Final Report Summary - APRES (The appropriateness of prescribing antibiotics in primary health care in Europe with respect to antibiotic resistance)
Executive Summary:
4.1.1. Executive summary
Despite the fact that over 90% of all antibiotics in Europe are prescribed in primary care settings, information on prescriptions and resistance patterns in the community are currently incomplete. So far, information on the prevalence of resistance to antimicrobial drugs in Europe has mainly been obtained from invasive strains collected in hospital settings. The aim of the APRES study was to investigate the appropriateness of antibiotic prescribing in primary care in Europe by collecting and combining patterns of antibiotic resistance patterns and antibiotic prescription patterns. We also evaluated the appropriateness of national antibiotic prescription guidelines in relation to resistance patterns.
Antibiotic resistance was studied in an opportunistic sample from the community in nine European countries (Austria, Belgium, Croatia, France, Hungary, Spain, Sweden, the Netherlands, and the UK). Studies by the European Surveillance of Antimicrobial Consumption have shown that these countries represent the whole range of low to high volumes of antibiotic use. Resistance data were collected by taking a nose swab from persons (N = 4,000 per country) visiting a primary care practice for a non-infectious disease. Staphylococcus aureus and Streptococcus pneumoniae were isolated in national laboratories and tested for resistance in a central laboratory (Maastricht University Medical Centre). Data on antibiotic prescriptions over the past 5 years were extracted from the electronic medical records of the General Practitioners (GPs) who collected the nose swabs. Combining these two datasets with existing treatment guidelines, APRES was able to investigate the appropriateness of antibiotic prescribing in primary care in Europe.
The APRES study has collected unique data concerning resistance patterns, prescription behaviours and treatment guidelines in primary care in nine European countries. It found that the adjusted S. aureus prevalence for patients older than 18 years was 21.6%, ranging from 12.1% in Hungary to 29.4% in Sweden. Except for the known high resistance against penicillin, the highest recorded resistance rate was found for azithromycin (from 1.6% in Sweden to 16.9% in France) and a total of 91 MRSA strains were isolated (the highest MRSA prevalence (2.1%) was reported in Belgium). For S. pneumoniae, the prevalence ranged from 1% in Austria and the United Kingdom to 4% in France. There was more variation in antibiotic resistance rates in the S. pneumoniae specimens, with high rates in Spain and low rates in Sweden.
For the prescription patterns, APRES found that the median and average number of packages prescribed per 100 active patients for the year 2010 was highest in Croatia and Hungary and lowest in Sweden, France and Austria. High variations in use between the different practices at a country level were reported in Hungary, Croatia and Belgium. We also collected and analysed primary care treatment guidelines for skin infections and found similar recommendations (mostly recommend Beta Lactam penicillins) across Europe, but variability in the advised dosage and limited use of scientific references focussed on antibiotic resistance patterns. Finally, we combined the treatment guidelines for skin infections presumably caused by S. aureus and antibiotic resistance patterns, and found that theoretical treatment effectiveness was generally high across Europe.
These results are valuable for policy makers across Europe, and provide the basis for evidence-based treatment guidelines that take into account resistance patterns for practicing GPs in primary care. By improving antibiotic use in Europe we can move towards controlling the resistance problem globally.
Project Context and Objectives:
4.1.2.1. Summary descripton of the project context
Since the discovery of penicillin [Fleming, 1929] antibiotics have made a major contribution to public health. Infectious diseases have been treated more effectively, and mortality from infectious diseases has fallen in developed countries, though the contribution of improvements in nutrition and hygiene should not be forgotten. Despite this progress, any new antibiotic inevitably leads to the development of resistance sooner or later [Levy, 1997] and over the last 50 years the increasing volume of antibiotics used has exerted selective pressure on susceptible bacteria and favoured the survival of resistant strains [Summers, 2002], some of which are resistant to more than one antibiotic. This has led to a race between increasing levels of resistance against available antibiotics and the development of new generations of antibiotics , and there is a risk that the race will be lost by the pharmaceutical companies [van den Boogaard, 2000]. The lack of new antibiotics in a setting of diminishing effectiveness of existing antibiotics will eventually be responsible for increased morbidity, higher mortality and lower life expectancy [Livermore, 2003; Levy, 2005; Harbarth & Samore, 2005].
The development of resistance starts with a genetic mutation, either intrinsic (spontaneous mutation) or by acquisition of a resistance gene from another bacterium. Resistance genes give rise to antibiotic degradation, the production of inactivating enzymes or alteration of the drug receptor site [Davies, 1997]. The survival and multiplication of resistant bacteria depends largely on selection pressures to which they are exposed in accordance with the Darwinian principle. If the selection pressure of excessive antibiotic use is reduced, resistant bacteria may be replaced by susceptible bacteria, especially because in other respects resistant bacteria may be less ‘fit’ than those susceptible [Lipsitch et al, 2000].
The degree of antibiotic resistance in a population is strongly correlated with the level of antibiotic usage and the ease with which bacteria can disseminate [van den Boogaard, 2000]. Hospitalized patients, especially in intensive care environments, with high exposure to antibiotics are particularly prone to colonisation and infection [Struelens, 1998]. However, more than 90% of antibiotics are consumed by outpatients [Goossens, 2004] and these represent the selection pressure on the commensal flora in community-dwelling persons. The commensal flora of community-dwelling persons is therefore becoming an important reservoir of resistant bacteria. However, we have almost no knowledge of the prevalence and pattern of antibiotic resistance in the commensal flora of community-dwelling persons.
When studying the antibiotic resistance pattern of the commensal flora in the community, many bacteria are eligible. For this project we have chosen to focus on Staphylococcus aureus and Streptococcus pneumoniae. As mentioned in the recent report of the European Academies Science Advisory Council [EASAC, 2007], major problems are among others encountered for S. aureus and S. pneumoniae especially in the community. S. aureus is a major concern due to community acquired methicillin resistant S. aureus (CA-MRSA) which causes severe skin infections and pneumonia. S. pneumoniae is a major concern because of its increasing resistance to macrolides and fluoroquinolones in patients with COPD, the third most common cause of death in Europe.
Fighting antibiotic resistance starts with restricted use of antibiotics. This leads to less selection pressure on the bacterial flora, circulating in the population, but also of the commensal flora in an individual. Several studies have described the effectiveness of altering antibiotic prescribing policies on antibiotic resistance [e.g. Seppala et al, 1997]. The enormous variation between countries in antibiotic consumption cannot be justified by differences in the burden of infectious diseases but is related to differences in prescribing habits, antibiotic policies and socio-economic and cultural aspects [Cars, 2001].
The European Surveillance of Antimicrobial Consumption (ESAC) carried out a study in 33 European countries which showed that outpatient antibiotic use varied from 10.2 defined daily doses (DDDs) per 1,000 inhabitants in Romania to 38.6 DDDs in Greece [Adriaenssens, 2011]. The high correlation between the volume of consumption of antibiotics in outpatient settings and the rate of antibiotic resistance as seen in hospitalized patients (Spearman rank correlation 0.65-0.84; all p-values <0.01) for different bacteria and antibiotic agents underlines the importance of restricted use of antibiotics [Goossens, 2005].
Information on the volume of the consumption of antibiotics is not sufficient to establish the appropriate use of antibiotics. For an analysis of appropriateness, information on patterns of antibiotic resistance is also necessary. If the use of an antibiotic is considered necessary, an appropriate choice of the antibiotic agent is of utmost importance in order to treat the patient’s infection effectively and also to prevent the development of resistance and/or the colonisation of resistant bacteria present by minimizing the selection pressure on the commensal flora. The choice of an antibiotic agent should therefore be guided by the resistance pattern of the pathogen causing the infection to be treated [Warren et al, 1999].
In routine daily primary care the resistance pattern of a pathogen is unlikely to be known before treatment is initiated and is usually only tested after initial treatment failure. As mentioned before, the antibiotic resistance pattern of the commensal flora in the community is a valid indicator for pathogens causing infectious diseases in the community. Empirical information on this resistance pattern in a population is therefore valuable for a) assessing the appropriateness of the prescribing of antibiotics by primary care physicians and b) formulating guidelines for appropriately prescribing antibiotics.
4.1.2.2. Summary of the main objectives
Study objectives: The appropriateness of prescribing antibiotics in primary care in Europe with respect to antibiotic resistance (APRES)
The overall study objective was to research antibiotic resistance patterns in bacteria in the community and to examine the appropriateness of prescribed antibiotics to community-dwelling patients in order to make evidence based recommendations that will improve the appropriateness of antibiotic prescribing in primary care in Europe.
Each Work Package (WP) had study objectives in order to meet the overall objective:
WP1: Provide a state-of-the-art literature review about the association between outpatient consumption of antibiotics and antibiotic resistance patterns in the community. Also, provide an overview of information sources and databases containing information about outpatient antibiotic consumption or resistance.
WP2: Establish the pattern of resistance of Staphylococcus aureus and Streptococcus pneumoniae isolated from nasal mucous swab samples in healthy persons consulting their primary care physician. Antibiotic resistance will be studied in nine European countries by taking nasal mucous swabs of persons (target N=4,000 per country) visiting a primary care physician for a non-infectious disease. S. aureus and S. pneumoniae are isolated by a national laboratory, and tested for resistance to 13 antibiotics by one central laboratory.
WP3: Determine the patterns of prescribing antibiotics (volume and type) by primary care physicians in each participating country. Data on antibiotic prescriptions over the past 5 years will be extracted from the electronic medical records of General Practitioners (GPs).
WP4: Perform an integrated analysis of the resistance (WP2) and prescription data (WP3) to assess the appropriateness of prescribing antibiotics in each country. The results will be related to relevant treatment guidelines in the nine participating countries ( focussing on skin infections which are often caused by S. aureus), in order to formulate evidence-based recommendations on antibiotic prescribing.
The interaction of the Work Packages is summarized in Figure 1 (APRES Attachment.pdf). In summary, the association between prescription behaviour (WP3) and resistance patterns (WP2) was analysed, and we linked the resistance patterns to the current national guidelines (WP4).
An important final objective was the dissemination of the study results. This was carried out via a number of different initiatives, including: publications in scientific journals (included in three PhD theses), the presentation of results at General Practitioner conferences (e.g. WONCA Europe), the publication of National Feedback Reports, and the GP Network co-ordinators actively informing national stakeholders in each country.
Project Results:
This chapter describes the main Science and Technology results from the APRES project. It has been split into the four main Work Packages, with first a presentation of the main outputs and then a summary of the main findings.
4.1.3.1. Work Package 1: Work Package Leader - University of Nottingham
Publication:
A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. Bell BG, Schellevis F, Stobberingh E, Goossens H, Pringle M. BMC Infectious Diseases, 2014, 14:13.
Report:
Work Package 1: The Literature Review (68 pages)
Authors: Brian Bell and Mike Pringle
Other
A collection of relevant databases of information on resistance and/or prescription patterns has been created and can be viewed on the APRES website.
Summary of main findings:
Greater use of antibiotics during the past 50 years has exerted selective pressure on susceptible bacteria and may have favoured the survival of resistant strains. Existing information on antibiotic resistance patterns from pathogens circulating among community-based patients is substantially less than from hospitalized patients on whom guidelines are often based. We therefore chose to assess the relationship between the antibiotic resistance pattern of bacteria circulating in the community and the consumption of antibiotics in the community.
Both grey literature and published scientific literature in English and other European languages was examined. Multiple regression analysis was used to analyse whether studies found a positive relationship between antibiotic consumption and resistance. A subsequent meta-analysis and meta-regression was conducted for studies for which a common effect size measure (odds ratio) could be calculated.
Electronic searches identified 974 studies but only 243 studies were considered eligible for inclusion by the two independent reviewers who extracted the data. A binomial test revealed a positive relationship between antibiotic consumption and resistance (p < 0.001) but multiple regression modelling did not produce any significant predictors of resistance. The meta-analysis generated a significant pooled odds ratio of 2.3 (95% confidence interval 2.2 to 2.5) with a meta-regression producing several significant predictors (F(10,77) = 5.82 p < 0.01). Countries in southern Europe produced a stronger link between consumption and resistance than other regions.
Using a large set of studies we found that antibiotic consumption is associated with the development of antibiotic resistance. A subsequent meta-analysis, with a subsample of the studies, generated several significant predictors. Countries in southern Europe produced a stronger link between consumption and resistance than other regions so efforts at reducing antibiotic consumption may need to be strengthened in this area. Increased consumption of antibiotics may not only produce greater resistance at the individual patient level but may also produce greater resistance at the community, country, and regional levels, which can harm individual patients.
4.1.3.2. Work Package 2: Work Package Leader - Maastricht University
Publications:
Prevalence and resistance of commensal Staphylococcus aureus, including meticillin-resistant S aureus, in nine European countries: a cross-sectional study. den Heijer CDJ, van Bijnen EME, Paget WJ, Pringle M, Goossens H, Bruggeman CA, Schellevis FG, Stobberingh EE, and the APRES Study Team. The Lancet Infectious Diseases, Volume 13, Issue 5, Pages 409 - 415, May 2013
doi:10.1016/S1473-3099(13)70036-7
Fusidic acid resistance in commensal Staphylococcus aureus in nine European countries.
den Heijer CDJ, van Bijnen EME, Paget WJ, Stobberingh EE, in collaboration with the APRES Study Team. Future Microbiology, in press.
Report:
Prevalence and resistance of commensal Staphylococcus aureus reports for each participating country, December 2012
Other:
- GP databases sent to each country on the prevalence and resistance of commensal S. aureus (December 2012)
- GP databases sent to each country on the prevalence and resistance of commensal S. pneumoniae (March 2014)
- Casper den Heijer, PhD student, graduated 2013
Summary of main findings:
Information about the prevalence of Staphylococcus aureus and Streptococcus pneumonia resistance to antimicrobial drugs has mainly been obtained from invasive strains, although the commensal microbiota is thought to be an important reservoir of resistance. We aimed to compare the prevalence of nasal S. aureus and S. pneumoniae carriage and antibiotic resistance, including meticillin-resistant S. aureus (MRSA), in healthy patients across nine European countries.
In this cross-sectional study, nasal swabs were obtained from 32,206 patients recruited by family doctors participating in existing nationwide family doctor networks in Austria, Belgium, Croatia, France, Hungary, Spain, Sweden, the Netherlands, and the UK. Eligible patients were aged 4 years or older (≥18 years in the UK) and presented with a non-infectious disorder. Swabs were sent to national microbiological laboratories for identification and isolation of S. aureus (Figure 2, APRES Attachment.pdf) . Antibiotic resistance testing was done at one central microbiological laboratory at Maastricht University. We established the genotypic structure of the isolated MRSA strains with the spa typing method.
S. aureus was isolated from 6,956 (21.6%) of 32,206 patients swabbed. The adjusted (age, sex and family doctor) S. aureus prevalence for patients older than 18 years ranged from 12.1% (Hungary) to 29.4% (Sweden) (Figure 3, APRES Attachment.pdf). Except for the known high resistance against penicillin, the highest recorded resistance rate was to azithromycin (from 1.6% in Sweden to 16.9% in France) (Table 1, APRES Attachment.pdf). In total, 91 MRSA strains were isolated, with an average prevalence of 1.3%, ranging from 0% in Sweden to 2.1% in Belgium. 53 different spa types were detected—the most prevalent were t002 (n=9) and t008 (n=8). For S. pneumoniae, the prevalence ranged from 1% in Austria and the United Kingdom to 4% in France (Figure 3, APRES Attachment.pdf). There was more variation in antibiotic resistance rates in the S. pneumoniae specimens, with highest rates in Spain and lowest rates in Sweden (Table 2, APRES Attachment.pdf).
In conclusion, the prevalence of S. aureus nasal carriage differed across the nine European countries assessed, even after correction for age, sex, and family doctor, and the prevalence of S. pneumoniae was low. Generally, the prevalence of resistance in S. aureus samples, including that of MRSA, was low. For S. pneumonaie there was more variation in resistance (e.g. Sweden versus Spain).
4.1.3.3. Work Package 3: Work Package Leader - University of Antwerpen
Publications:
In preparation
Report:
APRES: Work Package 3: Establishing the antibiotic prescribing patterns (58 pages)
Profs. Herman Goossens and Samuel Coenen, Ann Versporten and Dr. Niels Adriaenssens
Other:
- Data validation report (sent to all nine countries): national overview of antibiotic prescribing data
- Ann Versporten, PhD student
Summary of main findings:
Work Package 3 aimed to establish the pattern of prescribed antibiotics (volume and type) in primary care practices and its variation by diagnosis within and between nine European countries. It further aimed to describe variation of antibiotic prescription by patients’ age, gender and by diagnosis.
The selected networks of general practitioners retrieved anonymous antibiotic prescribing data from electronic medical records of all patients listed in the participating primary care practices. The study population was all patients who were prescribed an antibiotic in each practice, and the corresponding denominator, i.e. the number of people in the practice population and/or the number of active patients (defined as having visited the practice at least once in the previous 12 months). The main study covered the period from January 2006 to March 2011. The study mainly focused on antibiotic prescription data of the year 2010 as this this was the year when nasal swabs were collected (Work Package 2) and it was the most reliable and complete data.
Data validation included checking of data exhaustiveness and correctness of antibiotic volumes of use expressed in the number of packages and/or daily-defined doses (DDDs) per 100 active patients and/or listed patients for all years reported to the University of Antwerp. For each country, data were examined to make sure the WHO ATC/DDD classification methodology was correctly applied. As such, errors in ATC codes and/or DDDs were corrected. Inconsistencies were reported to the countries concerned and were subsequently corrected if possible. Aid was offered to countries encountering difficulties in the calculation of DDDs.
Overall, 208 practices of 9 countries reported at least for one year antibiotic use data. For the year 2010, data from 188 practices have been retained for further analyses. The median and average number of packages prescribed per 100 active patients for the year 2010 was highest for Croatia and Hungary and lowest for Sweden, France and Austria. On the other hand, Spain showed the highest overall volumes of antibiotic use if expressed in average number of DDD per 100 active patients for the year 2010.
Figure 4 (APRES Attachment.pdf) (expressed in DDD/100 active patients in the year 2010) highlights high variations in use between the different practices at country level, especially in Hungary, Belgium and Spain (biggest range between minimum and maximum of reported antibiotic use).
Analyses were performed for antibiotics at an ATC 3 level (pharmacological subgroups), at an ATC4 level (chemical subgroups) for age group and gender and an ATC5 level (substance level). We looked at antibiotics by diagnosis and assessed antibiotic use according to a set of disease-specific antibiotic prescribing quality indicators (APQI) to assess the quality of antibiotic prescribing in primary care [Adriaenssens et al, 2011]. Longitudinal trends were also assessed.
Finally, the APRES data was compared to ESAC-Net data (which employs national whole sales or reimbursement antibiotic consumption data for ambulatory care) and showed similar outcomes at country level (for proportional antibiotic use at ATC3 level, year 2010). Differences between countries were revealed to be higher than the differences within countries. In Austria, Hungary, Spain and Sweden, the APRES data showed a more than 5% higher proportional penicillin use compared to the ESAC-Net data . In Austria the APRES data showed more than 5% less macrolide use, while in Hungary the proportion of prescribed tetracyclines and quinolones was lower, probably due to the participation of pediatric practices. In the other countries differences in proportion were less than 5%.
In conclusion, APRES was able to collect valid data for the 9 countries participating to the APRES project. Our study analyzed antibiotic use volumes expressed in number of packages versus DDDs per 100 active patients for the year 2010. The collection of data following the standardized WHO ATC/DDD method was difficult to implement for some countries leaving some issues unresolved (underreporting of DDDs). The study could also highlight the difficulty of using DDDs for children (invalid for paediatric formulations) and it observed very different prescribing practices among the participating countries. Overall, countries with higher volumes of antibiotic use (Croatia, Hungary) also used more broad spectrum antibiotics and vice versa (Sweden).
4.1.3.4. Work Package 4: Work Package Leader - NIVEL
Publications:
The appropriateness of prescribing antibiotics in the community in Europe: study design.
van Bijnen EME, den Heijer CDJ, Paget WJ, Stobberingh EE, Verheij RA, Bruggeman CA, Pringle M, Goossens H, Schellevis FG. BMC Infectious Diseases 2011, 11:293 (28 October 2011)
Evidence-based primary care treatment guidelines for skin infections in Europe: a comparative analysis. Bijnen, EME van, Paget J, Heijer CDJ den, Stobberingh EE, Bruggeman CA, Schellevis FG. (2014). European Journal of General Practice, 23 January.
Reports:
- National Feedback Report - Austria (32 pages)
- National Feedback Report - Belgium (32 pages)
- National Feedback Report - Croatia (32 pages)
- National Feedback Report - France (32 pages)
- National Feedback Report - Hungary (32 pages)
- National Feedback Report - the Netherlands (32 pages)
- National Feedback Report - Spain (32 pages)
- National Feedback Report - Sweden (32 pages)
- National Feedback Report - United Kingdom (32 pages)
Other:
Evelien van Bijnen, PhD student
Summary of main findings:
Most antibiotics for human use are prescribed in primary care. Incorporating resistance data into treatment guidelines could improve appropriate prescribing, increase treatment effectiveness and control the development of resistance. We carried out two studies: 1) a review of primary care treatment guidelines for bacterial skin infections and an assessment of the extent to which the guidelines are based on antibiotic resistance data and 2) an assessment of the primary care treatment guidelines with respect to antimicrobial resistance (AMR) patterns (the recommendations were considered appropriate if resistance to the antibiotic did not exceed 20%).
In the first study, thirteen primary care treatment guidelines were obtained from eight countries across Europe. Both the treatment recommendations and the underlying evidence were assessed. The class and dose of recommended antibiotics were investigated and compared using the World Health Organisation’s standardized volume of Defined Daily Dose. Furthermore, the study investigated whether guidelines included references to scientific publications about antibiotic resistance data, and whether these were of national origin.
Guidelines were included regarding common skin infections in primary care: Impetigo, Cellulitis, Erysipelas, Folliculitis and Furuncle (Table 3, APRES Attachment.pdf). Results showed a high agreement across Europe: all recommended antibiotics are of the beta-lactam class and mainly small spectrum. The advised treatment durations are consistent; the dosages, however, vary considerably, with the highest dosages recommended in Sweden. Seven guidelines (54%) did not include scientific references related to resistance.
In the second study, we included primary care treatment guidelines for impetigo, cellulitis, folliculitis and furuncle. Treatment recommendations in all countries were congruent: most of the first-choice recommendations were beta-lactams, both for children and adults. AMR levels were low, except for penicillin (on average 73% resistance). Considerable variation in AMR levels between countries was found, with Sweden displaying the lowest levels and Spain the highest. In some countries resistance to penicillin and azithromycin was significantly higher in children (4-17 years) compared with adults.
The assessment of the primary care treatment guidelines found that there may be a lack of relevant national data on resistance. The study highlighted the need to collect more national resistance data (particularly regarding beta-lactams) to create stronger evidence-based treatment guidelines for skin infections in Europe.
The assessment of primary care treatment guidelines with respect to AMR found that most of the first- and second-choice recommendations in the treatment guidelines are appropriate for S. aureus associated skin infections in the community, except for two recommendations for penicillin. Given the variation in AMR levels between countries, age groups and health care settings, national data regarding AMR in the community should be taken into account when updating or developing primary care treatment guidelines.
National Feedback Reports
The data from the four Work Packages were collated for each country in the form of a National Feedback Report. The Reports included country specific recommendations and have been sent to all of the National GP Network Coordinators. The Reports will not be published in the public domain; it will be up to the National GP Coordinator, to use his/ her network to disseminate the findings (e.g. presentations at National Conferences, publications in National Journals and discussions with national authorities and stakeholders).
Potential Impact:
4.1.4.1. Impact of the project
The APRES project contributes to evidence in Europe on appropriate prescribing of antibiotics by primary care physicians in Europe. So far there has been very limited scientific knowledge on the appropriateness of prescribing antibiotics by primary care physicians which takes into account antibiotic resistance patterns in the community. This is partly due to a lack of information about the antibiotic resistance patterns of commensal bacteria in the community. The APRES project provides rates of antibiotic resistance in the community for S. aureus and S. pneumoniae, which frequently cause bacterial skin infections and pneumonia.
The results will also be immediately translated into recommendations for existing or new guidelines on the prescription of antibiotics by primary care physicians in general and for bacterial skin infections and pneumonia at a national level in the nine participating countries. APRES has prepared a National Feedback Report for each participating country and these will be communicated directly to the institutions responsible for issuing the guidelines in each country.
By applying the same methodology to collect data on antibiotic resistance in the community and prescription patterns valid comparisons can be made beyond the national level. In addition, the APRES project will complement knowledge on antibiotic resistance patterns established by previous collaborations on the European level in the EARSS and ESAC projects by providing new data in the community (e.g. the variation in antibiotic prescriptions between primary care practices).
The overview of databases and information sources on outpatient antibiotic prescriptions and antibiotic resistance (WP1) will facilitate the future monitoring of changes in antibiotic resistance and (the necessity for) changes in antibiotic prescribing.
4.1.4.2. Main dissemination activities
The APRES project aims to serve various users: scientists, policy makers, managers and professionals such as GPs. To reach each of these target groups, we have disseminated our results as follows:
- Scientific publications
- PhD theses
- Conferences: Presentations and Posters
- National Feedback Reports
- Final APRES Symposium
- The APRES website
Scientific publications
To reach a scientific audience, we have aimed to publish the APRES study results in peer-reviewed journals. It has been our policy to prefer publications in open access journals. For example, the APRES study protocol (Bijnen et al, 2012) and the WP1 literature review (Bell et al, 2013) were both published in BMC Infectious Diseases.
The articles that have been published are presented in Section 4.2. Below is a list of planned future publications:
Work Package 2:
Evaluation of phenotypic and molecular methods for identification of Streptococcus pneumonia.
Yahiaoui RY, den Heijer CDJ, Bruggeman CA, Stobberingh EE and the APRES Study Team.
Submitted
Work Package 3:
Antibiotic prescribing patterns in children: results from the APRES network.
Versporten et al
Antibiotic prescribing quality in primary care using disease-specific quality indicators: results from the APRES project
Adriaenssens et al
Work Package 4:
Primary care treatment guidelines for skin infections in Europe: appropriate regarding antimicrobial resistance in the community. van Bijnen EE, Paget WJ, den Heijer CDJ, Stobberingh EE, Versporten A, Goossens H, CA Bruggeman, FG Schellevis, in collaboration with the APRES Study Team. Submitted to BMC Family Practice
Other Partners within the APRES project:
Austria: Oral contraceptives and antibiotics. A cross-sectional study about patients´ knowledge in General Practice. Hoffmann K et al. Submitted - 2014
Spain: Prevalence and factors associated with Staphylococcus aureus and Streptococcus pneumoniae colonization in primary care patients. Boada A et al. Enferm Infecc Microbiol Clin. Submitted and under review 2014.
Spain: APRES sub-project. This study aims: a) to determine the association between Staphylococcus aureus and/or Streptococcus pneumoniae carriage and previous consumption of antibiotics in primary care patients in Catalonia and to identify associated factors, and b) to describe the impact of previous antibiotic consumption on antibiotic resistance in carriers and to identify associated factors. Pons-Vigués M et al. Planned for BMC Infectious Diseases.
PhD theses
Five PhD theses will result from the APRES project:
- Casper den Heijer, graduated 2013, Prevalence and resistance of the commensal flora in non-hospitalized patients, Maastricht University, the Netherlands
- Evelien van Bijnen, PhD student, VU University, Amsterdam, the Netherlands, expected 2014
- Ann Versporten, PhD student, University of Antwerp, Antwerp, Belgium, expected 2014
- Albert Boada, Spain, expected October 2014
- László R. Kolozsvári, University of Debrecen, Hungary, expected 2014
Conferences: Presentations and Posters
Presentation: European General Practice Research Network, Krakow, Poland, October 2011.
Evelien van Bijnen: The appropriateness of prescribing antibiotics in primary care in Europe with respect to antibiotic resistance
APRES Symposium: World Organization of Family Doctors (WONCA Conference-Europe), 4-7 June 2012, Vienna, Austria.
The Symposium was organised on 6 July and was attended by roughly 200 participants. Presentations:
- Knowledge on antibiotics in Austria (Kathryn Hoffman, Medizinische Universität Wien)
- Literature review on relationship between antibiotic prescription and resistance (Brian Bell, University of Nottingham)
- Antibiotic resistance in Europe (Casper den Heijer, Maastricht University)
- Antibiotic prescription in Europe (Samuel Coenen, University of Antwerpen)
- Antibiotic prescription guidelines in Europe (Evelien van Bijnen, NIVEL)
Presentation: CARE Day, Utrecht, the Netherlands, September 2012
Presentation: European General Practice Research Network, Krakow, Poland, October 2011.
Evelien van Bijnen: The appropriateness of prescribing antibiotics in primary care in Europe with respect to antibiotic resistance
Presentation: General Practice Research in Infectious diseases Network (GRIN) , 4-5 October 2013, Nice, France:
Assessment of antibiotic prescribing quality in primary care in six countries using disease-specific quality indicators. Niels Adriaenssens; Ann Versporten; Herman Goossens; Samuel Coenen and the APRES project group
Posters: European Congress of Clinical Microbiology and Infectious Diseases, 27-30 April 2013, Berlin, Germany:
1. The prevalence and resistance of commensal Staphylococcus aureus, including meticillin-resistant S. aureus, in nine European countries: a cross-sectional study. CDJ den Heijer, EME van Bijnen, WJ Paget, M. Pringle, H. Goossens, CA Bruggeman, F.G. Schellevis F, and EE Stobberingh and the APRES Study Team
2. Improving primary care treatment guidelines in Europe: importance of antibiotic susceptibility data. NIVEL: Evelien van Bijnen, John Paget, Francois Schellevis; Maastricht University: Casper den Heijer, Ellen Stobberingh, Cathrien Bruggeman in collaboration with the APRES Study Team
3. The appropriateness of prescribing antibiotics in primary care in Europe with respect to antibiotic resistance. Project poster. European Corner.
European Public Health Conference, 19-22 November 2014, Glasgow, Scotland
Submitted: The prevalence and resistance of commensal Staphylococcus aureus, including meticillin-resistant S. aureus, in nine European countries: a cross-sectional study. C.D.J. den Heijer, E.M.E. van Bijnen, W.J. Paget, M. Pringle, H. Goossens, C.A. Bruggeman, F.G. Schellevis and E.E. Stobberingh and the APRES Study Team
European Congress of Clinical Microbiology and Infectious Diseases, 10-13 May 2014, Barcelona, Spain.
Submitted: Fusidic acid resistance in Staphylococcus aureus nasal carriage strains in nine European countries. C.D.J. den Heijer, E.M.E. van Bijnen, W.J. Paget and E.E. Stobberingh, on behalf of the APRES Study Team
National Feedback Reports
The data from the different Work Packages were collated for each country in the form of a National Feedback Report. The Report includes country specific recommendations and has been sent to all National GP Network Coordinators. The Reports will not be published in the public domain. It will be up to the National GP Coordinator, to use his/ her network to disseminate the findings (e.g. presentations at National Conferences, publications in National Journals and discussions with national authorities and stakeholders).
Final APRES Symposium
We organised a final APRES Symposium at the end of the project on 27 and 28 February 2014 at the Royal Dutch Academy of Science in Amsterdam, the Netherlands. The first half day (27 February) was open to the APRES group and was aimed at summarising the findings of the project (approx. 40 participants).
The second day (approx. 75 participants) was an open to Symposium to discuss Antibiotics and and Resistance in Primary Care: the European Experience, with presentations by the Dutch Ministry of Health, ECDC, WHO Euro and international scientists:
- Welcome (Prof. Peter Groenewegen, Director of NIVEL)
- Antibiotic resistance as a health threat: implications for policy. (Philip van Dalen, Dutch Ministry of Health)
- Surveillance of antibiotic resistance and antibiotic consumption in Europe (Dr Dominique Monnet, ECDC)
- Antibiotics and resistance in the WHO Euro region (Dr Nienke van de Sande, WHO Euro)
- Key findings of the EU-funded APRES study (Prof. Francois Schellevis, NIVEL)
- Antibiotic prescription patterns in Europe (Prof. Herman Goossens, University of Antwerp)
- Antimicrobial resistance patterns in Europe (Dr Ellen Stobberingh, RIVM)
- The GRACE project: Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe (Prof. Theo Verheij, University of Utrecht)
- The Dutch Working Party on Antibiotic Policy (SWAB): treatment guidelines and stewardship activities in the Netherlands (Prof. Jan Prins, University of Amsterdam)
- The Dutch College of General Practitioners: treatment guidelines and antimicrobial resistance (Dr Jako Burgers, Dutch College of General Practitioners)
- Panel and Public discussion (moderated by Prof. Mike Pringle, University of Nottingham)
Discussion topics:
- The research agenda for the future
- The policy initiatives required now
- Communications with clinicians, managers and policy makers
APRES website
Dissemination activities were undertaken via the APRES website throughout the project, with a part for the general public and a part for professionals:
- An outline of the APRES project and partners
- General news updates
- A Newsletter (12 Newsletters were published between October 2010 and December 2012). These provided updates on the project and progress with data collection efforts.
- General background information about the APRES project e.g. contact information
- Information about the APRES Symposium 2014
List of Websites:
The address of the project website is: www.nivel.eu/apres
Contact details for the APRES project:
Prof. Francois Schellevis (Coordinator and Steering Committee Chair)
NIVEL - Netherlands Institute for Health Services Research
P.O. Box 1568 3500 BN Utrecht, the Netherlands
Email: f.schellevis@nivel.nl
Logo (see APRES Attachment.pdf)
Project Partners:
1. NIVEL (Stichting Nederlands Instituut voor onderzoek van de gezondheidszorgCoordinator, Work Package Leader, Participant/GP network
2. The University of Nottingham, United Kingdom: Work Package Leader, Participant
3. Universiteit Maastricht, the Netherlands: Work Package Leader, Participant/Laboratory
4. Universiteit Antwerpen, Belgium: Work Package Leader, Participant/Laboratory
5. Royal College of General Practitioners, United Kingdom Participant/GP network
6. Société Française de Médecine Générale, France: Participant/GP network
7. Sveučilišta u Zagrebu, Medicinski Fakultet, Croatia: Participant/GP Network/Laboratory
8. Allgemein Oeffentliches Krankenhaus der Elisabethinen, Austria: Participant/Laboratory
9. North Bristol National Health Service Trust, United Kingdom: Participant/Laboratory
10. Medizinische Universiät Wien, Austria: Participant/GP Network
11. Institut d’Investigació en Atenció Primària Jordi Gol, Spain: Participant/GP network & Institut Català de la Salut, Spain: Third Party/Laboratory
12. Debreceni Egyetem, Hungary: Participant/GP network/Laboratory
13. Katholieke Universiteit Leuven, Belgium: Participant/GP network
14. Jönköping County Council, Sweden: Participant/GP network/Laboratory
4.1.1. Executive summary
Despite the fact that over 90% of all antibiotics in Europe are prescribed in primary care settings, information on prescriptions and resistance patterns in the community are currently incomplete. So far, information on the prevalence of resistance to antimicrobial drugs in Europe has mainly been obtained from invasive strains collected in hospital settings. The aim of the APRES study was to investigate the appropriateness of antibiotic prescribing in primary care in Europe by collecting and combining patterns of antibiotic resistance patterns and antibiotic prescription patterns. We also evaluated the appropriateness of national antibiotic prescription guidelines in relation to resistance patterns.
Antibiotic resistance was studied in an opportunistic sample from the community in nine European countries (Austria, Belgium, Croatia, France, Hungary, Spain, Sweden, the Netherlands, and the UK). Studies by the European Surveillance of Antimicrobial Consumption have shown that these countries represent the whole range of low to high volumes of antibiotic use. Resistance data were collected by taking a nose swab from persons (N = 4,000 per country) visiting a primary care practice for a non-infectious disease. Staphylococcus aureus and Streptococcus pneumoniae were isolated in national laboratories and tested for resistance in a central laboratory (Maastricht University Medical Centre). Data on antibiotic prescriptions over the past 5 years were extracted from the electronic medical records of the General Practitioners (GPs) who collected the nose swabs. Combining these two datasets with existing treatment guidelines, APRES was able to investigate the appropriateness of antibiotic prescribing in primary care in Europe.
The APRES study has collected unique data concerning resistance patterns, prescription behaviours and treatment guidelines in primary care in nine European countries. It found that the adjusted S. aureus prevalence for patients older than 18 years was 21.6%, ranging from 12.1% in Hungary to 29.4% in Sweden. Except for the known high resistance against penicillin, the highest recorded resistance rate was found for azithromycin (from 1.6% in Sweden to 16.9% in France) and a total of 91 MRSA strains were isolated (the highest MRSA prevalence (2.1%) was reported in Belgium). For S. pneumoniae, the prevalence ranged from 1% in Austria and the United Kingdom to 4% in France. There was more variation in antibiotic resistance rates in the S. pneumoniae specimens, with high rates in Spain and low rates in Sweden.
For the prescription patterns, APRES found that the median and average number of packages prescribed per 100 active patients for the year 2010 was highest in Croatia and Hungary and lowest in Sweden, France and Austria. High variations in use between the different practices at a country level were reported in Hungary, Croatia and Belgium. We also collected and analysed primary care treatment guidelines for skin infections and found similar recommendations (mostly recommend Beta Lactam penicillins) across Europe, but variability in the advised dosage and limited use of scientific references focussed on antibiotic resistance patterns. Finally, we combined the treatment guidelines for skin infections presumably caused by S. aureus and antibiotic resistance patterns, and found that theoretical treatment effectiveness was generally high across Europe.
These results are valuable for policy makers across Europe, and provide the basis for evidence-based treatment guidelines that take into account resistance patterns for practicing GPs in primary care. By improving antibiotic use in Europe we can move towards controlling the resistance problem globally.
Project Context and Objectives:
4.1.2.1. Summary descripton of the project context
Since the discovery of penicillin [Fleming, 1929] antibiotics have made a major contribution to public health. Infectious diseases have been treated more effectively, and mortality from infectious diseases has fallen in developed countries, though the contribution of improvements in nutrition and hygiene should not be forgotten. Despite this progress, any new antibiotic inevitably leads to the development of resistance sooner or later [Levy, 1997] and over the last 50 years the increasing volume of antibiotics used has exerted selective pressure on susceptible bacteria and favoured the survival of resistant strains [Summers, 2002], some of which are resistant to more than one antibiotic. This has led to a race between increasing levels of resistance against available antibiotics and the development of new generations of antibiotics , and there is a risk that the race will be lost by the pharmaceutical companies [van den Boogaard, 2000]. The lack of new antibiotics in a setting of diminishing effectiveness of existing antibiotics will eventually be responsible for increased morbidity, higher mortality and lower life expectancy [Livermore, 2003; Levy, 2005; Harbarth & Samore, 2005].
The development of resistance starts with a genetic mutation, either intrinsic (spontaneous mutation) or by acquisition of a resistance gene from another bacterium. Resistance genes give rise to antibiotic degradation, the production of inactivating enzymes or alteration of the drug receptor site [Davies, 1997]. The survival and multiplication of resistant bacteria depends largely on selection pressures to which they are exposed in accordance with the Darwinian principle. If the selection pressure of excessive antibiotic use is reduced, resistant bacteria may be replaced by susceptible bacteria, especially because in other respects resistant bacteria may be less ‘fit’ than those susceptible [Lipsitch et al, 2000].
The degree of antibiotic resistance in a population is strongly correlated with the level of antibiotic usage and the ease with which bacteria can disseminate [van den Boogaard, 2000]. Hospitalized patients, especially in intensive care environments, with high exposure to antibiotics are particularly prone to colonisation and infection [Struelens, 1998]. However, more than 90% of antibiotics are consumed by outpatients [Goossens, 2004] and these represent the selection pressure on the commensal flora in community-dwelling persons. The commensal flora of community-dwelling persons is therefore becoming an important reservoir of resistant bacteria. However, we have almost no knowledge of the prevalence and pattern of antibiotic resistance in the commensal flora of community-dwelling persons.
When studying the antibiotic resistance pattern of the commensal flora in the community, many bacteria are eligible. For this project we have chosen to focus on Staphylococcus aureus and Streptococcus pneumoniae. As mentioned in the recent report of the European Academies Science Advisory Council [EASAC, 2007], major problems are among others encountered for S. aureus and S. pneumoniae especially in the community. S. aureus is a major concern due to community acquired methicillin resistant S. aureus (CA-MRSA) which causes severe skin infections and pneumonia. S. pneumoniae is a major concern because of its increasing resistance to macrolides and fluoroquinolones in patients with COPD, the third most common cause of death in Europe.
Fighting antibiotic resistance starts with restricted use of antibiotics. This leads to less selection pressure on the bacterial flora, circulating in the population, but also of the commensal flora in an individual. Several studies have described the effectiveness of altering antibiotic prescribing policies on antibiotic resistance [e.g. Seppala et al, 1997]. The enormous variation between countries in antibiotic consumption cannot be justified by differences in the burden of infectious diseases but is related to differences in prescribing habits, antibiotic policies and socio-economic and cultural aspects [Cars, 2001].
The European Surveillance of Antimicrobial Consumption (ESAC) carried out a study in 33 European countries which showed that outpatient antibiotic use varied from 10.2 defined daily doses (DDDs) per 1,000 inhabitants in Romania to 38.6 DDDs in Greece [Adriaenssens, 2011]. The high correlation between the volume of consumption of antibiotics in outpatient settings and the rate of antibiotic resistance as seen in hospitalized patients (Spearman rank correlation 0.65-0.84; all p-values <0.01) for different bacteria and antibiotic agents underlines the importance of restricted use of antibiotics [Goossens, 2005].
Information on the volume of the consumption of antibiotics is not sufficient to establish the appropriate use of antibiotics. For an analysis of appropriateness, information on patterns of antibiotic resistance is also necessary. If the use of an antibiotic is considered necessary, an appropriate choice of the antibiotic agent is of utmost importance in order to treat the patient’s infection effectively and also to prevent the development of resistance and/or the colonisation of resistant bacteria present by minimizing the selection pressure on the commensal flora. The choice of an antibiotic agent should therefore be guided by the resistance pattern of the pathogen causing the infection to be treated [Warren et al, 1999].
In routine daily primary care the resistance pattern of a pathogen is unlikely to be known before treatment is initiated and is usually only tested after initial treatment failure. As mentioned before, the antibiotic resistance pattern of the commensal flora in the community is a valid indicator for pathogens causing infectious diseases in the community. Empirical information on this resistance pattern in a population is therefore valuable for a) assessing the appropriateness of the prescribing of antibiotics by primary care physicians and b) formulating guidelines for appropriately prescribing antibiotics.
4.1.2.2. Summary of the main objectives
Study objectives: The appropriateness of prescribing antibiotics in primary care in Europe with respect to antibiotic resistance (APRES)
The overall study objective was to research antibiotic resistance patterns in bacteria in the community and to examine the appropriateness of prescribed antibiotics to community-dwelling patients in order to make evidence based recommendations that will improve the appropriateness of antibiotic prescribing in primary care in Europe.
Each Work Package (WP) had study objectives in order to meet the overall objective:
WP1: Provide a state-of-the-art literature review about the association between outpatient consumption of antibiotics and antibiotic resistance patterns in the community. Also, provide an overview of information sources and databases containing information about outpatient antibiotic consumption or resistance.
WP2: Establish the pattern of resistance of Staphylococcus aureus and Streptococcus pneumoniae isolated from nasal mucous swab samples in healthy persons consulting their primary care physician. Antibiotic resistance will be studied in nine European countries by taking nasal mucous swabs of persons (target N=4,000 per country) visiting a primary care physician for a non-infectious disease. S. aureus and S. pneumoniae are isolated by a national laboratory, and tested for resistance to 13 antibiotics by one central laboratory.
WP3: Determine the patterns of prescribing antibiotics (volume and type) by primary care physicians in each participating country. Data on antibiotic prescriptions over the past 5 years will be extracted from the electronic medical records of General Practitioners (GPs).
WP4: Perform an integrated analysis of the resistance (WP2) and prescription data (WP3) to assess the appropriateness of prescribing antibiotics in each country. The results will be related to relevant treatment guidelines in the nine participating countries ( focussing on skin infections which are often caused by S. aureus), in order to formulate evidence-based recommendations on antibiotic prescribing.
The interaction of the Work Packages is summarized in Figure 1 (APRES Attachment.pdf). In summary, the association between prescription behaviour (WP3) and resistance patterns (WP2) was analysed, and we linked the resistance patterns to the current national guidelines (WP4).
An important final objective was the dissemination of the study results. This was carried out via a number of different initiatives, including: publications in scientific journals (included in three PhD theses), the presentation of results at General Practitioner conferences (e.g. WONCA Europe), the publication of National Feedback Reports, and the GP Network co-ordinators actively informing national stakeholders in each country.
Project Results:
This chapter describes the main Science and Technology results from the APRES project. It has been split into the four main Work Packages, with first a presentation of the main outputs and then a summary of the main findings.
4.1.3.1. Work Package 1: Work Package Leader - University of Nottingham
Publication:
A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. Bell BG, Schellevis F, Stobberingh E, Goossens H, Pringle M. BMC Infectious Diseases, 2014, 14:13.
Report:
Work Package 1: The Literature Review (68 pages)
Authors: Brian Bell and Mike Pringle
Other
A collection of relevant databases of information on resistance and/or prescription patterns has been created and can be viewed on the APRES website.
Summary of main findings:
Greater use of antibiotics during the past 50 years has exerted selective pressure on susceptible bacteria and may have favoured the survival of resistant strains. Existing information on antibiotic resistance patterns from pathogens circulating among community-based patients is substantially less than from hospitalized patients on whom guidelines are often based. We therefore chose to assess the relationship between the antibiotic resistance pattern of bacteria circulating in the community and the consumption of antibiotics in the community.
Both grey literature and published scientific literature in English and other European languages was examined. Multiple regression analysis was used to analyse whether studies found a positive relationship between antibiotic consumption and resistance. A subsequent meta-analysis and meta-regression was conducted for studies for which a common effect size measure (odds ratio) could be calculated.
Electronic searches identified 974 studies but only 243 studies were considered eligible for inclusion by the two independent reviewers who extracted the data. A binomial test revealed a positive relationship between antibiotic consumption and resistance (p < 0.001) but multiple regression modelling did not produce any significant predictors of resistance. The meta-analysis generated a significant pooled odds ratio of 2.3 (95% confidence interval 2.2 to 2.5) with a meta-regression producing several significant predictors (F(10,77) = 5.82 p < 0.01). Countries in southern Europe produced a stronger link between consumption and resistance than other regions.
Using a large set of studies we found that antibiotic consumption is associated with the development of antibiotic resistance. A subsequent meta-analysis, with a subsample of the studies, generated several significant predictors. Countries in southern Europe produced a stronger link between consumption and resistance than other regions so efforts at reducing antibiotic consumption may need to be strengthened in this area. Increased consumption of antibiotics may not only produce greater resistance at the individual patient level but may also produce greater resistance at the community, country, and regional levels, which can harm individual patients.
4.1.3.2. Work Package 2: Work Package Leader - Maastricht University
Publications:
Prevalence and resistance of commensal Staphylococcus aureus, including meticillin-resistant S aureus, in nine European countries: a cross-sectional study. den Heijer CDJ, van Bijnen EME, Paget WJ, Pringle M, Goossens H, Bruggeman CA, Schellevis FG, Stobberingh EE, and the APRES Study Team. The Lancet Infectious Diseases, Volume 13, Issue 5, Pages 409 - 415, May 2013
doi:10.1016/S1473-3099(13)70036-7
Fusidic acid resistance in commensal Staphylococcus aureus in nine European countries.
den Heijer CDJ, van Bijnen EME, Paget WJ, Stobberingh EE, in collaboration with the APRES Study Team. Future Microbiology, in press.
Report:
Prevalence and resistance of commensal Staphylococcus aureus reports for each participating country, December 2012
Other:
- GP databases sent to each country on the prevalence and resistance of commensal S. aureus (December 2012)
- GP databases sent to each country on the prevalence and resistance of commensal S. pneumoniae (March 2014)
- Casper den Heijer, PhD student, graduated 2013
Summary of main findings:
Information about the prevalence of Staphylococcus aureus and Streptococcus pneumonia resistance to antimicrobial drugs has mainly been obtained from invasive strains, although the commensal microbiota is thought to be an important reservoir of resistance. We aimed to compare the prevalence of nasal S. aureus and S. pneumoniae carriage and antibiotic resistance, including meticillin-resistant S. aureus (MRSA), in healthy patients across nine European countries.
In this cross-sectional study, nasal swabs were obtained from 32,206 patients recruited by family doctors participating in existing nationwide family doctor networks in Austria, Belgium, Croatia, France, Hungary, Spain, Sweden, the Netherlands, and the UK. Eligible patients were aged 4 years or older (≥18 years in the UK) and presented with a non-infectious disorder. Swabs were sent to national microbiological laboratories for identification and isolation of S. aureus (Figure 2, APRES Attachment.pdf) . Antibiotic resistance testing was done at one central microbiological laboratory at Maastricht University. We established the genotypic structure of the isolated MRSA strains with the spa typing method.
S. aureus was isolated from 6,956 (21.6%) of 32,206 patients swabbed. The adjusted (age, sex and family doctor) S. aureus prevalence for patients older than 18 years ranged from 12.1% (Hungary) to 29.4% (Sweden) (Figure 3, APRES Attachment.pdf). Except for the known high resistance against penicillin, the highest recorded resistance rate was to azithromycin (from 1.6% in Sweden to 16.9% in France) (Table 1, APRES Attachment.pdf). In total, 91 MRSA strains were isolated, with an average prevalence of 1.3%, ranging from 0% in Sweden to 2.1% in Belgium. 53 different spa types were detected—the most prevalent were t002 (n=9) and t008 (n=8). For S. pneumoniae, the prevalence ranged from 1% in Austria and the United Kingdom to 4% in France (Figure 3, APRES Attachment.pdf). There was more variation in antibiotic resistance rates in the S. pneumoniae specimens, with highest rates in Spain and lowest rates in Sweden (Table 2, APRES Attachment.pdf).
In conclusion, the prevalence of S. aureus nasal carriage differed across the nine European countries assessed, even after correction for age, sex, and family doctor, and the prevalence of S. pneumoniae was low. Generally, the prevalence of resistance in S. aureus samples, including that of MRSA, was low. For S. pneumonaie there was more variation in resistance (e.g. Sweden versus Spain).
4.1.3.3. Work Package 3: Work Package Leader - University of Antwerpen
Publications:
In preparation
Report:
APRES: Work Package 3: Establishing the antibiotic prescribing patterns (58 pages)
Profs. Herman Goossens and Samuel Coenen, Ann Versporten and Dr. Niels Adriaenssens
Other:
- Data validation report (sent to all nine countries): national overview of antibiotic prescribing data
- Ann Versporten, PhD student
Summary of main findings:
Work Package 3 aimed to establish the pattern of prescribed antibiotics (volume and type) in primary care practices and its variation by diagnosis within and between nine European countries. It further aimed to describe variation of antibiotic prescription by patients’ age, gender and by diagnosis.
The selected networks of general practitioners retrieved anonymous antibiotic prescribing data from electronic medical records of all patients listed in the participating primary care practices. The study population was all patients who were prescribed an antibiotic in each practice, and the corresponding denominator, i.e. the number of people in the practice population and/or the number of active patients (defined as having visited the practice at least once in the previous 12 months). The main study covered the period from January 2006 to March 2011. The study mainly focused on antibiotic prescription data of the year 2010 as this this was the year when nasal swabs were collected (Work Package 2) and it was the most reliable and complete data.
Data validation included checking of data exhaustiveness and correctness of antibiotic volumes of use expressed in the number of packages and/or daily-defined doses (DDDs) per 100 active patients and/or listed patients for all years reported to the University of Antwerp. For each country, data were examined to make sure the WHO ATC/DDD classification methodology was correctly applied. As such, errors in ATC codes and/or DDDs were corrected. Inconsistencies were reported to the countries concerned and were subsequently corrected if possible. Aid was offered to countries encountering difficulties in the calculation of DDDs.
Overall, 208 practices of 9 countries reported at least for one year antibiotic use data. For the year 2010, data from 188 practices have been retained for further analyses. The median and average number of packages prescribed per 100 active patients for the year 2010 was highest for Croatia and Hungary and lowest for Sweden, France and Austria. On the other hand, Spain showed the highest overall volumes of antibiotic use if expressed in average number of DDD per 100 active patients for the year 2010.
Figure 4 (APRES Attachment.pdf) (expressed in DDD/100 active patients in the year 2010) highlights high variations in use between the different practices at country level, especially in Hungary, Belgium and Spain (biggest range between minimum and maximum of reported antibiotic use).
Analyses were performed for antibiotics at an ATC 3 level (pharmacological subgroups), at an ATC4 level (chemical subgroups) for age group and gender and an ATC5 level (substance level). We looked at antibiotics by diagnosis and assessed antibiotic use according to a set of disease-specific antibiotic prescribing quality indicators (APQI) to assess the quality of antibiotic prescribing in primary care [Adriaenssens et al, 2011]. Longitudinal trends were also assessed.
Finally, the APRES data was compared to ESAC-Net data (which employs national whole sales or reimbursement antibiotic consumption data for ambulatory care) and showed similar outcomes at country level (for proportional antibiotic use at ATC3 level, year 2010). Differences between countries were revealed to be higher than the differences within countries. In Austria, Hungary, Spain and Sweden, the APRES data showed a more than 5% higher proportional penicillin use compared to the ESAC-Net data . In Austria the APRES data showed more than 5% less macrolide use, while in Hungary the proportion of prescribed tetracyclines and quinolones was lower, probably due to the participation of pediatric practices. In the other countries differences in proportion were less than 5%.
In conclusion, APRES was able to collect valid data for the 9 countries participating to the APRES project. Our study analyzed antibiotic use volumes expressed in number of packages versus DDDs per 100 active patients for the year 2010. The collection of data following the standardized WHO ATC/DDD method was difficult to implement for some countries leaving some issues unresolved (underreporting of DDDs). The study could also highlight the difficulty of using DDDs for children (invalid for paediatric formulations) and it observed very different prescribing practices among the participating countries. Overall, countries with higher volumes of antibiotic use (Croatia, Hungary) also used more broad spectrum antibiotics and vice versa (Sweden).
4.1.3.4. Work Package 4: Work Package Leader - NIVEL
Publications:
The appropriateness of prescribing antibiotics in the community in Europe: study design.
van Bijnen EME, den Heijer CDJ, Paget WJ, Stobberingh EE, Verheij RA, Bruggeman CA, Pringle M, Goossens H, Schellevis FG. BMC Infectious Diseases 2011, 11:293 (28 October 2011)
Evidence-based primary care treatment guidelines for skin infections in Europe: a comparative analysis. Bijnen, EME van, Paget J, Heijer CDJ den, Stobberingh EE, Bruggeman CA, Schellevis FG. (2014). European Journal of General Practice, 23 January.
Reports:
- National Feedback Report - Austria (32 pages)
- National Feedback Report - Belgium (32 pages)
- National Feedback Report - Croatia (32 pages)
- National Feedback Report - France (32 pages)
- National Feedback Report - Hungary (32 pages)
- National Feedback Report - the Netherlands (32 pages)
- National Feedback Report - Spain (32 pages)
- National Feedback Report - Sweden (32 pages)
- National Feedback Report - United Kingdom (32 pages)
Other:
Evelien van Bijnen, PhD student
Summary of main findings:
Most antibiotics for human use are prescribed in primary care. Incorporating resistance data into treatment guidelines could improve appropriate prescribing, increase treatment effectiveness and control the development of resistance. We carried out two studies: 1) a review of primary care treatment guidelines for bacterial skin infections and an assessment of the extent to which the guidelines are based on antibiotic resistance data and 2) an assessment of the primary care treatment guidelines with respect to antimicrobial resistance (AMR) patterns (the recommendations were considered appropriate if resistance to the antibiotic did not exceed 20%).
In the first study, thirteen primary care treatment guidelines were obtained from eight countries across Europe. Both the treatment recommendations and the underlying evidence were assessed. The class and dose of recommended antibiotics were investigated and compared using the World Health Organisation’s standardized volume of Defined Daily Dose. Furthermore, the study investigated whether guidelines included references to scientific publications about antibiotic resistance data, and whether these were of national origin.
Guidelines were included regarding common skin infections in primary care: Impetigo, Cellulitis, Erysipelas, Folliculitis and Furuncle (Table 3, APRES Attachment.pdf). Results showed a high agreement across Europe: all recommended antibiotics are of the beta-lactam class and mainly small spectrum. The advised treatment durations are consistent; the dosages, however, vary considerably, with the highest dosages recommended in Sweden. Seven guidelines (54%) did not include scientific references related to resistance.
In the second study, we included primary care treatment guidelines for impetigo, cellulitis, folliculitis and furuncle. Treatment recommendations in all countries were congruent: most of the first-choice recommendations were beta-lactams, both for children and adults. AMR levels were low, except for penicillin (on average 73% resistance). Considerable variation in AMR levels between countries was found, with Sweden displaying the lowest levels and Spain the highest. In some countries resistance to penicillin and azithromycin was significantly higher in children (4-17 years) compared with adults.
The assessment of the primary care treatment guidelines found that there may be a lack of relevant national data on resistance. The study highlighted the need to collect more national resistance data (particularly regarding beta-lactams) to create stronger evidence-based treatment guidelines for skin infections in Europe.
The assessment of primary care treatment guidelines with respect to AMR found that most of the first- and second-choice recommendations in the treatment guidelines are appropriate for S. aureus associated skin infections in the community, except for two recommendations for penicillin. Given the variation in AMR levels between countries, age groups and health care settings, national data regarding AMR in the community should be taken into account when updating or developing primary care treatment guidelines.
National Feedback Reports
The data from the four Work Packages were collated for each country in the form of a National Feedback Report. The Reports included country specific recommendations and have been sent to all of the National GP Network Coordinators. The Reports will not be published in the public domain; it will be up to the National GP Coordinator, to use his/ her network to disseminate the findings (e.g. presentations at National Conferences, publications in National Journals and discussions with national authorities and stakeholders).
Potential Impact:
4.1.4.1. Impact of the project
The APRES project contributes to evidence in Europe on appropriate prescribing of antibiotics by primary care physicians in Europe. So far there has been very limited scientific knowledge on the appropriateness of prescribing antibiotics by primary care physicians which takes into account antibiotic resistance patterns in the community. This is partly due to a lack of information about the antibiotic resistance patterns of commensal bacteria in the community. The APRES project provides rates of antibiotic resistance in the community for S. aureus and S. pneumoniae, which frequently cause bacterial skin infections and pneumonia.
The results will also be immediately translated into recommendations for existing or new guidelines on the prescription of antibiotics by primary care physicians in general and for bacterial skin infections and pneumonia at a national level in the nine participating countries. APRES has prepared a National Feedback Report for each participating country and these will be communicated directly to the institutions responsible for issuing the guidelines in each country.
By applying the same methodology to collect data on antibiotic resistance in the community and prescription patterns valid comparisons can be made beyond the national level. In addition, the APRES project will complement knowledge on antibiotic resistance patterns established by previous collaborations on the European level in the EARSS and ESAC projects by providing new data in the community (e.g. the variation in antibiotic prescriptions between primary care practices).
The overview of databases and information sources on outpatient antibiotic prescriptions and antibiotic resistance (WP1) will facilitate the future monitoring of changes in antibiotic resistance and (the necessity for) changes in antibiotic prescribing.
4.1.4.2. Main dissemination activities
The APRES project aims to serve various users: scientists, policy makers, managers and professionals such as GPs. To reach each of these target groups, we have disseminated our results as follows:
- Scientific publications
- PhD theses
- Conferences: Presentations and Posters
- National Feedback Reports
- Final APRES Symposium
- The APRES website
Scientific publications
To reach a scientific audience, we have aimed to publish the APRES study results in peer-reviewed journals. It has been our policy to prefer publications in open access journals. For example, the APRES study protocol (Bijnen et al, 2012) and the WP1 literature review (Bell et al, 2013) were both published in BMC Infectious Diseases.
The articles that have been published are presented in Section 4.2. Below is a list of planned future publications:
Work Package 2:
Evaluation of phenotypic and molecular methods for identification of Streptococcus pneumonia.
Yahiaoui RY, den Heijer CDJ, Bruggeman CA, Stobberingh EE and the APRES Study Team.
Submitted
Work Package 3:
Antibiotic prescribing patterns in children: results from the APRES network.
Versporten et al
Antibiotic prescribing quality in primary care using disease-specific quality indicators: results from the APRES project
Adriaenssens et al
Work Package 4:
Primary care treatment guidelines for skin infections in Europe: appropriate regarding antimicrobial resistance in the community. van Bijnen EE, Paget WJ, den Heijer CDJ, Stobberingh EE, Versporten A, Goossens H, CA Bruggeman, FG Schellevis, in collaboration with the APRES Study Team. Submitted to BMC Family Practice
Other Partners within the APRES project:
Austria: Oral contraceptives and antibiotics. A cross-sectional study about patients´ knowledge in General Practice. Hoffmann K et al. Submitted - 2014
Spain: Prevalence and factors associated with Staphylococcus aureus and Streptococcus pneumoniae colonization in primary care patients. Boada A et al. Enferm Infecc Microbiol Clin. Submitted and under review 2014.
Spain: APRES sub-project. This study aims: a) to determine the association between Staphylococcus aureus and/or Streptococcus pneumoniae carriage and previous consumption of antibiotics in primary care patients in Catalonia and to identify associated factors, and b) to describe the impact of previous antibiotic consumption on antibiotic resistance in carriers and to identify associated factors. Pons-Vigués M et al. Planned for BMC Infectious Diseases.
PhD theses
Five PhD theses will result from the APRES project:
- Casper den Heijer, graduated 2013, Prevalence and resistance of the commensal flora in non-hospitalized patients, Maastricht University, the Netherlands
- Evelien van Bijnen, PhD student, VU University, Amsterdam, the Netherlands, expected 2014
- Ann Versporten, PhD student, University of Antwerp, Antwerp, Belgium, expected 2014
- Albert Boada, Spain, expected October 2014
- László R. Kolozsvári, University of Debrecen, Hungary, expected 2014
Conferences: Presentations and Posters
Presentation: European General Practice Research Network, Krakow, Poland, October 2011.
Evelien van Bijnen: The appropriateness of prescribing antibiotics in primary care in Europe with respect to antibiotic resistance
APRES Symposium: World Organization of Family Doctors (WONCA Conference-Europe), 4-7 June 2012, Vienna, Austria.
The Symposium was organised on 6 July and was attended by roughly 200 participants. Presentations:
- Knowledge on antibiotics in Austria (Kathryn Hoffman, Medizinische Universität Wien)
- Literature review on relationship between antibiotic prescription and resistance (Brian Bell, University of Nottingham)
- Antibiotic resistance in Europe (Casper den Heijer, Maastricht University)
- Antibiotic prescription in Europe (Samuel Coenen, University of Antwerpen)
- Antibiotic prescription guidelines in Europe (Evelien van Bijnen, NIVEL)
Presentation: CARE Day, Utrecht, the Netherlands, September 2012
Presentation: European General Practice Research Network, Krakow, Poland, October 2011.
Evelien van Bijnen: The appropriateness of prescribing antibiotics in primary care in Europe with respect to antibiotic resistance
Presentation: General Practice Research in Infectious diseases Network (GRIN) , 4-5 October 2013, Nice, France:
Assessment of antibiotic prescribing quality in primary care in six countries using disease-specific quality indicators. Niels Adriaenssens; Ann Versporten; Herman Goossens; Samuel Coenen and the APRES project group
Posters: European Congress of Clinical Microbiology and Infectious Diseases, 27-30 April 2013, Berlin, Germany:
1. The prevalence and resistance of commensal Staphylococcus aureus, including meticillin-resistant S. aureus, in nine European countries: a cross-sectional study. CDJ den Heijer, EME van Bijnen, WJ Paget, M. Pringle, H. Goossens, CA Bruggeman, F.G. Schellevis F, and EE Stobberingh and the APRES Study Team
2. Improving primary care treatment guidelines in Europe: importance of antibiotic susceptibility data. NIVEL: Evelien van Bijnen, John Paget, Francois Schellevis; Maastricht University: Casper den Heijer, Ellen Stobberingh, Cathrien Bruggeman in collaboration with the APRES Study Team
3. The appropriateness of prescribing antibiotics in primary care in Europe with respect to antibiotic resistance. Project poster. European Corner.
European Public Health Conference, 19-22 November 2014, Glasgow, Scotland
Submitted: The prevalence and resistance of commensal Staphylococcus aureus, including meticillin-resistant S. aureus, in nine European countries: a cross-sectional study. C.D.J. den Heijer, E.M.E. van Bijnen, W.J. Paget, M. Pringle, H. Goossens, C.A. Bruggeman, F.G. Schellevis and E.E. Stobberingh and the APRES Study Team
European Congress of Clinical Microbiology and Infectious Diseases, 10-13 May 2014, Barcelona, Spain.
Submitted: Fusidic acid resistance in Staphylococcus aureus nasal carriage strains in nine European countries. C.D.J. den Heijer, E.M.E. van Bijnen, W.J. Paget and E.E. Stobberingh, on behalf of the APRES Study Team
National Feedback Reports
The data from the different Work Packages were collated for each country in the form of a National Feedback Report. The Report includes country specific recommendations and has been sent to all National GP Network Coordinators. The Reports will not be published in the public domain. It will be up to the National GP Coordinator, to use his/ her network to disseminate the findings (e.g. presentations at National Conferences, publications in National Journals and discussions with national authorities and stakeholders).
Final APRES Symposium
We organised a final APRES Symposium at the end of the project on 27 and 28 February 2014 at the Royal Dutch Academy of Science in Amsterdam, the Netherlands. The first half day (27 February) was open to the APRES group and was aimed at summarising the findings of the project (approx. 40 participants).
The second day (approx. 75 participants) was an open to Symposium to discuss Antibiotics and and Resistance in Primary Care: the European Experience, with presentations by the Dutch Ministry of Health, ECDC, WHO Euro and international scientists:
- Welcome (Prof. Peter Groenewegen, Director of NIVEL)
- Antibiotic resistance as a health threat: implications for policy. (Philip van Dalen, Dutch Ministry of Health)
- Surveillance of antibiotic resistance and antibiotic consumption in Europe (Dr Dominique Monnet, ECDC)
- Antibiotics and resistance in the WHO Euro region (Dr Nienke van de Sande, WHO Euro)
- Key findings of the EU-funded APRES study (Prof. Francois Schellevis, NIVEL)
- Antibiotic prescription patterns in Europe (Prof. Herman Goossens, University of Antwerp)
- Antimicrobial resistance patterns in Europe (Dr Ellen Stobberingh, RIVM)
- The GRACE project: Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe (Prof. Theo Verheij, University of Utrecht)
- The Dutch Working Party on Antibiotic Policy (SWAB): treatment guidelines and stewardship activities in the Netherlands (Prof. Jan Prins, University of Amsterdam)
- The Dutch College of General Practitioners: treatment guidelines and antimicrobial resistance (Dr Jako Burgers, Dutch College of General Practitioners)
- Panel and Public discussion (moderated by Prof. Mike Pringle, University of Nottingham)
Discussion topics:
- The research agenda for the future
- The policy initiatives required now
- Communications with clinicians, managers and policy makers
APRES website
Dissemination activities were undertaken via the APRES website throughout the project, with a part for the general public and a part for professionals:
- An outline of the APRES project and partners
- General news updates
- A Newsletter (12 Newsletters were published between October 2010 and December 2012). These provided updates on the project and progress with data collection efforts.
- General background information about the APRES project e.g. contact information
- Information about the APRES Symposium 2014
List of Websites:
The address of the project website is: www.nivel.eu/apres
Contact details for the APRES project:
Prof. Francois Schellevis (Coordinator and Steering Committee Chair)
NIVEL - Netherlands Institute for Health Services Research
P.O. Box 1568 3500 BN Utrecht, the Netherlands
Email: f.schellevis@nivel.nl
Logo (see APRES Attachment.pdf)
Project Partners:
1. NIVEL (Stichting Nederlands Instituut voor onderzoek van de gezondheidszorgCoordinator, Work Package Leader, Participant/GP network
2. The University of Nottingham, United Kingdom: Work Package Leader, Participant
3. Universiteit Maastricht, the Netherlands: Work Package Leader, Participant/Laboratory
4. Universiteit Antwerpen, Belgium: Work Package Leader, Participant/Laboratory
5. Royal College of General Practitioners, United Kingdom Participant/GP network
6. Société Française de Médecine Générale, France: Participant/GP network
7. Sveučilišta u Zagrebu, Medicinski Fakultet, Croatia: Participant/GP Network/Laboratory
8. Allgemein Oeffentliches Krankenhaus der Elisabethinen, Austria: Participant/Laboratory
9. North Bristol National Health Service Trust, United Kingdom: Participant/Laboratory
10. Medizinische Universiät Wien, Austria: Participant/GP Network
11. Institut d’Investigació en Atenció Primària Jordi Gol, Spain: Participant/GP network & Institut Català de la Salut, Spain: Third Party/Laboratory
12. Debreceni Egyetem, Hungary: Participant/GP network/Laboratory
13. Katholieke Universiteit Leuven, Belgium: Participant/GP network
14. Jönköping County Council, Sweden: Participant/GP network/Laboratory