Study findings could lead to new biomarker targets for clinical laboratories working to identify AMR bacteria
Reducing and managing antimicrobial resistance (AMR) is a major goal of researchers and health systems across the globe. And it is the job of microbiologists and clinical laboratories to identify microbes that are AMR and those which are not to guide physicians as to the most appropriate therapies for patients with bacterial infections.
“AMR is a silent pandemic of much greater risk to society than COVID-19. In addition to 10 million deaths per year by 2050, the WHO estimates AMR will cost the global economy $100 trillion if we can’t find a way to combat antibiotic failure,” Timothy Barnett, PhD (above), Deputy Director and head of the Strep A Pathogenesis and Diagnostics team at Wesfarmers Centre of Vaccines and Infectious Diseases, told News Medical. Additional research may provide new targets for clinical laboratories tasked with identifying antimicrobial resistant bacteria. (Photo copyright: University of Western Australia.)
Rendering an Antibiotic Ineffective
According to the University of Oxford, about 1.2 million people died worldwide in 2019 due to AMR, and antimicrobial-resistant infections played a role in as many as 4.95 million deaths that same year. The World Health Organization (WHO) declared AMR one of the top ten global public health threats facing humanity.
While investigating antibiotic sensitivity of Group A Streptococcus—a potentially deadly bacteria often detected on the skin and in the throat—the Australian researchers uncovered a mechanism that enabled bacteria to absorb nutrients from their human host and evade the antibiotic sulfamethoxazole, a commonly-prescribed treatment for Group A Strep.
“Bacteria need to make their own folates to grow and, in turn, cause disease. Some antibiotics work by blocking this folate production to stop bacteria growing and treat the infection,” Timothy Barnett, PhD, Deputy Director of the Wesfarmers Centre of Vaccines and Infectious Diseases and head of the Strep A Pathogenesis and Diagnostics team, told News Medical.
“When looking at an antibiotic commonly prescribed to treat Group A Strep skin infections, we found a mechanism of resistance where, for the first time ever, the bacteria demonstrated the ability to take folates directly from its human host when blocked from producing their own. This makes the antibiotic ineffective and the infection would likely worsen when the patient should be getting better,” he added.
According to their study, the researchers identified an energy-coupling (ECF) factor transporter S component gene that allows Group A Strep to acquire extracellular reduced folate compounds that likely “expands the substrate specificity of an endogenous ECF transporter to acquire reduced folate compounds directly from the host, thereby bypassing the inhibition of folate biosynthesis by sulfamethoxazole.”
The study indicates that this new form of antibiotic resistance is indistinguishable under traditional testing used in microbiology and clinical laboratories, which in turn makes it difficult for clinicians to prescribe effective antibiotics to fight an infection.
Understanding AMR before It Is Too Late
The research suggests that understanding AMR is more complicated and intricate than previously thought. Barnett and his team believe their discovery is just the “tip of the iceberg” and that it will prove to be a far-reaching issue across other bacterial pathogens in addition to Group A Strep.
“Without antibiotics, we face a world where there will be no way to stop deadly infections, cancer patients won’t be able to have chemotherapy and people won’t have access to have life-saving surgeries,” Barnett told News Medical. “In order to preserve the long-term efficacy of antibiotics, we need to further identify and understand new mechanisms of antibiotic resistance, which will aid in the discovery of new antibiotics and allow us to monitor AMR as it arises.”
More research and clinical studies are needed before this discovery can become technology that clinical laboratories can use to test if microbes are AMR. The scientists at Wesfarmers Centre of Vaccines and Infectious Diseases are now developing testing methods to detect the presence of the antibiotic resistant mechanism and determine the best treatment options.
“It is vital we stay one step ahead of the challenges of AMR and, as researchers, we should continue to explore how resistance develops in pathogens and design rapid accurate diagnostic methods and therapeutics,” Kalindu Rodrigo, a PhD student in the Barnett lab and one of the authors of the study told News Medical. “On the other hand, equal efforts should be taken at all levels of the society including patients, health professionals, and policymakers to help reduce the impacts of AMR.”
Forte realized that the method of collecting the specimens was largely to blame, with the required “start-aim-start” midstream collection technique required by traditional polypropylene specimen cups at the root of the problem.
Healthcare professionals, whether working in clinical laboratories and anatomic pathology groups or hospitals and out-patient clinics, often are among the first to notice when gaps in the quality or integrity of medical laboratory test results exist. However, in this case, it was a general practice physician rather than a medical laboratorian or in vitro diagnostics (IVD) manufacturer that set out to solve the problem of poor urine specimen collection, which The Daily Telegraphreports results in 73% of the 65-million urine specimens collected annually by the NHS being unreliable. That’s 47.5-million unreliable medical laboratory specimens collected and tested yearly in the United Kingdom.
Accurate Urine Collection Brings Billions in Savings
Vincent Forte concluded that the quality gap in urine specimen collection for his female patients was preventing accurate first-time analysis, diagnosis, and targeted treatment. In 2001, he set out to re-engineer urine collection cups. His first design—“a simple flushable paper funnel, which rejected first-flow urine, collected midstream, and ejected the remainder”—established the underlying design principle behind the patented Peezy Midstream product, Giovanna Forte stated in the RSA blog post.
Giovanna Forte noted that the first version of the device, marketed in 2010, was a “funnel formed by flat-sheet film, with a unique container-acceptor,” with overflow duct and incorporating a compressed sponge that rejects the first 8-10 ml of urine. While the product was well received, Forte says the selling price was too expensive to meet the NHS requirement for cost savings. By 2012, the product evolved into an injected-modeled design, which cut production costs by 50%. By 2014, the ergonomically designed funnel was improved to incorporate the two most common urine collection tubes.
In a Forte Medical presentation, Giovanna Forte predicted that accurate urine collection could result in a £1.2-billion (US $1.56-billion) savings to the NHS.
A Design Week article described the testing process for developing the midstream specimen collection device as “similar to launching a website in beta,” with initial testing resulting in changes such as the creation of a flatter, rounder handle to make the product easier to hold.
“Within the NHS, I was allowed to attend clinics where evaluations were taking place and speak directly to the patients. This allowed me to find out what they thought of everything from instructions for use to the collection system itself,” Vincent Forte stated in the Design Week article. “All the information was fed back into our design engineers, who proposed an improved product made more simply at a lower price.”
The patented Peezy Midstream urine collection system rejects the first (often contaminated) 8-10 ml of urine, isolating and capturing the important midstream and rejecting the rest of the urine into the toilet. The product claims 98.5% accurate urine specimen collection and would improve the accuracy and reliability of the medical laboratory tests performed on urine samples collected with this device. (Photo copyright: Forte Medical.)
1. Peezy Midstream PE40, which collects urine into a traditional 30ml universal container; and
2. Peezy Midstream PE50, which collects urine into a lab-friendly 10ml primary tube designed to fit in laboratory analyzers.
“This simple solution … took 10 years and £2.6-million [US $3.38-million] to get right. It was achieved not by a multinational with deep pockets, but by a startup funded largely by friends, family, and a handful of angel investors, along with the goodwill of design and manufacturing partners,” Vincent Forte stated in the RSA blog post.
Specimen Capture Methods Lead to Careless Infection Control
“Thrusting one’s hands willingly into our own urine is hardly common practice. That we are expected to do so in order to capture an important specimen essential to diagnosis hardly chimes with the concept of modern medicine and leads to pretty shabby infection control by any standards,” she stated.
Still to come are clinical trials and papers in peer-reviewed medical journals that support the function of this medical device to improve patient care. It is notable, though, that the National Health System in the UK is collaborating with Forte Medical in certain ways to determine how the device can improve patient care. Dark Daily would like to hear from any medical laboratories in the UK and USA that are using this device when urine specimens are collected.