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What we do: Antimicrobial resistance

Researching ways to combat the growing problem of antimicrobial resistance (AMR) is a large part of what we do at the UCL Centre for Clinical Microbiology (CCM).

To celebrate World Antimicrobial Awareness Week (18th-24th November) we have created a video outlining many of the projects we are involved in. In the video, Professor Tim McHugh, the Centre Director, gives an introduction to our work and why AMR projects are such an important part of our research. You will also hear from other members of staff whose work is linked to fighting antimicrobial resistance.

You can learn more about the clinical trials and projects we are involved in below.
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Tuberculosis clinical trials (presented by Priya Solanki)

CCM has been involved in a number of tuberculosis (TB) clinical trials for both susceptible and drug resistant TB. We work closely with the TB Alliance, which is responsible for multiple studies, including REMoxTB (now complete), NIX, which is now complete and has been adapted into ZeNix and STAND, which is also now complete and has been adapted into SimpliciTB. These clinical trials test different combinations and regimens of TB drugs to try and identify the most effective (and simplest) treatment for TB treatment. NIX/ZeNix focusses on drug resistant TB infections, which generally require many months to years of treatment.

We also lead the microbiology for TB Practecal, run by MSF. This is a phase II/III clinical research project to find short, tolerable and effective treatments for people with drug-resistant tuberculosis (DR-TB). Our role within TB Practecal is mainly quality assurance and laboratory management.

As a result of the trials we are involved in, we have had the opportunity to be part of other related TB Alliance projects relating to Pretomanid. Pretomanid was developed by TB Alliance and is approved by the US FDA to treat extensively drug resistant TB (XDR-TB) or treatment-intolerant/non-responsive multidrug resistant TB (MDR-TB), in combination with bedaquiline and linezolid, as part of the BPaL regimen. Projects include the Pretomanid MIC ECOFF project and the Pretomanid resistance surveillance programme (PAEGIS), which are ongoing. The aim is to determine the breakpoint for Pretomanid, and further characterise the genetic basis for resistance. PAEGIS is a validation study which ensures quality through external quality assurance.

Identifying the effects of COVID-19 ward infection prevention control on hospital acquired bacterial infections and AMR (presented by Dr Linzy Elton)

This is a multi-site study funded by the British Society for Antimicrobial Chemotherapy and jointly run by the CCM, the Institute for Endemic Diseases in Sudan and HerpeZ in Zambia. The project is led by Dr Linzy Elton and all sites are part of the PANDORA-ID-NET consortium. Following on from research done here at the Royal Free Hospital, this pilot study, based in hospitals in Sudan and Zambia, this project is comparing the types of secondary bacterial infections acquired by patients, on COVID-19 and non-COVID-19 wards, using microbiological (culturing and antibiotic testing) and sequencing methods to identify species, as well as AMR transmission. The project is also looking at IPC guidelines on both types of wards to identify differences in, for example, personal protective equipment or antimicrobial stewardship.

This project is utilising Oxford Nanopore Sequencing technology, with UCL providing sequencing training. These platforms and the training programme will enable the teams in both countries to not only undertake sequencing for this project, but also set up a sequencing pipeline for the identification of multi-drug resistant bacteria in clinical settings. As part of PANDORA-ID-NET’s capacity development and training goals, the training is being recorded. The tutorials and further information on setting up sequencing can be found on PANDORA-ID-NET’s TGHN hub pages.

You can keep up with the project’s Twitter account here.

Diagnostics and our links with clinical research (presented by Kerry Roulston)

We also work closely with our clinical colleagues in a number of areas, including rapid diagnosis of infection and detection of antibiotic resistance. This is important, because it helps us promote the responsible use of antibiotics and reduce the risk of antibiotic resistance. One project we work on is the diagnosis of bloodstream infections. We take a sample of blood from a patient, grow any bacteria present in the blood (using agar plates) and then diagnose which organism is causing the infection and which antibiotics will be effective to treat it with.

The current methods in the laboratory can take a couple of days, and during this time the patient might be given a broad spectrum antibiotic in the meantime, which may be the incorrect antibiotic. Broad spectrum antibiotics also the patient’s risk of developing antibiotic resistant infections. We are currently evaluating more rapid essays to produce these results faster, and if we can do this, then we can ensure that the patient is on targeted narrow spectrum antibiotics sooner.

Another project Kerry is involved in aims to help improve patient outcomes and to reduce the risk of antibiotic resistance in relation to COVID-19. During the peaks of the pandemic we noticed that the patients in the intensive care unit who had COVID-19 appeared to develop infections with different types of bacteria compared to what is usually seen, including more drug resistant bacteria. We’re currently analysing the genomes of these bacteria in relation to ward and patient data, to try and understand the reasons for these changes. This means we can inform infection prevention and control practice going forward and reduce the risk patients in the future.

Tuberculosis sequencing pipeline (presented by Dr Pacôme Abdul)

TB clinical trials and research mainly rely on microbiological methods (e.g. culturing and drug sensitivity testing) to diagnose and identify drug resistant infections. Sometimes patients do not respond to treatment and it can be unclear whether they have become reinfected, or whether the drugs are not working properly. Until recently, the use of whole genome sequencing has been too expensive for routine use in many laboratories in low and middle income countries. We are trying to address this by developing and validating a sequencing pipeline using the Oxford Nanopore Technologies (ONT) platform. ONT sequencing requires less upfront costs and so is an attractive option for under resourced laboratories.

Dr Linzy Elton, Professor Neil Stoker and Dr Sylvia Rofael are validating this pragmatic pipeline so that it can be rolled out in the low and middle income sites that we support. Once optimised, we aim to provide the training and expertise required, so that

As part of our capacity development of the pipeline, Dr Pacôme Abdul from the Centre de Recherches Médicale de Lambaréné (CERMEL) in Gabon is spending 9 months with us so that he can take his experience back to CERMEL and continue its development there.

The hollow fibre model (presented by Zahra Sadouki)

Finding ways to repurpose existing antibiotics is a crucial factor in dealing with the global crisis. Zahra is a PhD student and her research investigates different combinations of existing antibiotics to figure out which are the most effective at killing harmful bacteria and preventing the bacteria from evolving resistance.

She does this by using an in-vitro laboratory model called the hollow fibre infection model.  This is exciting because most laboratory research of antibiotics uses static concertation's meaning the concentration of the antibiotic remains the same over time during the experiment. However, when a human takes a dose of an antibiotic their body begins to metabolise and excrete it. As the hollow fibre infection model is dynamic, we can mimic this change in antibiotic concentration.

This means the model allows us to test the same antibiotic concentrations reached in humans and track how the bacteria react to it. She then uses the data produced in the laboratory from the hollow fibre infection model experiments to design mathematical models that help explain the dynamics of what is really happening between the bacteria and antibiotic. The ultimate aim is to better understand the relationship and interaction between bacterial cells and antibiotic molecules as this will provide information to clinicians on best antibiotic prescribing and dosing.  

INHALE

Funded by the NIHR, the INHALE project is a multi-site project looking at molecular diagnostics tools for Hospital-Acquired and Ventilator-Associated Pneumonia in UK critical care, led at the CCM by Dr Vicky Enne.

Pneumonia is an infection of the lungs and is usually caused by bacteria, viruses or fungi. This infection, and the resulting inflammation, means that the lungs can't work properly. Antibiotics are critical to survival and are administered immediately at diagnosis, then refined after 2-3 days once the microbiology laboratory has grown and characterized the pathogen.

The use of molecular diagnostics potentially accelerate investigation, identifying pathogens and their antibiotic resistances within hours, not days, allowing early refinement of the patient's treatment. This should benefit both the patient, who will get the 'right' treatment more quickly and society, which can use antibiotics less wastefully. In a world threatened by increasing antibiotic resistance, these are potentially critical improvements…. But only if these systems work!

INHALE explores the potential of rapid molecular diagnostics in hospital-acquired and ventilator-associated pneumonia (HAP and VAP).

You can follow the INHALE Twitter account here.

PANDORA-ID-NET and the Networks of Excellence: capacity development and training

Apart from TB clinical trials, the CCM is also involved in other international partnerships, including PANDORA-ID-NET and the Networks of Excellence, mainly the Central African Network for Tuberculosis, HIV/AIDs and Malaria (CANTAM). Our role within these consortia is mainly to provide capacity development and training to our African sites, to enable them to plan, undertake and analyse their own research, which includes AMR.

The PANDORA-ID-NET consortia is comprised of 22 sites across 9 African and 4 European countries. It was awarded a €10 million grant funded by the European and Developing Countries Clinical Trials Partnership. PANDORA-ID-NET is a novel, multidisciplinary ‘One Health’ initiative that supports broad themes, including AMR, in Africa.

PANDORA-ID-NET’s mission is to develop and strengthen effective outbreak response capacities across all geographical regions in sub-Saharan Africa, in partnership with national governments and other international stakeholders. You can read more about the consortia on the PANDORA-ID-NET website.

CCM’s role within the network is to provide training and capacity development. Whilst much of this training has been conducted in-person, as a response to the COVID-19 pandemic, training has moved online. To facilitate this, we have set up a YouTube channel to provide access to training videos, as well as setting up a The Global Health Network (TGHN) hub page to provide our sites (and everyone) with access to training resources, documentation and webinar recordings.

PANDORA-ID-NET also has an active Twitter page which provides links to job opportunities, training and resources in Global Health, aimed at early career scientists in low and middle income countries.

CCM is part of CANTAM, a consortia of African and European sites, whose major aim is to build capacity in seven institutions in the three countries of Cameroon, Gabon and the Republic of Congo (RoC) for the conduct of clinical trials. CANTAM is also funded by the European and Developing Countries Clinical Trials Partnership. CCM’s main role is to provide support in the form of TB laboratory development and site visits. Dr Liã Bárbara Arruda and Dr Linzy Elton have conduced site visits in the Republic of Congo to assist with the setting up of a BSL3 laboratory facility for TB research at the Fondation Congolaise pour la Recherche Medicale (FCRM), as well as site visits to the Centre de recherche sur les filarioses et autres maladies tropicales (CRFilMT) and Laboratory for Tuberculosis Research and Pharmacology (LTRP) in Cameroon.