Tobacco products in the European Union Common Entry Gate (EU-CEG): A tool for monitoring the EU tobacco products directive.

INTRODUCTION: Under the European Union (EU) Tobacco Products Directive (2014/40/EU) (TPD), manufacturers and importers of tobacco products are required to report information to the European Commission (EC) and Member States (MS) on products intended to be placed on the market. We describe the distribution of notifications to the EU Common Entry Gate (EU-CEG) and identify key fields for improvement on reporting cigarettes or roll-your-own (RYO) tobacco. METHODS: A cross-sectional analysis of secondary data reported in the EU-CEG was conducted for tobacco products notified within EU-CEG between June 2016 and October 2019 for 12 EU MS. Analysis of compliance to specific regulations for priority additives that refer to cigarettes and RYO was conducted for 10 EU countries. RESULTS: Overall, 39170 tobacco products were notified. This included 16762 (42.8%) notifications of cigars, followed by cigarettes 11242 (28.7 %), waterpipes 3291 (8.4%), cigarillos (n=1783), pipe (n=1715), RYO (n=1635), chewing tobacco (n=1021), novel tobacco products (n=839), herbal products for smoking (n=535), other (n=258), nasal (n=74) and oral tobacco (n=15). In cigarettes and RYO tobacco products, the proportion of ingredients notified in all countries that contained an unknown Chemical Abstract Services (CAS) number was 3.8% and 2.1%, respectively. The proportion of underreporting flagging of priority additives ranged from 15.9% in Malta to 41.3% in Lithuania, the mean proportion of underreporting of the variable 'priority additive' for the 10 countries together was 24.7%. CONCLUSIONS: In the EU-CEG data base, for the period of analysis, a significant number of product notifications took place while large variations in the number of types of tobacco products notified across EU countries was noted. The timely monitoring of these data is needed so that products non-compliant within the EU-CEG system are assessed.

Antimicrobial drug use and resistance in Europe.

Our study confronts the use of antimicrobial agents in ambulatory care with the resistance trends of 2 major pathogens, Streptococcus pneumoniae and Escherichia coli, in 21 European countries in 2000-2005 and explores whether the notion that antimicrobial drug use determines resistance can be supported by surveillance data at national aggregation levels. The data obtained from the European Surveillance of Antimicrobial Consumption and the European Antimicrobial Resistance Surveillance System suggest that variation of consumption coincides with the occurrence of resistance at the country level. Linear regression analysis showed that the association between antimicrobial drug use and resistance was specific and robust for 2 of 3 compound pathogen combinations, stable over time, but not sensitive enough to explain all of the observed variations. Ecologic studies based on routine surveillance data indicate a relation between use and resistance and support interventions designed to reduce antimicrobial drug consumption at a national level in Europe.

Outpatient antibiotic use in the four administrations of the UK: cross-sectional and longitudinal analysis.

OBJECTIVES: We compared community antibiotic use in the four administrations of the UK with that in other European countries. PATIENTS AND METHODS: A cross-sectional analysis of 24 European countries and UK administrations in 2005 with longitudinal analysis of data from Belgium and UK from 1997 was performed. Antibiotic use was measured as defined daily doses per 1000 inhabitants per day (DID) or as prescriptions or packages per 1000 inhabitants per day (PID) with aggregate data from patients who received antibiotics in the primary care or outpatient setting. RESULTS: In 2005, there were marked differences in antibiotic prescriptions between the four UK administrations, for example, in descending order of DIDs, Northern Ireland and England ranked 8th and 24th, respectively, out of the 28 countries. DIDs for Northern Ireland were 37% greater than that for England. Longitudinal analysis showed that differences were present before devolution in 1999. Increase in the age of exemption from prescription charges in Wales in 2002 was not associated with significant change in use in comparison with the other UK countries. There were discrepancies between changes in DID and changes in PID, particularly in Belgium. This suggests that some changes in DID were due to changes in dosing or duration of the treatment rather than in the number of people treated and shows the importance of using both measures. CONCLUSIONS: The European Surveillance of Antimicrobial Consumption project has for the first time made data about antibiotic use in the four UK administrations publicly available. This reveals important practice variations that should stimulate research to explain differences and assess their consequences.

Antibiotic consumption in southern and eastern Mediterranean hospitals: results from the ARMed project.

OBJECTIVES: The intensity of antibiotic use in hospital settings is recognized as possibly the most important factor for the selection of antimicrobial resistance. Hospitals are therefore being encouraged to undertake surveillance and benchmarking of antimicrobial consumption patterns with a view to identify and rectify possible evidence of overuse or misuse. METHODS: As part of the ARMed project, antibiotic use in 25 hospitals from the southern and eastern Mediterranean countries of Cyprus, Egypt, Jordan, Lebanon, Malta, Tunisia and Turkey was assessed prospectively for 24 months during the years 2004-05. The surveillance focused primarily on systemic antibiotics used in hospital care, aggregated at the level of the active substance, in accordance with the Anatomic Therapeutic Chemical (ATC) classification. RESULTS: The median total antibiotic use during the study period was 112 defined daily doses per 100 bed-days (DDD/100BD), with an inter-quartile range of 84-428 DDD/100BD. The most common antibiotic groups prescribed were the extended-spectrum and combination penicillins, first- and third-generation cephalosporins and quinolones. Overall, a predominant consumption of wide-spectrum agents was noted, with a significant correlation between the levels of use of third-generation cephalosporins and carbapenems. CONCLUSIONS: Emphasis on wide-spectrum agents could explain one possible factor behind the documented high prevalence of resistance in important pathogens within these same hospitals and suggests the need for improved antibiotic stewardship and prescribing programmes, which may well be applicable to the whole region.

Increasing telithromycin resistance among Streptococcus pyogenes in Europe.

OBJECTIVES: To assess changes in macrolide and ketolide resistance among Streptococcus pyogenes in Europe and to examine the relationship of resistance to antimicrobial usage. METHODS: Clinical S. pyogenes isolates were collected from Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, UK, Croatia, Hungary, Poland, Slovak Republic and Slovenia during 2002-03 (n = 2165) and 2004-05 (n = 2333). Resistance to telithromycin (MIC > or = 2) and erythromycin (MIC > or = 0.5) was determined by CLSI broth microdilution. Changes in resistance over time and the relationship of resistance to antimicrobial use (European Surveillance of Antimicrobial Consumption data) were assessed. Telithromycin-resistant isolates were characterized by PFGE to determine genetic relatedness and by PCR to detect mef(A), erm(A) and erm(B). RESULTS: The erythromycin resistance rate during 2004-05 (11.6%) was similar to 2002-03 (10.4%). The proportion of macrolide-resistant isolates with the constitutive MLS(B) phenotype increased from 29.3% (2002-03) to 45.7% (2004-05). Telithromycin resistance increased from 1.8% in 2002-03 to 5.2% in 2004-05. For Western Europe, associations of telithromycin and erythromycin resistance, respectively, were found with azithromycin use (R2 = 0.52 and 0.60), clarithromycin use (R2 = 0.76 and 0.85) and total macrolide/lincosamide use (R2 = 0.75 and 0.69). For Eastern Europe, associations of antimicrobial use with resistance were not apparent. The 162 telithromycin-resistant isolates comprised 42 PFGE patterns with 68.5% in eight major PFGE groups. The erm(B) gene was detected in 155 of the 162 telithromycin-resistant isolates. CONCLUSIONS: Significant increases in telithromycin resistance occurred from 2002-03 to 2004-05 in Europe. Macrolide use appears to be a factor in the emergence of ketolide resistance among S. pyogenes in Western Europe.

Comparison of outpatient systemic antibacterial use in 2004 in the United States and 27 European countries.

The European Surveillance of Antimicrobial Consumption (ESAC) project collects data on antibacterial use in Europe, applying the Anatomic Therapeutic Chemical classification system and defined daily dose methodology, as recommended by the World Health Organization. Comparable data for the United States have been collected from IMS Health. The IMS Health sales data, processed according to ESAC methodology, suggest that outpatient antibacterial use in the United States is high (only 3 of 27 European countries used more) and is mainly characterized by a shift towards newer antibiotics.

Outpatient antibiotic use in Europe and association with resistance: a cross-national database study.

BACKGROUND: Resistance to antibiotics is a major public-health problem and antibiotic use is being increasingly recognised as the main selective pressure driving this resistance. Our aim was to assess outpatient use of antibiotics and the association with resistance. METHODS: We investigated outpatient antibiotic use in 26 countries in Europe that provided internationally comparable distribution or reimbursement data, between Jan 1, 1997, and Dec 31, 2002, by calculating the number of defined daily doses (DDD) per 1000 inhabitants per day, according to WHO anatomic therapeutic chemical classification and DDD measurement methodology. We assessed the ecological association between antibiotic use and antibiotic resistance rates using Spearman's correlation coefficients. FINDINGS: Prescription of antibiotics in primary care in Europe varied greatly; the highest rate was in France (32.2 DDD per 1000 inhabitants daily) and the lowest was in the Netherlands (10.0 DDD per 1000 inhabitants daily). We noted a shift from the old narrow-spectrum antibiotics to the new broad-spectrum antibiotics. We also recorded striking seasonal fluctuations with heightened winter peaks in countries with high yearly use of antibiotics. We showed higher rates of antibiotic resistance in high consuming countries, probably related to the higher consumption in southern and eastern Europe than in northern Europe. INTERPRETATION: These data might provide a useful method for assessing public-health strategies that aim to reduce antibiotic use and resistance levels.

The more antibacterial trade names, the more consumption of antibacterials: a European study.

Recent studies have shown large differences in the use of antibacterial agents among European countries. We found a relationship between community consumption and the number of trade names of oral antibacterial agents. This relationship was observed in countries in which consumption was high, as well as in countries in which it was low, and in markets that were opened or were not opened to the sale of copies of original agents.

Socioeconomic determinants of outpatient antibiotic use in Europe.

OBJECTIVES: Outpatient antibiotic consumption widely varies across Europe. The investigation of the causes of such variation may help to identify interventions that would improve the efficient use of antibiotics. The aim of this study was to assess the impact of socioeconomic determinants and the role played by information about bacterial resistance. METHODS: Comparable data on systemically administered antibiotics and socioeconomic determinants in 17 European countries were available between 2000 and 2005. We estimated an ad hoc econometric model by means of a hybrid log-log functional form and random effects generalised least squares regressions. Lagged values and the instrumental variable method were applied to address endogeneity of bacterial resistance and infections. Bacterial resistance was measured by the rate of penicillin non-susceptible Streptococcus pneumoniae isolates (PNSP) and methicillin-resistant Staphylococcus aureus (MRSA). RESULTS: The population income, demographic structure, density of general practitioners and their remuneration method appeared to be significant determinants of antibiotic consumption. Although countries with higher levels of bacterial resistance exhibited significantly higher levels of per capita antibiotic use, ceteris paribus, the responsiveness of antibiotic use to changes in bacterial resistance was relatively low (0.09-0.18). CONCLUSIONS: The study confirms that socioeconomic factors should be taken into account while explaining differences in outpatient antibiotic use across countries. The impact of supply-side factors and incentives attached to payment schemes for physicians need to be considered in government interventions to reduce inequalities and improve effectiveness in antibiotic utilisation.

Antibiotic use in ambulatory care in Europe (ESAC data 1997-2002): trends, regional differences and seasonal fluctuations.

PURPOSE: The ESAC project (European Study on Antibiotic Consumption) aims to collect antibiotic-use data through a European network of national surveillance systems. This paper reports on the retrospective data collection in ambulatory care for the period 1997-2002. METHODS: Valid data of antibiotic consumption of 24 European countries for 2002 and of 18 countries for the entire 6-year period was classified according to the Anatomical Therapeutic Chemical Classification (ATC) and expressed in defined daily dose (DDD) per 1000 inhabitants per day (DID). Overall and subgroup comparison of antibiotic consumption over time as well as between geographical clusters was performed. RESULTS: Total use of antibiotics in Europe remained at a median level of 20 DID in the period 1997-2002 with a wide variation between countries ranging from 9.8 DID in The Netherlands to 32.2 DID in France. A substantial increase in subclass consumption of co-amoxiclav and fluoroquinolones was noted while the use of narrow-spectrum penicillins, erythromycin, quinolones and sulfonamides decreased. Total consumption as well as seasonal fluctuations showed remarkable geographical clustering with low consumption and low variation between summer and winter in the North, high consumption patterns in the South and a mixed model in the East. CONCLUSIONS: Within the ESAC project, valid time series of antibiotic-use data are publicly available now, enabling to improve the study of determinants of use, the evaluation of governmental antibiotic consumption policies and the investigation of the associated emergence of antibiotic resistance.

Surveillance of outpatient antibiotic consumption in Spain according to sales data and reimbursement data.

OBJECTIVES: National data on antibiotic consumption are needed in order to interpret trends in antibiotic resistance. We compared antibiotic prescription reimbursement data and sales data in Spain. METHODS: Data covering the years 2002, 2004 and 2005 were examined. Reimbursement data for ambulatory care were provided by the Spanish Agency for Medicines and Healthcare Products and sales data by International Medical Statistics Health. Quantities were standardized using the defined daily dose per 1000 inhabitants per day (DID) in accordance with the anatomical therapeutic classification. RESULTS: Sales data increased from 26.33 DID in 2002 to 28.12 DID in 2004 and 28.93 DID in 2005. Estimates based on equivalent reimbursement data were ~30% lower and increased from 18.01 DID in 2002 to 18.48 DID in 2004 and 19.29 DID in 2005. The differences were greatest for amoxicillin, amoxicillin/clavulanic acid, clarithromycin and cefuroxime. CONCLUSIONS: Antibiotic consumption as estimated from reimbursement data is substantially less than that from sales data. This finding has major implications for national surveillance of antibiotic consumption.

European Surveillance of Antimicrobial Consumption (ESAC): quality indicators for outpatient antibiotic use in Europe.

BACKGROUND AND OBJECTIVE: Indicators to measure the quality of healthcare are increasingly used by healthcare professionals and policy makers. In the context of increasing antimicrobial resistance, this study aimed to develop valid drug-specific quality indicators for outpatient antibiotic use in Europe, derived from European Surveillance of Antimicrobial Consumption (ESAC) data. METHODS: 27 experts (15 countries), in a European Science Foundation workshop, built on the expertise within the European Drug Utilisation Research Group, the General Practice Respiratory Infections Network, the ESCMID Study Group on Primary Care Topics, the Belgian Antibiotic Policy Coordination Committee, the World Health Organization, ESAC, and other experts. A set of proposed indicators was developed using 1997-2003 ESAC data. Participants scored the relevance of each indicator to reducing antimicrobial resistance, patient health benefit, cost effectiveness and public health policy makers (scale: 1 (completely disagree) to 9 (completely agree)). The scores were processed according to the UCLA-RAND appropriateness method. Indicators were judged relevant if the median score was not in the 1-6 interval and if there was consensus (number of scores within the 1-3 interval was fewer than one third of the panel). From the relevant indicators providing overlapping information, the one with the highest scores was selected for the final set of quality indicators-values were updated with 2004 ESAC data. RESULTS: 22 participants (12 countries) completed scoring of a set of 22 proposed indicators. Nine were rated as relevant antibiotic prescribing indicators on all four dimensions; five were rated as relevant if only relevance to reducing antimicrobial resistance and public health policy makers was taken into account. A final set of 12 indicators was selected. CONCLUSION: 12 of the proposed ESAC-based quality indicators for outpatient antibiotic use in Europe have face validity and are potentially applicable. These indicators could be used to better describe antibiotic use in ambulatory care and assess the quality of national antibiotic prescribing patterns in Europe.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient antibiotic use in Europe.

BACKGROUND: The ESAC project, granted by DG SANCO of the European Commission, is an international network of surveillance systems, aiming to collect comparable and reliable data on antibiotic use in Europe. Data on outpatient antibiotic use were collected from 34 countries using the ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic antibiotics aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Outpatient antibiotic (ATC J01) use in 25 European countries, able to deliver valid data, was analysed. RESULTS: Total outpatient antibiotic use in 2003 varied by a factor of 3 between the country with the highest (31.4 DID in Greece) and the country with the lowest (9.8 DID in the Netherlands) use. General use patterns in individual countries as well as trends during the period 1997-2003 are described in this paper, while major antibiotic classes (penicillins, cephalosporins, macrolides/lincosamides/streptogramins and quinolones) will be analysed in detail in separate papers. CONCLUSION: The ESAC project established for the first time a credible alternative to industry sources for the collection of internationally comparable data on antibiotic use in Europe, based on cooperation between regulatory authorities, scientific societies, health insurers and professional organizations. These data provide a tool for assessing public health strategies aiming to optimize antibiotic prescribing.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient penicillin use in Europe.

BACKGROUND: Data on outpatient penicillin use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic penicillins aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Of the 'Penicillins' (J01C), outpatient use of narrow-spectrum penicillins (J01CE), broad-spectrum penicillins (J01CA), penicillinase-resistant penicillins (J01CF) and combinations with beta-lactamase inhibitors (J01CR) in 25 European countries was analysed in detail. RESULTS: Total outpatient penicillin use in 2003 varied by a factor of 4 between the country with the highest (15.27 DID in Slovakia) and lowest use (3.86 DID in the Netherlands). Narrow-spectrum penicillins, broad-spectrum penicillins and combinations with beta-lactamase inhibitors were used most in 4, 12 and 9 countries, respectively. Penicillin use increased by more than 1 DID in nine countries, whereas it decreased by more than 1 DID in two countries (Czech Republic, France). An increase of the use of combinations with beta-lactamase inhibitors by more than 10% in 10 countries coincided with an equal decrease of broad-spectrum penicillins in seven countries and narrow-spectrum penicillins in three countries. CONCLUSION: Penicillins represent the most widely used antibiotic class in all 25 participating countries; albeit with considerable variation of their use patterns. A distinct shift from narrow-spectrum penicillins to broad-spectrum penicillins, and specifically their combinations with beta-lactamase inhibitors, was observed during the period 1997-2003.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient cephalosporin use in Europe.

BACKGROUND: Data on outpatient cephalosporin use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic cephalosporins aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Use was analysed in detail, using the new ATC codes J01DB, J01DC, J01DD and J01DE, introduced in the 2005 issue of the WHO ATC index and assigned to the four cephalosporin generations. RESULTS: Total outpatient cephalosporin use in 2003 varied by a factor of 270 between the country with the highest (6.18 DID in Greece) and lowest (0.02 DID in Denmark) use. First-, second- and third-generation cephalosporins were used most in 6, 16 and 3 countries, respectively. We observed fourth-generation use (mainly cefepime) in ambulatory care in 11 countries. From 1997 to 2003 cephalosporin use decreased in 13 countries, in France by more than 1 DID. A relative increase of second-generation (mainly cefuroxime) or third-generation use (mainly cefpodoxime or cefixime) by more than 10% in 12 countries coincided with an equally large decrease of first-generation use in eight countries (mainly cefadroxil, cefalexin or cefatrizine). In six countries, first-generation use increased, second-generation use decreased or both occurred. CONCLUSION: The new ATC codes allow a more detailed description of outpatient cephalosporin use. The variation in antibiotic use in Europe is most extreme for this class of antibiotics, suggesting that in many countries in Europe these antibiotics are prescribed inappropriately.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe.

BACKGROUND: Data on outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic MLS aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Macrolide use was analysed in detail, using a classification based on their mean plasma elimination half-life. RESULTS: Total outpatient MLS use in 2003 varied by a factor of 11 between the country with the highest (9.36 DID in Greece) and lowest (0.85 DID in Sweden) use. MLS use showed high seasonal variation. Short-, intermediate- and long-acting macrolides were used most in 6, 18 and 1 countries, respectively (mainly erythromycin, clarithromyin and azithromycin, respectively). Lincosamide use was observed in all countries (mainly clindamycin) and substantial streptogramin use only in France (pristinamycin). From 1997 to 2003, MLS use increased in 14 countries and was most pronounced in Greece (increase of >5 DID). Except for Sweden, a relative increase of intermediate- (mainly clarithromycin) and/or long-acting (mainly azithromycin) macrolide use was observed, at the expense of short-acting macrolide (mainly erythromycin) use. CONCLUSION: The observed differences between European countries in the levels of MLS use and the extreme seasonal variations in their use suggest that this class of antibiotics is prescribed inappropriately in many countries. The MLS classification developed here facilitates a more comprehensive description of macrolide use in Europe. These data (collected as part of ESAC) could promote investigations that lead to a deeper understanding of the link between macrolide use and resistance.

European Surveillance of Antimicrobial Consumption (ESAC): outpatient quinolone use in Europe.

BACKGROUND: Data on outpatient quinolone use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic quinolones aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Because a new DDD for levofloxacin was published in the ATC 2004 index (0.5 g instead of 0.25 g) all data were recalculated accordingly. Quinolone use was analysed in detail, using a classification into three generations based on their pharmacokinetic and in vitro potency profiles, which determines the area of clinical use. RESULTS: Total outpatient quinolone use in 2003 varied by a factor of 12 between the country with the highest (3.10 DID in Portugal) and lowest (0.25 DID in Denmark) quinolone use. The second-generation quinolones represented more than 50% of the quinolone use (mainly ciprofloxacin) except for Croatia, where the first-generation was used most (mainly norfloxacin). In 22 countries, the use of second and/or third-generation quinolones increased at the expense of the use of first-generation quinolones. The new so-called respiratory quinolones (levofloxacin and moxifloxacin) represented more than 10% of quinolone use in 12 countries, with extreme seasonal variation in all these countries except for one. CONCLUSION: There has been a substantial change in the use pattern of quinolones between 1997 and 2003, since the introduction of quinolones that are effective for the treatment of respiratory tract infections. These quinolones are not the first-line antibiotics for this indication and therefore quinolone use should in general still be limited and not show substantial seasonal variation.

National campaigns to improve antibiotic use.

High levels of antibiotic consumption are driving levels of bacterial resistance that threaten public health. Nonetheless, antibiotics still provide highly effective treatments for common diseases with important implications for human health. The challenge for public education is to achieve a meaningful reduction in unnecessary antibiotic use without adversely affecting the management of bacterial infections. This paper focuses on the lessons learned from national campaigns in countries (Belgium and France) with high antibiotic use. Evaluation of these national campaigns showed the importance of television advertising as a powerful medium to change attitudes and perhaps also behaviour with regard to antibiotics. Moreover, in both countries, strong evidence suggested reduced antibiotic prescribing. However, adverse effects associated with a reduction in antibiotic prescribing were not monitored. We conclude that carefully designed mass education campaigns could improve antibiotic use nationally and should be considered in countries with high antibiotic use. However, these campaigns should employ techniques of social marketing and use appropriate outcome measures. The benefits and risks of such campaigns have been less well established in countries where antibiotic use is already low or declining.