Johanna Sandlund, MD, PhD, board certified clinical microbiologist at Singulex

Clostridium difficile infection is the leading cause of gastroenteritis-associated death and has become the most common cause of health care–associated infections in US hospitals. For long-term care facilities, CDI is a significant issue with a higher CDI incidence (33%) compared to acute care hospitals (15%) and clinics (12%).One quarter of all CDI cases in the US had onset in nursing homes.

Age is a factor. According to the Centers for Disease Control and Prevention, nursing home residents over the age of 85 have CDI incidence rates that are 100-fold higher than persons between 1 and 84 years of age.

As with most infections, CDI is contagious. Microorganisms can be spread from person-to-person by touch or by direct contact with contaminated objects and surfaces. Rapid, accurate, and effective diagnosis enables the right patients to be treated with antibiotics. Administering antibiotics to a patient with CDI will treat the infection, but administering the same antibiotics to someone who does not have CDI can led to increased susceptibility to infection. 

Accurate and reliable testing methodologies are critical, as false-negative or false-positive results are not only detrimental to patients, they burden labs and clinicians and lead to wasted resources. However, it is known that antimicrobial stewardship and infection control measures can drive CDI rates down.

Now, an ultrasensitive C. difficile toxins A/B assay in development, is demonstrating increased sensitivity and specificity, showing promise at addressing the challenges of the false-negative and false-positive rates associated with currently available tests.

The burden of CDI

C. difficile is a bacterium found in the air, water, soil, and in the feces of humans and animals. The bacteria’s spores are often spread in hospitals and nursing homes. Older adults in healthcare facilities are at most risk, though an increasing number of younger adults also develop CDI. This infection is characterized by diarrhea and in some cases also severe cramping, fever, nausea, and dehydration. CDI is the leading cause of gastroenteritis-associated death in the US.

According to a study funded by the CDC, C. difficile was responsible for over 450,000 infections and was associated with approximately 29,000 deaths in 2011. Additional reports suggest that these numbers have continued to rise in subsequent years. Healthcare costs related to CDI are estimated at $4.8 billion for acute care facilities alone.

Efficient and frequent diagnostic testing matters

Efficient and rapid diagnostic testing for CDI is needed to minimize delays in initiation of isolation and treatment for confirmed cases, while also allowing immediate discontinuation of treatment and isolation when testing is negative. However, delays in diagnosis are common in practice. Because many long-term facilities use off-site laboratories, improving the timeliness of diagnostic testing may be a particular challenge in this setting.

Frequency of testing has also been shown to lower CDI rates in the long-term care setting. Long-term care facilities generally test less frequently than acute care hospitals (2 vs. 50-100 tests/month/facility, respectively). A recent study demonstrated a single long-term care facility that tested more frequently (26 tests/month) had lower CDI rates (12%).

Currently available testing methodologies

There are two types of tests currently available for diagnosing CDI: molecular testing and immunoassays.

With molecular testing, nucleic acid amplification tests and polymerase chain reaction can identify with high sensitivity whether C. difficile is present in a person’s stool, but not whether the organisms are producing the disease-causing toxins. Molecular tests therefore often lead to false-positive results.

Immunoassays for C. difficile can detect the toxins that cause disease and are therefore much more specific to CDI than molecular tests; however, currently available immunoassays lack sensitivity and often lead to false-negative results. To compensate for this inadequacy, an additional immunoassay test that detects glutamate dehydrogenase (GDH), a biomarker produced by C. difficile bacteria, is combined with toxin testing to increase sensitivity.

The costs of ambiguity

The cost of treating — or not treating — patients based on tests that are inaccurate can be high for long-term care facilities as well as nursing homes and hospitals. Because clinicians know about the limitations of each test type, often institutions decide to test for C. difficile using both molecular and immunoassay methods. Insurance companies will not reimburse for several different types of testing, yet frequently the facility decides to take on that extra cost itself, understanding that doing so will cost less in the long run than the cost associated with the false positives and false negatives these tests can yield. Clinicians, laboratory technicians and healthcare administrators often express the need for a more sensitive toxin immunoassay test, given that detection of toxins is better correlated with presence of CDI.

A new approach shows promise

The ultrasensitive C. difficile toxin A/B assay in development by Singulex for use on the Singulex Clarity® system, an automated platform powered by Single Molecule Counting technology, offers excellent sensitivity in preliminary studies and may be a critical tool for diagnosing this life-threatening infection. Single Molecule Counting technology has been validated in clinical studies published in over 160 peer-reviewed publications.

In initial pilot studies, the automated Singulex Clarity C. difficile toxins A/B assay demonstrated the ability to detect disease-causing toxins at concentrations up to 100 times lower than commercially available immunoassay methods. The turnaround time is less than one hour, allowing for rapid detection and rule-out of suspected CDI.

The Single Molecule Counting–based C. difficile toxin A/B assay aims to be the first ultrasensitive test to offer physicians and laboratory workers the specificity intrinsic to toxin tests but at a sensitivity level that rivals molecular methods. The clinical goal is to help clinicians to safely rule out CDI with greater confidence and provide clinically actionable toxin detection in under an hour. Singulex plans to register the Singulex Clarity C. diff toxins A/B assay to the U.S. Food and Drug Administration in 2018.

Making an accurate CDI diagnosis is a challenge. What is needed is a single, cost-effective, rapid immunoassay with greater sensitivity. Only then can the diagnosis of CDI shift from a complex puzzle that requires multiple pieces of information to a straightforward process that leads to confident treatment decisions, while dramatically bringing down both the cost and incidence of CDI.

Johanna Sandlund, MD, PhD, is a board-certified clinical microbiologist at Singulex, a company pioneering next-generation C. difficile diagnostics.


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