Superbugs in India

Last week, I had the exciting opportunity to travel to Delhi for a meeting on Antimicrobial Resistance. This was thanks to the Longitude Prize, a prize fund seeking emerging diagnostic technology that will help solve the antimicrobial resistance (AMR) crisis. The meeting was planned to coincide with the opening of an exhibition on Superbugs and involved individuals from the UK and India who are active in either developing diagnostics for AMR or who have first-hand experience of the problems caused by AMR in healthcare.

The setting was appropriate, as AMR poses a serious problem in India. Antibiotics are easily available without a prescription, with strong, 3rd generation antibiotics often being used to treat conditions they will have no effect on. Within healthcare, cultures are rarely undertaken and we heard that healthcare practitioners can feel under pressure to prescribe antibiotics, else the patient will simply obtain one from a different healthcare practitioner who can then claim to have “cured” the illness. This misuse of antibiotics, coupled with ideal conditions for spreading resistance such as poor sanitation and overuse in non-healthcare settings, has made India a hotbed for antimicrobial resistance.

However, India’s government seems aware of the scale of the problem and is making efforts to tackle the issue. The importance given to the opening of the Superbugs exhibition is evidence of this, with attendance by government ministers, and its engaging exhibits will hopefully increase public understanding of the issues as it tours the country. At the meeting, we heard about innovative efforts of Indian start-ups and Universities to tackle AMR, activities which the government is supporting through grant funding and support. In fact, India has the second largest number of companies entered into the Longitude Prize, after the UK. There was talk at the meeting of how to further these efforts, such as the setting up of a sample repository to aid research into antimicrobial resistance.

Superbugs exhibition, Delhi

Superbugs exhibition, Delhi

A rapid antimicrobial susceptibility test is clearly needed both in the India and around the world. However, in order to bring such technology to market, changes and pressures are needed at a governmental level. Such changes are underway thanks to the efforts of active governments and healthcare organisations such as the World Health Organisation advising and implementing policies to ensure that in future, antibiotics will be prescribed based on a test result. We discussed the fact that the true value of diagnostics must be recognised, work that is being carried out by the recently formed consortium ValueDx. A rapid AST will not only provide optimal treatment for the patient concerned, but has far more wide reaching benefits in tackling antimicrobial resistance and safeguarding important antibiotics for where they are most needed.

There is growing momentum towards the implementation of a rapid AST in healthcare and it is clearly needed sooner rather than later. It has been encouraging to see the attitude of governments such as India’s towards tackling AMR. Efforts must be continued as there is a critical need for a test such as our rapid AST to become adopted into the clinical pathway in order to tackle the urgent problem of antimicrobial resistance.

New patient test could tell GPs if infections are antibiotic resistant in under two hours

A new rapid patient test which could identify whether bacteria isolated from clinical samples are antibiotic resistant in under two hours is being trialled on a range of antibiotics commonly used to treat urinary tract infections (UTIs). If successful, the test could transform decision-making around antibiotic choice by helping inform the five million antibiotic prescriptions written each year in the UK for UTIs.

The threat of antibiotic resistant strains of infection is an escalating global health concern and improved targeting of antibiotics is crucial in reducing the spread of resistance. Current susceptibility testing methods typically take two to three days to arrive back with a GP from hospital laboratories because they rely on detecting bacterial growth.

Now, a new test developed by University of Bristol spin-out company Vitamica,  aims to deliver results from lab to GP in under two hours.

The rapid antimicrobial susceptibility test (AST), uses novel optical technology to see inside bacteria cells and detect tiny movements indicating whether the cells are alive or not and could be antibiotic resistant. Based on technology developed at Bristol’s School of Physics, the test is being trialled using bacteria derived from human UTI samples on a range of antibiotics commonly used to treat them.

Dr Paul Meakin, Vitamica’s CEO, said: “Bacteria treated with an effective antibiotic will show alterations in these movements after only a few minutes, meaning that we very quickly tell whether an antibiotic is suitable for prescribing to an individual patient.

“The exciting news is that we have produced promising results for a range of antibiotics commonly used to treat urinary infections.  We now need to extend this testing to bacteria in other samples such as blood where sepsis is a real threat to life.”

Vitamica has now announced a bid to raise further funding to continue development of this pioneering antimicrobial susceptibility test and is seeking to raise a further £1.5 million to extend the programme of research over the next two years. 

Andy Allars, non-executive chairman of Vitamica, added: “Vitamica’s progress since last year has been very promising. Completing our next investment round by the end of 2019 will ensure we maintain momentum and can move confidently towards our next strategic milestones.”

What next for rapid AST?

A recent visit to ECCMID (European Congress of Clinical Microbiology and Infectious Diseases ) in Amsterdam served to highlight a conundrum in the antimicrobial susceptibility testing  (AST) market.  On the one hand the market is served with hugely sophisticated, automated modular equipment, giving high throughput capability with time to result of 5-6 hours.  On the other hand, for local, ‘near patient’ AST there is virtually nothing available.  However, scratch the surface and there is an impressive amount of effort and resources being directed towards proving the capability of new technologies in this space.

There’s no doubt about it, the established players are chipping away at the time to result, increasing the throughput, and releasing new panels of antibiotics.  But the essential technology remains the same: waiting for the target organisms to show growth or not in the presence of an antibiotic.  High definition imaging, data analysis and futuristic levels of automation without question serve the high volume market extremely well.  But is this where the entire future focus of AST needs to be? 

In our collective efforts to deliver ever-better, more personalised patient care is a new approach to AST needed?  A smaller-scale, more rapid capability, able to provide clinically-relevant, diagnostically accurate and timely result in a manner not yet attainable?

If this is a worthwhile goal, then hope exists in abundance.  The breadth of technologies being explored is impressive – and importantly, is distinct from the existing mainstream ‘growth imaging’ approach.  Technologies ranging from microcalorimetry, though microcantilevers and on to sensing of volatiles – the shift is towards determination of metabolic activity rather then measuring ‘growth’ itself.  There is of course no guarantee any of these approaches will prove to have the characteristics required of a clinically-relevant rapid AST method, but it is encouraging that there is an active pipeline of methods under development. 

Like many of the exciting young companies at ECCMID, at Vitamica we believe that a rapid AST fit for use in near-patient settings has a role in future healthcare services.Indeed, it is difficult to see how the UK Government’s target for reducing antibiotic prescribing without diagnostic evidence of need or appropriateness can be met without small-scale, local AST provision. And we have not even touched on how the issue of unnecessary antibiotic use can be tackled in low-middle income countries. Is this where near-patient rapid AST will really come to the forefront?

Vitamica completes seed funding round

Vitamica, a University of Bristol spin-out company, has closed its initial seed funding round.  This is a major milestone for the company which is developing a rapid diagnostic to determine the susceptibility of bacteria to antibiotics.  The investment will support further development of the prototype instrument and the expansion of validation trials.

Vitamica is working in an area of global importance: slowing the rise of antimicrobial resistance (AMR) among infectious bacteria.   Among the tools required by healthcare professionals to help slow the spread of AMR are rapid diagnostic tests that will show which antibiotics are effective against a patient’s infection.  This challenge is being addressed by Vitamica with its innovative rapid test technology.

Research led by Dr Massimo Antognozzi at the University of Bristol has shown that measuring tiny internal movements within bacteria could help doctors prescribe antibiotics more effectively in future.  These internal vibrations cease when microbes are killed by antibiotics, giving rise to the possibility of a new diagnostic test to help guide prescribing decisions.

With the support of a grant from Innovate UK, the company is making good progress with laboratory tests to study the interaction between commonly used antibiotics and a range of bacteria.  Dr Paul Meakin, Vitamica’s Chief Executive notes that, ‘the seed investment will make a big difference in the speed and scale of our testing programme.  We are extremely grateful for the support of the University of Bristol Enterprise Fund, managed by Parkwalk, Wyvern Seed Fund and a group of individual investors.  In what has been an exciting process we have been assisted greatly by the University of Bristol Research and Enterprise team, and by VWV Llp in finalising the legal documents.’ 

‘Vitamica now has the resources to push on with planned trials and demonstrate the capability of the technology in helping the fight against AMR’, concludes Dr Charlotte Bermingham, Vitamica’s Chief Technology Officer.

The Science Behind the Technology

Charlotte Bermingham is CTO at Vitamica, a newly incorporated University of Bristol spin-out. The company is based on work pioneered by CSO, Dr Massimo Antognozzi, at the University of Bristol and was set up together with Innova Partnerships. She joins Anna Fleming to discuss their innovative technology and its applications in the fight against antibiotic resistance.

Could you explain Vitamica’s technology? What does it do?

It’s basically a really fast way to determine whether bacteria are alive and if they are affected by antibiotics. The standard approach right now is to incubate them overnight and see if they grow and multiply, but this takes a long time – usually upwards of a day. Our technology is a simple optical technique that we use to image tiny fluctuations in the bacterial cell envelope, which only happen when that cell is alive. If the bacterium is living, you see lots of shimmering fluctuations, and if it’s dead, it looks still.

What applications might it have?

The main application is susceptibility testing. If you get an infection, a sample might be sent to a hospital, where they test it against different antibiotics to see what it’s resistant and susceptible to. At the moment, as I mentioned, it takes around a day to incubate the bacteria, and then you need another day for susceptibility testing. Ideally, you would want to do that before prescribing an antibiotic because otherwise, you might have a patient going home with an ineffective drug. On the other hand, if you wait for the results before prescribing you risk patients deteriorating dramatically over the two days it takes to run the tests.

Our technology could substantially reduce the time needed for testing because it doesn’t rely on bacterial growth to tell if the bacteria have survived a round of treatments.

How rapid is it? Would you say we’re heading towards being able to run susceptibility testing before a GP prescribes?

Ideally, yes. Right now we can do it in tens of minutes rather than tens of hours. We’re not sure exactly how fast it will eventually be because at this stage I’m doing everything manually. We want to automate which will speed it up.

 

Charlotte working in the lab at the University of Bristol

How does your approach differ from those of your competitors?

Growing bacteria over hours is the standard approach; the vast majority of susceptibility tests are done that way. It’s possible to automate the process, which takes it down to about a day, but you still have to culture the bacteria, which is slow. Even with a system detecting very early stage growth, you’re limited by the speed at which bacteria will grow. There are molecular mechanisms which detect fragments of DNA indicative of a certain resistance mechanism, but they’re most useful when looking for something specific. If you’re looking for MRSA you know what DNA to search for, whereas if you just want to know whether something’s resistant but you don’t know what mechanisms it’s using, you’re essentially going in blind.

Did you set out to fill this niche in the market or did the technology develop first and then an application become apparent?

The essence of the technology has been developed by Massimo Antognozzi’s lab over several years, albeit originally for a different purpose – to detect very sensitive mechanical sensors for force measurements. A few years ago, the Kasas group in Lausanne discovered that bacteria exhibit nanoscale fluctuations when alive, in experiments using very sensitive mechanical sensors.

We saw this paper and decided to repeat the experiments with more sensitive sensors. Then we realised because of the way the optics are set up in our system we could directly see the nanoscale fluctuations of individual bacteria, removing the need for mechanical sensors at all, making it a much simpler and more robust technique. We investigated the effect further and found we can monitor bacteria in real-time to determine whether they are alive and how they respond to various drugs or not.

Can you explain that in more detail? Roughly how does the system work?

We illuminate a sample of bacteria with low power laser light, such that only its lower surface is in the light field. The bacterium scatters the light and we image this scattered light on a high sensitivity camera. The key to our imaging method is that extremely small movements in the bacterium can be picked up because they affect the scattered light and cause intensity changes on the camera. So the shimmering we see is actually physical movement in the outer layers of the individual bacteria.

 

Preparing a sample for analysis

How did you get from there to where you are now?

We always had antimicrobial susceptibility in mind as a possible application, because it is such a big current problem and it sparked off us investigating the fluctuations as interdisciplinary research projects. Then we joined SetSquared’s ICURe scheme, which involved talking to potential users of our technology to find out where and how it could be applied, and to make contacts in relevant areas. After a few research grants, we won a prize from the Longitude Foundation to further develop the technology specifically for susceptibility testing, followed by an Innovate UK grant, which prompted us to set up the company, using Unit DX for our business base. It’s conveniently near the University, which makes for a smooth transition from the University labs to the “real world” such as the lab space at Unit DX. We also won funding from the BrisSynBio 4-Day MBA course at Unit DX, which has been very helpful in getting up and running.

What are your plans now – how you see the technology being used?

We want to see it being used in hospital laboratories for susceptibility testing – and we have a year to prove that this is feasible. During this time we will secure investment to build more prototypes and begin trials with clinical samples.

Vitamica are preparing to launch their website this week. In the meantime, please keep an eye on their twitter page.