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Carbapenem-resistant Klebsiella pneumoniae (CRKP) are of particular concern due to the spread of antibiotic resistance genes associated with mobile genetic elements. In this study, we collected 687 carbapenem-resistant strains recovered among clinical samples from 41 hospitals in nine Southern European countries (2016-2018). We identified 11 major clonal lineages, with most isolates belonging to the high-risk clones ST258/512, ST101, ST11, and ST307. bla KPC-like was the most prevalent carbapenemase-encoding gene (46%), with bla OXA-48 present in 39% of isolates. Through the combination and comparison of this EURECA collection with the previous EuSCAPE collection (2013-2014), we investigated the spread of high-risk clones circulating in Europe exhibiting regional differences. We particularly found bla KPC-like ST258/512 in Greece, Italy, and Spain, bla OXA-48 ST101 in Serbia and Romania, bla NDM ST11 in Greece, and bla OXA-48-like ST14 in Türkiye. Genomic surveillance across Europe thus provides crucial insights for local risk mapping and informs necessary adaptions for implementation of control strategies., (© 2024. The Author(s).)

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria., (© 2024. The Author(s).)

Objectives: To assess the mortality attributable to infections caused by carbapenem-resistant Enterobacterales (CRE) and to investigate the effect of clinical management on differences in observed outcomes in a multinational matched cohort study., Methods: A prospective matched-cohorts study (NCT02709408) was performed in 50 European hospitals from March 2016 to November 2018. The main outcome was 30-day mortality with an active post-discharge follow-up when applied. The CRE cohort included patients with complicated urinary tract infections, complicated intra-abdominal infections, pneumonia, or bacteraemia from other sources because of CRE. Two control cohorts were selected: patients with infection caused by carbapenem-susceptible Enterobacterales (CSE) and patients without infection. Matching criteria included type of infection for the CSE group, hospital ward of CRE detection, and duration of hospital admission up to CRE detection. Multivariable and stratified Cox regression was applied., Results: The cohorts included 235 patients with CRE infection, 235 patients with CSE infection, and 705 non-infected patients. The 30-day mortality (95% CI) was 23.8% (18.8-29.6), 10.6% (7.2-15.2), and 8.4% (6.5-10.6), respectively. The difference in 30-day mortality rates between patients with CRE infection when compared with patients with CSE infection was 13.2% (95% CI, 6.3-20.0), (HR, 2.57; 95% CI, 1.55-4.26; p < 0.001), and 15.4% (95% CI, 10.5-20.2) when compared with non-infected patients (HR, 3.85; 95% CI, 2.57-5.77; p < 0.001). The population attributable fraction for 30-day mortality for CRE vs. CSE was 19.28%, and for CRE vs. non-infected patients was 9.61%. After adjustment for baseline variables, the HRs for mortality were 1.87 (95% CI, 0.99-3.50; p 0.06) and 3.65 (95% CI, 2.29-5.82; p < 0.001), respectively. However, when treatment-related time-dependent variables were added, the HR of CRE vs. CSE reduced to 1.44 (95% CI, 0.78-2.67; p 0.24)., Discussion: CRE infections are associated with significant attributable mortality and increased adjusted hazard of mortality when compared with CSE infections or patients without infection. Underlying patient characteristics and a delay in appropriate treatment play an important role in the CRE mortality., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design., Methods and Findings: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability., Conclusion: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis., Trial Registration: ClinicalTrials.gov, (NCT03721302)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Members of the funder (MB, NK, SE) participated as authors on the study, reviewed the manuscript, and approved the final manuscript as submitted. All other authors have declared that no competing interests exist., (Copyright: © 2023 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

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.)

Background: Data on risk factors for carbapenem-resistant Enterobacterales (CRE) with wider applicability are needed to inform preventive measures and efficient design of randomised trials., Methods: An international matched case-control-control study was performed in 50 hospitals with high CRE incidence from March 2016 to November 2018 to investigate different aspects of infections caused by CRE (NCT02709408). Cases were patients with complicated urinary tract infection (cUTI), complicated intraabdominal (cIAI), pneumonia or bacteraemia from other sources (BSI-OS) due to CRE; control groups were patients with infection caused by carbapenem-susceptible Enterobacterales (CSE), and by non-infected patients, respectively. Matching criteria included type of infection for CSE group, ward and duration of hospital admission. Conditional logistic regression was used to identify risk factors., Findings: Overall, 235 CRE case patients, 235 CSE controls and 705 non-infected controls were included. The CRE infections were cUTI (133, 56.7%), pneumonia (44, 18.7%), cIAI and BSI-OS (29, 12.3% each). Carbapenemase genes were found in 228 isolates: OXA-48/like, 112 (47.6%), KPC, 84 (35.7%), and metallo-β-lactamases, 44 (18.7%); 13 produced two. The risk factors for CRE infection in both type of controls were (adjusted OR for CSE controls; 95% CI; p value) previous colonisation/infection by CRE (6.94; 2.74-15.53; <0.001), urinary catheter (1.78; 1.03-3.07; 0.038) and exposure to broad spectrum antibiotics, as categorical (2.20; 1.25-3.88; 0.006) and time-dependent (1.04 per day; 1.00-1.07; 0.014); chronic renal failure (2.81; 1.40-5.64; 0.004) and admission from home (0.44; 0.23-0.85; 0.014) were significant only for CSE controls. Subgroup analyses provided similar results., Interpretation: The main risk factors for CRE infections in hospitals with high incidence included previous colonization, urinary catheter and exposure to broad spectrum antibiotics., Funding: The study was funded by the Innovative Medicines Initiative Joint Undertaking (https://www.imi.europa.eu/) under Grant Agreement No. 115620 (COMBACTE-CARE)., Competing Interests: George L. Daikos reports personal fees from Pfizer, personal fees from MSD, outside the submitted work. Lionel K. Tan is an employee of and holds stocks and shares in GlaxoSmithKline. Pierluigi Viale reports grants from Shionogi and Gilead; personal fees from Shionogi, MSD, Allianz, Nordic, InfectoPharm, MundiPharm and Angelini, outside the submitted work. Jose María Reguera reports non-financial support from Pfizer. Lucía Valiente de Santis reports non-financial support from Pfizer. Julián Torre-Cisneros reports personal fees from MSD, Pfizer, Menarini, and Shionogi; and non-financial support from Pfizer, Shionogi and Gilead, outside the submitted work. Ángela Cano reports personal fees from Shionogi. Emmanuel Roilides reports personal fees from Amplyx, Astellas, Gilead, MSD, Pfizer, Scynexis, GSK and Shionogi, outside the submitted work. Marc J. Bonten reports grants paid to his institution from Janssen Vaccines, Novartis, CureVac and Merck; participation in Advisory Boards with payment to his institution from Spherecydes, Pfizer, Merck and Astra-Zeneca, and participation in Data Safety Monitoring Boards with payment to his institution from Sanofi. All other authors have no conflicts to declare., (© 2023 The Author(s).)

Objectives: This study aimed to evaluate the antibiotic prescription patterns of health workers in Eastern Uganda and more specifically whether they are in accordance with the Ugandan standard treatment guidelines and other indicators of appropriate antimicrobial prescription., Methods: Patient data were obtained from the health management information system of the outpatient department registers of Soroti and Mbale Regional Referral Hospitals from 2016-2018., Results: The prevalence of non-adherence to treatment guidelines when prescribing antibiotics was 82.6% (95% CI 81.4-83.7%). Guidelines were more likely to be adhered to when prescribing antibiotics for individuals aged 13-19 years compared with their counterparts aged 0-12 years [adjusted odds ratio (aOR) = 0.55, 95% CI 0.40-0.74]. When prescribing antibiotics for males, health workers were twice as likely not to adhere to guidelines compared with when prescribing for females (aOR = 2.09, 95% CI 1.61-2.72). When prescribing cephalosporins and nitroimidazoles, health workers were likely not to adhere to guidelines compared with when prescribing penicillin (cephalosporins, aOR = 1.92, 95% CI 1.28-2.86; nitroimidazoles, aOR = 1.70, 95% CI 1.09-2.65). Health workers were most likely not to follow guidelines when prescribing antibiotics in combination (two antibiotics, aOR = 1.27, 95% CI 1.03-1.56)., Conclusion: Non-adherence to treatment guidelines for an indicated diagnosis and inappropriate antibiotic prescription are significantly prevalent in Eastern Uganda. Health workers were more likely not to follow guidelines when prescribing for males, children up to 12 years of age and when prescribing cephalosporins, nitroimidazoles or double antibiotic combinations., Competing Interests: Competing interests None declared., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Most of the antimicrobial stewardship (AMS) literature has focused on antimicrobial consumption for the treatment of infections, for the prophylaxis of surgical site infection and for the prevention of endocarditis. The role of AMS for medical antibiotic prophylaxis (AP) has not been adequately addressed., Aims: To identify targets for AMS interventions for medical AP in adult patients., Sources: Targeted searches were conducted in PubMed., Content: The various indications for medical AP and relevant evidence from practice guidelines are outlined. The following were identified as potential targets for AMS interventions: (a) addressing under-utilization of antibiotic-sparing strategies (e.g. for recurrent urinary tract infections, recurrent soft-tissue infections, recurrent exacerbations associated with bronchiectasis or chronic obstructive pulmonary disease), (b) reducing unnecessary AP beyond recommended indications (e.g. for acute pancreatitis, bite wounds, or urinary catheter manipulations), (c) reducing the use of AP with a broader spectrum than necessary, (d) reducing the use of AP for longer than the recommended duration (e.g. AP for prevention of osteomyelitis in open fractures or AP in high-risk neutropenia), (e) evaluating the role of antibiotic cycling to prevent the emergence of resistance during prolonged AP (e.g. in recurrent urinary tract infections or prophylaxis for spontaneous bacterial peritonitis), and (f) addressing research gaps regarding appropriate indications or antibiotic regimens for medical prophylaxis., Implications: This review summarizes current trends in AP and proposes targets for AMS interventions., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

LAB-Net, the laboratory network of COMBACTE, has established itself as an indispensable network for clinical trials in infectious diseases that plays a crucial part across 30 clinical studies not only within, but also outside the COMBACTE consortium. Since its official launch in January 2013, LAB-Net has expanded more than threefold and in Q4 2020 it encompasses 841 labs across 41 countries in Europe. In addition, LAB-Net has crossed the European borders and collaborates with more than 300 laboratories spread across the globe. The tight collaboration with partners within COMBACTE and beyond contributed tremendously to the growth of LAB-Net over the years. A sustainable infrastructure beyond COMBACTE-NET is needed to ensure the smooth handover and continuity of the achievements made by the project.

Objective: The aim of this study was to determine the prevalence and antibiotic resistance patterns of bacterial isolates from inpatients and outpatients in Mbale and Soroti regional referral hospitals in Eastern Uganda., Methods: A retrospective analysis of culture and antibiotic sensitivity test results from the microbiology laboratories of the two tertiary hospitals was conducted for a 3-year period (January 2016-December 2018)., Results: Microbiology records of 3092 patients were reviewed and analysed, with 1305 (42.1%) samples yielding clinical isolates. The most prevalent isolates were Escherichia coli (n = 442; 33.9%), Staphylococcus aureus (n = 376; 28.8%), Klebsiella pneumoniae (n = 237; 18.2%), and Streptococcus pneumoniae (n = 76; 5.8%). High rates of antimicrobial resistance were detected across both Gram-negative and Gram-positive bacteria. Escherichia coli and K. pneumoniae were resistant to several agents such as amoxicillin/clavulanate (83.5%; 64.6%), cefotaxime (74.2%; 52.7%), ciprofloxacin (92.1%; 27.8%), gentamicin (51.8%; 76%), imipenem (3.2%; 10.5%), tetracycline (98%; 74.5%), and trimethoprim-sulfamethoxazole (74.1%; 74.3%), respectively. Staphylococcus aureus and S. pneumoniae exhibited the following resistance profile: cefoxitin (44.4%; 40.9%), chloramphenicol (69.1%; 27.6%) clindamycin (21.5%; 24.4%), gentamicin (83.2%; 66.9%), penicillin (46.5%; -) tetracycline (85.6%; 97.6%), trimethoprim-sulfamethoxazole (88%; 91.3%), and vancomycin (41.2%; -)., Conclusion: We observed high resistance rates to antibiotics among the majority of microorganisms that were isolated from the samples collected from patients in Eastern Uganda. Furthermore, measures should be undertaken locally to improve microbiology diagnostics and to prevent the spread of antibiotic-resistant strains as this impedes the optimal treatment of bacterial infections and narrows the choice of effective therapeutic options., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study aimed to explore the experiences and views of healthcare professionals on antibiotic prescription in Eastern Uganda., Methods: This was an exploratory qualitative study using semi-structured interviews. Participants included 16 healthcare professionals from Mbale and Soroti Regional Referral Hospitals. Additionally, two workshops were held (one in each hospital) with a total of 56 healthcare professionals to discuss the findings. Thematic analysis was used to analyse the data., Results: Healthcare professionals' prescriptions are influenced by (i) healthcare workers' perceptions and practices, (ii) patients' perceptions and beliefs, and (iii) contextual factors. Healthcare workers' prescriptions depend on the presence of bacterial infection and the severity of the condition, the availability and cost of medication, previous experience with antibiotic prescribing, patient characteristics, and trial and error. They also have limited knowledge and share little information on the use of antibiotics with patients. Patient factors included demand for a particular antibiotic, inability to afford expensive drugs, and limited knowledge about antibiotic use and resistance. Contextual factors that contributed to antibiotic prescribing were an overburdened healthcare system, the influence of pharmaceutical companies and pharmacies, the use of (treatment) guidelines, and difficulties with laboratory services., Conclusion: This study showed that healthcare professionals are aware of the problem of antibiotic resistance but do not feel ownership of the problem. Instead, they rather blame the overburdened system, local drug shops, pharmacies, drug representatives and patients. There is a need for a multisectoral and holistic approach toward fighting antibiotic resistance., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Carbapenem-resistant Acinetobacter spp. mainly Acinetobacter baumannii are frequently causing nosocomial infections with high mortality. In this study, the efficacy of the Eazyplex ® SuperBug Complete A system, based on loop-mediated isothermal amplification (LAMP), to detect the presence of carbapenemases in Acinetobacter spp. directly from bronchoalveolar lavage (BAL) samples was assessed. A total of 22 Acinetobacter spp. strains producing OXA-23, OXA-40, OXA-58, NDM, and IMP were selected. Eazyplex SuperBug Complete A kit, used with the Genie II device, is a molecular diagnostics kit that detects a selection of genes that express carbapenemases ( bla KPC , bla NDM , bla VIM , bla OXA-48 , bla OXA-23 , bla OXA-40 , and bla OXA-58 ). Negative BAL samples were identified, McFarland solutions were prepared from each of the 22 Acinetobacter strains and serial dilutions in saline solution were made to finally spike BAL samples to a concentration of 10 2 and 10 3 CFU/ml. Fifteen concentrations out of the 44 tested out did not provide detection of the carbapenemase-producing gene, all but one being at the lowest concentration tested at 10 2 CFU/ml; therefore, the limit of sensitivity is 10 3 CFU/ml. This assay represents the kind of advantages that investing in molecular diagnostics brings to the clinical practice, allowing the identification of carbapenemases in less than 30 min with a sensitivity of 10 3 CFU/ml., 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 © 2021 Moreno-Morales, Vergara, Kostyanev, Rodriguez-Baño, Goossens and Vila.)

Objectives/purpose: The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level., Methods: GAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. For this project, the Network operated by means of Delphi rounds, teleconferences and face-to-face meetings. The resulting costing framework takes a bottom-up approach to incorporate all relevant costs imposed by an AMR bacterial microbe in a patient, in an animal, or in the environment up through to the societal level., Results: The framework itemizes the epidemiological data as well as the direct and indirect cost components needed to build a realistic cost picture for AMR. While the framework lists a large number of relevant pathogens for which this framework could be used to explore the costs, the framework is sufficiently generic to facilitate the costing of other resistant pathogens, including those of other aetiologies., Conclusion: In order to conduct cost-effectiveness analyses to choose amongst different AMR-related interventions at local level, the costing of AMR should be done according to local epidemiological priorities and local health service norms. Yet the use of a common framework across settings allows for the results of such studies to contribute to cumulative estimates that can serve as the basis of broader policy decisions at the international level such as how to steer R&D funding and how to prioritize AMR amongst other issues. Indeed, it is only by building a realistic cost picture that we can make informed decisions on how best to tackle major health threats.

Introduction: The rapid worldwide spread of carbapenem-resistant Enterobacteriaceae (CRE) constitutes a major challenge. The aim of the EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA), which is part of the Innovative Medicines Initiative Joint Undertaking (IMI JU) funded COMBACTE-CARE project, is to investigate risk factors for and outcome determinants of CRE infections to inform randomised clinical trial designs and to provide a historical cohort that could eventually be used for future comparisons with new drugs targeting CRE., Methods: A multicentre (50 sites), multinational (11 European countries), analytical observational project was designed, comprising 3 studies. The aims of study 1 (a prospective cohort study) include characterising the features, clinical management and outcomes of hospitalised patients with intra-abdominal infection, pneumonia, complicated urinary tract infections and bloodstream infections caused by CRE (202 patients in each group). The main outcomes will be 30-day all-cause mortality and clinical response. Study 2 (a nested case-control study) will identify the risk factors for target infections caused by CRE; 248 selected patients from study 1 will be matched with patients with carbapenem-susceptible Enterobacteriaceae (1:1) and with hospitalised patients (1:3) and will provide a historical cohort of patients with CRE infections. Study 3 (a matched cohort study) will follow patients in study 2 in order to assess mortality, length of stay and hospital costs associated with CRE. All patients will be followed for 30 days. Different, up-to-date statistical methods will be applied to come to unbiased estimates for all 3 studies., Ethics and Dissemination: Before-study sites will be initiated, approval will be sought from appropriate regulatory agencies and local Ethics Committees of Research or Institutional Review Boards (IRBs) to conduct the study in accordance with regulatory requirements. This is an observational study and therefore no intervention in the diagnosis, management or treatment of the patients will be required on behalf of the investigation. Any formal presentation or publication of data collected from this study will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) for authorship., Trial Registration Number: NCT02709408., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Pneumococcal and Haemophilus influenzae type b (Hib) vaccines were introduced in our national immunisation program in April 2010. The aims of this retrospective, laboratory-based study were to determine the serotypes and antibiotic resistance of Streptococcus pneumoniae and H. influenzae isolates from middle ear fluid (MEF) collected before the introduction of immunization., Methods: S. pneumoniae (n = 128) and H. influenzae (n = 40) strains isolated from MEF of children with AOM between 1994 and 2011 were studied. MICs were determined by a microdilution assay. Serotyping of S. pneumoniae was done by Quellung method and PCR capsular typing was used for H. influenzae. Macrolide resistance genes were detected by PCR for erythromycin resistant S. pneumoniae (ERSP). DNA sequencing of ftsI gene was performed for ampicillin nonsusceptible H. influenzae., Results: The most common serotypes found among children with pneumococcal AOM were 19 F (20.3%), 6B (15.6%), and 19A (10.9%). The potential coverage rates by the PCV7, PCV10 and PCV13 of children aged < 5 years were 63.6%, 66.4% and 85.5%, respectively. Reduced susceptibility to oral penicillin was seen in 68.1%; resistance to erythromycin was 46.9%. We found erm(B) gene in 56.7% of the ERSP, mef(E) gene in 25%; 15% harbored both genes erm(B) + mef(E) and 3.3% had mutations of L4 ribosomal protein. Of the 40 H. influenzae isolates 97.5% were nontypeable. Nonsusceptibility to ampicillin occurred in 25%. Ampicillin resistance groups were: β-lactamase-positive ampicillin resistant (BLPAR) strains (10%), β-lactamase-negative ampicillin resistant (BLNAR) strains (12.5%) and β-lactamase-positive amoxicillin-clavulanate resistant (BLPACR) strains (2.5%). Among BLNAR and BLPACR most of the isolates (5/6) belonged to group II, defined by the Asn526Lys substitution., Conclusions: The levels of antibiotic resistance among S. pneumoniae and H. influenzae causing severe AOM in children are high in our settings. The existence of multidrug-resistant S. pneumoniae serotype 19A is of particular concern. The rate of BLNAR and BLPACR strains among H. influenzae isolates was 15%.