European Antibiotic Awareness Day (EAAD): any impact on antibiotic consumption and public awareness in Slovenia?

Objectives: To evaluate the impact of European Antibiotic Awareness Day (EAAD) on antibiotic consumption, improvements in general public awareness and antibiotic resistance in Slovenia. Methods: Outpatient data for the period from 2002 to 2016 and hospital antibiotic consumption data for 2004-16 were collected using the Anatomical Therapeutic Chemical (ATC) classification/DDDs. Outpatient antibiotic consumption data were expressed in DDDs/1000 inhabitants/day (DIDs), number of packages/1000 inhabitant-days and number of prescriptions/1000 inhabitants/year. Hospital consumption data were expressed in DIDs, number of DDDs/100 bed-days and number of DDDs/100 admissions. Segmented regression analysis of interrupted time series was used to estimate the effects of these interventions on antibiotic consumption. Results: During the 8 year period since establishing EAAD, a 9%-17% decrease in outpatient antibiotic consumption has been observed, depending on the measurement unit, which was a little more than in the 6 years prior to EAAD (7%-12%). The trend change in hospital consumption after EAAD was established remained small, with a highly non-significant P value. Eurobarometer data did not show an increase in knowledge on antibiotic use. Resistance of Streptococcus pneumoniae to penicillin and macrolides decreased during EAAD activities. Conclusions: EAAD activities were associated with a decreasing trend in community consumption. Owing to many other national activities on the prudent use of antimicrobials in outpatients and inpatients it is difficult to analyse the direct effect of EAAD.

The Impact of National Activities on Antibiotic Consumption in Hospitals and Different Departments over a 14-Year Period.

The aim of this study was to assess the use of antibiotics in hospitals and different departments over 14 years (2006-2019) and the impact of various national activities related to this, including national audits of the use of antibiotics for systemic use. The consumption of antibiotics for systemic use (J01) from all Slovenian hospitals (n = 29) and five departments (internal medicine, surgery, ICU (medicine, surgery), paediatrics and gynaecology/obstetrics) was collected. Total hospital consumption was expressed as the number of defined daily doses (DDDs) per 1000 inhabitants per day (DID), the number of DDDs/100 bed days and the number of DDDs/100 admissions. Over 14 years, J01 hospital consumption increased by 13.8%, expressed in DDDs/100 bed days (p = 0.002). In 2019, compared to 2006, the consumption of J01, expressed in DDD/100 bed days, increased from 19.9% to 33.1% in all departments, except intensive care units. J01 consumption expressed in DDD/100 admissions increased by 7.0% to 39.4% in all but paediatric wards (where it decreased by 12.7%). In all years, we observed large variations in the consumption of antibiotics in departments of the same type. The effectiveness of audit interventions aimed at optimizing antibiotic consumption exhibited notable variation across hospitals, with specialized facilities generally demonstrating superior outcomes compared to general hospitals.

Rotavirus vaccination in central Europe.

Each year, rotavirus (RV) infection is the leading cause of acute gastroenteritis requiring hospitalisation and of nosocomially transmitted diseases in children younger than 5 years across Central European Vaccination Awareness Group (CEVAG) countries; however, inadequate surveillance systems and lack of routine RV testing still exist in most CEVAG countries, making it difficult to accurately assess the present burden of acute RV gastroenteritis in the younger population. Furthermore, routine immunisation of infants with RV vaccines has not been implemented, and no official and uniform recommendations exist in most of the countries in these territories. The present study provides CEVAG country-specific estimates of the disease burden of RV gastroenteritis among the youngest population and presents evidence-based advice on the use of RV vaccines in the region, while providing a framework for vaccination at the national level.

Impact of the COVID-19 Pandemic on Community Consumption of Antibiotics for Systemic Use and Resistance of Invasive Streptococcus pneumoniae in Slovenia.

The present study aims to investigate the impact of the COVID-19 pandemic on community antibiotic consumption and the resistance of invasive Streptococcus pneumoniae (2015-2022) to penicillin in Slovenia. During the pandemic in 2020 and 2021, the total use of antibiotics for systemic use decreased by 23.5% and 24.3%, expressed in defined daily doses per 1000 inhabitants per day (DID), while the use of penicillins, macrolides and broad-spectrum penicillins decreased by 30%, 20% and by 17.5%, respectively, and that of broad-spectrum macrolides fell by 17.1%. The incidence of invasive pneumococcal diseases (IPD) in Slovenia had a large decline during the pandemic. Decreased resistance to macrolides was significantly associated with decreased use of macrolides, while for penicillins the correlation could not be statistically confirmed. The proportion of PCV13 serotypes in IPD in Slovenia decreased after the introduction of the vaccine in the national programme, falling from 81.6% in 2015 to 45.5% in 2022. We noticed a decrease in the serotypes 1, 14, 9V, 7F, 4, 6A and an increase in the serotypes 3, 8, 22F, 11A, 23A and 15A. National interventions during the COVID-19 pandemic substantially decreased outpatients' antibiotic consumption, as well as incidence and resistance of invasive S. pneumoniae.

Correlation between Antibiotic Consumption and Resistance of Invasive Streptococcus pneumoniae.

There is a lack of long-term studies that correlate different metrics of antibiotic consumption and resistance of invasive S. pneumoniae. The present study aims to investigate the correlation between national outpatients total antibiotic, penicillin and broad spectrum penicillins consumption expressed in daily doses per 1000 inhabitants per day (DID) with the ATC/DDDs, WHO version of 2019 (new version) and 2018 (old version), number of prescriptions per 1000 inhabitants per year (RxIDs) and number of packages per 1000 inhabitant per day (PIDs) with the resistance of invasive S. pneumoniae in Slovenia in the period from 2000 to 2018. The prevalence of penicillin resistance of invasive S. pneumoniae decreased by 47.13%, from 19.1% to 10.1%. Decline of resistance showed the highest correlation (R = 0.86) between RxIDs followed by PID (R = 0.85) and resistance of S. pneumoniae. Higher correlation between total use of antibiotics expressed in DID WHO version 2019 (R = 0.80) than for WHO version 2018 (R = 0.78) was found. Very high (R = 0.84) correlation between use of ß-lactams expressed in PID, and RxIDs (R = 0.82) and reasonable (R = 0.59) correlation expressed in DIDs version 2019 was shown as well. The consumption of broad -spectrum penicillins (J01CA and J01CR02) expressed in PID (R = 0.72) and RxIDs (0.57) correlated significantly with the resistance of S. pneumoniae as well. A new finding of this study is that RxIDs correlated better with the resistance of S. pneumoniae than total consumption of antibiotics expressed in DID and significant correlations exist between use of broad-spectrum penicillins expressed in PID and RxIDs.

Lack of correlation between reduced outpatient consumption of macrolides and macrolide resistance of invasive Streptococcus pneumoniae isolates in Slovenia during 1997-2017.

OBJECTIVES: The objective of this study was to investigate the correlation between decreased national consumption of macrolides and resistance of invasive Streptococcus pneumoniae isolates in Slovenia during 1997-2017. METHODS: A total of 4241 invasive S. pneumoniae isolates were collected in Slovenia from 1997 to 2017. The presence of erm(B), mef(E), mef(A) and erm(TR) genes was determined by PCR in 612 erythromycin-resistant isolates. Selected isolates carrying the mef(A) gene were further examined by pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) was performed for 161 erythromycin-resistant isolates from 2004 to 2009. RESULTS: Consumption of macrolides decreased by 42.5% between 1997 and 2017, and by 57.0% from the highest consumption during 1999 to 2017. Resistance of S. pneumoniae increased by 120.7% in the same period, from 5.8% in 1997 to 12.8% in 2017. The most prevalent serotypes among macrolide-resistant isolates were 14 (54.9%), 19A (9.0%), 19F (8.3%), 6B (7.2%), 6A (5.2%) and 9V (19; 3.0%). The most prevalent determinant of macrolide resistance in the observed period was erm(B) (43.0%; 263/612), followed by mef(A) (36.3%; 222/612) and mef(E) (14.9%; 91/612). During the study period, an increasing trend in serotype 14, mef(A)-carrying isolates was observed, with a peak in 2011 (P<0.001); 63/71 isolates (88.7%) with the mef(A) gene were clonally related and were related to the international England14-9 clonal cluster. CONCLUSIONS: The reason for the observed increase in macrolide resistance among invasive S. pneumoniae in Slovenia despite decreased macrolide consumption was spread of the England14-9 clonal cluster.

Severe Clostridium difficile-associated disease in children.

Three cases of Clostridium difficile-associated disease in children were detected within a short time interval. Intensive therapy was required in 2 cases with colectomy in one of them. One of the severe cases was community-acquired. Two patients had underlying diseases (Hirschprung disease, Down syndrome) and also tested positive for enteric viruses (rotavirus, calicivirus).

Hospital antibiotic management in Slovenia--results of the ABS maturity survey of the ABS International group.

BACKGROUND: The ever-increasing resistance to antibiotics is a serious worldwide problem. Antibiotic strategies for appropriate use of antimicrobials in hospitals are not well defined. METHODS: A questionnaire on "ABS maturity of hospitals" was the basis of an analysis as a part of an EU project. This questionnaire was sent to 12 hospitals in Slovenia including 11 general hospitals and one university hospital. MAIN FINDINGS: All 12 hospitals returned the questionnaires. Maturity of antibiotic strategies were considered moderate (3.74). Antibiotic consumption had the highest maturity ratio (4.44), followed by diagnostics (3.96), antibiotic-related relationships (3.58), antibiotic-related personnel development (3.44) and antibiotic-related organization (3.36). The availability of data on antibiotic consumption had the highest ranking; designation of and time resources for antibiotic officers were ranked lowest. CONCLUSION: In Slovenia the maturity of antibiotic strategies in general hospitals and in one university hospital is moderate. The data provide a basis for further development of antibiotic-related issues in hospitals.

Antibiotic consumption and resistance of gram-negative pathogens (collateral damage).

Antibiotics are commonly prescribed in community and hospital care. Overuse and misuse favors emergence and spread of resistant bacteria. The ATC/DDD methodology is commonly used for presenting the drug utilization data. In primary care, the consumption is usually expressed in DDD per 1,000 inhabitants per day, in hospital, preferably in DDD per 100 bed days and DDD per 100 admissions. The alternative metric is days of therapy (DOT), which needs IT support. Antibiotics have ecological adverse effects at individual and population level. Antibiotics select resistant bacteria among pathogens and normal flora. Broad-spectrum antibiotics, low dosage and prolonged antibiotic therapy favor the development of resistance. Although total use of antibiotics in hospital is much less than in the community, the intensity of use magnified by cross infection ensures a multitude of resistant bacteria in today's hospitals. Reversal of resistance is complex and might persist for many years despite the introduction of antimicrobial containment and stewardship programs.

Legal framework of antimicrobial stewardship in hospitals (LEASH): a European Society of Clinical Microbiology and Infectious Diseases (ESCMID) cross-sectional international survey.

Antimicrobial stewardship (AMS) is the cornerstone activity in the combat against antimicrobial resistance. In order to ensure sustainable deployment and development of AMS, a strategic and regulatory framework needs to be provided by national healthcare authorities. Experts from 32 European countries, Israel and Turkey were invited to participate in a cross-sectional internet-based survey from October 2016 to May 2017 on the legal framework and mandatory components (structures, activities) of AMS in hospitals, i.e. components required by legislation or regulations. We collected data from 25 countries and two regions (in countries with federal health administration). Laws regulating AMS existed in seven countries and one region. Other health ministry regulations were applicable in 13 countries and one region. National strategies and/or action plans approved by ministries of health were in place in 13 countries and one region. Conversely, five countries and one region had no regulation of AMS in hospitals. Funding for AMS in hospitals was provided in five countries and one region. Eight countries and one region reported mandatory AMS structures and activities complying with the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) structure, policy and practice indicators. In 10/27 cases, however, the mandatory AMS activities were not being fully carried out. The survey showed heterogeneous legal frameworks for AMS in hospitals, and in many countries it was even lacking. The situation may be critical in countries with poor control of antimicrobial use and resistance. Recent international initiatives calling on policy-makers to address the threat of antimicrobial resistance could yield improvement.

Macrolide resistance rates in respiratory pathogens in Slovenia following reduced macrolide use.

The aim of this study was to investigate the association between decreased use of macrolides and resistance of common respiratory pathogens in Slovenia from 1999 to 2004. Over a 6-year period the consumption of macrolides in Slovenia decreased by 21.3%, from 3.81 defined daily doses/1000 inhabitants per day (DID) to 3.0 DID. The use of short-acting, intermediate-acting and long-acting subclasses of macrolides decreased by 50%, 18% and 13%, respectively. In the same period, resistance of invasive strains of Streptococcus pneumoniae increased from 4.6% to 11.1% and resistance of non-invasive strains of S. pneumoniae and Streptococcus pyogenes increased from 12.8% to 20.2% and from 7.4% to 12.5%, respectively. Resistance increased significantly more in children than in adults (P=0.05) and was significantly correlated with increased use of intermediate-acting macrolides (r=0.94 for non-invasive S. pneumoniae and r=0.96 for S. pyogenes) in children. Resistance of Haemophilus influenzae and Moraxella catarrhalis was low and did not change. In children and adults, the emergence and spread of multidrug-resistant strains of invasive S. pneumoniae was observed. The decline in total macrolide use was not paralleled by reduced macrolide resistance rates of S. pyogenes and S. pneumoniae during the 6-year period. There was a strong correlation between the use of intermediate-acting macrolides and macrolide resistance of S. pyogenes and S. pneumoniae in children. Further reduction in the use of intermediate- and long-acting macrolides should be encouraged.

The long-term effects of restrictive interventions on consumption and costs of antibiotics.

In the last decade, Slovenia introduced restrictive measures for some antibiotic classes in ambulatory care as well as regulatory interventions to reduce costs. The aim of this study was to analyse the effects of these interventions on consumption and costs of antibiotics in ambulatory care. Consumption data were expressed in defined daily doses/1000 inhabitants per day (DID), number of packages/1000 inhabitants per day and number of prescriptions/1000 inhabitants per year. In 2000, Slovenia introduced restrictive measures for prescription of amoxicillin/clavulanic acid (AMC) and fluoroquinolones, in 2005 for oral third-generation cephalosporins and in 2009 for macrolides. Segmented regression analysis of interrupted time series was used to estimate the effects of restrictive interventions on antibiotic consumption. Total outpatient consumption of antibacterial drugs decreased by 29.65% from 20.27 DID in 1999 to 14.26 DID in 2012. Three years after the introduction of restrictions, consumption of AMC, fluoroquinolones and macrolides decreased by 29.3%, 23.8% and 28.8%, respectively, compared with the year before the intervention, and of non-restricted antibiotics by 3.3% (in 2003). Twelve years after the introduction of restrictive interventions, use of AMC and fluoroquinolones decreased by 28.1% and 28.5%, respectively, and use of non-restricted antibiotics by 18.8% (in 2012). In the same time period, the costs of AMC and fluoroquinolones were reduced by 63.3% and 52.4%, respectively, and of non-restricted antibiotics by 46.9%. Restrictive interventions in ambulatory care are effective in reducing antibiotic consumption and costs. Restrictive interventions had a significantly greater impact on consumption 3 years post-intervention than after 12 years.

The influence of a sustained multifaceted approach to improve antibiotic prescribing in Slovenia during the past decade: findings and implications.

INTRODUCTION: Rising antibiotic resistance has become an increasing public health problem. There is a well-established correlation between antibiotic consumption and antimicrobial resistance. Consequently, measures to rationalize the prescribing of antibiotics should reduce the resistant strains. Following a 24% increase in antibiotic consumption at the end of the 1990s, multiple activities were designed and introduced by the Health Insurance Institute of Slovenia (ZZZS) and other organizations in Slovenia at the end of 1999. These activities reduced the antibiotic consumption by 18.7% by 2002. These measures have continued. OBJECTIVE: To study changes in antibiotic utilization from 1995 to 2012 alongside the multiple interventions and their consequences, including changes in resistance patterns. METHODS: This was a retrospective observational study involving all patients dispensed at least one ZZZS prescription for an antibiotic in Slovenia. Utilization was expressed in defined daily doses per thousand inhabitants per day. Multifaceted interventions were conducted over time involving all key stakeholder groups, that is, the Ministry of Health, ZZZS, physician groups and patients. These included comprehensive communication programs as well as prescribing restrictions for a number of antibiotics and classes. RESULTS: From 1999 to 2012, antibiotic consumption decreased by 2-9% per year, with an overall decrease of 31%. There were also appreciable structural changes. Overall antibiotic utilization and the utilization of 7 out of 10 antibiotics significantly decreased after multiple interventions. The resistance of Streptococcus pneumoniae to penicillin decreased in line with decreased utilization. However, its resistance to macrolides increased from 5.4 to 21% despite halving of its utilization. The resistance of Escherichia coli to fluoroquinolones doubled from 10 to 21% despite utilization decreasing by a third. Expenditures on antibiotics decreased by 53%. CONCLUSION: Multiple demand-side measures introduced following increased utilization significantly decreased subsequent antibiotic utilization and associated costs. However, there was variable impact on antibiotic resistance. Additional targeted activities are planned to further reduce antibiotic prescribing and resistance.

The use and resistance to antibiotics in the community.

The frequency of resistance to antibiotics among common community-acquired pathogens, and the number of drugs to which they are resistant have been increasing worldwide. The relationship between antibiotic usage and resistance is strongly supported by data from several studies. Countries with the highest per capita antibiotic consumption have the highest resistance. The emergence of penicillin-resistant Streptococcus pneumoniae is related to high consumption of antibiotics in general, as well as to increased use of aminopenicillins and/or probably to wider use of oral cephalosporins. Increased consumption of macrolides, especially the long-acting ones, correlates significantly with the level of macrolide resistance of group A streptococci and S. pneumoniae while increased use of oral cephalosporins might be associated with the increase of beta-lactamase-producing strains of Moraxella catarrhalis. Trimethoprim/sulphamethoxazole resistance is strongly associated with resistance to penicillin. A rise in consumption of fluoroquinolones is consonant with a higher rate of resistance to quinolones of S. pneumoniae, Escherichia coli and other Gram-negative bacteria. Paediatric bacterial isolates are more often resistant to various antimicrobial agents than isolates from adult patients; this higher resistance rate may be due to more frequent antimicrobial treatments in children, and extensive child to child transmission. Reliable data on antimicrobial consumption and resistance should form a basis for national policies devised to reduce the resistance of microorganisms to antibiotics.

Prevention of nosocomial lower respiratory tract infections in patients after intracranial artery aneurysm surgery with a short course of antimicrobials.

Nosocomial infections at a department of neurosurgery were followed prospectively. In 1999, a high incidence of nosocomial lower respiratory tract infections (NLRTI) was observed in patients after intracranial artery aneurysm surgery (ICAAS). From February to December 2000, a short course of ciprofloxacin and co-trimoxazole was given prophylactically to all patients with ICAAS. The incidence of nosocomial infections in patients after ICAAS fell from 78.4 to 30.9% (P<0.0001). The incidence of NLRTI fell from 43.3 to 13.6% (P<0.0001) and the incidence of urinary tract infections from 12.4 to 2.5% (P=0.015). No significant change in antibiotic sensitivity at the department was observed. Antibiotic use decreased from 100.4 defined daily doses (DDD) to 85.4 DDD per 100 bed-days.

Antibiotic policies in Central Eastern Europe.

To assess the antibiotic policies in Central Eastern European (CEE) countries, a questionnaire on the prevalence of resistance, antibiotic consumption data for ambulatory and hospital care and antibiotic policies, was mailed to national representatives. Data on antibiotic resistance and consumption of antibiotics at national levels are limited and vary considerably among countries. The importance of surveillance data in altering perceptions of the prevalence of resistance is shown by the comparison of surveillance data and interview data. Interview data without surveillance data produced the widest range of estimates of the prevalence of resistance in streptococcus pneumonia -5% in Lithuania and 82% in Belarus. The average consumption of antibiotics in ambulatory care in eight CEE countries in 2001 was 19.35 defined daily doses (DDD)/1000 inhabitants per day, (range 13.1 - 24.8 DDD) and in hospitals in six CEE countries was 2.2 DDD/1000 inhabitants per day (range 1.3-4.5). Over the counter sales of antibiotics are available in some countries. Antibiotic policy interventions do not exist or only apply to specific problems or interventions. Better implementation of antibiotic interventions and education on antibiotic use should be a high priority in this region. An effective strategy requires close co-operation, consultations and partnership at national and international level in particular, via existing international organisations.

Risk factors for colonization with ampicillin and high-level aminoglycoside-resistant enterococci during hospitalization in the ICU and the impact of prior antimicrobial exposure definition: a prospective cohort study.

The aim of our prospective cohort study was to determine the incidence, genetic relatedness and risk factors for colonization with ampicillin and high-level aminoglycoside-resistant enterococci (ARHLARE) among patients hospitalized in the intensive care unit. During 15-month period, we included 105 patients. The only independent risk factor for ARHLARE colonization was days of cefotaxime/ceftriaxone therapy [odds ratio (OR): 1.13; 95% confidence interval (CI) 1.10-1.27; P  =  0.045]. Patients with higher total use of antibiotics, patients on prolonged mechanical ventilation, and patients with urinary tract infection (UTI), were also found to be at increased risk to become colonized with ARHLARE. Pulsed-field gel electrophoresis suggested multifocal origin of the majority of the colonizing strains. Our results show that an increase in total antibiotic consumption for 10 defined daily doses (DDD)/patient increased the odds of colonization with ARHLARE for 36%. Further efforts to optimize antimicrobial use in high risk patients are proposed.

Immunization of high-risk paediatric populations: Central European Vaccination Awareness Group recommendations.

Over the last decade, childhood immunization has substantially reduced morbidity and mortality from vaccine-preventable diseases. However, particular paediatric risk groups, such as those with comorbidities, may not be adequately vaccinated despite being more susceptible to complications and death from certain infectious diseases. This may be due to lack of immunization recommendations, lack of awareness, or incomplete adherence to existing guidelines. Furthermore, recommendations for immunization can be inconsistent across Europe. An expanded initiative from the Central European Vaccination Awareness Group aims to raise awareness of the different high-risk paediatric groups, differentiate them according to their specific risk, and formalise a guidance statement for the immunization of each population.