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Aim The aim of this article was to evaluate the influence of different demand-side measures to enhance the prescribing of generics in ambulatory care based on cross-national comparisons. Methods An observational retrospective study was conducted using administrative databases from across Europe, documenting changes in reimbursed utilization and expenditure of different proton pump inhibitors (PPIs) and statins between 2001 and 2007, alongside different reforms to enhance prescribing efficiency. Utilization was converted to defined daily doses (DDDs) and expenditures were converted to euros. Demand-side measures were collated under the ‘4 Es’-education, engineering, economics and enforcement-to enable comparisons on the nature and intensity of reforms between countries. Results There were considerable differences in the utilization of generics and patent-protected PPIs and statins among Western European countries. Decreased utilization of omeprazole and simvastatin, alongside increased utilization of esomeprazole, atorvastatin and rosuvastatin, was seen in countries with limited demand-side measures to counteract commercial pressures. Prescribing restrictions, or a combination of education, prescribing targets and financial incentives, had the greatest influence on enhancing the utilization of omeprazole and simvastatin. For example, there was a threefold reduction in the utilization of atorvastatin in Austria following prescribing restrictions. Multiple demand-side interventions generally had a greater influence than single interventions, with the impact appearing additive. Multiple interventions coupled with initiatives to lower prices of generics considerably enhanced prescribing efficiency. Conclusion This cross-national study has demonstrated considerable variation in the utilization and expenditure of PPIs and statins across Europe, providing opportunities to further improve prescribing efficiency. The ‘4 Es’ do provide an understandable methodology to document and compare the influence of different demand-side measures, with the influence varying by their extent and intensity. Further reforms are essential given current financial pressures. Consequently, further research will concentrate on the potential to develop a scoring system to help predict the possible impact of different demand-side measures on future utilization patterns. Published in: Expert Rev Pharmacoecon Outcomes Res. 2010;10:707-22.

BackgroundAntibiotic resistance poses a considerable public health threat, with data-driven stewardship a main prevention measure. While quantifying antibiotic consumption is a key component of antibiotic stewardship programmes, the choice of denominator for calculating this metric can impact comparative analyses and trend evaluations substantially, influencing targeted stewardship interventions.AimWe aim to evaluate how using hospital sector-specific antibiotic consumption rate denominators at country level impacts country rankings and trends, addressing the limitations of the commonly used 'defined daily doses (DDD) per 1,000 inhabitants per day' metric.MethodsHospital antibiotic consumption data from ESAC-Net and denominator data from Eurostat ('inhabitants,' 'bed-days' and 'discharges') for 2017-2021 were used to calculate hospital antibiotic consumption rates for 24 reporting European Union/ European Economic Area (EU/EEA) countries. Countries were ranked by their consumption rates and trends were analysed to assess the effects of using different denominators.ResultsCountry rankings and 5-year trend analyses varied depending on the denominator used. Antibiotic consumption rates were more similar when using hospital activity-based denominators 'bed-days' and 'discharges' compared with the population-based 'inhabitants' denominator. Differences in country rankings and trends were also seen among rates derived using 'bed-days' and 'discharges'.ConclusionThe study underscores the importance of using hospital activity-based denominators such as 'bed-days' and 'discharges' when evaluating hospital antibiotic consumption. ESAC-Net's historical reliance on only 'DDD per 1,000 inhabitants per day' is challenged, advocating for the use of multiple hospital activity-based denominators. Corresponding hospital activity denominators for ESAC-Net data will more effectively inform national hospital antibiotic stewardship interventions.

We present a 70-year-old female patient diagnosed with epidermal growth factor receptor-mutated metastatic non-small cell lung cancer (T4N2M1a), who developed afatinib-induced toxic epidermal necrolysis (TEN). We have also performed a PubMed/Medline literature review to detect other possible cases of TEN/Stevens-Johnson syndrome associated with afatinib treatment and found only 5 other cases reported. To our best knowledge, this is the first case of afatinib-induced TEN successfully treated with cyclosporine., (© 2024 British Pharmacological Society.)

We observed a rebound in consumption of antibacterials for systemic use (ATC J01) in the community sector in the European Union/European Economic Area during 2021 and 2022, after an observed decrease between 2019 and 2020. The rates in 2022 returned to pre-COVID-19-pandemic levels and were exceeded in 13 countries. Although these patterns could partly be a result of changes in disease transmission during the study period, it could also reflect a lost opportunity to strengthen and reinforce prudent antibiotic use.

Background: Antimicrobials are some of the most prescribed drugs by junior doctors, but studies suggest most medical graduates feel unprepared for their future prescribing tasks. The aim of the present study was to compare the self-reported preparedness to prudently prescribe antimicrobials of final-year medical students in Croatia in 2015 and 2019., Methods: The same self-reported web-based survey on the preparedness to prescribe antibiotics was used in both 2015 and 2019. All final-year students at all four medical schools in Croatia (Osijek, Rijeka, Split, and Zagreb) were invited to participate in both 2015 and 2019. Preparedness scores were divided into "topic preparedness scores" and "global preparedness scores". Topic preparedness scores represented the percentage of students at a medical school who felt sufficiently prepared for each topic. They were first established at a medical school level and then at the national level. Global preparedness scores were determined for each student separately and then calculated at the medical school and national levels., Results: The country's global preparedness score, representing the average proportion of topics in which students felt sufficiently prepared, was slightly higher in 2015 compared with the 2019 results (62.7% vs. 56.5%; p = 0.191). Croatian students reported higher preparedness in 2015 than in 2019 for 25 out of 27 topics included in the survey. The majority of students reported a need for more education on antibiotic use both in 2015 and 2019 (78.0% vs. 83.0%; p = 0.199)., Conclusions: Despite increasing antimicrobial stewardship activities in various healthcare settings, medical students who are about to start prescribing antibiotics on their own do not feel sufficiently prepared to do so. Antimicrobial stewardship programs should be designed to incorporate undergraduate medical student education, for instance, as a specific, mandatory course or integrated into other courses, such as clinical pharmacology.

Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients only into responders and non-responders. The aim of this study was to elucidate whether metastatic melanoma patients with complete and sustained response to immunotherapy exhibit differences in gut microbiome composition among themselves, and whether those differences were associated with specific dietary habits. Shotgun metagenomic sequencing revealed that patients who exhibited a complete response after more than 9 months of treatment (late responders) exhibited a significantly higher beta-diversity ( p = 0.02), with a higher abundance of Coprococcus comes (LDA 3.548, p = 0.010), Bifidobacterium pseudocatenulatum (LDA 3.392, p = 0.024), and lower abundance of Prevotellaceae ( p = 0.04) compared to early responders. Furthermore, late responders exhibited a different diet profile, with a significantly lower intake of proteins and sweets and a higher intake of flavones ( p < 0.05). The research showed that metastatic melanoma patients with a complete and sustained response to immunotherapy were a heterogeneous group. Patients with a late complete response exhibited microbiome and dietary habits which were previously associated with an improved response to immunotherapy.

At the 2015 World Health Assembly, UN member states adopted a resolution that committed to the development of national action plans (NAPs) for antimicrobial resistance (AMR). The political determination to commit to NAPs and the availability of robust governance structures to assure sustainable translation of the identified NAP objectives from policy to practice remain major barriers to progress. Inter-country variability in economic and political resilience and resource constraints could be fundamental barriers to progressing AMR NAPs. Although there have been regional and global analyses of NAPs from a One Health and policy perspective, a global assessment of the NAP objectives targeting antimicrobial use in human populations is needed. In this Health Policy, we report a systematic evidence synthesis of existing NAPs that are aimed at tackling AMR in human populations. We find marked gaps and variability in maturity of NAP development and operationalisation across the domains of: (1) policy and strategic planning; (2) medicines management and prescribing systems; (3) technology for optimised antimicrobial prescribing; (4) context, culture, and behaviours; (5) operational delivery and monitoring; and (6) patient and public engagement and involvement. The gaps identified in these domains highlight opportunities to facilitate sustainable delivery and operationalisation of NAPs. The findings from this analysis can be used at country, regional, and global levels to identify AMR-related priorities that are relevant to infrastructure needs and contexts., Competing Interests: Declaration of interests EC has consulted for or received speaker fees from Pfizer and bioMérieux on educational material related to antibiotic resistance and antimicrobial stewardship. LSPM has consulted for or received speaker fees from bioMérieux, Pfizer, Eumedica, Kent Pharma, Umovis Lab, Shionogi, Pulmocide, Sumitovant, and received research grants from the National Institute for Health and Care Research (NIHR), CW+ (ie, the official charity of Chelsea and Westminster Hospital National Health Service Foundation Trust), Infectopharm, and LifeArc. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

BackgroundIn 2019, the World Health Organization published the 21st Model list of Essential Medicines and updated the Access, Watch Reserve (AWaRe) antibiotics classification to improve metrics and indicators for antibiotic stewardship activities. Reserve antibiotics are regarded as last-resort treatment options.AimWe investigated hospital-sector consumption quantities and trends of Reserve group antibiotics in European Union/European Economic Area countries and the United Kingdom (EU/EEA/UK).MethodsHospital-sector antimicrobial consumption data for 2010-2018 were obtained from the European Centre for Disease Prevention and Control. Antibacterials' consumption for systemic use (Anatomical Therapeutic Chemical classification (ATC) group J01) were included in the analysis and expressed as defined daily doses (DDD) per 1,000 inhabitants per day. We defined reserve antibiotics as per AWaRe classification and applied linear regression to analyse trends in consumption of reserve antibiotics throughout the study period.ResultsEU/EEA/UK average hospital-sector reserve-antibiotic consumption increased from 0.017 to 0.050 DDD per 1,000 inhabitants per day over the study period (p = 0.002). This significant increase concerned 15 countries. In 2018, four antibiotics (tigecycline, colistin, linezolid and daptomycin) constituted 91% of the consumption. Both absolute and relative (% of total hospital sector) consumption of reserve antibiotics varied considerably (up to 42-fold) between countries (from 0.004 to 0.155 DDD per 1,000 inhabitants per day and from 0.2% to 9.3%, respectively).ConclusionAn increasing trend in reserve antibiotic consumption was found in Europe. The substantial variation between countries may reflect the burden of infection with multidrug-resistant bacteria. Our results could guide national actions or optimisation of reserve antibiotic use.

Objectives: The aim of the study was to assess the impact of the COVID-19 pandemic on antimicrobial consumption (AMC) in the hospital sector in Croatia by analysing data reported to the European Surveillance of Antimicrobial Consumption Network (ESAC-Net) between 2016 and 2020., Methods: AMC was measured as the number of DDDs/1000 inhabitants/day and as the number of DDDs/100 bed days. To assess trends, linear regression was performed. To assess the impact of the pandemic on AMC, the compound annual growth rate was calculated for the years preceding the pandemic based on which AMC for 2020 was forecasted and compared with the actual consumption., Results: While hospital AMC expressed as DDDs/1000 inhabitants/day between 2019 and 2020 decreased by 17%, when expressed as DDDs/100 bed days, an 8% increase was observed. Hospital consumption of antibacterials for systemic use in the 5 year period did not significantly change when expressed as DDDs/1000 inhabitants/day, while it statistically significantly increased when expressed as DDDs/100 bed days. An increasing trend in consumption of broad-spectrum antimicrobials was found., Conclusions: During the pandemic there was an increase in hospital AMC with a shift towards broad-spectrum antimicrobials requiring further in-depth qualitative analysis based on patient-level data. Contrasting results obtained using different denominators indicate that the metric DDDs/1000 inhabitants/day is not sensitive enough to evaluate hospital AMC. When assessing hospital AMC, the population under surveillance should be relevant for healthcare context. Antimicrobial stewardship remains one of the most important strategies to tackle antimicrobial resistance and antimicrobial surveillance methods must be as sensitive as possible., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Studies suggest that the incidence of coinfections in patients with the coronavirus disease 2019 (COVID-19) is low, but a large number of patients receive antimicrobials during hospitalisation. This may fuel a rise in antimicrobial resistance (AMR). We conducted a multicentre point-prevalence survey in seven tertiary university hospitals (in medical wards and intensive care units) in Croatia, Italy, Serbia and Slovenia. Of 988 COVID-19 patients, 521 were receiving antibiotics and/or antifungals (52.7%; range across hospitals: 32.9-85.6%) on the day of the study. Differences between hospitals were statistically significant (χ 2 (6, N = 988) = 192.57, p < 0.001). The majority of patients received antibiotics and/or antifungals within 48 h of admission (323/521, 62%; range across hospitals: 17.4-100%), their most common use was empirical (79.4% of prescriptions), and pneumonia was the main indication for starting the treatment (three-quarters of prescriptions). The majority of antibiotics prescribed (69.9%) belonged to the "Watch" group of the World Health Organization AWaRe classification. The pattern of antimicrobial use differed across hospitals. The data show that early empiric use of broad-spectrum antibiotics is common in COVID-19 patients, and that the pattern of antimicrobial use varies across hospitals. Judicious use of antimicrobials is warranted to prevent an increase in AMR.

We present a European Union/European Economic Area-wide overview of the changes in consumption of antibacterials for systemic use (ATC J01) in the community between 2019 and 2020 as reported to the European Surveillance of Antimicrobial Consumption Network. Overall antibiotic consumption decreased by 18.3% between 2019 and 2020, the largest annual decrease in the network's two-decade history. We observed a strong association between the level of community antibiotic consumption in 2019 and the size of the decrease between 2019 and 2020.

Aim: To decrease the incidence and resistance rates of extended-spectrum β-lactamases (ESBL) Klebsiella pneumoniae (KP) by restriction of the use of third-generation cephalosporins (3GCs) and fluoroquinolones. Methods: Consumption of 3GCs, fluoroquinolones, and carbapenems in association with ertapenem and fluoroquinolone-resistant KP isolates, were analyzed in 21 months by autoregressive integrated moving average models. A follow-up analysis was performed 5 years later. Results: Consumption of 3GCs decreased significantly during the postintervention period. Their restriction was associated with a decrease in ertapenem-resistant KP isolates by 17.5%. Fluoroquinolone, 3GCs, and carbapenem use did not significantly predict the percentage of ertapenem-resistant KP isolates. Fluoroquinolone, but not cephalosporin use, significantly predicted the percentage of fluoroquinolone-resistant isolates, with an increase of 1 defined daily dose (DDD) of fluoroquinolone/100 occupied bed-days (OBDs) corresponding to a 0.32% increase of fluoroquinolone-resistant isolates ( p  = 0.008). A decrease of 1 DDD of carbapenem/100 OBD was associated with a 16.94% increase of fluoroquinolone-resistant isolates ( p  = 0.007). Five years later, the consumption of all three antimicrobial classes increased significantly compared with the 2011-2013 period, whereas ertapenem-resistant KP rates significantly decreased. Conclusion: This study may bring a valuable contribution to the understanding of the intricate association between antibiotic consumption and bacterial resistance. Reporting a spectrum of different results could present a useful basis for more profound research of various interventions' effects.

Objectives: To evaluate the quality of antimicrobial prescribing, at the Department of Internal Medicine University Hospital Centre Rijeka, by assessing the necessity for antimicrobial treatment and adherence to the local Guidelines for hospital antimicrobial drug use and to compare results with previously conducted point prevalence surveys (PPSs)., Methods: A PPS was conducted on 7th May 2019. Demographic and relevant clinical data of each patient receiving systemic antimicrobials were recorded anonymously in a patient-specific form. The appropriateness of antibiotic prescribing was assessed as adherence to the fourth edition of the Guidelines for hospital antimicrobial drug use., Key Findings: One hundred and seventy-one patients were hospitalized at the Department of Internal Medicine; 37.4% (n = 64) of patients received 102 prescriptions for an antimicrobial drug [62.8% (n = 64) of prescriptions were for intravenous and 37.2% (n = 38) for oral administration]. Of these, 52 were treated for an identified existing infection, 5 were treated for an unknown indication and 7 received antibiotics as prophylaxis. The necessity for antimicrobial treatment was unclear in 19.3% (n = 11) of cases. The antimicrobials were prescribed according to the Guidelines in 65.4% (n = 34) of cases. Adherence to the Guidelines when treating lower respiratory tract infections, urinary tract infections and gastrointestinal tract infections was 47.8%, 55.6% and 92.9%, respectively., Conclusions: Our study revealed antibiotic prescription frequency similar to EU/EEA average and high percentage of unjustified antimicrobial treatment introduction. The rate of adherence to the Guidelines was lower than those observed in western countries. The results lay a basis for tailoring antimicrobial stewardship programs/activities., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Publication and implementation of clinical guidelines is an important educational measure that considerably helps physicians in choosing appropriate antimicrobial drug., Objectives: To evaluate long-term changes in antimicrobial prescribing habits before and after publishing the guidelines and to determine the factors that influence physician's decision to prescribe an antimicrobial drug., Methods: The study among general practitioners in Primorsko-Goranska County was conducted in three periods (January 2009, January 2011 and April 2019) by using a structured questionnaire that included general data about the physician, questions about their habits in antibiotic prescribing, criteria that influenced decision to prescribe antibiotics and antimicrobial agent(s) preferred in treating common infections., Results: Concomitant chronic (non-pulmonary) disease was the most important factor influencing decision to prescribe an antimicrobial drug. Over 88% of physicians that completed the survey declared themselves as rational prescribers of antimicrobials but more than half of them (53.3%) sometimes prescribed an antibiotic even though it was not indicated compared to 75% of self-reported non-rational prescribers (P ˂ 0.05). Self-reported adherence to the guidelines increased from 34.6% in 2011 to 51.8% in 2019., Conclusion: The research showed improvement in physicians' knowledge in choosing the right antibiotic based on the analysis of answers but indicated the necessity for improving communication skills and empowering physicians not to prescribe antibiotics 'just in case' because of diagnostic uncertainty or patient demand. Further qualitative research is needed to understand physicians' prescribing behaviour and decision-making processes in order to develop interventions that will effectively improve the use of antibiotics., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Despite some earlier significant discoveries and widespread vaccination successful practices, the history of understanding immunological mechanisms is actually relatively short and associated only with the second half of the 20th century when, among other things, the laws of activation of these mechanisms are crucial for transplantation medicine. Among the first experts in Croatia who turned to these topics was Šime Vlahović. Born in Split, he graduated and received his PhD in Zagreb. He worked on the problems of transplant immunology from 1963 to 1965 at the eminent centers in the United States. He was the head of the Rijeka Department of Physiology at the Faculty of Medicine from 1965 to 1977, since 1976 as a full professor. He was the winner of the Ruđer Bošković award and many others, but his crucial contribution to the medical heritage of Rijeka and Croatia is certainly less known. Based on family archives and memories, this work will attempt to at least partially correct that gap. Thanks to the immunological preparation of Šime Vlahović, as well as, of course, a large team led by surgeon Vinko Frančišković, in January 1971, the first kidney transplant was performed in Croatia from a living relative (mother to son), a year later from a cadaver, and in the decades following that, an experimental liver and pancreas transplant program has been developed in Rijeka. Today, we can only speculate about the intriguing directions of the development of the Rijeka Transplant and Immunology School, which would have been led by Šime Vlahović, had he not passed away at the age of less than 45.

Background: Surveillance of antimicrobial consumption (AMC) is important to address inappropriate use. AMC data for countries in the European Union (EU) and European Economic Area (EEA) and Eastern European and Central Asian countries were compared to provide future guidance. Methods: Analyses of 2014-2018 data from 30 EU/EEA countries of the European Surveillance of Antibiotic Consumption network (ESAC-Net) and 15 countries of the WHO Regional Office for Europe (WHO Europe) AMC Network were conducted using the Anatomical Therapeutic Chemical (ATC) classification and Defined Daily Dose (DDD) methodology. Total consumption (DDD per 1000 inhabitants per day) of antibacterials for systemic use (ATC group J01), relative use (percentages), trends over time, alignment with the WHO Access, Watch, Reserve (AWaRe) classification, concordance with the WHO global indicator (60% of total consumption should be Access agents), and composition of the drug utilization 75% (DU75%) were calculated. Findings: In 2018, total consumption of antibacterials for systemic use (ATC J01) ranged from 8.9 to 34.1 DDD per 1000 inhabitants per day (population-weighted mean for ESAC-Net 20.0, WHO Europe AMC Network 19.6, ESAC-Net Study Group, and WHO Europe AMC Network Study Group). ESAC-Net countries consumed more penicillins (J01C; 8.7 versus 6.3 DDD per 1000 inhabitants per day), more tetracyclines (J01A; 2.2 versus 1.2), less cephalosporins (J01D; 2.3 versus 3.8) and less quinolones (J01M; 1.7 versus 3.4) than WHO Europe AMC Network countries. Between 2014 and 2018, there were statistically significant reductions in total consumption in eight ESAC-Net countries. In 2018, the relative population-weighted mean consumption of Access agents was 57.9% for ESAC-Net and 47.4% for the WHO Europe AMC Network. For each year during 2014-2018, 14 ESAC-Net and one WHO Europe AMC Network countries met the WHO global monitoring target of 60% of total consumption being Access agents. DU75% analyses showed differences in the choices of agents in the two networks. Interpretation: Although total consumption of antibacterials for systemic use was similar in the two networks, the composition of agents varied substantially. The greater consumption of Watch group agents in WHO Europe AMC Network countries suggests opportunities for improved prescribing. Significant decreases in consumption in several ESAC-Net countries illustrate the value of sustained actions to address antimicrobial resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © World Health Organization 2021. Licensee Frontiers Media SA.)

Background: Healthcare professionals are increasingly expected to lead antimicrobial stewardship (AMS) initiatives. This role in complex healthcare environments requires specialized training., Objectives: Little is known about the types of AMS training programmes available to clinicians seeking to play a lead role in AMS. We aimed to identify clinicians' awareness of AMS training programmes, characteristics of AMS training programmes available and potential barriers to participation., Methods: AMS training programmes available were identified by members of the ESCMID Study Group for Antimicrobial Stewardship (ESGAP) via an online survey and through an online search in 2018. Individual training programme course coordinators were then contacted (September-October 2018) for data on the target audience(s), methods of delivery, intended outcomes and potential barriers to accessing the training programme., Results: A total of 166/250 ESGAP members (66%) responded to the survey, nominating 48 unique AMS training programmes. An additional 32 training programmes were identified through an online search. AMS training programmes were from around the world. Less than half (44.4%) of respondents were aware of one or more AMS training programmes available, with pharmacists more aware compared with medical doctors and other professionals (73% versus 46% and 25%, respectively). AMS training programmes were most commonly delivered online (59%) and aimed at medical doctors (46%). Training costs and a lack of recognition by health professional societies were the most frequently cited barriers to participation in AMS training programmes., Conclusions: The development of a systematic inventory of AMS training programmes around the globe identifies opportunities and limitations to current training available. Improving access and increasing awareness amongst target participants will support improved education in AMS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

One of the core elements of antibiotic stewardship is surveillance and monitoring of quantity of antibiotic use. This requires tools for measuring the quantity of antibiotic use. However, these metrics have not been standardized, and different metrics are used across different countries, regions and individual healthcare settings. In the literature, there is much controversy on the most appropriate metric for monitoring antibiotic use. Several authors have questioned the relevance of DDDs, which are recommended by the WHO, while others still prefer using DDDs as the best available metric. The results of the recent DRIVE-AB project suggest that a combination of metrics may be the best approach, since all metrics have limitations and provide different perspectives., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Investments to reduce the spread of antimicrobial resistance (AMR) in the European Union have been made, including efforts to strengthen prudent antimicrobial use. Using segmented regression, we report decreasing and stabilising trends in data reported to the European Surveillance of Antimicrobial Consumption Network and stabilising trends in data reported to the European Antimicrobial Resistance Surveillance Network. Our results could be an early indication of the effect of prioritising AMR on the public health agenda.

Objectives: To explore inpatients experiences and views with regard to antibiotics in five European hospitals., Methods: Qualitative study where a patient-centred framework was used to explore inpatients' experiences concerning antibiotic treatment. A purposeful sample of inpatients treated with antibiotics in five hospitals participated in interviews (all centres) and focus groups (Switzerland only)., Results: A total of 31 interviews (five in Belgium, ten in Croatia, nine in France, five in the Netherlands and two in Switzerland) and three focus groups (in Switzerland, 11 participants) were performed. The median age of participants was 61 years (range 33-86 years). The following main themes emerged: (a) patients trust doctors to take the best decisions for them even though communication concerning different antibiotic-related aspects is often insufficient, (b) patients feel that doctors do not prioritize communication due to time constraints and do not seem to adapt information based on patients' preferences, (c) patients differ in their wish to be informed but overall want to be informed on the main aspects in an understandable way, (d) patients often find reassurance in sharing information about their antibiotic treatment with close family, (e) professionals should explore patients' preferences to be involved or not in shared decision making for antibiotic treatment., Conclusion: Inpatients often doubt their ability to understand medical information and trust their physicians to take the best decisions for them. Tailored strategies that inform hospitalized patients, acknowledging their concerns and preferences, may be useful to promote patient involvement and to improve communication regarding antibiotic use., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: We aimed to assess patient-related determinants potentially influencing antibiotic use., Methods: Studies published in MEDLINE until 30 September 2015 were searched. We included: qualitative studies describing patients' self-reported determinants of antibiotic use; and quantitative studies on either self-reported or objectively assessed determinants associated with antibiotic use. Whenever possible, reported determinants were categorized as 'barriers' or 'facilitators' of responsible antibiotic use., Results: A total of 87 studies from 33 countries were included. Seventy-five (86.2%) were quantitative and described self-reported (45/75, 60.0%), objectively assessed (20/75, 26.7%) or self-reported and objectively assessed (10/75, 13.3%) patient-related determinants. Twelve (12/87, 13.8%) were qualitative studies or had a qualitative and quantitative component. Eighty-six of the studies (98.8%) concerned the outpatient setting. We identified seven broad categories of determinants having an impact on different aspects of antibiotic use (in descending order of frequency): demographic and socio-economic characteristics, patient-doctor interactions (e.g. counselling), treatment characteristics (e.g. administration frequency), attitudes (e.g. expecting antibiotics), access to treatment (e.g. patients' direct costs), characteristics of the condition for which the antibiotic was prescribed (e.g. duration of symptoms), knowledge (e.g. regarding indications for treatment). Most determinants were classified as 'barriers' to responsible antibiotic use., Conclusion: A large variety of patient-related determinants impact antibiotic use. The most easily 'modifiable' determinants concern patient-doctor interactions, treatment characteristics and knowledge. Data from the inpatient setting and low- and middle-income countries were underrepresented. Further studies should develop and test interventions that take these determinants into account with the ultimate aim of improving responsible use of antibiotics., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To determine the prevalence of potentially serious drug-drug interactions (DDIs) and their relationship with gender and age, among elderly in South Africa., Methods: A cross-sectional study was conducted using pharmaceutical claims data for 2013, for a total of 103 420 medical scheme beneficiaries' ≥65 years. All medications dispensed within one calendar month where the days' supply of medication dispensed overlapped, were grouped as one prescription. DDIs per prescription were then identified using the Mimica Matanović/Vlahović-Palčevski DDI protocol. Results were interpreted using effect sizes, that is Cramér's V, Cohen's d and Cohen's ƒ 2 ., Key Findings: A total of 331 659 DDIs were identified on 235 870 (25.8%, N = 912 713) prescriptions (mean 0.36 (SD 0.7) (95% CI, 0.36 to 0.37)). Women encountered 63.5% of all DDIs. Effect sizes for the association between DDIs and age group (Cramér's V = 0.06), and gender (Cramér's V = 0.05) was negligible. There was no difference between men and women regarding the mean number of DDIs identified per prescription (Cohen's d = 0.10). The number of medicine per prescription (ƒ 2 = 0.51) was the biggest predictor of the DDIs. The most frequent interacting drug combinations were between central nervous system medicines (30.6%)., Conclusion: Our study is the first to report the prevalence of potentially serious DDIs among an elderly population in the South African private health sector utilising the Mimica Matanović/Vlahović-Palčevski DDI protocol. Overall, we identified DDIs in approximately 26% of the prescriptions in our study. Age and gender were not found to be predictors of potentially serious DDIs., (© 2017 Royal Pharmaceutical Society.)

The prescribing of medicines is a fundamental component of care for the elderly; however, there is increasing concern with polypharmacy and its impact on morbidity, mortality and costs. As a result, long-term prescription-medicine use and the prevalence of polypharmacy in the elderly in the Republic of Srpska were analyzed. The findings were subsequently used to suggest potential future measures. A retrospective study of all elderly patients during 2005-2010 stratified by age group (three groups), sex and long-term medicine use was performed. Polypharmacy (five or more medicines) increased from 1.4% of the elderly taking medicines long-term to 3.6% by 2010, with 53.6% of elderly taking two or more medicines long-term. The most prevalent diseases were cardiovascular diseases and diabetes. Most prescriptions were in accordance with recent guidelines; however, there was a concern with appreciable prescribing of digoxin and aminophylline. Whilst polypharmacy rates are low in the Republic, the increasing rate is a concern. Further studies are planned.

Antibiotic stewardship is a necessity given the worldwide antimicrobial resistance crisis. Outpatient antibiotic use represents around 90% of total antibiotic use, with more than half of these prescriptions being either unnecessary or inappropriate. Efforts to improve antibiotic prescribing need to incorporate two complementary strategies: changing healthcare professionals' behaviour, and modifying the healthcare system. In this review, we present a broad perspective on antibiotic stewardship in primary care in high and high-middle income country settings, focussing on studies published in the last five years. We present the limitations of available literature, discuss perspectives, and provide suggestions for where future work should be concentrated.

We surveyed European medical schools regarding teaching of prudent antibiotic prescribing in the undergraduate curriculum. We performed a cross-sectional survey in 13 European countries (Belgium, Croatia, Denmark, France, Germany, Italy, Netherlands, Norway, Serbia, Slovenia, Spain, Switzerland, United Kingdom) in 2013. Proportional sampling was used, resulting in the selection of two to four medical schools per country. A standardized questionnaire based on literature review and validated by a panel of experts was sent to lecturers in infectious diseases, medical microbiology and clinical pharmacology. In-depth interviews were conducted with four lecturers. Thirty-five of 37 medical schools were included in the study. Prudent antibiotic use principles were taught in all but one medical school, but only four of 13 countries had a national programme. Interactive teaching formats were used less frequently than passive formats. The teaching was mandatory for 53% of the courses and started before clinical training in 71%. We observed wide variations in exposure of students to important principles of prudent antibiotic use among countries and within the same country. Some major principles were poorly covered (e.g. reassessment and duration of antibiotic therapy, communication skills). Whereas 77% of the respondents fully agreed that the teaching of these principles should be prioritized, lack of time, mainly due to rigid curriculum policies, was the main reported barrier to implementation. Given the study design, these are probably optimistic results. Teaching of prudent antibiotic prescribing principles should be improved. National and European programmes for development of specific learning outcomes or competencies are urgently needed., (Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Quality indicators are increasingly used as a tool to achieve safe and quality clinical care, cost-effective therapy, for professional learning, remuneration, accreditation and financial incentives. A substantial number focus on drug therapy but few address the introduction of new medicines even though this is a burning issue. The objective was to describe the issues and challenges in designing and implementing a transparent indicator framework and evaluation protocol for the introduction of new medicines and to provide guidance on how to apply quality indicators in the managed entry of new medicines. Quality indicators need to be developed early to assess whether new medicines are introduced appropriately. A number of key factors need to be addressed when developing, applying and evaluating indicators including dimensions of quality, suggested testing protocols, potential data sources, key implementation factors such as intended and unintended consequences, budget impact and cost-effectiveness, assuring the involvement of the medical professions, patients and the public, and reliable and easy-to-use computerized tools for data collection and management. Transparent approaches include the need for any quality indicators developed to handle conflict of interests to enhance their validity and acceptance. The suggested framework and indicator testing protocol may be useful in assessing the applicability of indicators for new medicines and may be adapted to healthcare settings worldwide. The suggestions build on existing literature to create a field testing methodology that can be used to produce country-specific quality indicators for new medicines as well as a cross international approach to facilitate access to new medicines., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups.

Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are effectiveness, safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies showed dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. These concerns resulted in extensive activities pre- to post-launch to manage its introduction., Objective: To (i) review authority activities across countries, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications based on post-launch activities., Methodology: (i) Descriptive review and appraisal of activities regarding dabigatran, (ii) development of guidance for key stakeholder groups through an iterative process, (iii) refining guidance following post launch studies., Results: Plethora of activities to manage dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions and monitoring of prescribing post launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, peri-, and post-launch activities. Post-launch activities include increasing use of patient registries to monitor the safety and effectiveness of new drugs in clinical practice., Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.

Purpose: The purpose of this study was to determine the prevalence of inappropriate prescribing to the elderly and to identify possible gender-related differences in prescribing certain potentially inappropriate medications (PIMs) to outpatients by using large administrative prescription database., Methods: Medications prescribed for elderly outpatients (≥ 65 years) in Primorsko-Goranska County, Croatia, who received five or more different drugs simultaneously in 2010, were analyzed. The prevalence of potentially inappropriate drugs prescribed to the elderly was assessed using the new comprehensive protocol developed by authors Mimica Matanović and Vlahović-Palčevski., Results: A total of 62.4 % of patients received at least one medication with unfavorable benefit/risk ratio in the elderly. Female patients were given inappropriate medications in a significantly higher percentage than men (69.3 % vs. 50.5 %; p < 0.001). The average number of prescriptions for PIMs that should have been avoided with certain diseases or conditions was 0.88 per patient in the survey. The most common drug combination potentially leading to serious drug-drug interactions (DDIs) included an angiotensin-converting enzyme (ACE) inhibitor and a potassium supplement., Conclusions: Our study has shown that every tenth medication prescribed to a patient > 65 years and receiving five or more drugs was potentially inappropriate. Elderly women were prescribed PIMs more often than men. Drugs of concern in female patients were benzodiazepines, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs). In male patients, there was a significantly higher proportion of possible interactions with warfarin, theophylline, and medications affecting the cardiovascular system, such as ACE inhibitors and amiodarone.

Purpose: Screening tools for detecting potentially inappropriate medications (PIMs) represent an important way to assess drug prescribing in the elderly. Recently, we introduced a new comprehensive tool to detect both PIMs and clinically important drug-drug interactions (DDI). The aim of the study was to assess the applicability of the new tool., Methods: The new tool was used to detect PIMs and DDI and to assess their relation to morbidity and hospital admissions. It was also compared to the widely used Beers criteria. The study population included 454 consecutive patients aged ≥65 years who were acutely admitted to the Department of Internal Medicine of the University Hospital of Osijek. The Naranjo protocol was used to analyze the causal relationship between a drug and an adverse event., Results: According to the new protocol, 44 % patients were taking PIMs, while 33 % patients were taking drugs with potentially serious DDIs. In 11 % of the overall number of patients, the cause of admission was adverse drug reaction (ADR), and among contributing drugs, 44 % were potentially inappropriate according to our protocol. Gastrointestinal bleeding was the most common diagnosis causing ADR-associated admission, and in 72 % cases, either PIM or a potentially serious DDI was involved., Conclusion: The new Croatian tool detected a high number of patients taking PIMs and/or having potentially important drug-drug interactions. The tool also detected almost half of the drugs contributing to ADR-associated admission. We expect the tool to be useful in prescription evaluation for the elderly inpatient and outpatient population.

Purpose: The aim of this study was to determine the prevalence and pattern of unlicensed and off-label drugs prescribed to hospitalized children at the Department of Paediatrics, University Hospital Rijeka, Croatia., Methods: A prospective cross-sectional study was performed on 1 day each month during a 12 month period and included all hospitalized children and adolescents., Results: A total of 1,643 prescriptions for 198 different drugs were prescribed to 531 out of 691 (77%) hospitalized patients. Forty-six percent of the different drugs were prescribed in an unlicensed or off-label manner. Of all drug prescriptions, 25% were either unlicensed or off-label. Forty-eight percent of the patients received either an unlicensed or off-label drug. The most frequently prescribed off-label drugs were proton pump inhibitors., Conclusion: Unlicensed and off-label drug use is common. It is not illegal and may be clinically appropriate but is associated with a number of clinical, safety, and ethical issues. Regulatory authorities should use existing clinical evidence on the use of off-label and unlicensed drugs in decision making. Marketing authorization holders and national regulatory authorities should monitor for any safety concerns associated with unlicensed and off-label drug use and take appropriate measures as well as identify research priorities and mandate clinical studies to resolve important questions.

Unlabelled: European countries strive to enhance prescribing efficiency. This includes renin-angiotensin drugs following the availability of generic angiotensin-converting enzyme inhibitors (ACEIs)., Aims: To compare angiotensin receptor blocker utilization and expenditure patterns in Austria and Croatia following prescribing restrictions, as well as with other European countries introducing different supply- and demand-side measures. Lastly, to appraise the impact of generic losartan in Croatia on utilization of patented angiotensin receptor blockers., Method: Observational retrospective study principally between 2001 and 2007, using defined daily doses and €/1000 inhabitants/year. Demand-side measures were based on the four 'E's - education, engineering, economics and enforcement., Results: Greater intensity of follow-up of prescribing restrictions in Croatia enhanced utilization of ACEIs versus Austria. There was high utilization of ACEIs in Scotland following intensive demand-side measures, similar to Austria and Croatia. Demand-side measures in Spain (Catalonia) and Sweden also appeared to moderate angiotensin receptor blockers utilization. The combination of measures helped stabilize expenditure on renin-angiotensin drugs when adjusted for population sizes despite appreciable increases in volumes. The only exception was Portugal, with less intensive measures., Conclusion: Multiple and intensive demand-side measures enhanced prescribing efficiency. The more intense follow-up of ARB prescribing restrictions in Croatia had a greater influence on subsequent utilization patterns than Austria. Both findings confirm earlier studies. Reforms also favorably enhanced the prescribing of generic losartan once available.

Introduction: European countries need to learn from each other to address unsustainable increases in pharmaceutical expenditures., Objective: To assess the influence of the many supply and demand-side initiatives introduced across Europe to enhance prescribing efficiency in ambulatory care. As a result provide future guidance to countries., Methods: Cross national retrospective observational study of utilization (DDDs - defined daily doses) and expenditure (Euros and local currency) of proton pump inhibitors (PPIs) and statins among 19 European countries and regions principally from 2001 to 2007. Demand-side measures categorized under the "4Es" - education engineering, economics, and enforcement., Results: Instigating supply side initiatives to lower the price of generics combined with demand-side measures to enhance their prescribing is important to maximize prescribing efficiency. Just addressing one component will limit potential efficiency gains. The influence of demand-side reforms appears additive, with multiple initiatives typically having a greater influence on increasing prescribing efficiency than single measures apart from potentially "enforcement." There are also appreciable differences in expenditure (€/1000 inhabitants/year) between countries. Countries that have not introduced multiple demand side measures to counteract commercial pressures to enhance the prescribing of generics have seen considerably higher expenditures than those that have instigated a range of measures., Conclusions: There are considerable opportunities for European countries to enhance their prescribing efficiency, with countries already learning from each other. The 4E methodology allows European countries to concisely capture the range of current demand-side measures and plan for the future knowing that initiatives can be additive to further enhance their prescribing efficiency.

Postmarketing drug surveillance refers to the monitoring of drugs once they reach the market after clinical trials. It evaluates drugs taken by individuals under a wide range of circumstances over an extended period of time. Such surveillance is much more likely to detect previously unrecognized positive or negative effects that may be associated with a drug. The majority of postmarketing surveillance concern adverse drug reactions (ADRs) monitoring and evaluation. Other important postmarketing surveillance components include unapproved or off-label drug use, problems with orphan drugs, and lack of paediatric formulations, as well as issues concerning international clinical trials in paediatric population. The process of evaluating and improving the safety of medicines used in paediatric practice is referred to as paediatric pharmacovigilance. It requires special attention. Childhood diseases and disorders may be qualitatively and quantitatively different from their adult equivalents. This may affect either benefit or risk of therapies (or both), with a resulting impact on the risk/benefit balance. In addition, chronic conditions may require chronic treatment and susceptibility to ADRs may change throughout the patient's lifetime according to age and stage of growth and development. Therefore, paediatric pharmacovigillance aspects need to be tailored to a number of variables based on heterogeneity of paediatric population. This chapter will summarize and discuss the key issues.

Aim: The aim of this article was to evaluate the influence of different demand-side measures to enhance the prescribing of generics in ambulatory care based on cross-national comparisons., Methods: An observational retrospective study was conducted using administrative databases from across Europe, documenting changes in reimbursed utilization and expenditure of different proton pump inhibitors (PPIs) and statins between 2001 and 2007, alongside different reforms to enhance prescribing efficiency. Utilization was converted to defined daily doses (DDDs) and expenditures were converted to euros. Demand-side measures were collated under the '4 Es'--education, engineering, economics and enforcement--to enable comparisons on the nature and intensity of reforms between countries., Results: There were considerable differences in the utilization of generics and patent-protected PPIs and statins among Western European countries. Decreased utilization of omeprazole and simvastatin, alongside increased utilization of esomeprazole, atorvastatin and rosuvastatin, was seen in countries with limited demand-side measures to counteract commercial pressures. Prescribing restrictions, or a combination of education, prescribing targets and financial incentives, had the greatest influence on enhancing the utilization of omeprazole and simvastatin. For example, there was a threefold reduction in the utilization of atorvastatin in Austria following prescribing restrictions. Multiple demand-side interventions generally had a greater influence than single interventions, with the impact appearing additive. Multiple interventions coupled with initiatives to lower prices of generics considerably enhanced prescribing efficiency., Conclusion: This cross-national study has demonstrated considerable variation in the utilization and expenditure of PPIs and statins across Europe, providing opportunities to further improve prescribing efficiency. The '4 Es' do provide an understandable methodology to document and compare the influence of different demand-side measures, with the influence varying by their extent and intensity. Further reforms are essential given current financial pressures. Consequently, further research will concentrate on the potential to develop a scoring system to help predict the possible impact of different demand-side measures on future utilization patterns.