Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE)
Funding: Department for International Development (DFID), 2017-2021
LSHTM investigators: David Mabey (PI), Amit Bhasin, Chrissy Roberts, Clare Chandler, Heidi Hopkins, Coll Hutchison, John Bradley, Rashida Ferrand, Shunmay Yeung
Other UK and international collaborators: Quique Bassat, Vilada Chansamouth, John Crump, Ethel Dauya, Nick Feasey, David Lalloo, Hla Hla Win, Yoel Lubell, Mayfong Mayxay, Claudious Muserere, Paul Newton, Antonio Mario Sitoe, Wah Win Htike, Zaw Lynn Aung
Fever is one of the most common symptoms that leads to health-care seeking and hospital admission across sub-Saharan Africa and Asia. However, little is known about the causes of febrile illness in these regions. Without access to reliable diagnostic facilities, and without evidence on which to base treatment guidelines, in most cases treatment is empiric and too often results in overuse of antimicrobial medicines.
The FIEBRE study will help to address these information gaps, using a standard clinical, laboratory and social science protocol, in five representative sites – in Lao PDR, Malawi, Mozambique, Myanmar and Zimbabwe – with a high burden of infectious disease and few or no existing data. The study will rigorously investigate causes of febrile illness, and antibacterial resistance, in inpatients and outpatients of all ages. Qualitative work will describe how care-seekers, clinicians, and other stakeholders conceptualise fever, and appropriate antimicrobial use. The results of this study will enable us to design new, evidence-based algorithms for the management of febrile illness. Archived patient samples will provide a basis for future evaluation of novel diagnostics, and rational approaches to disease surveillance.
How do policymaker perceptions of antimicrobial resistance drive behaviour and policies for appropriate antimicrobial use? A case study of Pakistan.
Staff: Johanna Hanefeld, Mishal Khan, Helena Legido-Quigley
Co-Is: Ana Mateus (RVC), Rumina Hasan(Aga Khan University, Pakistan)
The research proposed is for a pump prime award to determine how policymakers’ perceptions of Antimicrobial Resistance (AMR) drive their behaviour and selection of policy options aimed at appropriate use of antimicrobials, focusing on one lower middle income country: Pakistan. Applying qualitative methods and engaging a multidisciplinary team with human and animal health expertise, it will map policy actors and their networks, drawing on the Social Construction Framework, to identify how motivation, social constructions, power relations and contextual factors shape policy maker behaviour. Research findings will be essential to achieving the ESRC’s underlying objective to identify the specific economic factors, cultural norms, experiences and practices relating to antibiotics that enable the best strategies for action, by providing concrete knowledge and tools for working with policymakers in low- and middle-income countries (LMICs) as they adapt and adopt national policies for appropriate use of antimicrobials.
Key questions this research will address include:
- Who are the key policy actors to engage for effective implementation of interventions and policies concerning appropriate antimicrobial use? How are these actors currently, and potentially, connected?
- How are the selected policy options socially constructed and how do social constructions reinforce or weaken support or opposition for the selected policies?
- What other motivations, power relations and contextual factors drive the selection of specific policies?
- How do these differ among different groups of policymakers identified under objective 1 (e.g. animal health versus human health or political affiliation)?
- Based on analysis of the questions above, how do policies for appropriate use need to be presented and framed to ensure that essential groups of policy actors engage with and respond to these effectively?
Beyond non-inferiority: a practical trial design for optimising antibiotic treatment duration
Staff: Matteo Quartagno (LSHTM, MRC-CTU)
Co-Is: Professor James Carpenter (LSHTM and CTU), professor Sarah Walker (CTU), professor Max Parmar (CTU) and Dr Patrick Phillips (CTU).
There is substantial interest in investigating the use of shorter durations of antibiotic treatment for bacterial infections to counter the global threat of AMR. Classic designs compare two arbitrarily chosen durations in a non-inferiority trial. Given their important limitations (including arbitrary non-inferiority margins), our aim was therefore to develop new alternative designs to optimise duration of treatment.
Our main idea was to recast the problem of determining an optimal duration as estimating the shape of the `Duration-Response Curve’ (DRC), by means of flexible regression modelling strategies.
Impact of combination therapy on transmission of resistant malaria parasites
Title: Multi-drug resistance in malaria under combination therapy: assessment of specific markers and development of innovative, rapid and simple diagnostics (MALACTRES)
Funding: European Commission Seventh Framework Programme (EU FP7)
Collaborators: Royal Tropical Institute, The Netherlands (Coordinator); The Prince Leopold Institute of Tropical Medicine, Belgium; Centre Muraz, Burkina Faso; Kilimanjaro Christian Medical Centre, Tanzania; Foresite Diagnostics, UK; Biomolecular Sensing and Diagnostics Agrotechnology and Food Innovations, The Netherlands.
MALACTRES is a consortium of researchers aiming to tackle multi-drug resistance in malaria under combination therapy. With partners in Europe and Africa, the overall objective is to assess specific genetic markers in Plasmodium falciparum for ACT resistance and to develop innovative, rapid and simple diagnostics for malaria.
A large external network of collaborators has been built, including groups who are running clinical trials from which parasite material can be used for a detailed analysis of known and candidate drug resistance markers. Such markers have previously been investigated at LSHTM. Well-known genetic mutations in the pfcrt and pfmdr1 genes play a role in resistance to most ACT partner drugs and have been sequenced from several geographical locations. The characterisation of new candidate genes, pfATPase6, pfubp-1, pfnhe-1 and pfmrp has begun.
PCR and sequencing protocols are under development and will be applied to field samples, starting with those collected in clinical trials in Kenya and Tanzania in 2009/10. We will look for changes in genotype in our candidates between pre– and post-treatment samples and in successfully infected mosquitoes. This will indicate whether or not any particular genotype survives better and has a transmission advantage in the presence of an ACT, providing evidence of a potential role in ACT resistance.
Gadalla NB, Elzaki SE, Mukhtar E, Warhurst DC, El-Sayed B, Sutherland CJ. 2010. Dynamics of pfcrt alleles CVMNK and CVIET in chloroquine-treatedSudanese patients infected with Plasmodium falciparum. Malar J. Mar 12;9(1):74.
Multi-disciplinary research of drug resistance in Malaria
Staff: Sutherland C.
Funding: PHE and UNITAID