Resistance is futile

Antimicrobial resistance is one of the defining healthcare challenges of our time. As more bacteria become resistant to the drugs designed to treat them, we face the possibility of a return to a pre-antibiotic age of infectious disease.

Already, 700,000 deaths each year are being attributed to antimicrobial resistance, a figure that could surge to ten million by 2050 if the situation is not rectified. We are seeing the likes of drugresistant hospital infections (such as MRSA and C. difficile), multi-drugresistant pneumonia, and a barely treatable strain of gonorrhoea. This is clearly a complex problem, with no straightforward solution. However, one key piece of the puzzle will be minimising inappropriate antibiotic use. At present, antibiotics are prescribed far more than they ought to be. The Centers for Disease Control and Prevention (CDC) estimates that up to half of antibiotic use in humans, and much of antibiotic use in animals, is unnecessary and inappropriate. Improving ‘antibiotic stewardship’ – being responsible about how they’re taken – would make everyone safer.

Unfortunately, the issue is compounded by a lack of rapid diagnostic tests. Since traditional culture-based tests can take days to return results, antibiotics are often prescribed before the patient has a definitive diagnosis. Often, this means they end up taking antibiotics for nonbacterial infections.

As Dr Maria Daniela Angione, a researcher at Trinity College Dublin, explains, rapid detection is important for several reasons – not just for reducing antimicrobial resistance, but also for controlling the further spread of disease.

“The current tests to identify bacterial infection require cell cultures, or they are based on immunoassay tests or PCR, which are extremely time consuming and require access to specialist facilities,” she says. “In the primary care setting, the gold standard for urinary tract infections, for example, is still cell culture, which takes three days for the bacteria identification.”

Financial issues

While there are currently a few techniques available for rapidly detecting infections, their use is hampered by price.

“They are based on an antigen detection test, but they are quite expensive and require specialised equipment,” she says. “So there is a clear need for rapid detection of viruses and bacteria. Ideally this should be lowcost and applicable at the point of care, or without the assistance of highly trained medical personnel.”Angione is currently working on a device that could dramatically improve the situation. Specifically, she has developed an electronic chip that will be integrated into a sensing platform and used as a disposable diagnostic tool.

“I’m trying to develop a rapid and accurate test to detect and identify bacteria,” she explains. “The active layer of the chip is a molecularly engineered biopolymeric material with specific functionalities in a multiarray setting. It will enable clinicians to determine the appropriate antibiotic therapy in multiple infections and diseases, potentially improving the clinical outcomes for patients and reducing the inappropriate use of antibiotics.”

With a background in electronic device development, advanced materials development, and biomolecules, Angione is drawing on an interesting blend of expertise. The upshot is that her device is like nothing else on the market today. Incredibly, she thinks the tool could one day be available for purchase, enabling a DIY approach to diagnosis. “In ten years time, what I’d love is this technology to be available not only in the hospitals, not only to be used by doctors, but also available for everybody in the pharmacy,” she says. “Anyone who needs it could go and buy a disposable chip in the same way as we currently buy a pregnancy test, and would be able to use it at home. Then if needed, they could get an antibiotic prescription or an antiviral therapy prescribed by the GP.”

While this goal may sound like a pipe dream, it could become reality in the not-too-distant future. Angione’s work has already reached a good stage of maturity and is beginning to generate respectable commercial interest.

“We are running some preclinical trials, working in collaboration with clinicians and talking to many companies here in Ireland,” she says.

“The technology is performing quite well so far. While we were running the market feasibility study we got in touch with a few world-leading pharmaceutical companies and they expressed a huge interest.”

Of course, she does not anticipate that bringing the device to market will be an easy ride. Since it is so unlike the others out there, and the underlying technology is so disruptive, it may be harder to convince pharmaceutical companies of its competitiveness.

Break the walls down

On top of that, there are societal barriers to dismantle before the technology is widely accepted.

“The first barrier that I see is related to the patients – they may have some expectations when they go to the GP, and clinicians might be reluctant to update their traditional approach that has been in use for so many years,” she says. “Also, the pharmaceutical companies need to produce new antibiotics but they have little funding to invest in this area. So it’s not just the development of the technology that is a challenge.”All this said, she holds high hopes for the future, pointing out that the device’s advantages speak for themselves. As it uses integrated circuits and low-cost electronic components, it is not only sensitive but cheap and easy to make. This means it could be suitable for use in remote, low-income settings – not to mention available in the pharmacy.

“It could facilitate diagnosis and enable a targeted therapeutic plan at an early stage of bacterial or viral infection, reducing the healthcare cost,” Angione explains.

In the short term, she is hoping to work together with industry and clinicians to source more funding.

“Of course it’s a long process, but there are a few opportunities so I’m hoping to develop tools to validate the technology, bringing it to the market as soon as possible,” she says. “We hope that growing interest will generate the support required to a point of commercialisation.”

Developing the perfect rapid diagnostic test

The perfect new diagnostic would answer four key questions, which could inform diagnosis and treatment with the correct antibiotic, before any antibiotics are given.

Is the infection causing the illness bacterial or viral?

A diagnostic test able to indicate whether a patient has a bacterial infection could dramatically reduce unnecessary antibiotic prescription for viral infections, particularly in the primary care setting. In most countries, around 80% of antibiotics are used in the community, rather than the hospital, with around half of this use thought to be inappropriate.

If bacterial, what type of bacteria is causing the infection?

A diagnostic that could not only detect a bacterial infection, but also quickly confirm the type of bacteria causing it, would allow doctors to tailor treatment, and potentially decrease reliance on broad-spectrum drugs.

Are the bacteria that are causing the infection resistant to available antibiotics?

Diagnostic tests that detect resistance can direct doctors away from potentially inappropriate antibiotics and towards those more likely to be effective. In acute settings, ruling out even one or two therapies can save a patient’s life.

Are the bacteria that are causing the infection susceptible to existing drugs?

A diagnostic that could rapidly measure the susceptibility of the infecting bacteria to existing antibiotics would be even more useful than one that detects resistance, because it gives the doctor greater confidence that the drug they choose will be effective. This would help to minimise inappropriate use of antibiotics.

There is a need for diagnostics that can be deployed widely throughout both the developed and developing world. These might be used at home, or in pharmacies, primary care clinics or hospitals. These diagnostics have three important functions.

Firstly, they will improve patient treatment by getting the right drug to the right patient quickly. Secondly, they will allow existing drugs to go further and last longer. Thirdly, they may reduce the need to develop new ‘broad-spectrum’ drugs, which are often the hardest drugs to find.

In order to achieve these aims, it is necessary to have diagnostics available in the right settings, which may differ by country as well as ensuring that financial rewards, culture and systems support their use.

Ultimately, what is needed is high-quality, affordable rapid diagnostics that can be rolled out as widely as possible.