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Recent data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) show a large increase of +57% in

The number of cases of

We collected data from 10 EU/EEA countries on 240 COVID-19 outbreaks occurring from July−October 2021 in long-term care facilities with high vaccination coverage. Among 17,268 residents, 3,832 (22.2%) COVID-19 cases were reported. Median attack rate was 18.9% (country range: 2.8–52.4%), 17.4% of cases were hospitalised, 10.2% died. In fully vaccinated residents, adjusted relative risk for COVID-19 increased with outbreak attack rate. Findings highlight the importance of early outbreak detection and rapid containment through effective infection prevention and control measures.

Objectives Data on cephalosporin consumption in the community were collected from 30 EU/EEA countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of the main subgroups of cephalosporins. Methods For the period 1997–2017, data on consumption of cephalosporins (i.e. first-, second-, third- and fourth-generation cephalosporins; ATC subgroups J01DB, J01DC, J01DD and J01DE, respectively) in the community and aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Cephalosporin consumption was analysed based on ATC-4 subgroup, and presented as trends, seasonal variation, presence of change-points and compositional changes. Results In 2017, cephalosporin consumption in the community expressed in DDD per 1000 inhabitants per day varied by a factor of 285 between countries with the highest (Greece) and the lowest (the Netherlands) consumption. Cephalosporin consumption did not change significantly between the first quarter of 1997 and the last quarter of 2017. Seasonal variation decreased significantly over time. Proportional consumption of second- and third-generation cephalosporins significantly increased over time compared with that of first-generation cephalosporins, and proportional consumption of fourth-generation cephalosporins significantly decreased compared with that of second- and third-generation cephalosporins. Conclusions Despite considerable variation between countries in the composition of cephalosporin consumption and trends over time, a significant shift towards consumption of more broad-spectrum cephalosporins in the community was observed across the EU/EEA during 1997–2017.

Objectives Data on the consumption of macrolides, lincosamides and streptogramins (MLS) in the community were collected from 30 EU/European Economic Area (EEA) countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in composition of the main subgroups of MLS. Methods For the period 1997–2017, data on consumption of MLS, i.e. ATC group J01F, in the community and aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Consumption of MLS was analysed and presented as trends, seasonal variation, presence of change-points and compositional changes, using a classification based on mean plasma elimination half-life for macrolides. Results In 2017, consumption of MLS in the community expressed in DDD per 1000 inhabitants per day varied by a factor of 13 between countries with the highest (Greece) and the lowest (Sweden) consumption. Consumption of MLS did not change significantly up to 2003, after which it significantly increased up to 2007. No significant change was observed after 2007. Consumption of MLS showed high seasonal variation. The proportional consumption of long-acting macrolides significantly increased over time compared with that of intermediate-acting macrolides, and proportional consumption of the latter increased compared with that of short-acting macrolides. Conclusions Consumption of MLS did not change significantly over time during 2007–2017, while the proportional consumption of long-acting macrolides increased. Seasonal variation remained high, which suggests that MLS are still prescribed inappropriately in many countries.

We assessed the impact of COVID-19 on healthcare workers (HCWs) from data on 2.9 million cases reported from nine countries in the EU/EEA. Compared to non-HCWs, HCWs had a higher adjusted risk of hospitalization (IRR 3.0 [95% CI 2.2-4.0]), but not death (IRR 0.9, 95% CI 0.4-2.0).Article Summary LineHealthcare workers are hospitalized more frequently than non-healthcare workers when adjusting for age, sex, and comorbidities.

Objectives This article introduces a series of articles on antibiotic consumption in the community between 1997 and 2017, which provide an update of previous articles covering the periods 1997–2003 and 1997–2009. Methods In this article, differences in participating countries, the ATC/DDD classification system, and data collection, validation and analysis between the current and previous series are described. Results In the previous series, 33 European countries provided valid data for further analysis, while the current series focused on 30 countries belonging to the EU or the European Economic Area (EEA). For both series, data were collected in accordance with the WHO ATC classification system. While the previous series reported data in accordance with the ATC/DDD index 2011, the current series employed the ATC/DDD index 2019. Both series focused on consumption of antibacterials for systemic use (ATC J01) and collected data expressed in DDD per 1000 inhabitants per day and packages per 1000 inhabitants per day. When studying consumption expressed in packages per 1000 inhabitants per day, countries reporting total care data, i.e. community and hospital sector combined, were included in the previous series but excluded in the current series. While the previous series used non-linear mixed models to evaluate time trends in antibiotic consumption, the current series allowed for inclusion of change-points with a data-driven location. In addition, both series assessed the composition and quality of antibiotic consumption in the EU/EEA. Conclusions The updated analyses of two decades of ESAC-Net data provide the most comprehensive and detailed description of antibiotic consumption in the community in Europe.

Objectives This tutorial describes and illustrates statistical methods to detect time trends possibly including abrupt changes (referred to as change-points) in the consumption of antibiotics in the community. Methods For the period 1997–2017, data on consumption of antibacterials for systemic use (ATC group J01) in the community, aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology and expressed in DDD (ATC/DDD index 2019) per 1000 inhabitants per day. Trends over time and presence of common change-points were studied through a set of non-linear mixed models. Results After a thorough description of the set of models used to assess the time trend and presence of common change-points herein, the methodology was applied to the consumption of antibacterials for systemic use (ATC J01) in 25 EU/European Economic Area (EEA) countries. The best fit was obtained for a model including two change-points: one in the first quarter of 2004 and one in the last quarter of 2008. Conclusions Allowing for the inclusion of common change-points improved model fit. Individual countries investigating changes in their antibiotic consumption pattern can use this tutorial to analyse their country data.

Objectives The quality of antibiotic consumption in the community can be assessed using 12 drug-specific quality indicators (DSQIs) developed by the European Surveillance of Antimicrobial Consumption (ESAC) project. We compared quality in 2009 and 2017 in the EU/European Economic Area (EEA) and evaluated the impact of using different DDD values (ATC/DDD indices 2011 and 2019) for the 2009 quality assessment using these DSQIs and a joint scientific opinion (JSO) indicator. Methods We calculated the 12 DSQIs and the JSO indicator for 2017 and for 2009 for EU/EEA countries able to deliver values. For each of the indicators we grouped the 2017 and 2009 indicator values into four quartiles. To evaluate changes in quality between 2009 and 2017, we used the quartile distribution of the 2009 indicator values in 30 EU/EEA countries as benchmarks. In addition, we compared the quality assessment for 2009 using the ATC/DDD indices 2011 and 2019. Results In 2017, a difference in the quality of antibiotic consumption in the community between northern and southern EU/EEA countries remained, but also several eastern EU/EEA countries shifted towards lower quality. Quality of antibiotic consumption decreased between 2009 and 2017 in particular indicator values for penicillin, quinolone, relative β-lactam and broad- versus narrow-spectrum antibiotic consumption, and seasonal variation. Using different ATC/DDD indices did not substantially change countries’ ranking based on their DSQI values. Conclusions The quality of antibiotic consumption in the community as measured by the DSQIs further decreased between 2009 and 2017, especially in Southern and Eastern European countries. A continuous effort to improve antibiotic consumption is essential to reduce antibiotic consumption in general and the use of broad-spectrum antibiotics in particular.

The cumulative incidence of coronavirus disease (COVID-19) cases is showing similar trends in European Union/European Economic Area countries and the United Kingdom confirming that, while at a different stage depending on the country, the COVID-19 pandemic is progressing rapidly in all countries. Based on the experience from Italy, countries, hospitals and intensive care units should increase their preparedness for a surge of patients with COVID-19 who will require healthcare, and in particular intensive care.

An alert regarding an outbreak of carbapenem-resistant Klebsiella pneumoniae carrying bla NDM-1 and bla OXA-48 carbapenemase-encoding genes was sent by Germany to European Union (EU)/European Economic Area (EEA) countries in October 2019. Since only limited whole genome sequencing (WGS) data on bla NDM-1- and bla OXA-48-positive K. pneumoniae were available in the public domain, national public health reference or equivalent expert laboratories from EU/EEA countries were invited to share WGS data from their national collections with the European Centre for Disease Prevention and Control (ECDC) to investigate the international dissemination of this epidemic strain. The analysis identified a Finnish case with an isolate closely related to the German outbreak strain and with an epidemiological link to St. Petersburg, Russia. In addition, several other clusters of genetically related bla NDM-1- and bla OXA-48-positive K. pneumoniae unrelated to the German outbreak strain but affecting numerous EU/EEA countries were identified. The aim of this follow-up investigation was to characterise these clusters based on the integrated analysis of the WGS dataset on bla NDM-1 - and bla OXA-48-positive K. pneumoniae submitted from 13 EU/EEA countries and additional epidemiological data.

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.

Currently, surveillance of livestock-associated meticillin-resistant Staphylococcus aureus (LA-MRSA) in humans in Europe is not systematic but mainly event-based. In September 2014, the European Centre for Disease Prevention and Control (ECDC) initiated a questionnaire to collect data on the number of LA-MRSA from human samples (one isolate per patient) from national/regional reference laboratories in European Union/European Economic Area (EU/EEA) countries in 2013. Identification of LA-MRSA as clonal complex (CC) 398 by multilocus sequence typing (MLST) was preferred, although surrogate methods such as spa-typing were also accepted. The questionnaire was returned by 28 laboratories in 27 EU/EEA countries. Overall, LA-MRSA represented 3.9% of 13,756 typed MRSA human isolates, but it represented ≥ 10% in five countries (Belgium, Denmark, Spain, the Netherlands and Slovenia). Seven of the reference laboratories did not type MRSA isolates in 2013. To monitor the dispersion of LA-MRSA and facilitate targeted control measures, we advocate periodic systematic surveys or integrated multi-sectorial surveillance., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Antibiotic resistance, either intrinsic or acquired, is a major obstacle for treating bacterial infections. Aim Our objective was to compare the country-specific species distribution of the four Gram-negative species Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter species and the proportions of selected acquired resistance traits within these species. Method We used data reported for 2016 to the European Antimicrobial Resistance Surveillance Network (EARS-Net) by 30 countries in the European Union and European Economic Area. Results The country-specific species distribution varied considerably. While E. coli accounted for 31.9% to 81.0% (median: 69.0%) of all reported isolates, the two most common intrinsically resistant species P. aeruginosa and Acinetobacter spp. combined (PSEACI) accounted for 5.5% to 39.2% of isolates (median: 10.1%). Similarly, large national differences were noted for the percentages of acquired non-susceptibility to third-generation cephalosporins, carbapenems and fluoroquinolones. There was a strong positive rank correlation between the country-specific percentages of PSEACI and the percentages of non-susceptibility to the above antibiotics in all four species (rho > 0.75 for 10 of the 11 pairs of variables tested). Conclusion Countries with the highest proportion of P. aeruginosa and Acinetobacter spp. were also those where the rates of acquired non-susceptibility in all four studied species were highest. The differences are probably related to national differences in antibiotic consumption and infection prevention and control routines.

European Antimicrobial Resistance Genes Surveillance Network (EURGen-Net) capacity survey group (Portugal): Manuela Caniça, Vera Manageiro, A survey on the epidemiological situation, surveillance and containment activities for carbapenemase-producing Enterobacteriaceae (CPE) was conducted in European countries in 2018. All 37 participating countries reported CPE cases. Since 2015, the epidemiological stage of CPE expansion has increased in 11 countries. Reference laboratory capability, dedicated surveillance and a specific national containment plan are in existence in 33, 27 and 14 countries, respectively. Enhanced control efforts are needed for CPE containment in Europe. info:eu-repo/semantics/publishedVersion

Unnecessary and inappropriate use of antibiotics in human healthcare is a major driver for the development and spread of antimicrobial resistance; many countries are implementing measures to limit the overuse and misuse of antibiotics e.g. through the establishment of antimicrobial use reduction targets. We performed a review of antimicrobial use reduction goals in human medicine in Transatlantic Taskforce on Antimicrobial Resistance partner countries. On 31 March 2017, the European Centre for Disease Prevention and Control sent a questionnaire to National Focal Points for Antimicrobial Consumption and the National Focal Points for Antimicrobial Resistance in 28 European Union countries, Iceland and Norway. The same questionnaire was sent to the TATFAR implementers in Canada and the United States. Thirty of 32 countries replied. Only nine countries indicated that they have established targets to reduce antimicrobial use in humans. Twenty-one countries replied that no target had been established. However, 17 of these 21 countries indicated that work to establish such targets is currently underway, often in the context of developing a national action plan against antimicrobial resistance. The reported targets varied greatly between countries and can be a useful resource for countries willing to engage in the reduction of antibiotic use in humans.

Burden of AMR Collaborative Group:National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal (Prof M Caniça PhD, Vera Manageiro PhD) Free PMC Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300481/ Background: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). Methods: We estimated the incidence of infections with 16 antibiotic resistance–bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011–12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. Findings: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148–763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480–38 430) attributable deaths and 874 541 (768 837–989 068) DALYs. The burden for the EU and EEA was highest in infants (aged

Evaluating trends in antibiotic resistance and communicating the results to a broad audience are important for dealing with this global threat. The Drug Resistance Index (DRI), which combines use and resistance into a single measure, was developed as an easy-to-understand measure of the effectiveness of antibiotic therapy. We demonstrate its utility in communicating differences in the effectiveness of antibiotic therapy across countries.We calculated the DRI for countries with data on antibiotic use and resistance for the disease-causing organisms considered by the WHO as priority pathogens:41 countries had the requisite data and were included in the study. Resistance and use rates were highly variable across countries, butThe DRI is a useful indicator of the problem of resistance. By combining data on antibiotic use with resistance, it captures a snapshot of how the antibiotics a country typically uses match their resistance profiles. This single measure of the effectiveness of antibiotic therapy provides a means of benchmarking against other countries and can, over time, indicate changes in drug effectiveness that can be easily communicated.

Summary Background The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. Methods We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. Findings We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa , and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus . Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori , and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae , and Salmonella typhi were included in the high-priority tier. Interpretation Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae , and H pylori . Funding World Health Organization.

Currently, surveillance of livestock-associated meticillin-resistant

The members of the European Survey on Carbapenemase-Producing Enterobacteriaceae, (EuSCAPE) Working Group are: Portugal—Manuela Caniça and Vera Manageiro BACKGROUND: Gaps in the diagnostic capacity and heterogeneity of national surveillance and reporting standards in Europe make it difficult to contain carbapenemase-producing Enterobacteriaceae. We report the development of a consistent sampling framework and the results of the first structured survey on the occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in European hospitals. METHODS: National expert laboratories recruited hospitals with diagnostic capacities, who collected the first ten carbapenem non-susceptible clinical isolates of K pneumoniae or E coli and ten susceptible same-species comparator isolates and pertinent patient and hospital information. Isolates and data were relayed back to national expert laboratories, which made laboratory-substantiated information available for central analysis. FINDINGS: Between Nov 1, 2013, and April 30, 2014, 455 sentinel hospitals in 36 countries submitted 2703 clinical isolates (2301 [85%] K pneumoniae and 402 (15%) E coli). 850 (37%) of 2301 K pneumoniae samples and 77 (19%) of 402 E coli samples were carbapenemase (KPC, NDM, OXA-48-like, or VIM) producers. The ratio of K pneumoniae to E coli was 11:1. 1·3 patients per 10 000 hospital admissions had positive clinical specimens. Prevalence differed greatly, with the highest rates in Mediterranean and Balkan countries. Carbapenemase-producing K pneumoniae isolates showed high resistance to last-line antibiotics. INTERPRETATION: This initiative shows an encouraging commitment by all participants, and suggests that challenges in the establishment of a continent-wide enhanced sentinel surveillance for carbapenemase-producing Enterobacteriaeceae can be overcome. Strengthening infection control efforts in hospitals is crucial for controlling spread through local and national health care networks. European Centre for Disease Prevention and Control info:eu-repo/semantics/publishedVersion

OBJECTIVESTo develop common indicators, relevant to both EU member states and the United States, that characterize and allow for meaningful comparison of antimicrobial stewardship programs among different countries and healthcare systems.DESIGNModified Delphi process.PARTICIPANTSA multinational panel of 20 experts in antimicrobial stewardship.METHODSPotential indicators were rated on the perceived feasibility to implement and measure each indicator and clinical importance for optimizing appropriate antimicrobial prescribing.RESULTSThe outcome was a set of 33 indicators developed to characterize the infrastructure and activities of hospital antimicrobial stewardship programs. Among them 17 indicators were considered essential to characterize an antimicrobial stewardship program and therefore were included in a core set of indicators. The remaining 16 indicators were considered optional indicators and included in a supplemental set.CONCLUSIONSThe integration of these indicators in public health surveillance and special studies will lead to a better understanding of best practices in antimicrobial stewardship. Additionally, future studies can explore the association of hospital antimicrobial stewardship programs to antimicrobial use and resistance.Infect Control Hosp Epidemiol 2016:1–11

Invasive infections with Mycobacterium chimaera were reported in patients with previous open chest surgery and exposure to contaminated heater-cooler units (HCUs). We present results of the surveillance of clinical cases and of contaminated HCUs as well as environmental investigations in Germany up until February 2016. Clinical infections occurred in five male German cases over 50 years of age (range 53–80). Cases had been exposed to HCUs from one single manufacturer during open chest surgery up to five years prior to onset of symptoms. During environmental investigations, M. chimaera was detected in samples from used HCUs from three different countries and samples from new HCUs as well as in the environment at the manufacturing site of one manufacturer in Germany. Our investigation suggests that at least some of the M. chimaera infections may have been caused by contamination of HCUs at manufacturing site. We recommend that until sustainable measures for safe use of HCUs in operation theatres are implemented, users continue to adhere to instructions for use of HCUs and Field Safety Notices issued by the manufacturer, implement local monitoring for bacterial contamination and continuously check the websites of national and European authorities for current recommendations for the safe operation of HCUs.

PURPOSE: To compare the shape of the capsulotomy, its change, and its impact on visual quality over 1 year using the femtosecond laser system from the manual technique. METHODS: In this two-center cross-sectional study from May 2012 to June 2013, each patient had femtosecond laser-assisted cataract surgery in one eye (FLACS group) and conventional phacoemulsification cataract surgery in the other eye (CPCS group). An evaluation of the capsulotomy was performed using retroillumination slit-lamp photographs at 7 days, 6 months, and 1 year after surgery. Effective lens position (ELP), refractive error, and corrected distance visual acuity (CDVA) were analyzed. RESULTS: Thirty-three patients were included in the study. Diameters of capsulorhexis were more precise and deviation surfaces were lower in the FLACS group than in the CPCS group at each evaluation ( P < .05). Femtosecond laser capsulotomies were less modified over time than manual continuous curvilinear capsulorhexis. No significant differences were observed for CDVA, refractive error, and ELP between groups. CONCLUSIONS: More precise capsulotomy sizing can be achieved with the femtosecond laser compared to continuous curvilinear capsulorhexis. Femtosecond laser capsulotomies are less modified over time but did not improve ELP or visual quality. [ J Refract Surg. 2017;33(1):44–49]

Association between previous antibiotic use and emergence of antibiotic resistance has been reported for several microorganisms. The relationship has been extensively studied, and although the causes of antibiotic resistance are multi-factorial, clear evidence of antibiotic use as a major risk factor exists. Most studies are carried out in countries with high consumption of antibiotics and corresponding high levels of antibiotic resistance, and currently, little is known whether and at what level the associations are detectable in a low antibiotic consumption environment. We conduct an ecological, retrospective study aimed at determining the impact of antibiotic consumption on antibiotic-resistant Pseudomonas aeruginosa in three hospitals in Norway, a country with low levels of antibiotic use. We construct a sophisticated statistical model to capture such low signals. To reduce noise, we conduct our study at hospital ward level. We propose a random effect Poisson or binomial regression model, with a reparametrisation that allows us to reduce the number of parameters. Inference is likelihood based. Through scenario simulation, we study the potential effects of reduced or increased antibiotic use. Results clearly indicate that the effects of consumption on resistance are present under conditions with relatively low use of antibiotic agents. This strengthens the recommendation on prudent use of antibiotics, even when consumption is relatively low.

The original and successful business model of return on investment being sufficiently attractive to the pharmaceutical industry to encourage development of new antibacterial molecules and related diagnostics has been compromised by increasing development costs and regulatory hurdles, resulting in a decreasing chance of success and financial return. The supply of new effective agents is diminishing along with the number of companies engaged in antibacterial research and development. The BSAC Working Party on The Urgent Need:Regenerating Antibacterial Drug Discovery and Development identified the need to establish, communicate and apply the true health and economic value of antibacterials, along with the adoption of meaningful incentives, as part of the future model for antibacterial development. Robust data are needed on the cost of resistance and ineffective treatment of bacterial infection, along with national and local holistic analyses of the cost-benefit of antibacterials. An understanding of the true health and economic value of antibacterials and the cost of resistance across healthcare systems needs to be generated, communicated and used in order to set a pricing and reimbursement structure that is commensurate with value. The development and economic model of antibacterial use needs to be rebuilt based on this value through dialogue with the various stakeholders, including the pharmaceutical industry, and alternative incentives from 'push' to 'pull' and funding models, such as public/private partnerships, agreed. A research and development model that succeeds in developing and delivering new antibacterial agents that address the health needs of society from start to finish, 'from cradle to grave', must be established.

Unlike most other drugs that only affect individual patients if used incorrectly for self-medication, misused antibiotics add to the global risk of increased spread of bacterial resistance. This review focuses on self-medication with antibiotics in Europe and its determinants. High prevalence of self-medication with antibiotics has been repeatedly found in Southern and Eastern European countries that also report high levels of antibiotic resistance. Despite being illegal, over the counter dispensation of systemic antibiotics occurs in several European Union Member States. A second major source of self-medication is the availability of "leftover" antibiotics which results from either patient non-compliance or dispensation of a larger number of tablets than needed for one single course. The potentially modifiable factors associated with self-medication are: availability of antibiotics without prescription, pack-based antibiotic dispensing system, misconceptions of the general public about the efficacy of antibiotics for minor illnesses and prescribing of antibiotics for minor ailments by physicians. Measures that may reduce and prevent self-medication include dispensation of exact tablet quantities in pharmacies as already implemented e.g. in the UK, Netherlands, the Czech Republic and the United States, and enforcement of existing laws prohibiting over-the-counter sales of antibiotics. Such measures should be embedded in a general policy to change the culture of antibiotic use by improving awareness of the general public and professionals about antibiotics and the risks associated with their use as well as reducing misconceptions about the need for antibiotics for minor ailments.

Sir, Anthony R. White, on behalf of the BSAC Working Party on The Urgent Need: Regenerating Antibacterial Drug Discovery and Development, has reviewed the economics of antibacterial resistance and its control.1 In this letter, we add to the current knowledge base on this issue by providing a historical perspective on the public health need for antibacterial agents active against emerging multidrug-resistant bacteria and the sales of selected agents, chosen as examples, that responded to this need in previous decades. Data on the worldwide sales of these agents and their dates of approval in the USA were obtained from MedAdNews (http://www.pharmalive.com/med-ad-news), as well as companies’ annual reports (Figure 1). Figure 1. Worldwide sales of patented antibacterial agents chosen as examples, 1985–2012. These agents targeted multidrug-resistant bacteria that were prevalent at the time of their launch. Data do not include sales of generic versions of the same agents ... In the mid-1980s, the rapid emergence of multidrug-resistant Gram-negative bacteria such as extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae2 and ceftazidime-resistant Pseudomonas aeruginosa3 highlighted the need for antibacterial agents active against these resistant bacteria. Imipenem/cilastatin, the first carbapenem, was approved in 1985 and immediately responded to this need. From the mid-1980s into the 1990s, imipenem/cilastatin was used to treat patients infected with such multidrug-resistant Gram-negative bacteria (Figure 1). Meropenem, a second carbapenem, was approved in 1996 and its sales rapidly increased. In 2013, meropenem and imipenem/cilastatin are still essential antibacterial agents for the treatment of healthcare-associated infections, especially in severely ill or immunocompromised patients.4,5 Both are classified by the WHO as critically important antimicrobials in human medicine.6 During the last two decades, several other antibacterial agents active against emerging multidrug-resistant bacteria, and thus responding to the public health need, have reached substantial sales (Figure 1). Piperacillin/tazobactam, approved in 1993, found its market in the 2000s, in particular as an agent to treat healthcare-associated infections. Linezolid, approved in 2000 as the first oxazolidinone, and daptomycin, approved in 2003 as the first lipopeptide, quickly found their markets as agents to treat infections with Gram-positive bacteria, in particular methicillin-resistant Staphylococcus aureus. The sales of linezolid, which is available for both intravenous and oral use, should soon reach a similar level to that of ciprofloxacin in the late 1990s to early 2000s (Figure 1). The only exception to these trends may be tigecycline, approved in 2005 as the first glycylcycline, but did not yet reach annual worldwide sales of US$500 million (Figure 1). The increasing use of carbapenems, together with the varying quality of infection control practices, has led to the emergence of carbapenem-resistant Gram-negative bacteria. As early as the late 1980s, the percentage of P. aeruginosa isolates that were resistant to carbapenems started to increase.7 In 2007, the number of carbapenem-resistant P. aeruginosa infections in the European Union was estimated at 141 900 annually and the number of multidrug-resistant P. aeruginosa infections in the USA at 72 250 annually.8,9 More recently, carbapenemase-producing Enterobacteriaceae have emerged and are now spreading globally, including in the European Union.10–13 The generally favoured option for the treatment of patients infected by multiresistant carbapenemase-producing bacteria is colistin, an old antibiotic that has now become an essential drug in hospitals. The consequence of the increasing use of colistin, however, is the inevitable rise of colistin resistance, with high percentages of resistance already occurring in K. pneumoniae infections in some European hospitals,14,15 leading to clinical situations where there is no straightforward option for treatment. In 2009, a joint report from the European Centre for Disease Prevention and Control and the European Medicines Agency, in a collaboration with ReAct—Action on Antimicrobial Resistance, highlighted the gap between increasing antimicrobial resistance in Europe and the urgent need for new antibacterial agents active against resistant bacteria, in particular to treat multidrug-resistant Gram-negative infections.8 Although comparable to the need for agents to treat patients with multidrug-resistant Gram-negative infections (in particular those caused by ESBL-producing bacteria) in the mid-1980s and the 1990s, the current public health need for new antibacterial agents is still currently not being addressed. The succession of cycles of public health need followed by antibacterial productivity, as illustrated by White,1 that prevailed since the discovery of antibiotics seems to have come to a halt. Two recent reviews of the antibacterial research and development pipeline confirm that, despite some progress, there are currently only a few compounds in development with activity against multidrug-resistant Gram-negative bacteria, in particular metallo-carbapenemase (e.g. New Delhi metallo-β-lactamase)-producing Enterobacteriaceae or P. aeruginosa, or against multidrug-resistant Acinetobacter spp.16,17 This historical perspective shows that, in the presence of a public health need, antibacterial agents that targeted emerging multidrug-resistant bacteria quickly found their market and reached annual worldwide sales of US$500 million or above, sometimes reaching the ‘blockbuster’ threshold of US$1 billion for worldwide sales annually before the 10th full year after their launch (Figure 1). This observation goes against the common view that new antibacterial agents have a small potential market of less than US$500 million annually.18 It provides an insight into what would be the potential market, considering the current public health need and current economic model,1 for a novel antibacterial agent active against carbapenem-resistant Gram-negative bacteria.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide. A wide range of factors have been suggested to influence the spread of MRSA. The objective of this study was to evaluate the effect of antimicrobial drug use and infection control practices on nosocomial MRSA incidence in a 426-bed general teaching hospital in Northern Ireland.The present research involved the retrospective collection of monthly data on the usage of antibiotics and on infection control practices within the hospital over a 5 year period (January 2000-December 2004). A multivariate ARIMA (time-series analysis) model was built to relate MRSA incidence with antibiotic use and infection control practices.Analysis of the 5 year data set showed that temporal variations in MRSA incidence followed temporal variations in the use of fluoroquinolones, third-generation cephalosporins, macrolides and amoxicillin/clavulanic acid (coefficients = 0.005, 0.03, 0.002 and 0.003, respectively, with various time lags). Temporal relationships were also observed between MRSA incidence and infection control practices, i.e. the number of patients actively screened for MRSA (coefficient = -0.007), the use of alcohol-impregnated wipes (coefficient = -0.0003) and the bulk orders of alcohol-based handrub (coefficients = -0.04 and -0.08), with increased infection control activity being associated with decreased MRSA incidence, and between MRSA incidence and the number of new patients admitted with MRSA (coefficient = 0.22). The model explained 78.4% of the variance in the monthly incidence of MRSA.The results of this study confirm the value of infection control policies as well as suggest the usefulness of restricting the use of certain antimicrobial classes to control MRSA.

Background: Self-medication with antibiotics occurs among the population in Europe, particularly in southern and eastern countries. We studied the impact of predisposing factors (e.g. attitudes and knowledge concerning antibiotic use and self-medication) and enabling factors (country wealth and healthcare system factors) on self-medication with antibiotics in Europe.Methods: In this follow-up of a previous European survey, we interviewed a subsample of 1101 respondents. A multilevel analysis with two levels (respondent and country) was performed. Variables that were statistically significantly different between users and non-users of self-medication were considered for inclusion into the multilevel regression analyses.Results: Predisposing factors included individual-level characteristics. High perceived appropriateness of self-medication with antibiotics for bronchitis and an attitude favouring antibiotic use for minor ailments were related to a higher likelihood of self-medication. Enabling factors included individual and country data. At the individual level, perceived availability of antibiotics without a prescription was related to increased probability of self-medication. At the country level, higher gross domestic product (wealth) and exact dispensation of prescribed tablet quantities by pharmacies were independently associated with lower likelihood of self-medication.Conclusions: Interventions aimed at preventing self-medication should include public education, enforcing regulations regarding the sale of antibiotics, and implementing laws for dispensing exact prescribed tablet quantities in pharmacies. With the included determinants, we explained almost all the variance at the country level, but not at the individual level. Future studies to increase our understanding of determinants of self-medication with antibiotics should focus on individual-level factors such as doctor-patient relationships and patient satisfaction.

During the last decade, the efforts to combat multidrug-resistant (MDR) microorganisms mainly focused on gram-positive bacteria, namely, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. While a large number of hospitals have implemented more rigorous infection

The aim of the study was to investigate the potential spread of gentamicin resistant (GENR) Escherichia coli isolates or GENR determinants from a Danish university hospital to the waste water environment. Waste water samples were collected monthly from the outlets of the hospital bed wards and the inlet of the related waste water treatment plant (WWTP) from October 2002 to August 2003. Waste water samples were also collected monthly from a residential area in the same period to be able to compare the prevalence of GENRE. coli isolates from hospital related and residential waste water. The waste water isolates were compared to GENRE. coli isolates obtained consecutively from September 2002 to September 2003 from patients mainly with urinary tract infections at the hospital with respect to Pulsed Field Gel Electrophoresis (PFGE) profiles. All isolates were investigated for GENR mechanisms (aac(3)-II, aac(3)-IV, ant(2″)-I, armA), phenotypic resistance pattern, and virulence genes (hlyA, chuA, sfaS, fogG, malX, traT, iutA, fyuA, iroN, cnf1) to investigate if the hospital and waste water could be reservoirs of antimicrobial resistance and virulence. The ability for GENR determinants to transfer horizontally was investigated by mating experiments.A total of 38, 15, 21, and two GENRE. coli were isolated from patients, the hospital outlets, the inlet of the WWTP, and the residential area, respectively. GENRE. coli were more prevalent in waste water from the hospital and the WWTP than in waste water from the residential area. PFGE profiling revealed no spread of specific patient isolates to the waste water. The aac(3)-II gene was detected both in patient and waste water isolates. Furthermore horizontal transfer of the aac(3)-II gene of patient origin to a recipient was shown in vitro, indicating a potential spread of the gene from patient isolates to waste water isolates. Regardless of origin, most isolates exhibited multi-resistance and contained several virulence genes.In conclusion, our study showed a possible spread of aac(3)-II from the hospital to the waste water. Most of the GENRE. coli isolates from both patients and waste water had a multi-resistant phenotype and contained virulence genes and should therefore be considered reservoirs of antimicrobial resistance and virulence genes. Keywords: Escherichia coli, Gentamicin, Dissemination, Antimicrobial resistance, Virulence

Summary We studied the relationship between meticillin-resistant Staphylococcus aureus (MRSA) prevalence in the Aberdeen Royal Infirmary and in the surrounding community (Grampian region: 500 000 inhabitants). We calculated the monthly %MRSA for both hospital and community from January 1996 to February 2002. A dynamic regression model was adjusted to measure any relationship between both series. The monthly %MRSA in the community was strongly related to the monthly %MRSA observed one month before in the hospital ( R 2 =90.8%). We found no relationship with antimicrobial community use, although we have previously reported a strong correlation between prior use of antibiotics and incidence of MRSA in the hospital. By using time-series analysis techniques, we demonstrated that variations in MRSA prevalence in the hospital are quickly followed by similar variations in MRSA prevalence in the surrounding community. These results suggest that the reason for the increase in MRSA prevalence in the community was a hospital MRSA outbreak. Screening at patient discharge should be evaluated as a new measure to control spread of MRSA in the community.

Hospitals in the northeast of Scotland have experienced methicillin-resistant Staphylococcus aureus (MRSA) outbreaks since 1997. Several infection control measures were introduced sequentially to control MRSA, and antibiotic use has been monitored. From January 1997 to December 2004, data on the monthly percentage of non-duplicate MRSA infections (%MRSA) were collated from an intervention hospital (IH) and a control hospital (CH). Both hospitals introduced the use of alcohol hand gel in November 2002. Furthermore, the IH introduced an environmental MRSA swabbing programme in March 2001, chlorine disinfection of the environment in September 2001, discharge screening in December 2001, admission screening in November 2003 and environmental audits in March 2004. Multivariate dynamic regression analysis was used to evaluate the longitudinal effects of these interventions as measured by new clinical cases of MRSA. At the IH, the %MRSA increased between January 1998 and January 2001 and then decreased. At the CH, the %MRSA increased from January 1997 to December 2004. Introduction of alcohol hand gel was associated with an absolute decrease in %MRSA of 21% and 30%, respectively, for the IH and CH. At the IH, introduction of chlorine disinfection and environmental swabbing were, respectively, associated with a decrease in %MRSA of 27% immediately and 32% 3 months later. Discharge screening and environmental audit did not significantly affect %MRSA, whereas admission screening was associated with a 22% decrease in %MRSA 4 months later. Increasing macrolide use was associated with increasing %MRSA in both hospitals, and increasing quinolone use was associated with increasing %MRSA in the CH. Implementation of stepwise infection control measures was associated with a decrease in %MRSA in the IH. Introduction of an alcohol gel for hand hygiene was associated with a decrease in %MRSA in both hospitals. Antibiotic use also affects %MRSA, in particular that of macrolides and quinolones.