Smartphones at the ready - antibiotic-resistant microbes6 April 2017
To fight the looming threat of antibiotic-resistant microbes, an interdisciplinary team of engineering and pharmaceutical researchers at the University of California, Los Angeles, have invented a smartphone attachment that can identify bacteria’s resistance levels without the need for trained lab technicians. Dr Aydogan Ozcan, leading professor at the bio and nanophotonics laboratory at the electrical engineering and bioengineering department, speaks to Bradford Keen about how this device will be a vital tool for resource-deprived areas.
Jeevan Chaudhary braces against the chill as he trudges through the snow with his overladen shopping cart. An outbreak of an unrecognisable but highly contagious flu is tearing through the US, racking up a body count worse than any war or natural disaster hitherto seen. Chaudhary is stocking up supplies for the long wait to an unpredictable end.
Fortunately, this worrying scenario is contained within the dystopian future of Emily St John Mandel’s novel, Station Eleven. However, medical experts around the globe warn that something similar could soon become reality.
Last year, Dame Sally Davies, chief medical officer in the UK, cautioned that the “antibiotic apocalypse” may have already arrived, with 50,000 people dying in Europe and the US every year from infections previously treatable with antibiotics. The Review on Antimicrobial Resistance issued a report with the number of deaths set to climb to the millions by 2050.
A major problem is that pharma companies are not producing new antibiotics. The US Food and Drug Administration (FDA) reported in 2015 that it has approved only nine new antibiotics in the past decade.
In an article in Pharmaceutical Journal, a reason cited for this poor growth rate was that pharma companies do not regard antibiotics as having a worthwhile return on investment. This is especially so when antibiotics are meant to be used only for the most dire bacterial infections and for a short treatment period. And, all the while, bacteria are growing immune to existing antibiotics. In January 2017, for instance, a woman in the US who had previously travelled to India died from what doctors called a ‘superbug’ resistant to 26 different types of antibiotics.
“I think this is the harbinger of future trouble,” said Dr James Johnson, a professor of infectious diseases medicine at the University of Minnesota, of the death, in an interview with STAT News.
Dr Aydogan Ozcan from the University of California, Los Angeles (UCLA) shares this grim view: “Antimicrobial-resistant bacteria are posing a severe threat to global public health. In particular, they are becoming more common in bacterial pathogens responsible for high-mortality diseases such as pneumonia, diarrhoea and sepsis. If we don’t work on it globally, it will be extremely difficult to fight, since we might lose almost all of our first-line antibiotics.”
There’s an app for that
While Ozcan is not developing antibiotics, he has been wielding a sword in this mammoth battle for about ten years now. Leading professor at the bio and nanophotonics laboratory at the electrical engineering and bioengineering department at UCLA, and professor with the Howard Hughes Medical Institute, Ozcan and his team recently designed an automated diagnostic-test reader that can be used with a smartphone to conduct antimicrobial susceptibility testing (AST).
The 3D-printed portable attachment holds a 96-well testing plate illuminated from above by LEDs, while the smartphone’s camera senses any changes in light transmission in each well, which contain a different dose selected from a range of antibiotics. These images are sent to a server, where they are tested for antimicrobial susceptibility.
The lowest concentration of antibiotic that prevented the growth of bacteria is used to track drug resistance. The microbe is either susceptible or resistant to antibiotics, which guides treatment.
The results arrive in about a minute, and they’re not only fast but accurate, too.
“Our results showed that the mobile-phone-based reader meets the FDA-defined criteria for laboratory testing, with a detection accuracy of 98.20%,” Ozcan says. Minimum inhibitory concentration showed an accuracy of 95.12% and a drug-susceptibility interpretation accuracy of 99.23%.
The power lies in the design’s simplicity, as it will render obsolete the need for trained diagnosticians and expensive laboratories to test bacteria’s susceptibility. The obvious advantages are significant, Ozcan says: “We believe this mobile reader could reduce the cost barrier for routine testing, and assist in tracking bacterial resistance globally.”
The handheld AST reader is about 195×98×100mm and weighs 620g. In a study published in Nature, co-authored by Ozcan, contributors estimated that the cost of all the components required for the device totalled about $100. An automated AST platform, on the other hand, costs about $30,000, and is heavier and bulkier. However, the writers say that the more expensive platform, while not mobile in the same sense as the handheld reader, is able to perform more AST-related functions such as the Kirby-Bauer Disk diffusion interpretation.
Ozcan’s breakthrough is certainly significant. The Global Web Index reported in 2016 that the average household has 3.64 connected devices, with the wealthier households in possession of one device more than the lowest quartile. The digital revolution has been spinning for quite some time and it shows no signs of slowing.
“The rapid improvements of the hardware, software and high-end imaging and sensing technologies embedded in our phones transform them into cost-effective and extremely powerful platforms to run biomedical tests, for example, and perform scientific measurements that would normally require advanced laboratory instruments.
“This continuing trend will help us transform how medicine, engineering and sciences are practised and taught globally,” Ozcan says.
Mobile phones allow sensing and diagnostic measurements and tests in telemedicine, mobile health, point-of-care and environmental applications.
“I was lucky to realise this transformation early on,” Ozcan says, “and invested intellectually a significant portion of my lab on this topic. In the past ten years, we have made major contributions to the field.”
Ozcan’s department could not have achieved this impressive result alone. He says it was “extremely important” for the interdisciplinary skill sets of multiple teams to join forces.
“In addition to my lab, the labs of Omai Garner, an assistant professor of pathology and laboratory medicine in the health sciences department, and Dino Di Carlo, a professor of bioengineering in the engineering department, were also in this interdisciplinary project, taking it all the way from solid engineering to clinical testing against FDA-approved gold standard approaches.”
The number of deaths from antibiotic-resistant microbes in places such as the US and Europe, which have plentiful resources, is troubling. Poorer nations are affected more severely with a lack of personnel, laboratories and equipment to perform AST, making it harder to combat the spread of these organisms.
“Our new smartphone-based technology can help put laboratory-quality testing into much wider adoption,” Ozcan says.
A limitation of this technology, however, is its reliance on a rather expensive machine to prepare the 96-well microtiter plate, which is used to deposit drug concentrations in each well and fill them with microbes that need testing.
“Regardless,” Ozcan says, “our technology is especially useful in resource-limited settings, given its ability to remove the need for a trained diagnostician, enabling local technicians to conduct high-throughput AST. In fact, clinical microbiology is rapidly progressing toward automation.
“Multiple platforms are available for automated organism identification, including smart incubators and proteomic identification.”
Ozcan says his team’s results and the demonstrated platform are congruent with the future of clinical microbiology diagnostic labs, where the gold standard for AST testing and broth microdilution can be automated for turbidity reading and antibiotic prescription.
Ozcan has co-founded a mobile diagnostics company, Cellmic, and is in the process of licensing the handheld reader with UCLA’s Office of Technology Licensing.
“We are hopeful that it might be a product in the market in the next two years,” he says.
Paired with the smartphone’s wireless connectivity and digital record-keeping ability, the hope is that this platform can enable widespread and simple collection of drug-resistance profiles for spatio-temporal tracking, which Ozcan says could be useful for isolating and eliminating drug-resistant strains of harmful microbes.
While humanity is not yet in such a desperate bind as Station Eleven’s Jeevan Chaudhary, the future of antibiotic resistance is uncertain. Thankfully, innovative thinking and designs such as UCLA’s handheld AST reader are helping the fight against bacterial resistance, saving money, resources and, most importantly, lives.
New detective device
Led by Dr Thomas Thundat, a professor in the department of chemical and materials engineering at the University of Alberta, an interdisciplinary team has designed a device to be used in clinical laboratories for rapid detection of harmful bacteria and its resistance to antibiotics.
A bimaterial cantilever (a plank that looks like a diving board), with an embedded microfluidic channel about 25 times smaller than the width of a hair, changes mass and bends when bacteria is detected in the sample. The channel’s internal surfaces are chemically functionalised with receptors to capture the bacteria. Once captured, different antibiotics are added to the samples and any changes to the cantilever are monitored.
Bacterial adsorption – which refers to the adhesion of atoms, ions or molecules to a surface – is what is responsible for changes in the cantilever’s resonance frequency (mass) and adsorption stress (bending).
What makes the device so conclusive is its third means of detection. Shining infrared light on to the bacteria will cause the light to vibrate and generate heat, providing a nanomechanical infrared spectrum for selective identification.
The device provides greater sensitivity, selectivity and stability than other methods, and can be analysed in real time through nanotechnology. Existing laboratory methods require about 24 hours for results.
Previous cantilever methods have been used to detect harmful bacteria, but they have been subject to quality issues due to liquid damping. Improving the design to include a microfluidic channel within the cantilever reduces the liquid flow and the resultant signal-to-noise ratio. The cantilever, with liquid inside of it, can be excited in a vacuum, which improves mass resolution.
Thundat told Phys.org that the device can be used not only to quickly identify harmful bacteria, but also to test tiny fluid sample sizes millions of times smaller than a raindrop.
Thundat says his work is “purely basic and does not involve clinical samples”.
“At this time, we are demonstrating the technology,” he explains. “Eventually, we will do clinical samples, once we establish collaboration with clinicians.”
It may be too early to call it just yet, but breakthroughs such as the microfluidic cantilever and the AST reader at least give hope to patients and healthcare providers that more effective treatment options will be found, while saving vital time.