the use of endoscopes, especially therapeutic endoscopic procedures (bronchoscopy, endoscopic retrograde cholangiopancreatography) is challenged by bacteriological contamination and ineffective disinfection after use. Flexible endoscopes can be cleaned and disinfected but not sterilized after use. This implies the risk of biofilm formation occasionally leading to serious infections. In The Netherlands there is no generally accepted guideline for control of microbiological hygiene of endoscopes. Process control of the disinfection procedure does not guarantee absence of biofilm.

The research focuses on bacteriological surveillance of endoscope reprocessing, biofilm formation inside endoscope channels and the microorganisms involved in microbial transmission. The project is performed in cooperation with the Department of BioMedical Engineering, University of Groningen.


Project 8: Antimicrobial stewardship Project
Project staff: dr. Ron Hendrix, prof. dr. Alex W. Friedrich
Funding: EU
Cooperation: dr. Jerome Lo Ten Fo, Medical Microbiologist, Jan-Willem Dik, PhD student, dr. Jan Arends, Medical Microbiologist, dr. dr. Bhanu Sinha, Arts Microbioloog, Kasper Wilting, Arts Infectioloog

Between 1983 and 1987, 16 new drug entities were approved in the infectious diseases arena, compared to 7 agents from 1998 to 2002 and 5 agents from 2003 to 2007. These numbers indicate that the development of novel antimicrobial agents is coming to a grinding halt. In conjunction with a decline in antimicrobial development, an increase in multidrug–resistant organisms (MDROs) has also occurred. Several studies have indicated that infection with an MDRO is associated with higher rates of morbidity and mortality, longer length of stay, and greater cost of hospitalization. Current efforts to thwart the siege of MDROs and to address the lack of development of antimicrobial agents center on antimicrobial stewardship.

The primary goal of antimicrobial stewardship is ‘‘to optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms and the emergence of resistance.’’

Within this project a Dutch-German ABS-programm is created.

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Antimicrobial stewardship efforts are directly dependent on reports from the Clinical Microbiology Laboratory (CML), so good communication between the laboratory, pharmacy, infectious diseases department, participating in the stewardship team is essential. In the Dutch situation the clinical microbiologist being a MD and member of the antibiotic stewardship team guaranties this prompt communication. For guiding empirical antimicrobial therapy, unit-specific and tailored antibiograms should be developed, regularly updated, and provided to the antibiotic stewardship team and clinicians at the bedside. Such antibiogram data should be used for evaluation of trends in important antimicrobial resistance rates and for education of clinicians regarding optimal antimicrobial use. For guiding personalized antimicrobial therapy, patient-specific culture and susceptibility data, patient clinical status data and pharmacology data are needed by the antibiotic stewardship team. These data allow for a prospective audit of antimicrobial use with feedback to the prescriber by the antibiotic stewardship team on the level of the individual patient.

A major challenge to an effective stewardship is to obtain antimicrobial susceptibility data from the CML in a timely and efficient manner. Reducing the analytic turnaround time is therefore essential to this program. Adequate ICT systems are essential for the real-time presentation and analysis of data from several sources (e.g., pharmacy, electronic medical record, and laboratory) making personalized medicine in the field of infectious diseases possible.

Routine evaluation of antibiotic prescriptions and feedback to al prescribes by the antibiotic stewardship team is essential for long-lasting effects. The antibiotic stewardship program not only makes care a lot safer but is also a potent tool for cost reduction programs within the hospital environment.

Antimicrobial stewardship

There are 2 core strategies, both proactive, that provide the foundation for an antimicrobial stewardship program. These strategies are not mutually exclusive.

  • Prospective audit with intervention and feedback
    Prospective audit of antimicrobial use with direct interaction and feedback to the prescriber, performed by a team including at least an infectious diseases physician a clinical-microbiologist and a clinical pharmacist can result in reduced inappropriate use of antimicrobials (rating: A-I).

  • Formulary restriction and preauthorization
    Formulary restriction and preauthorization requirements can lead to immediate and significant reductions in antimicrobial use and cost (rating: A-II) and may be beneficial as part of a multifaceted response to a nosocomial outbreak of infection (rating: B-II). The use of preauthorization requirements as a means of controlling antimicrobial resistance is less clear, because a long-term beneficial impact on resistance has not been established, and in some circumstances, use may simply shift to an alternative agent with resulting increased resistance (rating: B-II). In institutions that use preauthorization to limit the use of selected antimicrobials, monitoring overall trends in antimicrobial use is necessary to assess and respond to such shifts in use (rating: B-III).

  • institution of a 72-hour automatic stop order
    The institution of a 72-hour stop order for intravenous administered antibiotics provides an excellent reflection point for streamlining or de-escalation of therapy but also for a parenteral to oral conversion of antibiotics.

The following elements should be considered and prioritized as supplements to the core active antimicrobial stewardship.

Strategies based on local practice patterns and resources.

  • Guidelines and clinical pathways
    Multidisciplinary development of evidence-based practice guidelines incorporating local microbiology and resistance patterns can improve antimicrobial utilization (rating: A-I). Guideline implementation can be facilitated through provider education and feedback on antimicrobial use and patient outcomes (rating: AIII).

  • Antimicrobial order forms
    Antimicrobial order forms can be an effective component of antimicrobial stewardship (rating: B-II) and can facilitate implementation of practice guidelines.

  • Streamlining or de-escalation of therapy
    Streamlining or de-escalation of empirical antimicrobial therapy on the basis of culture results and elimination of redundant combination therapy can more effectively target the causative pathogen, resulting in decreased antimicrobial exposure and substantial cost savings (rating: A-II).

  • Dose optimization
    Optimization of antimicrobial dosing based on individual patient characteristics, causative organism, site of infection, and pharmacokinetic and pharmacodynamic characteristics of the drug is an important part of antimicrobial stewardship (rating: A-II).

  • Parenteral to oral conversion
    A systematic plan for parenteral to oral conversion of antimicrobials with excellent bioavailability, when the patient’s condition allows, can decrease the length of hospital stay and health care costs (rating: AI). Development of clinical criteria and guidelines allowing switch to use of oral agents can facilitate implementation at the institutional level (rating: A-III).

Schematic representation of an Antibiotic Stewardship Program

The antibiotic Stewardship Program can be implemented in all kinds of health-care facilities ranging from large training hospitals to small community hospitals and to rehabilitation clinics, tertiary care facilities and even outpatients populations. Depending on the local needs and opportunities one or more building blocks of this schematic representation can be activated.

Schematic representation of an Antibiotic Stewardship Program

The Clinical Microbiology Laboratory
The clinical microbiology laboratory plays a critical role in the timely identification of microbial pathogens and the performance of susceptibility testing (rating: AII). Prioritization of tested antimicrobials and selective reporting of susceptibility profiles (e.g., not routinely reporting susceptibility of S. aureus to rifampin to prevent inadvertent monotherapy with rifampin) can aid in the prudent use of antimicrobials and direct appropriate therapy based on local guidelines. In addition to routine susceptibility testing, the clinical microbiology laboratory should be actively involved in resistance surveillance. Local antibiograms with pathogen-specific susceptibility data should be updated at least annually, to optimize expert-based recommendations for empirical therapy. Computerized surveillance can facilitate more-frequent monitoring of antimicrobial resistance trends, as well as provide ICU- or ward-specific data and inpatient versus outpatient data, recognizing that different parts of a health care institution can have very different patterns of antimicrobial use and resistance. Besides qualitative determination of antimicrobial resistance or susceptibility, periodic review of MICs can detect early trends of emerging resistance, even within the “susceptibility” cut-offs. Kirby-Bauer disk-diffusion methods can be used to perform the D test for inducible clindamycin resistance for S. aureus [158], as well as provide quick screenings for extended spectrum β-lactamase– and AmpC β-lactamase–containing organisms. Finally, the laboratory is an important partner with infection control in the identification and molecular epidemiologic investigation of local outbreaks of infection. The development of rapid resistance testing will facilitate the surveillance of organisms such as MRSA and VRE, allowing the more rapid implementation of infection control measures to prevent secondary spread. Clonal characterization of resistant strains through molecular typing can help focus appropriate interventions, leading to a reduction in nosocomial infections with associated cost savings. If antimicrobial resistance is due to a clonal outbreak, antimicrobial interventions may be of limited value, compared with infection control interventions. If resistant strains are diverse, antimicrobial interventions may be required.

Antimicrobial use and susceptibility trends Surveillance
A major consequence of the computerization of the health care environment is the availability of digitally encoded data on antimicrobial usage, patient treatment and bacterial susceptibility. Data from these databases would allow monitoring, possibly even in real time, trends in bacterial susceptibility and provide the opportunity for fast adjustments within the antibiotic stewardship programs in order to prevent the harmful effects of emerging MDRO. Such data would also be valuable for monitoring the effects of stewardship interventions and for identifying areas (e.g., specific antimicrobials, hospital locations, and clinical services) that require special attention. Another use for antimicrobial utilization and bacterial susceptibility data is in cross-institutional benchmarking and providing data to regional and national databases to allow large-scale tracking of trends.

Computer-Assisted Strategies
The increasing computerization of the hospital environment offers new opportunities for the implementation of antibiotic stewardship programs. These opportunities have primarily been associated with implementation of computerized physician order-entry systems in hospitals but can also be used for educational purposes. These educational purposes may be as simple as a link to the institution’s guidelines for therapy, or as sophisticated as computerized expert systems that integrate patient-specific, pharmacological and microbiology data in clinical decision aids guiding therapy. Since education is essential for any program that is designed to influence prescribing behaviours, strategies are needed to disperse information in an accurate and timely fashion. Since personnel can change over time, it is also important that the message be repeated routinely. Effective implementation and prolonged use of an antibiotic stewardship program should only be supported by clinical decision aids but should also incorporate e-learning and alerting strategies. The whole computerized system of e-learning, alerts and clinical decision aids provides a very powerful tool for infectious disease management.

Outcome Measurements
The change in antimicrobial usage is the most common outcome measured in studies of antibiotic stewardship programs. Common outcome variables related to antimicrobial usage include quantity of total antimicrobial use, quantity of targeted antimicrobial use, duration of therapy, percentage of oral versus intravenous drug administration, and antimicrobial drug expenditures. Expenditures for antimicrobials are often measured to demonstrate the direct cost savings associated with antibiotic stewardship programs. The proportion of appropriate antimicrobial use may also be measured but to accomplish this, formal rules formulating the correct use of antibiotics must be formulated prior to the start of the program. Clinical criteria should also be included as targets in a program to demonstrate that a change in antimicrobial usage does not have a deleterious effect on patient outcomes. Common clinical outcomes include all-cause mortality, infection-related mortality, duration of hospitalization, and rates of readmission. Microbiologic outcomes include the percentage of organisms resistant to a certain antimicrobial, percentage of multidrug-resistant organisms, or number of infections due to specified
organisms. The overall goal of these programs however remains the improvement in antimicrobial usage (either a decrease in overall usage, decrease in use of targeted antimicrobials, or an increase in appropriate therapy) and therefore promoting patient safety.

Financial impact
It is important for clinicians and administrators to distinguish between clinical, microbiological and financial goals at the outset of program development. Even though the majority of antimicrobial stewardship programs are financially self-sustaining, it is important to remember that programs will not save money forever, nor should that be the goal. A focus on prevention of resistance and appropriate de-escalation of therapy will allow for sustained cost avoidance at a minimum, while optimizing patient care safety. There are data evaluable detailing the financial benefits of antimicrobial stewardship. A 5-year analysis of an antibiotic stewardship program in Kentucky between 1998 and 2002, showed a decrease in antimicrobial expenditures by 25%, or $1,401,146. In addition, antimicrobial cost per inpatient day decreased from $21.14 in 1998 to $16.24 in 2002. In another study in Chicago it was shown that maintaining an antibiotic stewardship program to improve care for bacteraemia is cost-effective from the hospital perspective. The estimate of $2367 per QALY gained for the program intervention compares favourably with many currently funded healthcare interventions and services.


Project 9: Development and Implementation of Health Technology for Antibiotic Stewardship & Hygienic Stewardship
Funding: EU
Project staff: dr Lisette van Gemert-Pijnen, dr Ron Hendrix, prof dr Alex W. Friedrich
Cooperation: dr Jerome R. Lo Ten Foe , dr Bhanu Sinha

- The University of Twente
- The department of Medical Microbiology UMCG
- Certe

Resistance against antimicrobials is increasing due to extensive or inappropriate prescribing and usage of anti-infective drugs. Resistant bacteria are a serious threat to  safety and health of patients and citizens. In order to safeguard the effectiveness of anti-infective drugs in the future, the Dutch Working Party on Antibiotic Policy (SWAB) and the Inspectorate of Health (IGZ) proposed three ways to improve antibiotic management. These consist of publishing of guidelines regarding optimized prescribing of antibiotics, containing resistance by means of infection prevention, and the implementation Antibiotic Teams (A-Team) at local hospitals to carry out Antimicrobial Stewardship Programs (ASP). An ASP consists of a continuous and routine monitoring of antibiotic prescribing and usage practices to optimize patient treatment,  to ensure the cost effectiveness of therapy and finally to curtail the negative effects of antibiotics use, mainly the development of resistance. Further development of ASP is a key issue in fighting Antimicrobial Resistance and Health Care Associated Infections. This requires an innovative approach of ASP which is connected with Hygiene Stewardship and Diagnostic Stewardship, and interwoven with public health. In order to realize and implement ASP-HSP and DSP the UMCG collaborates with the University of Twente to develop interactive applications for sustainable implementation in hospitals, nursing homes and public health. Verweissymbol[Link]


Project 10: MALDI-TOF for Anaerobes: European Network for Rapid Identification of Anaerobic Infections (ENRIA)
Leadpartner: prof. dr. Alex. W. Friedrich, prof. dr. Elisabeth Nagy, Szeged, Hungary
Funding: Reference diagnostic: EU/Interreg
Coordinators: dr. Linda Veloo, prof. dr. Arie Jan van Winkelhoff
Bruker Daltonics, Bremen, Germany
Groningen: dr. Greetje Kampinga, dhr. Rik Winter

Anaerobic infections belong to Europe’s neglected infectious diseases and are most often underestimated in their importance. However, they are important pathogens, composing the majority of bacterial flora on the mucosa and other bacterial ecologic systems in humans, animals and the environment. Furthermore, anaerobes are today a key technology for the growing biofermentor-based energy industry. Knowledge is still lacking on the importance of anaerobes as human pathogens, and their role of being a possible reservoir for virulence and resistance genes in the microecosystem. Furthermore, scientific evaluation is necessary to understand the possible impact of the use of anaerobes in biofermentors on the health of humans and animals. Therefore, a rapid and correct species identification of anaerobes becomes today an indispensable prerequisite.

Different to aerobic bacteria, classic identification of anaerobes remained cumbersome and difficult in standardization over the last decades. In consequence, anaerobic bacteria remain mostly un-identified in clinical microbiological practice. MALDI-TOF technology has recently opened the possibility to detect also anaerobic bacteria. Unfortunately, due to lack of quality and the limited standardization of the strain collections used, MALDI-TOF technology is of limited use for time being.

Therefore, in collaboration with the ESCMID Study group of Anaerobic Infections and Bruker Daltonics, a new European Network for Rapid Identification of Anaerobes (ENRIA) has been initiated. It is coordinated by the Dutch expert centre for anaerobic bacteria at the Department of Medical Microbiology at the University Medical Center Groningen (UMCG) in the Netherlands and the Hungarian reference laboratory for anaerobic infections at the University of Szeged in Hungary. Since many years, both expert centers, together with other European expert groups in anaerobes organize national and international capacity building workshops for the identification and resistance testing of anaerobes and are leading in the culture-based and molecular research on anaerobic -including oral and gut- microbiology.

ENRIA initiaitve
In the following 3 years, ENRIA will set up i.), an international and well-characterized anaerobic strain collection comprising the 100 most important anaerobic species, including parodontogenic bacteria. This strain collection will be analyzed using culture- and sequence-based methods and analyzed with MALDI-TOF to be added to the Bruker Daltonics database. ii.) ENRIA will offer international capacity building workshops for the standardization of MALDI-TOF-use in anaerobic bacteria. iii.) Finally, participating laboratories will perform a quality certification for the rapid identification of anaerobic bacteria with excellent quality using classical detection methods and MALDI-TOF.

The initiators, Prof. Alex W. Friedrich Chair of Medical Microbiology and Head of the Dutch expert centre for anaerobes at the University of Groningen and Prof. Dr. Elisabeth Nagy, head of the institute of medical microbiology in Szeged and chair of the ESGAI envision hereby the chance of a European-wide revival of rapid identification of anaerobic infections, combined with excellence in detection quality. This builds finally the basis for correct microbiological diagnostics, appropriate clinical management and further basic and applied research in the field of anaerobic infections.
How to participate in ENRIA?

Laboratories that are interested in participating in ENRIA are welcome to contact the project coordinators via [].


Project 11: Detection, differentiation and clinical relevance of Shigella species and Enteroinvasive Escherichia coli (EIEC).
Project staff: John W.A. Rossen, PhD, Medical Molecular Microbiologist, Maaike J.C. van den Beld, PhD student, Mithila Ferdous, PhD student, prof. Dr. Alexander W. Friedrich, PI.

RIVM: Frans A.G. Reubsaet, PhD, Microbiologist, Senior Researcher
(extern) Certe: Mirjam A.M.D. Kooistra-Smid, PhD, Medical Molecular Microbiologist, Richard F. de Boer, PhD, molecular biologist.

Shigella species are so related to Escherichia coli that they should be classified as one distinctive species in the genus Escherichia.Disposition in two genera is maintained because of clinical reasons. Shigella species can cause dysentery and other mild to severe diarrheal episodes, whereas E. coli is a known commensal. However, also different pathogenic types of E. coli are described, one of them being Enteroinvasive E. coli (EIEC). This type shares the invasive nature with Shigella species, and may cause similar clinical symptoms. However, little is known about the clinical relevance of infections with EIEC.  Shigella can be distinguished from E. coli based on its physiological and biochemical characteristics. Discrimination between Shigella and EIEC can be complicated by negative conventional tests. Genetically, Shigella and EIEC are closer related than any of the other E. coli types and they both possess the large Invasion Plasmid (pINV). In addition, EIEC and Shigella both harbor the ipaH-gene, a multicopy gene present on both the pINV and the chromosome. Molecular techniques targeting the ipaH-gene, frequently used in the detection of pathogens from stool, cannot distinguish Shigella and EIEC. Furthermore, some of the EIEC strains possess normal E. coli characteristics, complicating the identification of EIEC against the background of other E. coli present in stool samples. As in the Netherlands only infections with Shigella species are notifiable, the improvement of diagnostics enabling distinguishing between Shigella and EIEC is key.

The aims of this study are (1) to facilitate differentiation between Shigella and EIEC, and to facilitate detection and selection of these organisms from stool samples, (2) to characterize EIEC and Shigella strains, both phenotypically and genotypically, (3) determine genetic population structure and perform molecular epidemiology of imported EIEC using next-generation sequencing and (4) determine the clinical relevance of infections with EIEC, in relation to infections with Shigella.


Project 12: Prevalence of gut-related antibiotic resistant microorganisms (VRE and ESBL) in hospitals of the Dutch-German region.
Funding: EU
Project staff: Xuewei Zhou (AIOS Medical Microbiology), Jan Arends (Medical Microbiologist), Greetje Kampinga (Medical Microbiologist), Dirk Borst (Infection control practitioner), John Rossen (Medical Molecular Microbiologist Senior Researcher), prof. dr. Alex Friedrich.

The epidemiology and trends of antimicrobial resistance of microorganism are changing continuously, even within small regions. Relevant and important gut-related antimicrobial resistant microorganism nowadays are vancomycin-resistant Enterococcus faecium (VREfm) and extended spectrum beta-lactamase (ESBL) - producing bacteria. For VREfm, rates are increasing worldwide. Moreover a recent rise of the VanB-subtype, including strains expressing a low MIC, has been reported. For ESBL, especially CTX-M related enterobacteriacae are disseminating worldwide. Though there are still differences in types of ESBL found in different countries, with particular genotypes associated with different geographical regions.
Hospital transfer of patients within different regions, but also between close border regions, such as The Netherlands and Germany, can contribute to a spread of antibiotic resistant micro-organism within the relevant hospitals. It is of great importance to understand the epidemiology of the changing antimicrobial resistance and to keep informed of risk factors within in the different but connected institutions. Continuously studies are needed to come with adequate measures and policies with regard to infection prevention and clinical advices. Until now, there are no regional recent data yet of the prevalence of the aforementioned microorganisms. By means of this study, we aim to get a notice of these regional data.

Therefore the aim of this project is to determine the prevalence of gut-related antibiotic resistant microorganisms (VRE and ESBL) in hospitals of the Dutch-German region.


Project 13: STEC-ID-net
Funding: all collaborating institutions, EurSafety Health-net
Project staff: Mirjam Kooistra-Smid, PhD, Medical Molecular Microbiologist, Researcher, Richard de Boer, PhD, molecular biologist, Peter Croughs, medical microbiologist, Ingrid Friesema, PhD, epidemiologist, dr. Daan Notermans, medical microbiologist, Bert Wolters, Medical Doctor, Public Health, Mariska Petrignani, Medical Doctor, Public Health,Tizza Zomers, MSc, Researcher, Toos Waegemaekers, Medical Doctor, Public Health  dr. Alewijn Ott, medical microbiologist, John Rossen, PhD, Medical Molecular Microbiologist, Senior Researcher, prof. dr. Alex Friedrich.
Collaboration: Certe, STAR-MDC Rotterdam, GGD Groningen, GGD Drenthe, GGD Rotterdam Rijnmond, RIVM, UMCG

Shiga toxin-producing E. coli (STEC) can cause a broad spectrum of diseases comprising mild gastroenteritis, hemorrhagic colitis and the hemolytic uremic syndrome (HUS). In particular, STEC strains belonging to serogroups O26, O103, O104, O111, O121, O145 and O157 are known causative agents of outbreaks and serious illness and are usually called HUS-associated E. coli (HUSEC).

Since 2008 the LCI-guidelines for detection of STEC in The Netherlands have changed, based on results of a nationwide study (van Duynhoven et al., CMI 2008. 14:437-45). Detection of STEC in the Netherlands was traditionally limited to the detection of serogroup O157, but laboratories were encouraged to use techniques (such as PCR) targeting Shiga toxin-coding genes, enabling detection of non-O157 serogroups.

Currently, approximately 1/3 of public health laboratories in The Netherlands use PCR diagnostics for detection of STEC (stx1/stx2), but 2/3 still use only (CT-) SMAC culturing for the detection of STEC O157. Using PCR diagnostics for STEC, the detection rate of STEC increased significantly (de Boer et al., JCM 2010. 48:4140-6) leading to a major increase in work burden at the Public Health Services (PHS). On the other hand, laboratories that only use (CT-) SMAC for detection of STEC still are not able to detect public health relevant non-O157 infections. Anyway, the notification of STEC in the Netherlands rose 5-fold from 2008 to 2011. This is due to the increased use of PCR-based diagnostics but probably also to a real increase of infections.
The variability in diagnostic assays, the unclear infection control and public health impact as well as the variability of public health action demand improvement of STEC diagnostics and surveillance. The PHS requires additional information on the isolate and a molecular risk assessment.

At the 2012 Scientific spring meeting of the KNVM& NVMM we proposed a three-level diagnostic approach for STEC-infection in the Netherlands using an established diagnostic scheme (Friedrich et al., JCM 2004. 42:4697-701)

Based on this, we implemented and validated a partly modified algorithm enabling a fast discrimination of hypervirulent HUSEC from less virulent STEC leading to a microbiological risk assessment in a diagnostic setting. Furthermore, it enables the detection of viable STEC in stool samples. The first single center pilot-analysis shows an improved detection of STEC and HUSEC. In order to prove feasibility, the STEC-ID-net was set up. A prospective cohort study will be performed in 2013-2014 to achieve data on which recommendations can be based for new STEC diagnostics in the Netherlands. Within STEC-ID-net a number of institutes (Certe, STAR-MDC, RIVM, PHS Groningen, PHS Drenthe, PHS Rotterdam-Rijnmond and UMCG collaborate and combine their expertise in order to optimize the identification of pathogenic STEC and HUSEC, STEC surveillance and the public health response.  In this project  usefulness of additional culture and molecular methods for improving the risk assessment of a STEC or EHEC infection for patient and public health is studied. Furthermore, this study will build the basis for further scientific evidence of the microbiological prevalence of STEC, EHEC and HUSEC in the Netherlands. The research is also focused on phenotypic and molecular subtyping of STEC, EHEC and HUSEC isolates using state-of-the- art techniques, like next generation sequencing.


aan de bovenkant van de bladzijde

Principal investigator

Alexander W. FriedrichAlexander W. Friedrich
Prof. dr., Genomics for Infection Prevention -
Professor and Chair for Medical Microbiology

Tel: +31.(0)50 361 5939
Mail: Alex Friedrich


John W. A. RossenJohn W. A. Rossen
PhD, Medical Molecular Microbiologist
Senior Researcher

Tel: +31.(0)50 361 1143
Mail: John W. A. Rossen

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Dr. John W. A. Rossen has a 20 year history in molecular microbiology. Starting in basic research he switched to more clinically related research in 2004. He is responsible for molecular detection and typing of microorganisms in the department. In 2008, he obtained his Medical Molecular Microbiologist registration with the Dutch Society of Medical Microbiology. His research focuses on the epidemiology and the molecular detection and further characterization (Epi- and pathotyping) of emerging pathogens. Moreover, his research group investigates the applied use of (new) molecular and high-throughput technology to improve risk assessment and infection prevention.



Artur SabatArtur Sabat, PhD,
Senior Researcher

Tel: +31.(0)50 361 2281
Mail: Artur Sabat


Ieneke van der GunIeneke van der Gun, PhD,
Scientific Project Coordinator
Tel: +31.(0)50 361 0964
Mail: Ieneke van der Gun


Eric BathoornEric Bathoorn
MD, PhD, Arts Microbioloog - Bacteriologie
Senior Researcher
Tel: +31.(0)50 361 4660
Mail: Eric Bathoorn


Adriana TamiAdriana Tami
MD, PhD, Medical Microbiology
Senior Researcher
Tel: +31.(0)50 361 5169
Mail: Adriana Tami


Lisette van Gemert-PijnenLisette van Gemert-Pijnen, PhD,
Coordinator eHealth
Tel: +31 (53) 4896050
Mail: Lisette van Gemert-Pijnen


Mirjam Koostra-SmidMirjam Kooistra-Smid, PhD,
Medisch Moleculair Microbioloog
Tel: +31 (06) 12 60 75 83
Mail: Mirjam Kooistra-Smid

Department for Medical
Microbiology and Infection Control
University of Groningen,
University Medical Center Groningen
De Brug, hpc EB 80
Hanzeplein 1,
9713 GZ Groningen Nederland

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