Singulex - Difficile measures

Clostridium difficile infection (CDI) is a type of bacteria that infects the bowels and causes a wide range of symptoms, including fever, loss of appetite, a rapid heart rate, abdominal cramping, nausea and diarrhoea. The disease most commonly affects people who have recently taken a course of antibiotics in a hospital or care-home environment. What's more, CDI is difficult to detect accurately without testing, precisely because of the number of ways the illness can manifest.

Medical company Singulex is now claiming a significant breakthrough in the fight against it. The business is pitching its investigational Singulex Clarity C. diff toxins A/B immunoassay as a way to perform rapid ultrasensitive precision measurement of specifically chosen biomarkers, which quickly reveal whether or not C. difficile toxins are present in patients' samples. According to Dr Glen Hansen, an associate professor at the University of Minnesota, and the director of Clinical Microbiology and Molecular Diagnostics at Hennepin County Medical Center in the US, the new device should be seen as a powerful addition to a hospital's arsenal.

Hansen explains that the history of CDI testing has been marked by two problems that persisted into the modern era. The first is the battle to correctly identify the malady before an outbreak scenario occurs, particularly among at-risk groups, which is especially pertinent as the current generation of commercially available diagnostics tests are lacking in sensitivity to the infection. The second issue is the struggle to prevent the pendulum swinging too far in the other direction and overdiagnosing every case of diarrhoea as a symptom of the disease.

Who is at risk?

Although it is believed that CDI is largely confined to hospitals, there is some evidence that more people from the community may be at risk of catching C. difficile than was previously thought. Meanwhile, a number of different groups in the clinical space remain particularly vulnerable to the infection, including patients who have received previous courses of antibiotics. CDI also tends to show up in cases concerning transplant patients, acute illness sufferers and people who are on the polar extremes of age.

There are a number of highprofile studies, one in the UK and one in the US, showing that free toxin detection is more closely associated with the disease than not.

Diagnosing CDI is based on the premise that it is a toxin-mediated disease. Scientists say the organism behind the illness produce a number of toxins capable of causing gastrointestinal disease, typically classified as either toxin A or B. Each can disrupt the integrity of the mucous membrane, often leading to diarrhoea in the patient. However, as previously mentioned, the symptoms of the illness can manifest across a wide spectrum of disease, ranging from mild diarrhoea to life-threatening colitis. Moreover, there are also cases of individuals who can appear asymptomatic, while still having been colonised with toxigenic C. difficile.

"Earlier generations of C. difficile tests relied exclusively on toxin A as their primary target," Hansen explains. "Many of these were early immunoassay antibody tests, and we have come to learn now with outbreak scenarios that there may be a small percentage of the population, around 5-15%, that carry only toxin B," he reveals. "Most cases of CDIs involve organisms that express both toxin A and B together, so most commercial assay demarcate toxin B as their primary target. The risk of missing toxigenic cases by targeting only toxin B is very small - less than 1%. So, most commercial laboratorybased assays demarcate toxin B as their primary target."

According to Hansen, there is still a debate within the medical community over whether or not the detection of a gene on a molecular assay - toxin A or B - is more likely to spot an infected patient than testing for the by-products of that gene.

"There are a number of high-profile studies, one in the UK and one in the US, showing that free toxin detection is more closely associated with the disease than not," Hansen says. "The reason that those findings come out that way is that we tend to see acute disease associated more with higher levels of toxin. It's not always that simple, but certainly if you have higher levels of toxin, you are at higher risk of having significant levels of infection. So, free toxin testing is the idea of testing the actual production of the toxin, which we detect via antibody to the toxin (free toxin), in a diagnostic specimen versus the detection of the gene itself."

Testing for C. difficile has gone through a number of different iterations. Since the discovery in 1978 that the bacterium was associated with human disease, several generations of tests to identify it have fluctuated in popularity. However, Hansen is enthusiastic about the abilities of Singulex's new development to improve staff detection rates of the malady in health institutions.

Free toxin testing is the idea of testing the actual production of the toxin... in a diagnostic specimen versus the detection of the gene itself.

"Detection is at the heart of what makes CDI such a contemporary issue, because the illness associated with CDI can range from very mild asymptomatic diarrhoea, that presents as a couple of bowel movements in a 24 hour period, to a life-threatening sickness," Hansen declares. "So, the spectrum of disease that we see with CDI is much larger and wider than we deal with in other infections," he continues. "Normally, we rely on laboratory testing, but it needs to be in conjunction with the clinical perspective of whether or not a treating physician believes that a patient's diarrhoea could be attributable to CDI, because there is a wide spectrum of symptoms that we see with patients."

Hansen's general perspective is that Singulex's new device could provide busy doctors with a rapid multifunctional assay that allows them to investigate incidents of CDI among hospitalised patients in a highly sensitive, specific and rapid fashion. Anything that can reliably detect free toxin levels at a level of sensitivity that matches molecular-based testing is an improvement over current standards - and an advancement in fighting C. difficile. Indeed, the Clarity C. diff toxins A/B assay specifically aims to be the first ultrasensitive enzyme-linked immunosorbent assay test on the market that offers physicians and laboratorians the specificity intrinsic to toxin tests, but comes with a level of sensitivity that rivals molecular methods. The company says that findings in previous studies have demonstrated that, when compared with other currently available testing options, the Singulex system offers its clients quicker results, better sensitivity and enhanced specificity in the detection of both types of toxins associated with the presence of C. difficile in stool samples.

Getting it done

Hansen stresses how important a contribution to the field of C. difficile detection he hopes the Singulex Clarity C. diff toxins A/B immunoassay could make. It can bring together the sensitive testing required with the ability to tie free toxin-based tests to patients' samples, providing physicians with a test result that better correlates with the disease.

"This is a very unique assay that allows us to be able to interrogate the ability of a diagnostic specimen at a single molecule level, to look for more reliable clinical markers, which are free toxins, at a level in which the sensitivities can now match molecular-based testing," Hansen says. "When hospitalised patients have true signs of symptoms of CDI, we don't want to run into a scenario where we are missing these diagnoses."

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