Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 across a London regional network. METHODS: We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE positive patients. Genomes of IMP-encoding CPE isolates were overlayed with patient contacts to imply potential transmission events. RESULTS: Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, E. coli); 86% (72/84) harboured an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68/72). Phylogenetic analysis of IncHI2 plasmids identified three lineages showing significant association with patient contacts and movements between four hospital sites and across medical specialities, which was missed on initial investigations. CONCLUSIONS: Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multi-modal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks.

Towards optimizing carbapenem selection in stewardship strategies: a prospective propensity score-matched study of ertapenem versus class 2 carbapenems for empirical treatment of third-generation cephalosporin-resistant Enterobacterales bacteraemia.

BACKGROUND: Third-generation cephalosporin-resistant Enterobacterales (3GCRE) are increasing in prevalence, leading to greater carbapenem consumption. Selecting ertapenem has been proposed as a strategy to reduce carbapenem resistance development. However, there are limited data for the efficacy of empirical ertapenem for 3GCRE bacteraemia. OBJECTIVES: To compare the efficacy of empirical ertapenem and class 2 carbapenems for the treatment of 3GCRE bacteraemia. METHODS: A prospective non-inferiority observational cohort study was performed from May 2019 to December 2021. Adult patients with monomicrobial 3GCRE bacteraemia receiving carbapenems within 24 h were included at two hospitals in Thailand. Propensity scores were used to control for confounding, and sensitivity analyses were performed in several subgroups. The primary outcome was 30 day mortality. This study is registered with clinicaltrials.gov (NCT03925402). RESULTS: Empirical carbapenems were prescribed in 427/1032 (41%) patients with 3GCRE bacteraemia, of whom 221 received ertapenem and 206 received class 2 carbapenems. One-to-one propensity score matching resulted in 94 pairs. Escherichia coli was identified in 151 (80%) of cases. All patients had underlying comorbidities. Septic shock and respiratory failure were the presenting syndromes in 46 (24%) and 33 (18%) patients, respectively. The overall 30 day mortality rate was 26/188 (13.8%). Ertapenem was non-inferior to class 2 carbapenems in 30 day mortality (12.8% versus 14.9%; mean difference -0.02; 95% CI: -0.12 to 0.08). Sensitivity analyses were consistent regardless of aetiological pathogens, septic shock, source of infection, nosocomial acquisition, lactate levels or albumin levels. CONCLUSIONS: Ertapenem may be of comparable efficacy to class 2 carbapenems in the empirical treatment of 3GCRE bacteraemia.

Addition of probenecid to oral ß-lactam antibiotics: a systematic review and meta-analysis.

OBJECTIVES: To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral ß-lactams. METHODS: Medline and EMBASE were searched from inception to December 2021 for all English language studies comparing the addition of probenecid (intervention) with an oral ß-lactam [flucloxacillin, penicillin V, amoxicillin (±â€Šclavulanate), cefalexin, cefuroxime axetil] alone (comparator). ROBINS-I and ROB-2 tools were used. Data on antibiotic therapy, infection diagnosis, primary and secondary outcomes relating to pharmacokinetics and clinical outcomes, plus adverse events were extracted and reported descriptively. For a subset of studies comparing treatment failure between probenecid and control groups, meta-analysis was performed. RESULTS: Overall, 18/295 (6%) screened abstracts were included. Populations, methodology and outcome data were heterogeneous. Common populations included healthy volunteers (9/18; 50%) and those with gonococcal infection (6/18; 33%). Most studies were crossover trials (11/18; 61%) or parallel-arm randomized trials (4/18; 22%). Where pharmacokinetic analyses were performed, addition of probenecid to oral ß-lactams increased total AUC (7/7; 100%), Cmax (5/8; 63%) and serum t½ (6/8; 75%). Probenecid improved PTA (2/2; 100%). Meta-analysis of 3105 (2258 intervention, 847 control) patients treated for gonococcal disease demonstrated a relative risk of treatment failure in the random-effects model of 0.33 (95% CI 0.20-0.55; I2 = 7%), favouring probenecid. CONCLUSIONS: Probenecid-boosted ß-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid-boosted oral ß-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy studies are required.

A Real-world Evaluation of a Case-based Reasoning Algorithm to Support Antimicrobial Prescribing Decisions in Acute Care.

BACKGROUND: A locally developed case-based reasoning (CBR) algorithm, designed to augment antimicrobial prescribing in secondary care was evaluated. METHODS: Prescribing recommendations made by a CBR algorithm were compared to decisions made by physicians in clinical practice. Comparisons were examined in 2 patient populations: first, in patients with confirmed Escherichia coli blood stream infections ("E. coli patients"), and second in ward-based patients presenting with a range of potential infections ("ward patients"). Prescribing recommendations were compared against the Antimicrobial Spectrum Index (ASI) and the World Health Organization Essential Medicine List Access, Watch, Reserve (AWaRe) classification system. Appropriateness of a prescription was defined as the spectrum of the prescription covering the known or most-likely organism antimicrobial sensitivity profile. RESULTS: In total, 224 patients (145 E. coli patients and 79 ward patients) were included. Mean (standard deviation) age was 66 (18) years with 108/224 (48%) female sex. The CBR recommendations were appropriate in 202/224 (90%) compared to 186/224 (83%) in practice (odds ratio [OR]: 1.24 95% confidence interval [CI]: .392-3.936; P = .71). CBR recommendations had a smaller ASI compared to practice with a median (range) of 6 (0-13) compared to 8 (0-12) (P < .01). CBR recommendations were more likely to be classified as Access class antimicrobials compared to physicians' prescriptions at 110/224 (49%) vs. 79/224 (35%) (OR: 1.77; 95% CI: 1.212-2.588; P < .01). Results were similar for E. coli and ward patients on subgroup analysis. CONCLUSIONS: A CBR-driven decision support system provided appropriate recommendations within a narrower spectrum compared to current clinical practice. Future work must investigate the impact of this intervention on prescribing behaviors more broadly and patient outcomes.

Investigating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Surface and Air Contamination in an Acute Healthcare Setting During the Peak of the Coronavirus Disease 2019 (COVID-19) Pandemic in London.

BACKGROUND: We evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface and air contamination during the coronavirus disease 2019 (COVID-19) pandemic in London. METHODS: Prospective, cross-sectional, observational study in a multisite London hospital. Air and surface samples were collected from 7 clinical areas occupied by patients with COVID-19 and a public area of the hospital. Three or four 1.0-m3 air samples were collected in each area using an active air sampler. Surface samples were collected by swabbing items in the immediate vicinity of each air sample. SARS-CoV-2 was detected using reverse-transcription quantitative polymerase chain reaction (PCR) and viral culture; the limit of detection for culturing SARS-CoV-2 from surfaces was determined. RESULTS: Viral RNA was detected on 114 of 218 (52.3%) surfaces and in 14 of 31 (38.7%) air samples, but no virus was cultured. Viral RNA was more likely to be found in areas immediately occupied by COVID-19 patients than in other areas (67 of 105 [63.8%] vs 29 of 64 [45.3%]; odds ratio, 0.5; 95% confidence interval, 0.2-0.9; P = .025, χ2 test). The high PCR cycle threshold value for all samples (>30) indicated that the virus would not be culturable. CONCLUSIONS: Our findings of extensive viral RNA contamination of surfaces and air across a range of acute healthcare settings in the absence of cultured virus underlines the potential risk from environmental contamination in managing COVID-19 and the need for effective use of personal protective equipment, physical distancing, and hand/surface hygiene.

Development and Delivery of a Real-time Hospital-onset COVID-19 Surveillance System Using Network Analysis.

BACKGROUND: Understanding nosocomial acquisition, outbreaks, and transmission chains in real time will be fundamental to ensuring infection-prevention measures are effective in controlling coronavirus disease 2019 (COVID-19) in healthcare. We report the design and implementation of a hospital-onset COVID-19 infection (HOCI) surveillance system for an acute healthcare setting to target prevention interventions. METHODS: The study took place in a large teaching hospital group in London, United Kingdom. All patients tested for SARS-CoV-2 between 4 March and 14 April 2020 were included. Utilizing data routinely collected through electronic healthcare systems we developed a novel surveillance system for determining and reporting HOCI incidence and providing real-time network analysis. We provided daily reports on incidence and trends over time to support HOCI investigation and generated geotemporal reports using network analysis to interrogate admission pathways for common epidemiological links to infer transmission chains. By working with stakeholders the reports were co-designed for end users. RESULTS: Real-time surveillance reports revealed changing rates of HOCI throughout the course of the COVID-19 epidemic, key wards fueling probable transmission events, HOCIs overrepresented in particular specialties managing high-risk patients, the importance of integrating analysis of individual prior pathways, and the value of co-design in producing data visualization. Our surveillance system can effectively support national surveillance. CONCLUSIONS: Through early analysis of the novel surveillance system we have provided a description of HOCI rates and trends over time using real-time shifting denominator data. We demonstrate the importance of including the analysis of patient pathways and networks in characterizing risk of transmission and targeting infection-control interventions.

Informing antimicrobial management in the context of COVID-19: understanding the longitudinal dynamics of C-reactive protein and procalcitonin.

BACKGROUND: To characterise the longitudinal dynamics of C-reactive protein (CRP) and Procalcitonin (PCT) in a cohort of hospitalised patients with COVID-19 and support antimicrobial decision-making. METHODS: Longitudinal CRP and PCT concentrations and trajectories of 237 hospitalised patients with COVID-19 were modelled. The dataset comprised of 2,021 data points for CRP and 284 points for PCT. Pairwise comparisons were performed between: (i) those with or without significant bacterial growth from cultures, and (ii) those who survived or died in hospital. RESULTS: CRP concentrations were higher over time in COVID-19 patients with positive microbiology (day 9: 236 vs 123 mg/L, p < 0.0001) and in those who died (day 8: 226 vs 152 mg/L, p < 0.0001) but only after day 7 of COVID-related symptom onset. Failure for CRP to reduce in the first week of hospital admission was associated with significantly higher odds of death. PCT concentrations were higher in patients with COVID-19 and positive microbiology or in those who died, although these differences were not statistically significant. CONCLUSIONS: Both the absolute CRP concentration and the trajectory during the first week of hospital admission are important factors predicting microbiology culture positivity and outcome in patients hospitalised with COVID-19. Further work is needed to describe the role of PCT for co-infection. Understanding relationships of these biomarkers can support development of risk models and inform optimal antimicrobial strategies.

Rapid Detection of Azole-Resistant Aspergillus fumigatus in Clinical and Environmental Isolates by Use of a Lab-on-a-Chip Diagnostic System.

Aspergillus fumigatus has widely evolved resistance to the most commonly used class of antifungal chemicals, the azoles. Current methods for identifying azole resistance are time-consuming and depend on specialized laboratories. There is an urgent need for rapid detection of these emerging pathogens at point-of-care to provide the appropriate treatment in the clinic and to improve management of environmental reservoirs to mitigate the spread of antifungal resistance. Our study demonstrates the rapid and portable detection of the two most relevant genetic markers linked to azole resistance, the mutations TR34 and TR46, found in the promoter region of the gene encoding the azole target cyp51A. We developed a lab-on-a-chip platform consisting of: (i) tandem-repeat loop-mediated isothermal amplification; (ii) state-of-the-art complementary metal-oxide-semiconductor microchip technology for nucleic acid amplification detection; and (iii) a smartphone application for data acquisition, visualization, and cloud connectivity. Specific and sensitive detection was validated with isolates from clinical and environmental samples from 6 countries across 5 continents, showing a lower limit of detection of 10 genomic copies per reaction in less than 30 min. When fully integrated with a sample preparation module, this diagnostic system will enable the detection of this ubiquitous fungus at the point-of-care, and could help to improve clinical decision making, infection control, and epidemiological surveillance.

COVID-19 and the potential long-term impact on antimicrobial resistance.

The emergence of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has required an unprecedented response to control the spread of the infection and protect the most vulnerable within society. Whilst the pandemic has focused society on the threat of emerging infections and hand hygiene, certain infection control and antimicrobial stewardship policies may have to be relaxed. It is unclear whether the unintended consequences of these changes will have a net-positive or -negative impact on rates of antimicrobial resistance. Whilst the urgent focus must be on controlling this pandemic, sustained efforts to address the longer-term global threat of antimicrobial resistance should not be overlooked.

Detecting carbapenemase-producing Enterobacterales (CPE): an evaluation of an enhanced CPE infection control and screening programme in acute care.

OBJECTIVES: The transmission of carbapenemase-producing Enterobacterales (CPE) poses an increasing healthcare challenge. A range of infection prevention activities, including screening and contact precautions, are recommended by international and national guidelines. We evaluated the introduction of an enhanced screening programme in a multisite London hospital group. METHODS: In June 2015, an enhanced CPE policy was launched in response to a local rise in CPE detection. This increased infection prevention measures beyond the national recommendations, with enhanced admission screening, contact tracing and environmental disinfection, improved laboratory protocols and staff/patient education. We report the CPE incidence and trends of CPE in screening and clinical cultures and the adoption of enhanced CPE screening. All non-duplicate CPE isolates identified between April 2014 and March 2018 were included. RESULTS: The number of CPE screens increased progressively, from 4530 in July 2015 to 10 589 in March 2018. CPE detection increased from 18 patients in July 2015 (1.0 per 1000 admissions) to 50 patients in March 2018 (2.7 per 1000 admissions). The proportion of CPE-positive screening cultures remained at approximately 0.4% throughout, suggesting that whilst the CPE carriage rate was unchanged, carrier identification increased. Also, 123 patients were identified through positive CPE clinical cultures over the study period; there was no significant change in the rate of CPE from clinical cultures per 1000 admissions (P = 0.07). CONCLUSIONS: Our findings suggest that whilst the enhanced screening programme identified a previously undetected reservoir of CPE colonization in our patient population, the rate of detection of CPE in clinical cultures did not increase.

A multilevel neo-institutional analysis of infection prevention and control in English hospitals: coerced safety culture change?

Despite committed policy, regulative and professional efforts on healthcare safety, little is known about how such macro-interventions permeate organisations and shape culture over time. Informed by neo-institutional theory, we examined how inter-organisational influences shaped safety practices and inter-subjective meanings following efforts for coerced culture change. We traced macro-influences from 2000 to 2015 in infection prevention and control (IPC). Safety perceptions and meanings were inductively analysed from 130 in-depth qualitative interviews with senior- and middle-level managers from 30 English hospitals. A total of 869 institutional interventions were identified; 69% had a regulative component. In this context of forced implementation of safety practices, staff experienced inherent tensions concerning the scope of safety, their ability to be open and prioritisation of external mandates over local need. These tensions stemmed from conflicts among three co-existing institutional logics prevalent in the NHS. In response to requests for change, staff flexibly drew from a repertoire of cognitive, material and symbolic resources within and outside their organisations. They crafted 'strategies of action', guided by a situated assessment of first-hand practice experiences complementing collective evaluations of interventions such as 'pragmatic', 'sensible' and also 'legitimate'. Macro-institutional forces exerted influence either directly on individuals or indirectly by enriching the organisational cultural repertoire.

Addressing the Unknowns of Antimicrobial Resistance: Quantifying and Mapping the Drivers of Burden.

The global threat of antimicrobial resistance (AMR) has arisen through a network of complex interacting factors. Many different sources and transmission pathways contribute to the ever-growing burden of AMR in our clinical settings. The lack of data on these mechanisms and the relative importance of different factors causing the emergence and spread of AMR hampers our global efforts to effectively manage the risks. Importantly, we have little quantitative knowledge on the relative contributions of these sources and are likely to be targeting our interventions suboptimally as a result. Here we propose a systems mapping approach to address the urgent need for reliable and timely data to strengthen the response to AMR.

Serial Clustering of Late-Onset Group B Streptococcal Infections in the Neonatal Unit: A Genomic Re-evaluation of Causality.

Background: Invasive Group B streptococcus (GBS) is a major cause of serious neonatal infection. Current strategies to reduce early-onset GBS disease have no impact on late-onset disease (LOD). Although GBS LOD is viewed as a sporadic event in the community, LOD arising within the neonatal intensive care unit (ICU) raises questions about mode of acquisition. Methods: Following a cluster of 4 GBS LOD cases, enhanced surveillance for all GBS LOD was undertaken over 2 years in the neonatal ICU supported by neonatal rectal screening. GBS isolates were serotyped and genome-sequenced. Results: Twelve late -onset invasive GBS episodes were identified (incidence 0.6/1000 live births). Genomic analysis revealed that 11/12 GBS isolates (92%) were linked to at least one other LOD isolate. Isolates from the first cluster were serotype V, resistant to macrolides and lincosamides, and sequencing confirmed isolates were indistinguishable, or distinguishable by only one SNP difference, from each other. Rectal carriage was rare. Prospective surveillance identified three further clusters of LOD due to serotypes Ia (3 cases), Ib (2 cases), and III (2 cases), that would not have been identified without surveillance and genome sequencing, leading to a re-evaluation of interventions required to prevent GBS LOD. Conclusion: Acquisition routes for LOD GBS in the neonatal ICU are poorly understood; cases may not necessarily be sporadic. Within this neonatal ICU, our data suggest that a single case of LOD GBS sepsis should be considered a potential nosocomial transmission event warranting prompt investigation, heightened infection prevention vigilance and action where required.

Fast and expensive (PCR) or cheap and slow (culture)? A mathematical modelling study to explore screening for carbapenem resistance in UK hospitals.

BACKGROUND: Enterobacteriaceae are a common cause of hospital infections. Carbapenems are a clinically effective treatment of such infections. However, resistance is on the rise. In particular, carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) are increasingly common. In order to limit spread in clinical settings, screening and isolation is being recommended, but many different screening methods are available. We aimed to compare the impact and costs of three algorithms for detecting CP-CRE carriage. METHODS: We developed an individual-based simulation model to compare three screening algorithms using data from a UK National Health Service (NHS) trust. The first algorithm, "Direct PCR", was highly sensitive/specific and quick (half a day), but expensive. The second, "Culture + PCR", was relatively sensitive/specific but slower, requiring 2.5 days. A third algorithm, "PHE", repeated the "Culture + PCR" three times with an additional PCR. Scenario analysis was used to compare several levels of CP-CRE prevalence and coverage of screening, different specialities as well as isolation strategies. Our outcomes were (1) days that a patient with CP-CRE was not detected and hence not isolated ("days at risk"), (2) isolation bed days, (3) total costs and (4) mean cost per CP-CRE risk day averted per year. We also explored limited isolation bed day capacity. RESULTS: We found that although a Direct PCR algorithm would reduce the number of CP-CRE days at risk, the mean cost per CP-CRE risk day averted per year was substantially higher than for a Culture + PCR algorithm. For example, in our model of an intensive care unit, during a year with a 1.6% CP-CRE prevalence and 63% screening coverage, there were 508 (standard deviation 15), 642 (14) and 655 (14) days at risk under screening algorithms Direct PCR, Culture + PCR and PHE respectively, with mean costs per risk day averted of £192, £61 and £79. These results were robust to sensitivity analyses. CONCLUSIONS: Our results indicate that a Culture + PCR algorithm provides the optimal balance of cost and risk days averted, at varying isolation, prevalence and screening coverage scenarios. Findings from this study will help clinical organisations determine the optimal screening approach for CP-CRE, balancing risk and resources.

Quantifying where human acquisition of antibiotic resistance occurs: a mathematical modelling study.

BACKGROUND: Antibiotic-resistant bacteria (ARB) are selected by the use of antibiotics. The rational design of interventions to reduce levels of antibiotic resistance requires a greater understanding of how and where ARB are acquired. Our aim was to determine whether acquisition of ARB occurs more often in the community or hospital setting. METHODS: We used a mathematical model of the natural history of ARB to estimate how many ARB were acquired in each of these two environments, as well as to determine key parameters for further investigation. To do this, we explored a range of realistic parameter combinations and considered a case study of parameters for an important subset of resistant strains in England. RESULTS: If we consider all people with ARB in the total population (community and hospital), the majority, under most clinically derived parameter combinations, acquired their resistance in the community, despite higher levels of antibiotic use and transmission of ARB in the hospital. However, if we focus on just the hospital population, under most parameter combinations a greater proportion of this population acquired ARB in the hospital. CONCLUSIONS: It is likely that the majority of ARB are being acquired in the community, suggesting that efforts to reduce overall ARB carriage should focus on reducing antibiotic usage and transmission in the community setting. However, our framework highlights the need for better pathogen-specific data on antibiotic exposure, ARB clearance and transmission parameters, as well as the link between carriage of ARB and health impact. This is important to determine whether interventions should target total ARB carriage or hospital-acquired ARB carriage, as the latter often dominated in hospital populations.

Exploring the Use of C-Reactive Protein to Estimate the Pharmacodynamics of Vancomycin.

BACKGROUND: C-reactive protein (CRP) pharmacodynamic (PD) models have the potential to provide adjunctive methods for predicting the individual exposure response to antimicrobial therapy. We investigated CRP PD linked to a vancomycin pharmacokinetic (PK) model using routinely collected data from noncritical care adults in secondary care. METHODS: Patients receiving intermittent intravenous vancomycin therapy in secondary care were identified. A 2-compartment vancomycin PK model was linked to a previously described PD model describing CRP response. PK and PD parameters were estimated using a Non-Parametric Adaptive Grid technique. Exposure-response relationships were explored with vancomycin area-under-the-concentration-time-curve (AUC) and EC50 (concentration of drug that causes a half maximal effect) using the index, AUC:EC50, fitted to CRP data using a sigmoidal Emax model. RESULTS: Twenty-nine individuals were included. Median age was 62 (21-97) years. Fifteen (52%) patients were microbiology confirmed. PK and PD models were adequately fitted (r 0.83 and 0.82, respectively). There was a wide variation observed in individual Bayesian posterior EC50 estimates (6.95-48.55 mg/L), with mean (SD) AUC:EC50 of 31.46 (29.22). AUC:EC50 was fitted to terminal CRP with AUC:EC50 >19 associated with lower CRP value at 96-120 hours of therapy (100 mg/L versus 44 mg/L; P < 0.01). CONCLUSIONS: The use of AUC:EC50 has the potential to provide in vivo organism and host response data as an adjunct for in vitro minimum inhibitory concentration data, which is currently used as the gold standard PD index for vancomycin therapy. This index can be estimated using routinely collected clinical data. Future work must investigate the role of AUC:EC50 in a prospective cohort and explore linkage with direct patient outcomes.

Involving citizens in priority setting for public health research: Implementation in infection research.

BACKGROUND: Public sources fund the majority of UK infection research, but citizens currently have no formal role in resource allocation. To explore the feasibility and willingness of citizens to engage in strategic decision making, we developed and tested a practical tool to capture public priorities for research. METHOD: A scenario including six infection themes for funding was developed to assess citizen priorities for research funding. This was tested over two days at a university public festival. Votes were cast anonymously along with rationale for selection. The scenario was then implemented during a three-hour focus group exploring views on engagement in strategic decisions and in-depth evaluation of the tool. RESULTS: 188/491(38%) prioritized funding research into drug-resistant infections followed by emerging infections(18%). Results were similar between both days. Focus groups contained a total of 20 citizens with an equal gender split, range of ethnicities and ages ranging from 18 to >70 years. The tool was perceived as clear with participants able to make informed comparisons. Rationale for funding choices provided by voters and focus group participants are grouped into three major themes: (i) Information processing; (ii) Knowledge of the problem; (iii) Responsibility; and a unique theme within the focus groups (iv) The potential role of citizens in decision making. Divergent perceptions of relevance and confidence of "non-experts" as decision makers were expressed. CONCLUSION: Voting scenarios can be used to collect, en-masse, citizens' choices and rationale for research priorities. Ensuring adequate levels of citizen information and confidence is important to allow deployment in other formats.

Articulating citizen participation in national anti-microbial resistance plans: a comparison of European countries.

Background: National action plans determine country responses to anti-microbial resistance (AMR). These plans include interventions aimed at citizens. As the language used in documents could persuade certain behaviours, we sought to assess the positioning and implied responsibilities of citizens in current European AMR plans. This understanding could lead to improved policies and interventions. Methods: Review and comparison of national action plans for AMR (NAP-AMR) obtained from the European Centre for Disease Prevention and Control (plans from 28 European Union and four European Economic Area/European Free Trade Association countries), supplemented by European experts (June-September 2016). To capture geographical diversity, 11 countries were purposively sampled for content and discourse analyses using frameworks of lay participation in healthcare organization, delivery and decision-making. Results: Countries were at different stages of NAP-AMR development (60% completed, 25% in-process, 9% no plan). The volume allocated to citizen roles in the plans ranged from 0.3 to 18%. The term 'citizen' was used by three countries, trailing behind 'patients' and 'public' (9/11), 'general population' (6/11) and 'consumers' (6/11). Increased citizen awareness about AMR was pursued by ∼2/3 plans. Supporting interventions included awareness campaigns (11/11), training/education (7/11) or materials during clinical encounters (4/11). Prevention of infection transmission or self-care behaviours were much less emphasized. Personal/individual and social/collective role perspectives seemed more frequently stimulated in Nordic countries. Conclusion: Citizen roles in AMR plans are not fully articulated. Documents could employ direct language to emphasise social or collective responsibilities in optimal antibiotic use.

Understanding the mechanisms and drivers of antimicrobial resistance.

To combat the threat to human health and biosecurity from antimicrobial resistance, an understanding of its mechanisms and drivers is needed. Emergence of antimicrobial resistance in microorganisms is a natural phenomenon, yet antimicrobial resistance selection has been driven by antimicrobial exposure in health care, agriculture, and the environment. Onward transmission is affected by standards of infection control, sanitation, access to clean water, access to assured quality antimicrobials and diagnostics, travel, and migration. Strategies to reduce antimicrobial resistance by removing antimicrobial selective pressure alone rely upon resistance imparting a fitness cost, an effect not always apparent. Minimising resistance should therefore be considered comprehensively, by resistance mechanism, microorganism, antimicrobial drug, host, and context; parallel to new drug discovery, broad ranging, multidisciplinary research is needed across these five levels, interlinked across the health-care, agriculture, and environment sectors. Intelligent, integrated approaches, mindful of potential unintended results, are needed to ensure sustained, worldwide access to effective antimicrobials.