Holistic Approach Towards Unravelling Antibiotic Resistance in East Africa

The potential harm that increasing levels of antibacterial resistance (ABR) will have on human health is vast, as a consequence the effects of this will be felt across society and at the economic level. It is predicted that by 2050, 10 million lives per year and a cumulative 100 trillion US Dollars of economic output may be lost worldwide. In order to address this looming problem a co-ordinated global response is required to try and halt the rise of ABR. Efforts are underway to tackle the rise in resistance, however agenda-setting is dominated by High Income Countries (HICs) and may not reflect priorities or needs of Low and Middle Income Countries (LMICs), where the levels of resistance and also the types of disease caused by bacteria may be different.

One of the most vulnerable regions to the increase in antibiotic resistance is Africa where, in comparison to other regions of the world, the burden of infectious diseases is highest. The economic, cultural and ethnic diversity of Africa mean that the problems surrounding ABR across African countries are likely be distinct from other regions of the world, and therefore require regional solutions and approaches. For example, the availability of antibiotics can be patchy, and the routes of access to antibiotics are variable (including traditional healers, public and private medical practitioners and over-the-counter antibiotic access). Social, cultural and lifestyle drivers of ABR in Africa also have specific features - closer communal living in cities with variable water/sanitation, and closer animal husbandry in rural communities.

This project aims to address ABR in Africa and fill the gaps in knowledge. The research will target three main areas that comprise the problem: the bacteria that are antibiotic resistance and cause disease; the amount of antibiotics that are used to treat disease; and the behaviour of humans that governs how antibiotics are used and supplied. The three elements incorporate epidemiological, economic, cultural and societal factors that interact and contribute to the problem.

Bringing together research covering these 3 elements will provide a holistic view of ABR in East Africa. The project will establish a surveillance network across Uganda, Kenya and Tanzania that is comprised of sentinel sites that monitors and characterized the ABR bacteria that cause disease at that location, maps the use of antibiotics in the sentinel hospitals and the surrounding communities, and captures the behaviour and attitudes of humans that is responsible for their use in these setting. The project also recognises antibiotics are not exclusively used for human medicine, therefore our surveillance will also cover the use of antibiotics in veterinary medicine in the linked communities to provide a 'One Health' view. Using a multidisciplinary approach, encompassing, microbiology, genomics, epidemiology, statistics, social sciences and geography, we will seek to explore and describe the relationships between the elements, and identify the drivers of ABR.

Using this knowledge, we will identify interventions, such as public health and infection control measures and legislation changes, that can be made to control ABR at national and regional level. At the global level, the output of this project will add to the worldwide picture of ABR. This information will also be of value to global development agencies such as the WHO and FAO, to direct funding into effective interventions critical to the region.

Researchers investigating antibacterial resistance (ABR) where there is a paucity of information are faced with challenges of data collection, linkage and resolution. We have designed our experimental workflows to utilize techniques and methods that will provide high-resolution and accurate data.

A crucial element of our project is the quantification and characterisation of the clinical burden of ABR. Working with microbiology labs that form the consortium's network, we will standardize Antibiotic Sensitivity Testing (AST) methodologies across labs, so that it meets EUCAST/CLSI guidelines, generating robust and comparable data. We will implement WGS within ABR within the surveillance network, and develop bioinformatics to enable local and international comparison of data for key indicator ABR organisms. We will deploy an intuitive user-friendly bioinformatics web application (microreact.net) to enable network laboratories to view WGS data contextually (i.e. in a geographic and phylogenetic context, with accompanying meta-data).

In order to gather antibiotic usage data across multiple sites we will equip researchers with mobile devices running EpiCollect software, to record quantitate and qualitative antibiotic data gathered from interviews. EpiCollect allows the generation of custom questionnaires, and uploading of data in the field, to a remote server which displays on a project website that can be used for data analysis and visualisation. The software also records geospatial information to enable geographically mapping of data. Simulated scenarios and in-depth interviews will be conducted to examine attitudes and behaviours around antibiotic prescription, administration and adherence. EpiCollect will also be utilized for this work to promote data linkage. Integrated mathematical and statistical analyses will be undertaken on our multi-disciplinary datasets to help construct and parameterise mechanistic models of the genesis and spread of ABR in East Africa.

A key deliverable of this project is the development and provision of a microbiological surveillance network in East Africa. The network will provide a mechanism for antibacterial resistance (ABR) surveillance, gathering high quality diagnostic and phenotypic data for ABR pathogens, and will allow stakeholders to identify and provide early warning of resistances spreading within the region. A high-resolution view of ABR pathogens identified by the network will be provided by whole gene sequencing (WGS), to allow stakeholders to identify the genetic basis of resistance in isolates, and also identify high risk clones that are spreading locally, or are imported into the region from elsewhere.

The primary initial beneficiaries will be members of the microbiology network laboratories receiving training in microbiological testing, and also whole genome sequence analysis within clinical microbiology. As a result of the network structure, we anticipate that this will trickle down to connected laboratories, facilitating the extended use of data. Data-sharing with other regions will promote a more complete understanding of pathogen epidemiology and ABR.

WGS data can be used to identify local spread of drug resistance clones and also identify potential reservoirs of drug resistant pathogens. Evidence from the network will point to areas within the hospitals and the community where spread is more likely, and therefore help target resources and infection control initiatives more effectively. For healthcare policy makers at the national level, this information will help identify where there are gaps in policy, or there are changes required, which will more effectively combat the growing threat of ABR. Consequently we anticipate that the consortium's actives will help inform stewardship guidelines for usage and treatment guidelines. The WGS data for the antibiotic resistant organisms will be of interest to around the world researchers interested in understanding pathogen evolution and the spread of AMR. The availability of accompanying high quality phenotypic data will also be of value to researchers interested in the genetic basis of resistance.

The work of the consortium will help legislators and government officials ascertain the extent and nature of the ABR problem in their country, and consequently provide evidence the risk that these pose. Our analysis of the behaviours and attitudes to antibiotics will highlight the drivers of resistance in their population that may require legislation to control the supply and use of antibiotics for human and animal consumption.

Our study across multiple sites and countries in East Africa will benefit governmental organizations and NGO's involved in the provision and management of public health, providing both country-specific and regional perspectives of ABR. This will inform where resource should be targeted, and also where policy co-ordination is required.