A systematic review on the excess health risk of antibiotic-resistant bloodstream infections for six key pathogens in Europe.

BACKGROUND: Antimicrobial resistance is a global threat, which requires novel intervention strategies, for which priority pathogens and settings need to be determined. OBJECTIVES: We evaluated pathogen-specific excess health burden of drug-resistant bloodstream infections (BSIs) in Europe. METHODS: A systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, and grey literature for the period January 1990 to May 2022. STUDY ELIGIBILITY CRITERIA: Studies that reported burden data for six key drug-resistant pathogens: carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, third-generation cephalosporin or CR Escherichia coli and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Excess health outcomes compared with drug-susceptible BSIs or uninfected patients. For MRSA and third-generation cephalosporin E. coli and K. pneumoniae BSIs, five or more European studies were identified. For all others, the search was extended to high-income countries. PARTICIPANTS: Paediatric and adult patients diagnosed with drug-resistant BSI. INTERVENTIONS: Not applicable. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna-Briggs Institute assessment tool. METHODS OF DATA SYNTHESIS: Random-effect models were used to pool pathogen-specific burden estimates. RESULTS: We screened 7154 titles, 1078 full-texts and found 56 studies on BSIs. Most studies compared outcomes of drug-resistant to drug-susceptible BSIs (46/56, 82.1%), and reported mortality (55/56 studies, 98.6%). The pooled crude estimate for excess all-cause mortality of drug-resistant versus drug-susceptible BSIs ranged from OR 1.31 (95% CI 1.03-1.68) for CR P. aeruginosa to OR 3.44 (95% CI 1.62-7.32) for CR K. pneumoniae. Pooled crude estimates comparing mortality to uninfected patients were available for vancomycin-resistant Enterococcus and MRSA BSIs (OR of 11.19 [95% CI 6.92-18.09] and OR 6.18 [95% CI 2.10-18.17], respectively). CONCLUSIONS: Drug-resistant BSIs are associated with increased mortality, with the magnitude of the effect influenced by pathogen type and comparator. Future research should address crucial knowledge gaps in pathogen- and infection-specific burdens to guide development of novel interventions.

Frequency of bloodstream infections caused by six key antibiotic-resistant pathogens for prioritization of research and discovery of new therapies in Europe: a systematic review.

BACKGROUND: To prioritize healthcare investments, ranking of infections caused by antibiotic-resistant bacteria should be based on accurate incidence data. OBJECTIVES: We performed a systematic review to estimate frequency measures of antimicrobial resistance for six key bacteria causing bloodstream infections (BSI) in European countries. DATA SOURCES: We searched PubMed, Web of Science, Embase databases, and the ECRAID-Base Epidemiological-Network platform. STUDY ELIGIBILITY CRITERIA: We included studies and surveillance systems assessing resistance-percentage, prevalence, or incidence-density of BSI because of carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli, third-generation cephalosporins-resistant E. coli and K. pneumoniae, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus. METHODS: Reviewers independently assessed published data and evaluated study quality with the modified Joanna Briggs Institute critical appraisal tool. Pooled estimates were determined using random effects meta-analysis. Consistency of data was assessed using random effects meta-regression (Wald test, p > 0.05). RESULTS: We identified 271 studies and 52 surveillance systems from 32 European countries. Forty-five studies (16%) reported on BSI, including 180 frequency measures most commonly as resistance-percentage (88, 48.9%). Among 309 frequency measures extracted from 24 (46%) surveillance systems, 278 (89%) were resistance-percentages. Frequency measures of methicillin-resistant S. aureus and vancomycin-resistant E. faecium BSI were more frequently reported from Southern Europe and Western Europe (80%), whereas carbapenem-resistant P. aeruginosa BSI from Northern Europe and Western Europe (88%). Highest resistance-percentages were detected for carbapenem-resistant A. baumannii (66% in Central Eastern Europe) and carbapenem-resistant K. pneumoniae (62.8% in Southern Europe). Pooled estimates showed lower resistance-percentages in community versus healthcare-associated infections and in children versus adults. Estimates from studies and surveillance systems were mostly consistent among European regions. The included data was of medium quality. DISCUSSION: Pathogen-specific frequency measures of antimicrobial resistance in BSI are insufficient to inform antibiotic stewardship and research and development strategies. Improving data collection and standardization of frequency measures is urgently needed.

Excess resource use and cost of drug-resistant infections for six key pathogens in Europe: a systematic review and Bayesian meta-analysis.

BACKGROUND: Quantifying the resource use and cost of antimicrobial resistance establishes the magnitude of the problem and drives action. OBJECTIVES: Assessment of resource use and cost associated with infections with six key drug-resistant pathogens in Europe. METHODS: A systematic review and Bayesian meta-analysis. DATA SOURCES: MEDLINE (Ovid), Embase (Ovid), Econlit databases, and grey literature for the period 1 January 1990, to 21 June 2022. STUDY ELIGIBILITY CRITERIA: Resource use and cost outcomes (including excess length of stay, overall costs, and other excess in or outpatient costs) were compared between patients with defined antibiotic-resistant infections caused by carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, CR or third-generation cephalosporin Escherichia coli (3GCREC) and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium, and patients with drug-susceptible or no infection. PARTICIPANTS: All patients diagnosed with drug-resistant bloodstream infections (BSIs). INTERVENTIONS: NA. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna Briggs Institute assessment tool, incorporating case-control, cohort, and economic assessment frameworks. METHODS OF DATA SYNTHESIS: Hierarchical Bayesian meta-analyses were used to assess pathogen-specific resource use estimates. RESULTS: Of 5969 screened publications, 37 were included in the review. Data were sparse and heterogeneous. Most studies estimated the attributable burden by, comparing resistant and susceptible pathogens (32/37). Four studies analysed the excess cost of hospitalization attributable to 3GCREC BSIs, ranging from -€ 2465.50 to € 6402.81. Eight studies presented adjusted excess length of hospital stay estimates for methicillin-resistant S. aureus and 3GCREC BSIs (4 each) allowing for Bayesian hierarchical analysis, estimating means of 1.26 (95% credible interval [CrI], -0.72 to 4.17) and 1.78 (95% CrI, -0.02 to 3.38) days, respectively. CONCLUSIONS: Evidence on most cost and resource use outcomes and across most pathogen-resistance combinations was severely lacking. Given the importance of this evidence for rational policymaking, further research is urgently needed.

Modelling antimicrobial resistance transmission to guide personalized antimicrobial stewardship interventions and infection control policies in healthcare setting: a pilot study.

Infection control programs and antimicrobial stewardship have been proven effective in reducing the burden of diseases due to multidrug-resistant organisms, but quantifying the effect of each intervention is an open issue. For this aim, we propose a model to characterize the effect of interventions at single ward level. We adapted the Ross-Macdonald model to describe hospital cross-transmission dynamics of carbapenem resistant Klebsiella pneumoniae (CRKP), considering healthcare workers as the vectors transmitting susceptible and resistant pathogens among admitted patients. The model parameters were estimated from a literature review, further adjusted to reproduce observed clinical outcomes, and validated using real life data from a 2-year study in a university hospital. The model has been further explored through extensive sensitivity analysis, in order to assess the relevance of single interventions as well as their synergistic effects. Our model has been shown to be an effective tool to describe and predict the impact of interventions in reducing the prevalence of CRKP colonisation and infection, and can be extended to other specific hospital and pathological scenarios to produce tailored estimates of the most effective strategies.

EPI-Net One Health reporting guideline for antimicrobial consumption and resistance surveillance data: a Delphi approach.

Strategic and standardised approaches to analysis and reporting of surveillance data are essential to inform antimicrobial resistance (AMR) mitigation measures, including antibiotic policies. Targeted guidance on linking full-scale AMR and antimicrobial consumption (AMC)/antimicrobial residues (AR) surveillance data from the human, animal, and environmental sectors is currently needed. This paper describes the initiative whereby a multidisciplinary panel of experts (56 from 20 countries-52 high income, 4 upper middle or lower income), representing all three sectors, elaborated proposals for structuring and reporting full-scale AMR and AMC/AR surveillance data across the three sectors. An evidence-supported, modified Delphi approach was adopted to reach consensus among the experts for dissemination frequency, language, and overall structure of reporting; core elements and metrics for AMC/AR data; core elements and metrics for AMR data. The recommendations can support multisectoral national and regional plans on antimicrobials policy to reduce resistance rates applying a One Health approach.

The antimicrobial resistance travel tool, an interactive evidence-based educational tool to limit antimicrobial resistance spread.

BACKGROUND: International travel has been recognized as a risk factor contributing to the spread of antimicrobial resistance (AMR). However, tools focused on AMR in the context of international travel and designed to guide decision-making are limited. We aimed at developing an evidence-based educational tool targeting both healthcare professionals (HCPs) and international travellers to help prevent the spread of AMR. METHODS: A literature review on 12 antimicrobial-resistant bacteria (ARB) listed as critical and high tiers in the WHO Pathogen Priority List covering four key areas was carried out: AMR surveillance data; epidemiological studies reporting ARB prevalence data on carriage in returning travellers; guidance documents reporting indications on screening for ARB in returning travellers and recommendations for ARB prevention for the public. The evidence, catalogued at country-level, provided the content for a series of visualizations that allow assessment of the risk of AMR acquisition through travel. RESULTS: Up to January 2021, the database includes data on: (i) AMR surveillance for 2.018.241 isolates from 86 countries; (ii) ARB prevalence of carriage from 11.679 international travellers and (iii) 15 guidance documents published by major public health agencies. The evidence allowed the development of a consultation scheme for the evaluation of risk factors, prevalence of carriage, proportion and recommendations for screening of AMR. For the public, pre-travel practical measures to minimize the risk of transmission were framed. CONCLUSIONS: This easy-to-use, annually updated, freely accessible AMR travel tool (https://epi-net.eu/travel-tool/overview/), is the first of its kind to be developed. For HCPs, it can provide a valuable resource for teaching and a repository that facilitates a stepwise assessment of the risk of AMR spread and strengthen implementation of optimized infection control measures. Similarly, for travellers, the tool has the potential to raise awareness of AMR and outlines preventive measures that reduce the risk of AMR acquisition and spread.

White Paper: Bridging the gap between surveillance data and antimicrobial stewardship in the outpatient sector-practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.

BACKGROUND: The outpatient setting is a key scenario for the implementation of antimicrobial stewardship (AMS) activities, considering that overconsumption of antibiotics occurs mainly outside hospitals. This publication is the result of a joint initiative by the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks, which is aimed at formulating a set of target actions for linking surveillance data with AMS activities in the outpatient setting. METHODS: A scoping review of the literature was carried out in three research areas: AMS leadership and accountability; antimicrobial usage and AMS; antimicrobial resistance and AMS. Consensus on the actions was reached through a RAND-modified Delphi process involving over 40 experts in infectious diseases, clinical microbiology, AMS, veterinary medicine or public health, from 18 low-, middle- and high-income countries. RESULTS: Evidence was retrieved from 38 documents, and an initial 25 target actions were proposed, differentiating between essential or desirable targets according to clinical relevance, feasibility and applicability to settings and resources. In the first consultation round, preliminary agreement was reached for all targets. Further to a second review, 6 statements were re-considered and 3 were deleted, leading to a final list of 22 target actions in the form of a practical checklist. CONCLUSIONS: This White Paper is a pragmatic and flexible tool to guide the development of calibrated surveillance-based AMS interventions specific to the outpatient setting, which is characterized by substantial inter- and intra-country variability in the organization of healthcare structures, maintaining a global perspective and taking into account the feasibility of the target actions in low-resource settings.

White Paper: Bridging the gap between surveillance data and antimicrobial stewardship in long-term care facilities-practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.

BACKGROUND: In long-term care facilities (LTCFs) residents often receive inappropriate antibiotic treatment and infection prevention and control practices are frequently inadequate, thus favouring acquisition of MDR organisms. There is increasing evidence in the literature describing antimicrobial stewardship (AMS) activities in LTCFs, but practical guidance on how surveillance data should be linked with AMS activities in this setting is lacking. To bridge this gap, the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks joined their efforts to provide practical guidance for linking surveillance data with AMS activities. MATERIALS AND METHODS: Considering the three main topics [AMS leadership and accountability, antimicrobial usage (AMU) and AMS, and antimicrobial resistance (AMR) and AMS], a literature review was performed and a list of target actions was developed. Consensus on target actions was reached through a RAND-modified Delphi process involving 40 experts from 18 countries and different professional backgrounds adopting a One Health approach. RESULTS: From the 25 documents identified, 25 target actions were retrieved and proposed for expert evaluation. The consensus process produced a practical checklist including 23 target actions, differentiating between essential and desirable targets according to clinical relevance and feasibility. Flexible proposals for AMS team composition and leadership were provided, with a strong emphasis on the need for well-defined and adequately supported roles and responsibilities. Specific antimicrobial classes, AMU metrics, pathogens and resistance patterns to be monitored are addressed. Effective reporting strategies are described. CONCLUSIONS: The proposed checklist represents a practical tool to support local AMS teams across a wide range of care delivery organization and availability of resources.

TReND in Africa: Toward a Truly Global (Neuro)science Community.

TReND is a volunteer-scientist run charity dedicated to promoting research and education on the African continent. Focusing on neuroscience, we discuss approaches to address some of the factors that currently stifle Africa's scientific development and our experience in implementing them.

New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins.

The ADAR proteins deaminate adenosine to inosine in double-stranded RNA which is one of the most abundant modifications present in mammalian RNA. Inosine can have a profound effect on the RNAs that are edited, not only changing the base-pairing properties, but can also result in recoding, as inosine behaves as if it were guanosine. In mammals there are three ADAR proteins and two ADAR-related proteins (ADAD) expressed. All have a very similar modular structure; however, both their expression and biological function differ significantly. Only two of the ADAR proteins have enzymatic activity. However, both ADAR and ADAD proteins possess the ability to bind double-strand RNA. Mutations in ADARs have been associated with many diseases ranging from cancer, innate immunity to neurological disorders. Here, we will discuss in detail the domain structure of mammalian ADARs, the effects of RNA editing, and the role of ADARs in human diseases.

Identification of Spen as a Crucial Factor for Xist Function through Forward Genetic Screening in Haploid Embryonic Stem Cells.

In mammals, the noncoding Xist RNA triggers transcriptional silencing of one of the two X chromosomes in female cells. Here, we report a genetic screen for silencing factors in X chromosome inactivation using haploid mouse embryonic stem cells (ESCs) that carry an engineered selectable reporter system. This system was able to identify several candidate factors that are genetically required for chromosomal repression by Xist. Among the list of candidates, we identify the RNA-binding protein Spen, the homolog of split ends. Independent validation through gene deletion in ESCs confirms that Spen is required for gene repression by Xist. However, Spen is not required for Xist RNA localization and the recruitment of chromatin modifications, including Polycomb protein Ezh2. The identification of Spen opens avenues for further investigation into the gene-silencing pathway of Xist and shows the usefulness of haploid ESCs for genetic screening of epigenetic pathways.

The crystal structure of the Split End protein SHARP adds a new layer of complexity to proteins containing RNA recognition motifs.

The Split Ends (SPEN) protein was originally discovered in Drosophila in the late 1990s. Since then, homologous proteins have been identified in eukaryotic species ranging from plants to humans. Every family member contains three predicted RNA recognition motifs (RRMs) in the N-terminal region of the protein. We have determined the crystal structure of the region of the human SPEN homolog that contains these RRMs-the SMRT/HDAC1 Associated Repressor Protein (SHARP), at 2.0 Å resolution. SHARP is a co-regulator of the nuclear receptors. We demonstrate that two of the three RRMs, namely RRM3 and RRM4, interact via a highly conserved interface. Furthermore, we show that the RRM3-RRM4 block is the main platform mediating the stable association with the H12-H13 substructure found in the steroid receptor RNA activator (SRA), a long, non-coding RNA previously shown to play a crucial role in nuclear receptor transcriptional regulation. We determine that SHARP association with SRA relies on both single- and double-stranded RNA sequences. The crystal structure of the SHARP-RRM fragment, together with the associated RNA-binding studies, extend the repertoire of nucleic acid binding properties of RRM domains suggesting a new hypothesis for a better understanding of SPEN protein functions.