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Tuberculosis: MMM is helping the UK lead the world in getting new DNA technologies ready for patient care

Our scientists have led an international team to show we can diagnose patients faster, cheaper and more effectively by analysing the DNA of the bacteria infecting patients.

DNA analysis technology has been evolving rapidly over the last 20 years, but this is the first time the technique has been used on such a large scale, in a busy, real-life setting.

Researchers all over the world went head-to-head with the ‘traditional’ methods. They showed that DNA analysis was able to detect Tuberculosis and predict which antibiotics should be used up to eight times faster, so patients could receive the right treatment sooner. They were also able to detect and respond to potential outbreaks more rapidly to prevent infections spreading. Surprisingly for such a cutting-edge technique- it also cost less.

MMM is proud to show that world-leading UK-based science can lead to improvements in the treatment of patients.

Dr. Louise Pankhurst, who wrote the report published in Lancet Infectious Diseases, said:
“This is a really exciting time to be working in infectious disease research. The UK is poised to become the first country in the world to replace traditional tuberculosis diagnosis with whole genome sequencing. Our study has shown how this will dramatically speed up the time taken to diagnose TB, helping patients be placed on the most effective treatment as soon as possible and reducing the risk of disease transmission.”

A full press release is  available from the University of Oxford: Scientists use DNA technology to diagnose cases of TB faster. Also available via  Public Health England and Oxford University Hospitals NHS Foundation Trust.

You can read more about our work on TB:

Global team aims for faster TB diagnosis

Teamwork: how we work together to study TB 

and previous publications on the use of Whole Genome Sequencing to study TB

Walker et al, Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study, Lancet Infectious Diseases 2015

Waler et al, Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study, Lancet Infectious Diseases 2013

 

Pneumonia is increasing – and we need to plan for it

Why are diagnoses of pneumonia increasing?  This is the question that our Research Statistician, Phuong Quan, (and other scientists from MMM), set out to answer in a paper published this week.

We looked at the hospital database of all people admitted to hospital, and found that admissions for pneumonia had almost tripled over the space of 15 years, an alarming increase. We started investigating what was going on.

Was it because we are now diagnosing pneumonia differently?

When a patient comes to hospital with symptoms of a chest infection, there are lots of things we can call it.  ‘Pneumonia’ means that there is irritation and infection in the lungs, to the point where we can see it on a chest xray. Like this:

 

If the patient has all the symptoms of an chest infection (such as cough, fever, and increased amounts sputum) but has a clear chest on the xray and on listening, we call this a ‘lower respiratory tract infection’ or LRTI. We can also call it ‘bronchitis’. This means the airways (the small tubes that carry air to the lungs) may be infected and irritated, but the lungs themselves are ok.  If someone already has a condition known as Chronic Obstructive Pulmonary Disease (COPD), or they have asthma, then we tend to call these chest infections, ‘exacerbations of COPD’ or ‘exacerbations of asthma’.

We wondered whether Doctors had started diagnosing more pneumonia, where 10 years ago it would have been called bronchitis, or LRTI. If this were the case, we’d expect a decrease in other diagnoses to correspond with the increase in pneumonia. However we found that admissions for all respiratory infections were going up. Whilst we couldn’t rule out some changes in diagnosis, this clearly wasn’t the sole cause.

Was it because GPs were just referring more patients to hospital?

There has been a lot of focus in recent years on an increasing reliance on hospital care. There is a perception that GPs are referring more people to hospital who might have otherwise have been treated at home. Others are concerned that the NHS 111 system means that more people are advised to go to hospital. If this were happening, we’d expect more, relatively well, people to be coming to hospital.

 

We looked how unwell people were when they came to hospital with pneumonia. Using the results of blood tests to look at the immune response, and  other markers such as kidney function, actually we found very little change over the years. It didn’t look like the increase in pneumonia was just due to an increase in less-sick patients either.

What else could it be?

We know that over the years, due to advances in living conditions, healthcare and lifestyles, we have an increasingly ageing population, and it is older adults who are at most risk of pneumonia. We know that we’ve seen a large increase in overall number of people come to hospital as well. However when we looked, we couldn’t attribute this three-fold increase in pneumonia admissions to these.

Are the bugs changing? 

We did notice that the bugs causing pneumonia appeared to be changing. Whilst the percentage of cases of pneumonia due to bacteria like Streptococcus stayed much the same, pneumonia due to the ‘Enterobacteriaceae’ family (E. coli, Klebsiella and Enterobacter for instance) was steadily increasing.  This wasn’t enough to explain the total increase, but it does raise the question of whether these bacteria are becoming more able to cause infections in humans, or whether something else is happening. We have researchers looking into this now. This is concerning because the Enterobacteriaceae family are more difficult to treat than Streptococci, as they are resistant to more antibiotics. If we are seeing more difficult to treat infections, we may be forced to use stronger antibiotics, and patients may not do as well.

In summary, it was apparent that there wasn’t a simple explanation for the increase in pneumonia. It’s not just changing names, it’s not just risk-averse GPs, and it’s not just an ageing population.  It appears there is a genuine increase in pneumonia in our region. This has been reported before, but never with this level of detailed investigation. 

Whilst we’ll continue looking to find out the cause, the main take home message of the paper is that pneumonia is likely to continue to increase. More patients with pneumonia means more demands on hospital services, more antibiotics being given out, and more patients needing time off, or social care support, as they recover.  We, and the healthcare service as a whole, needs to prepare for this.

 

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The original paper is available on open access here: http://thorax.bmj.com/content/early/2016/02/17/thoraxjnl-2015-207688.short?rss=1

 This research has been possible with use of the Infections in Oxford Research Database (IORD) – you can read more about it here.

 This work was supported by the National Institute for Health Research Oxford Biomedical Research Centre and the Oxford NIHR Health Protection Research Unit, a NIHR Research Methods Fellowship  and a Medical Research Council UK Clinical Research Training Fellowship.

Images: pixabay and pneumonia xray- wikipedia

Superbugs sharing antibiotic ‘bulletproof armor’

How do superbugs learn to be ‘antibiotic bulletproof’? 

Our researchers have recently been working with scientists from the USA to study superbug transmission. Actually, they studied the emergence of lots of different superbugs within one hospital over five years.

What was strange was that they found many different types of bacteria all sharing similar genetic ‘armor’. If antibiotics are like bullets, this was armor that could prevent even our strongest, last-line effective antibiotics (Carbapenems) from getting through. These bacteria, known as CPE (carbapenemase-producing Enterobacteriaceae) all knew how to produce their own, specific ‘bacterial armor’, which was rendering our last-line antibiotics ineffective. This meant that patients had to be treated with older, more toxic, or less effective antibiotics, and didn’t do as well. We needed to understand how this was happening.

We knew from lots of other studies that it can take a long time (in terms of bacterial lifetimes) for bacteria to develop entirely new armor – so surely they didn’t all learn to create this independently?

Our researchers studied the DNA of 281 different bacteria. Like humans, bacteria contain DNA – a complete instruction manual on ‘how to be a bacteria’.  Unlike humans, they can also carry extra small loops of genetic information we call plasmids – DNA ‘booklets’ containing handy (but not essential) information, like how to scavenge extra nutrients, or inactivate antibiotics. Previous work has shown that bacteria can share these booklets between one another to transfer useful information.

 

 

What our researchers found was that the ‘bacterial armor’ recipe for bulletproof material (contained on a gene called “KPC”) was being shared via these plasmid ‘booklets’. They also found that the bacteria were also effectively ripping out the page with the armor recipe and putting it in new plasmid ‘booklets’, and sharing these as well.  The researchers compared this to ‘russian dolls’ – recipe within page within booklet within bacteria…all being shared around.  What was also remarkable was that completely different species of bacteria within the same family could all share the KPC ‘bulletproof recipe’  between each other on plasmid booklets. The rate at which these bacteria shared information around in this way was far higher than had been expected, or seen, before.

 

The family of bacteria (Enterobacteriaceae)  sharing this information then caused difficult-to-treat, antibiotic-resistant blood, urine and chest infections. In fact, this family of bacteria is the leading cause of bloodstream infections in the world. They also live harmlessly around us, and play important roles in the ecosystem, in the guts, and human health. Many scientists believe they pose the greatest threat to human health in the near future, because they can spread easily, infect almost anyone, and they are becoming untreatable much faster than other bacteria.

This study helps us understand how genetically well-equipped bacteria are developing and spreading new armor faster than we can come up with new antibiotic ‘weapons’. Bacteria can effectively talk to one another, sharing information, adapting it, and sharing it again.  It tells us we need to find out where these bacteria are sharing information and spreading, and prevent this. We need rigorous hygiene and monitoring, not just of patients, but the environment around them as well.

We know doctors, patients and the farm industry all overuse antibiotics.   This research tells us in the strongest, simplest terms we need to learn to use less – otherwise very soon there will be no effective antibiotics left. If you don’t fire antibiotic bullets, bacteria don’t need to learn to make bulletproof armor.


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More Information:

Update 10/4/16 :  The full paper is at: http://aac.asm.org/lens/aac/60/6/3767#figures

The preprint (released at the time of this article)  http://biorxiv.org/content/early/2015/12/02/033522.full-text.pdf+html

A previous published study of this outbreak is also available: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25561339/

Read about another University of Oxford study on plasmids and antibiotic resistance:  http://www.ox.ac.uk/news/science-blog/puzzle-plasmids

This publication presents independent research commissioned by the Health Innovation  Challenge Fund, a parallel funding partnership between the Department of Health and Wellcome Trust, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford, and NIHR Oxford Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance.

Key Researchers:

Anna Sheppard,  Bioinformatician, who does the complex DNA analysis and has written the publication.

Nicole  Stoesser, Doctor and Scientist from the John Radcliffe Hospital, Oxford, who extracted the DNA from many of the samples and analysed the data

Amy Mathers, Doctor and Scientist from Virginia, USA, who collected the samples and leads the Infection Prevention and Control Team

For any questions, please contact dona.foster@ndm.ox.ac.uk

 All images: www.pixabay.com, no attribution and free for commercial/noncommercial use

The story behind the story

The Team MMM Story represents just a small part of the huge amount of work that goes on, and the many, many different people who contribute to what we do.

We have strived for scientific accuracy where possible, (though admittedly DNA doesn’t always turn out pink). Whilst we have nominated particular groups for particular steps, in reality many people are involved at multiple stages- our Research Assistants analyse data, our Post Docs do Bioinformatics…

If you want to read the Journal articles which inspired the story here they are:

Sequencing bacterial genomes can be used to study Tuberculosis outbreaks:

Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007-12, with whole pathogen genome sequences: an observational study. Lancet Respir Med. 2014

Genome sequences can be used to predict antibiotic resistance:

Prediction of Staphylococcus aureus antimicrobial resistance by whole-genome sequencing. J Clin Microbiol. 2014

Predicting antimicrobial susceptibilities for Escherichia coli and Klebsiella pneumoniae isolates using whole genomic sequence data. J Antimicrob Chemother. 2013

Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study. 2015

The Team we’ve portrayed is the Modernising Medical Microbiology team based in Oxford – the Crook/Peto Research Group, part of the Nuffield Department of Medicine in the University of Oxford. We’re also part of a larger collaboration with groups in Birmingham, Brighton and Leeds, who work to develop experimental science into techniques that can improve the treatment of patients with infections.

Originally we wanted to show our results being used to directly inform patient care, however this work is cutting edge, and at this moment in time our results are not being used directly by the Doctors looking after patients. However they are reported to Public Health England, who use the information to help them look for sources of Tuberculosis spread. Our research group has been at the forefront of turning this technique into a valuable tool for use in patient care. Together with Researchers in Birmingham, it will be trialled by the Department of Health

Some exciting work is coming out of our pilot suggesting we will be able to use genomics to predict antibiotic resistance in Tuberculosis. Watch this space!

Our original plans also had our group leads and heads in the middle of everything, supporting every step as 10-armed octopuses… They are involved every step of the way, from discussing what type of chemicals to use to extract DNA, to how phylogenetic trees are put together, to how we securely store terabytes of genomic data… Team MMM relies on their continuous awesomeness to function.

Even making the comic strip was a teamwork exercise in itself. Once the idea was put out, our Assistant Lab Manager, Ali Vaughan recruited a group of interested individuals to help with the project. A number of ideas were brainstormed, together with a narrative, and we decided upon the comic-book narrative. Ali managed to persuade, cajole and guide each group into posing for a picture, with varying degrees of enthusiasm… Our scientists acted as a reality-and-scientific-accuracy check throughout, and the whole thing was put together by a couple of our team, Amy Mason and Nicola Fawcett, using nothing more fancy than standard iPhone Apps and Microsoft Office tools.

The main message we wanted to portray is how many different disciplines are involved in the work we do. Genomics at a small scale is difficult enough. However if you’ll be responsible for sequencing hundreds of samples a month, storing all the data securely, and conducting the analysis, you really need a well-oiled team working together.

The team represented can be found in the Oxford Staff section (in no particular order) lead by:

Group Heads and PIs:
Derrick Crook
Tim Peto

Senior Statistician and unofficial Head-of-most-things:
Sarah Walker

And there will be many, many more people involved who we haven’t directly mentioned here, but without whom our work wouldn’t be possible.

We hope you enjoy it! Any feedback or discussion, please contact or tweet us: @modmedmicro or via this website

The MMM Team

 

-originally published 2014, updated Dec2015

Mykrobe: A laptop program to predict response to antibiotics

Scientists working with Modernising Medical Microbiology have developed a new computer program to help keep antibiotics effective.

The program: Mykrobe Predictor , can run on a laptop, and in a few minutes  can analyse bacterial DNA from a patient’s infection and predict which antibiotics will work.

They have released the software to download free at: http://www.mykrobe.com

The software is being evaluated by Modernising Medical Microbiology researchers in Brighton, Leeds and Oxford, to see in three UK hospitals to see whether it could help speed up diagnosis of drug-resistant infections and enable doctors to better target the prescription of antibiotics.

The  software, developed by Phelim Bradley, Dr Zamin Iqbal and colleagues at the Wellcome Trust Centre for Human Genetics, University of Oxford, runs on a standard laptop or tablet without the need for any specialist expertise. It can analyse the entire genetic code of a bacterium in under three minutes, once a bacterial sample has been cultured and its DNA has been sequenced.

The study, published this week in  Nature Communications, showed that it can accurately predict antibiotic resistance in both Staphylococcus Aureus (including MRSA) and tuberculosis (TB).

If this software can be combined with quick methods of extracting DNA from the bacteria causing infections, it could potentially lead to Doctors accurately diagnosing infections within hours of patients becoming unwell, meaning patients get the right treatment faster.

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Further Information:

You can learn more about how our researchers are working on speeding up the process of DNA extraction here: MMM Researcher Luke Anson on Extracting Bacterial DNA

mykrobe

Click here to see  a video of MyKrobe in action, analysing Staphylococcus Aureus DNA

The Wellcome Trust press Release can be found here

The full research paper is available here

The Iqbal Lab blog is here