Strategies to reduce the burden of antibiotic resistance in China

Antimicrobial resistance (AMR) and particularly resistance to antibiotics (ABR) has become one of the most complex public health challenges globally. Estimates have suggested that by 2050 AMR will be responsible for 10 million deaths, of which 4.73 million are in Asia, with an associated reduction of 2% to 3.5% in Gross Domestic Product (GDP) that will cost the world up to 100 trillion USD. Our collaborative research and training programme will bring together international experts at leading universities in China and the UK to tackle antibiotic resistance, the type of AMR that is the most pressing concern for human health. China is estimated to be the second largest consumer of antibiotics in the world, with widespread and often inessential use in both humans and livestock. Widespread consumption leads to antibiotic residues in water and soil that may exacerbate the development and transmission of resistance through organisms and chemicals in the environment. Studies have investigated the epidemiology and pattern of drug-resistant infections in China, but the size of the health and economic burdens caused by ABR on a national level and the role of the environment in the development and transmission of drug resistance are still unclear.

Most ABR research in China has focused on specific bacteria in hospital patients, selected food animals, or isolated determinants. Better evidence and broader understanding of environmental, community, economic and health care drivers and burdens of ABR based on a systems perspective that recognises interactions between these areas is urgently needed, as are evaluation tools to measure the effectiveness of different ABR-reducing intervention strategies. Due to a dense population, an intensive livestock breeding industry and massive antibiotic use, Eastern China is a key region for controlling antibiotic use and ABR. Our research aims to bridge these key evidence gaps and strengthen disciplinary and methodological research skills, through a set of closely linked projects that will generate the holistic knowledge which is needed to design, deliver and monitor targeted strategies to limit ABR in China and comparable settings. We will also establish sustainable partnerships with cross-disciplinary research expertise that is currently lacking in China and strengthen capacity in policy-relevant research. Since antibiotic resistant infections and their genetic components spread rapidly through international travel, research into ways of reducing the burden of ABR in China is important not only for populations in China and the wider Asian region, but globally.

Through three linked programmes of work based at three leading universities in China, supported by UK academics from a wide range of disciplines, we will:
1. Estimate the economic burden of AMR and determine the cost-effectiveness of potential intervention strategies
2. Design and evaluate a tailored intervention to modify antibiotic prescribing behaviour among health professionals and reduce antibiotic consumption among outpatients
3. Measure human exposure to antibiotics from environmental and livestock sources, estimate their health effects & develop tools for risk assessment and monitoring of environmental exposures to antibiotics and antibiotic-resistant genes
4. Gather evidence on current patterns of antibiotic use and the implementation of ABR-related policies and regulations at local, regional and national levels
5. Produce evidence-based recommendations on optimising antibiotic use, monitoring ABR and assessing the success of strategies to reduce ABR in China
6. Build cross-institutional and international collaborative groups to increase China's research capacity in a range of relevant disciplines and methodologies, as well as in the design and conduct of inter-disciplinary research.

WP1 will develop and optimise a digital intervention to reduce unnecessary antibiotic prescribing in lower level health facilities drawing on theory, evidence and our own effective interventions. We will use participatory co-design, qualitative research with up to 60 clinicians and patients and a feasibility trial to ensure all elements of the intervention are acceptable and feasible. A cluster randomised controlled trial will then compare the intervention with usual care in 55 practices and 1642 patient consultations. The primary outcome will be reduced antibiotic usage, with non-inferiority in clinical outcomes.

WP2 comprises six linked studies in three representative areas of East China, to gather evidence on and analyse the inter-relationships between antibiotic use, occurrence and transmission of ABR in the environment, animals and humans. The studies will include assessment of antibiotic exposure in population cohorts from survey and urine (n = 3,300) and identification of types and frequencies of ABR genes in humans and food animals; analysis of antibiotic residues and ABR genes in the aquatic environment, including wastewater; mixed methods research into drivers and practices associated with antibiotic use (600 families); and analysis of the national policy context (with expert and stakeholder input) to propose strategies and systems for optimising and monitoring antibiotics use.

WP3 will estimate the health and economic burden of ABR in China and the cost effectiveness of different antibiotic-reducing interventions. The analysis will draw on national surveillance data, published literature, a prospective observational cohort study in 50 representative hospitals to determine rates of infection, resistance, length of stay, mortality and cost and findings from WP1 and WP2. A decision analysis model will be developed to determine the costs and health effects of antibiotic exposure, resistant infection and different prescribing interventions.

Beneficiaries of the research
This research will inform policy and practice to reduce ABR, which will benefit people living in China, Asia and to some extent globally. ABR is known to be a significant burden to the health and economic wellbeing of people in China and other LMIC. Our work will generate evidence of i) effectiveness and cost effectiveness of an intervention to reduce antibiotic prescribing and demand; ii) environmental transmission pathways and priority targets for limiting antibiotic exposures; and iii) the magnitude of the ABR burden and cost-effective strategies for reducing it. Resulting policy and practice recommendations will help to inform behaviour, service, system and regulatory changes. This will have a potentially transformative effect on control and prevention of ABR infections in China and is likely to be transferable to other LMIC settings. As ABR is spread rapidly through international travel, reducing ABR in this region will reduce global transmission.
Our collaborative work will strengthen the research links between China and UK, promote the exchange of expertise and produce internationally excellent research. The UK team will contribute their expertise in research methods (especially large anthropological studies, observational studies, environmental and wastewater epidemiology and behaviour change intervention design) and support the China partners through training and joint research activities. This will enable the collaborating partners to develop their ABR research programmes, which will benefit both researchers and research users in China in the longer term.
Engagement activities
Throughout the research project we will involve key stakeholders with roles in managing antibiotic use, antimicrobial stewardship and reduction of ABR in humans, food animals and the acquatic environment. Research findings will be translated into short policy briefings with recommendations tailored to fit with existing policies in China and to influence current practice in health care, agricultural and urban settings. The credibility of research findings will be indicated to stakeholders through peer-reviewed publications in internationally recognised journals and presentations at academic conferences in China, the UK and internationally. We will develop context-appropriate strategies to engage wider publics through digital and other media. At the end of the project we will host a meeting for all relevant stakeholders, at which we will present (and disseminate) summaries of the research and where we will (in partnership with stakeholders) establish how our results are best implemented.
Anticipated benefits
We anticipate the proposed research will inform the design of future antibiotic stewardship (ABS) interventions as well as the research to evaluate these interventions, and improved strategies both to optimise antibiotic use and to monitor ABR. WS1 aims to produce an effective intervention to reduce antibiotic use for RTI by at least 10% that can be easily implemented nationwide. WS2 will indicate specific livestock industries where ABR gene transmission to employees and thence to the wider population is particularly prevalent, enabling government and local authorities to prioritise the improvement of farm management and food preparation practices to minimise risks. WS3 will provide the first robust estimates of the national burden of AMR and cost-effective interventions to reduce it, enabling ABS implementing agencies to maximise the efficiency of health care resource use. Improved ABS in health care contexts will reduce the number of patients suffering side effects from unnecessary antibiotics and increase the number of health care workers and institutions able to meet antibiotic prescribing regulations. Reduced antibiotic prescribing to humans and reduced transmission from livestock and water sources will reduce the prevalence of ABR infections, with potential to transfer these benefits across Asia.