Mathematical modelling for antibiotic resistance control policy: do we know enough?

BACKGROUND: Antibiotics remain the cornerstone of modern medicine. Yet there exists an inherent dilemma in their use: we are able to prevent harm by administering antibiotic treatment as necessary to both humans and animals, but we must be mindful of limiting the spread of resistance and safeguarding the efficacy of antibiotics for current and future generations. Policies that strike the right balance must be informed by a transparent rationale that relies on a robust evidence base. MAIN TEXT: One way to generate the evidence base needed to inform policies for managing antibiotic resistance is by using mathematical models. These models can distil the key drivers of the dynamics of resistance transmission from complex infection and evolutionary processes, as well as predict likely responses to policy change in silico. Here, we ask whether we know enough about antibiotic resistance for mathematical modelling to robustly and effectively inform policy. We consider in turn the challenges associated with capturing antibiotic resistance evolution using mathematical models, and with translating mathematical modelling evidence into policy. CONCLUSIONS: We suggest that in spite of promising advances, we lack a complete understanding of key principles. From this we advocate for priority areas of future empirical and theoretical research.

Measuring the impact of Ebola control measures in Sierra Leone.

Between September 2014 and February 2015, the number of Ebola virus disease (EVD) cases reported in Sierra Leone declined in many districts. During this period, a major international response was put in place, with thousands of treatment beds introduced alongside other infection control measures. However, assessing the impact of the response is challenging, as several factors could have influenced the decline in infections, including behavior changes and other community interventions. We developed a mathematical model of EVD transmission, and measured how transmission changed over time in the 12 districts of Sierra Leone with sustained transmission between June 2014 and February 2015. We used the model to estimate how many cases were averted as a result of the introduction of additional treatment beds in each area. Examining epidemic dynamics at the district level, we estimated that 56,600 (95% credible interval: 48,300-84,500) Ebola cases (both reported and unreported) were averted in Sierra Leone up to February 2, 2015 as a direct result of additional treatment beds being introduced. We also found that if beds had been introduced 1 month earlier, a further 12,500 cases could have been averted. Our results suggest the unprecedented local and international response led to a substantial decline in EVD transmission during 2014-2015. In particular, the introduction of beds had a direct impact on reducing EVD cases in Sierra Leone, although the effect varied considerably between districts.

The WHO costing and budgeting tool for national action plans on antimicrobial resistance-a practical addition to the WHOle toolkit.

Objectives: The development of national action plans (NAPs) for antimicrobial resistance (AMR) has been promoted and supported by the WHO, with recent support in the form of costing and budgeting tools to aid in finance-allocation decisions within governments. Methods: In this brief report we review this WHO costing and budgeting tool, discuss the strengths and weaknesses, and consider its place alongside other health economics and policy-support tools developed. Results: We call for future analyses of the costs of AMR NAPs to consider costs beyond that of only implementation, through use of other available, open-access data and tools. These include the Global Antimicrobial Resistance and Use Surveillance System (GLASS) data and One Health tools already within the existing 'WHO toolbox'. Conclusions: We suggest that future work on evaluating AMR along the impact pipeline use this toolbox where possible, ensuring empirical work is in turn open access.

Do you see the problem? Visualising a generalised 'complex local system' of antibiotic prescribing across the United Kingdom using qualitative interview data.

Antimicrobial resistance (AMR) is often referred to as a complex problem embedded in a complex system. Despite this insight, interventions in AMR, and in particular in antibiotic prescribing, tend to be narrowly focused on the behaviour of individual prescribers using the tools of performance monitoring and management rather than attempting to bring about more systemic change. In this paper, we aim to elucidate the nature of the local antibiotic prescribing 'system' based on 71 semi-structured interviews undertaken in six local areas across the United Kingdom (UK). We applied complex systems theory and systems mapping methods to our qualitative data to deepen our understanding of the interactions among antibiotic prescribing interventions and the wider health system. We found that a complex and interacting set of proximal and distal factors can have unpredictable effects in different local systems in the UK. Ultimately, enacting performance management-based interventions in the absence of in-depth contextual understandings about other pressures prescribers face is a recipe for temporary solutions, waning intervention effectiveness, and unintended consequences. We hope our insights will enable policy makers and academics to devise and evaluate interventions in future in a manner that better reflects and responds to the dynamics of complex local prescribing systems.

The Commercial Determinants of Health and Evidence Synthesis (CODES): methodological guidance for systematic reviews and other evidence syntheses.

BACKGROUND: The field of the commercial determinants of health (CDOH) refers to the commercial products, pathways and practices that may affect health. The field is growing rapidly, as evidenced by the WHO programme on the economic and commercial determinants of health and a rise in researcher and funder interest. Systematic reviews (SRs) and evidence synthesis more generally will be crucial tools in the evolution of CDOH as a field. Such reviews can draw on existing methodological guidance, though there are areas where existing methods are likely to differ, and there is no overarching guidance on the conduct of CDOH-focussed systematic reviews, or guidance on the specific methodological and conceptual challenges. METHODS/RESULTS: CODES provides guidance on the conduct of systematic reviews focussed on CDOH, from shaping the review question with input from stakeholders, to disseminating the review. Existing guidance was used to identify key stages and to provide a structure for the guidance. The writing group included experience in systematic reviews and other forms of evidence synthesis, and in equity and CDOH research (both primary research and systematic reviews). CONCLUSIONS: This guidance highlights the special methodological and other considerations for CDOH reviews, including equity considerations, and pointers to areas for future methodological and guideline development. It should contribute to the reliability and utility of CDOH reviews and help stimulate the production of reviews in this growing field.

Sankey diagrams can clarify 'evidence attrition': A systematic review and meta-analysis of the effectiveness of rapid diagnostic tests for antimicrobial resistance.

OBJECTIVES: To demonstrate, using the example of a new systematic review of rapid diagnostic tests, how Sankey diagrams, alongside the PRISMA guidelines, can (i) facilitate reporting of the quality of the evidence base and (ii) help assess evidence syntheses when studies use heterogeneous outcomes. METHODS: Systematic review and meta-analysis of experimental and observational studies which included at least one prescribing or clinical outcome of RDTs in hospital in-patients. Sub-group analysis was used to assess heterogeneity in summary effect estimates. A Sankey diagram was then used to show the pattern and quality of evidence on RDT outcomes. RESULTS: 57 studies from 14 countries were included. The introduction of RDTs did not significantly reduce in-hospital mortality (RR 0.83, 95% CI 0.60 - 1.15) or length of stay (weighted mean difference = -0.36, 95% CI -1.67 to 0.96). There was high heterogeneity in outcomes. CONCLUSION: There is no clear evidence that the routine use of RDTs for bacterial identification and antibiotic susceptibility testing improves clinical outcomes in hospital in-patients. Sankey diagrams may be a useful further way succinctly to present the pattern and quality of evidence in systematic reviews, especially when it is heterogeneous and not easily amenable to meta-analysis.

NIMble innovation-a networked model for public antibiotic trials.

Antibiotic research and development is at an inflection point. Faced with ongoing problems with commercial innovation, we argue for a networked public approach to support and coordinate existing research and development initiatives by sustainably moving promising compounds through clinical trials. We propose a global public infrastructure of institutes tasked with (1) conducting all trial stages up to market authorisation, including small-scale compound production; (2) negotiating licensing agreements for global production and distribution by industry partners; and (3) using public purchasing agreements or subscription models to ensure commercially viable drug production at equitable prices. We invite stakeholders to consider our Networked Institute Model's benefits for unblocking the public and private antibiotic pipeline.

Quality and Utility of Information Captured by Surveillance Systems Relevant to Antimicrobial Resistance (AMR): A Systematic Review.

Health surveillance systems are considered vital for combatting antimicrobial resistance (AMR); however, the evidence-base on the effectiveness of these systems in providing information that can be used by healthcare professionals, or the acceptability of these systems by users, has not been reviewed. A systematic review was conducted of a number of databases to synthesise the evidence. The review identified 43 studies that met the inclusion criteria, conducted in 18 countries and used 11 attributes in their assessment of surveillance systems. The majority of systems evaluated were for monitoring the incidence of tuberculosis. The studies found that most surveillance systems were underperforming in key attributes that relate to both effectiveness and acceptability. We identified that two features of systems (ease of use and users' awareness of systems) were associated with greater acceptability and completeness of systems. We recommend prioritising these for the improvement of existing systems, as well as ensuring consistency in the definition of attributes studied, to allow a more consistent approach in evaluations of surveillance systems, and to facilitate the identification of the attributes that have the greatest impact on the utility of data produced.

Antimicrobial resistance and COVID-19: Intersections and implications.

Before the coronavirus 2019 (COVID-19) pandemic began, antimicrobial resistance (AMR) was among the top priorities for global public health. Already a complex challenge, AMR now needs to be addressed in a changing healthcare landscape. Here, we analyse how changes due to COVID-19 in terms of antimicrobial usage, infection prevention, and health systems affect the emergence, transmission, and burden of AMR. Increased hand hygiene, decreased international travel, and decreased elective hospital procedures may reduce AMR pathogen selection and spread in the short term. However, the opposite effects may be seen if antibiotics are more widely used as standard healthcare pathways break down. Over 6 months into the COVID-19 pandemic, the dynamics of AMR remain uncertain. We call for the AMR community to keep a global perspective while designing finely tuned surveillance and research to continue to improve our preparedness and response to these intersecting public health challenges.

A framework for identifying and mitigating the equity harms of COVID-19 policy interventions.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic. Governments have implemented combinations of "lockdown" measures of various stringencies, including school and workplace closures, cancellations of public events, and restrictions on internal and external movements. These policy interventions are an attempt to shield high-risk individuals and to prevent overwhelming countries' healthcare systems, or, colloquially, "flatten the curve." However, these policy interventions may come with physical and psychological health harms, group and social harms, and opportunity costs. These policies may particularly affect vulnerable populations and not only exacerbate pre-existing inequities but also generate new ones. METHODS: We developed a conceptual framework to identify and categorize adverse effects of COVID-19 lockdown measures. We based our framework on Lorenc and Oliver's framework for the adverse effects of public health interventions and the PROGRESS-Plus equity framework. To test its application, we purposively sampled COVID-19 policy examples from around the world and evaluated them for the potential physical, psychological, and social harms, as well as opportunity costs, in each of the PROGRESS-Plus equity domains: Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, Plus (age, and disability). RESULTS: We found examples of inequitably distributed adverse effects for each COVID-19 lockdown policy example, stratified by a low- or middle-income country and high-income country, in every PROGRESS-Plus equity domain. We identified the known policy interventions intended to mitigate some of these adverse effects. The same harms (anxiety, depression, food insecurity, loneliness, stigma, violence) appear to be repeated across many groups and are exacerbated by several COVID-19 policy interventions. CONCLUSION: Our conceptual framework highlights the fact that COVID-19 policy interventions can generate or exacerbate interactive and multiplicative equity harms. Applying this framework can help in three ways: (1) identifying the areas where a policy intervention may generate inequitable adverse effects; (2) mitigating the policy and practice interventions by facilitating the systematic examination of relevant evidence; and (3) planning for lifting COVID-19 lockdowns and policy interventions around the world.

Impact of a multiplex PCR point-of-care test for influenza A/B and respiratory syncytial virus on an acute pediatric hospital ward.

Patients with respiratory infections are often managed presumptively until confirmation of infection status. We assessed the impact of introducing the Enigma® MiniLab™ FluAB-RSV point-of-care test (POCT) on patients admitted with a suspected respiratory virus driven illness in an acute pediatric ward. This utilized a before and after design (respiratory viral seasons 2013/14 versus 2014/15). Following POCT implementation, oseltamivir prescribing increased in patients with influenza (OR = 12.7, P = 0.05, 95% CI [1.0, 153.8]). A reduction in the average reimbursement charges without a change in the length of stay was observed. Modeling suggested that laboratory test cost savings could be achieved if the POCT cost £30 and was used for screening, followed by the respiratory viral panel for RSV and influenza negative patients. A rapid POCT for influenza A/B and RSV infections in pediatric inpatients may improve oseltamivir prescribing, strengthen antimicrobial stewardship, reduce reimbursement charges and decrease laboratory costs.