Drivers of Resistance in Uganda and Malawi: The DRUM Consortium

Lead Research Organisation: Liverpool School of Tropical Medicine
Department Name: Clinical Sciences

Abstract

The discovery and development of antibiotics is one of the great scientific achievements of the 20th Century, however it rapidly became clear that bacteria quickly become resistant to these lifesaving agents, and the spread of antibiotic-resistant bacteria is now a problem of global concern. The poorest nations on Earth frequently have the greatest burden of severe and life threatening infections, and these nations are likely to suffer most from the spread of untreatable bacteria. There is much that is unknown about how antibiotic resistance spreads globally and this is particularly true of sub-Saharan Africa, where diagnostic laboratories are not commonly available.
The "Drivers of Resistance in Uganda and Malawi" or DRUM Consortium will address how human behaviour and antibacterial usage in the home, around animals and in the wider environment in urban and rural areas of Uganda and Malawi contributes to the spread of antibiotic resistance in bacteria. The consortium is especially interested in the common bacteria E. coli and K. pneumoniae. E. coli is an example of a bacteria that often causes infections in the community, but may also spread around hospitals, whereas K. pneumoniae is a key cause of hospital acquired infections, particularly amongst vulnerable groups such as premature babies. We have chosen to study these bacteria together as they are from the same family and are able to share traits that make them resistant to antibiotics.
The DRUM consortium plans to investigate which aspects of behaviour are most important in spreading antibiotic resistance by surveying human behaviour in relation to antibiotics, water, sanitation and hygiene and by investigating bacterial behaviour in response to these stimuli. We plan to use cutting edge mathematical techniques to "model" which behaviours are most important and then use this information to work with policy experts in Uganda and Malawi to design potential interventions to prevent them from spreading further.

Technical Summary

The Drivers of Resistance in Uganda and Malawi, or DRUM Consortium aims to build an agent based model of the drivers of antimicrobial resistance transmission, using data from urban, peri-urban and rural settings in Uganda and Malawi to inform the model.

We will undertake five packets of work to build the model;
1. Longitudinally collect microbiological data from humans, animals and the environment of households at two levels of sampling intensity and genomically characterise the bacteria isolated;
2. Produce data on the intensity of antibiotic use across human and agricultural domains; the reasons for antibiotic use - and non-use - in different contexts; and drivers that are amenable to change;
3. As these are enteric pathogens, transmitted via the faecal oral route, we will provide a comprehensive outline of WASH behaviours and associated faecal exposure;
4. Determine the evolutionary trajectories of AMR development related to local antibiotic usage to understand if local usage and exposure patterns of antibiotics drive resistance emergence and persistence;
5. Quantify the economic burden from AMR and assess the value for money of potential interventions to tackle it.
At the same time, we will describe the barriers that exist in the AMR policy community and how these can be addressed in through implementing AMR strategic/action plans. The resulting information will be fed back to the policy community. We will use the relationships we develop in this workstream to develop and, in the future, trial interventions based on the output of the model.

Planned Impact

In Low and Middle Income countries (LMIC), there is a high incidence of severe bacterial infection and a critical lack of accessible health system infrastructure to diagnose and appropriately treat bacterial infections and widespread availability of antimicrobials without prescription. This situation is responsible for a huge burden of morbidity and mortality, and is increasing selective pressure for the emergence of AMR pathogens. In many LMIC settings, extended spectrum betalactamase (ESBL) producing infections are locally untreatable due to unavailability of carbapenems or other reserve antibiotics.
The DRUM consortium will base its activities in urban, peri-urban and rural settings in Malawi and Uganda and is focusing on ESBL E. coli (ESBL-E) and K. pneumoniae (ESBL-K) bloodstream infections. These organisms share AMR phenotypes and genes and belong to the same family of bacteria. E. coli, however, are both community acquired and nosocomial, whereas K. pneumoniae are archetypal nosocomial AMR pathogens. Operating in urban, peri-urban and rural settings will enable us to evaluate AMR transmission at different human and animal population densities, with different levels of affluence, WASH infrastructure, burden of infectious diseases and different access to antimicrobials.
We propose a truly interdisciplinary approach, from laboratory to policy implementation to impact on this problem. To minimise AMR emergence and persistence, we will therefore describe the molecular epidemiology of AMR E. coli and K. pneumoniae in the human, animal and environmental context in which antimicrobials are used. Understanding the drivers of AMR transmission within the complex interplay between bacteria, humans, animals, and the environment is key to designing and implementing appropriate, safe, acceptable, and effective interventions. The DRUM Consortium envisages multiple pathways to impact.
1. We aim to have a AMR transmission model developed that can be used by policymakers to understand where evidence gaps remain and to test planned interventions. As part of this work, the model will be developed as a robust, user friendly piece of software. Our predictive model of AMR emergence to leverage fitness against pathogens. The model will be used to predict interventions that are most likely to succeed and this will inform applications to trial intervention strategies.
2. Our consortium includes a plan to identify key figures in AMR policy across multiple sectors in both settings that we will work with to disseminate our findings and to develop intervention strategies.
3. Packaging evidence into multiple 'products' through different formats and media. Our engagement strategy will be used to inform how to best package the evidence for each influential stakeholder. It will also inform the best time and route for the information to be delivered based on the stakeholder mapping. Targeted evidence products such as policy briefs and media briefings will be developed, and evidence dialogues will be held as appropriate. We will also discuss evidence at regional and global forums. Evidence will be disseminated to the research community through attendance at national and international conferences and peer reviewed publication.
We therefore expect that communities throughout East and Southern Africa will benefit from this study, through the development of strategies that will mitigate the spread of antimicrobial resistant bacteria. This in turn will reduce the incidence of locally untreatable bacterial infections.

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