One Health Drivers of Antibacterial Resistance in Thailand

Antibacterial Resistance (ABR) is a significant source of excess mortality in Overseas Development Assistance (ODA) countries and constitutes a major, increasing threat to wellbeing and economic development. Antimicrobial Resistance (AMR), predominantly ABR, is estimated to have caused 38,000 deaths and an economic loss of 1.2 billion US$ in Thailand in 2010. Because of good record keeping and surveillance, Thailand has been used as an exemplar for characteristics of ABR in ODA countries. ABR is common in human, environmental and animal bacterial isolates. However, ABR has mostly been studied separately in discrete sectors (e.g. hospital patients or poultry). The key drivers of ABR relevant to human health cannot be pinpointed in this way because the selection and transmission of ABR results from interactions between humans, animals, and the environment. A "One Health" approach to the problem is required.

During this consortium project, we will study the Enterobacteriaceae family bacteria Klebsiella pneumoniae (Kp) and Escherichia coli (Ec), which reside in the human and animal gut, are common in environments contaminated with faeces, are are considered a significant threat to human health in Thailand. They are commonly carbapenem- and/or 3rd-generation cephalosporin-resistant (3GCR), which are drugs commonly used for serious infections. Carbapenem-resistant Enterobacteriaceae (CRE) are also recognised by WHO as one of the highest priority pathogens globally for which new ABs are urgently needed. Ec and Kp cause a range of infections in hospitalized patients (e.g. surgical site, intra-abdominal, pneumonia, sepsis) and serious community-acquired infections (e.g. complicated urinary tract infection, pyogenic liver abscess, meningitis). The prevalence of 3GCR Kp and Ec in human infections in Thailand has been increasing from less than 10% in 1999 to 50% in 2016, and of carbapenem-resistant Kp from none prior to 2010 to 10%-20% in 2016.

Our consortium's vision is to build a holistic picture of the drivers of ABR in Thailand and to use this information to benefit the Thai people, and as an exemplar for other ODA countries. The term "driver" may refer to: 1) a material condition or substance, such as a chemical (e.g. an Antibiotic), which, at a particular concentration, selects for the increased prevalence of ABR bacteria; 2) an action, such as exposing bacteria to that chemical by taking an antibiotic; or 3) a socioeconomic condition or circumstance which accounts for that action (e.g. the economic necessity to keep working in the face of illness). A full understanding of ABR drivers at every level is important for the design of effective and appropriate interventions to limit ABR. Hence, this interdisciplinary consortium will investigate them all.

Our study area will be the Mae Klong-Ta Chin Basin, which covers an area of 80x80 km in the central and western part of Thailand. This is the area where the Mae Klong and Ta Chin rivers run from their mountain sources along the Thai-Myanmar border (Mae Klong river) and upper central Thailand (Ta Chin river) down to the Gulf of Thailand. The study area includes districts spread over five provinces (Karnchanaburi, Ratchaburi, Samut Songkram, Samut Sakorn and Nakornprathom). Both rivers enter the study site and run through areas where there are numerous factories, animal farms, rice fields, fruit orchards and communities, allowing multiple possible drivers to be considered in our work.

Our work will run alongside Thailand's National Strategic Plan on AMR, giving us a perfect opportunity to embed our findings in annual reviews of the Strategic Plan, influencing policy and having a relatively short term and direct impact on human health in Thailand. Our engagement and stakeholder activities will also facilitate dissemination of our findings into other countries within the same global region, and comparisons with other projects across the globe will yield added value.

Our strategy for investigating drivers of antibacterial drug resistance in Thailand will be first to rank the influence of different material substances and actions that drive the increased prevalence of 3rd Generation Cephalosporin resistant Escherichia coli and Klebsiella pneumoniae, and Carbapenem Resistant Enterobacteriaceae in Thailand. We will do this by quantifying these bacteria and also chemicals (including antibacteirals) in humans, animals, and the environment, and ranking how strongly these chemicals can select for antibacterial drug resistance, and how well the various identified bacteria compete with and/or pass their resistance to other bacteria. We will then ascertain the importance of different actions in determining the abundance of the chemicals and bacteria under study. We will do this by ranking the contribution of different possible sources of resistant bacteria, by measuring the scale of antibacterial use in different human and animal populations and by using risk factor analysis to consider the relative importance of different actions as drivers of enteric colonisation of 3rd Generation Cephalosporin resistant Escherichia coli and Klebsiella pneumoniae, and Carbapenem Resistant Enterobacteriaceae. We will then conduct focused social science research to investigate the social, cultural, and economic drivers associated with antibacterial use and with heightened risks of human exposure to resistant bacteria. These diverse types of data will be used to construct a dynamic multilevel model of resistance transmission and containment. This phased approach will enable us to integrate our workstreams and identify antibacterial drug resistance-reducing interventions with the best likelihood of success. At all stages we will engage with Thai stakeholders and policy makers identified during the development phase, increasing impact

Health and Welfare of the Thai people, and those from other countries.
There is a significant burden of disease and economic cost of antibacterial drug resistance (ABR) in Thailand; estimated as 38,000 extra deaths and 1.2 billion US dollars of economic cost in 2010. Since ABR has risen world-wide since that time, inevitably the health and well-being cost of ABR in Thailand will also have risen and is set to rise further in future. Rates of carriage of resistance to last resort antibacterial drugs has risen, and some key first-line drugs have been rendered essentially useless. Our aim is to understand the drivers of ABR selection and spread in a One Health context, and uncover interventions designed to reduce ABR, and/or the incidence of infection. This would have a potentially transformative effect on healthcare in Thailand. It is likely that what we learn will be transferable to other countries, particularly neighbouring countries where ABR is also a significant burden, but where a response to the threat of ABR is less developed. In order to meet this challenge and improve human health, we need to have impact in Policy Engagement and Public Engagement, at all levels from our study site to the entire South East Asia region. One major advantage of the timing of our proposed work is that it is framed by the implementation and review of Thailand's National Strategic Plan on Antimicrobial Resistance, which has set key targets for reducing infection, reducing antimicrobial usage in humans and animals, and reducing the burdon of resistance. Our work will synergise with Thai and WHO surveillance work, and our synthesis will be extremely valuable both in bench-marking success and informing modification of the Strategic Plan.

Farming/Veterinary Industry.
Over-use of antibacterial drugs and other polluting chemical in Thai agriculture may reduce its economic efficiency. Better farm management practices would not only reduce the reliance on chemicals, but they would improve agricultural yields and so economic growth. Our anthropological work and engagement and training events will uncover farm management practices, and potential leverage points that might be used to encourage more efficient practice, whether this is to reduce ABR or not.