Nonculture Molecular Tests Speed Diagnosis of Bloodstream Infections

The T2Bacteria Panel (T2Biosystems; Lexington, Mass.) can rapidly and accurately diagnoses bloodstream infections (BSIs) caused by five common bacteria, according to a study published May 14 in the Annals of Internal Medicine.

Blood cultures, which are the gold standard for diagnosing BSIs, are known to be insensitive and have a long time to results. Development of nonculture-based diagnostic tests for BSIs are a top priority for patient care and antibiotic stewardship.

The U.S. Food and Drug Administration (FDA) recently cleared the T2Bacteria panel that can directly detect bacteria in whole blood samples. The nonculture test that uses both polymerase chain reaction amplification and T2 magnetic resonance in a closed system to identify the most common ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli), that together account for about half of organisms responsible for positive blood cultures.

“We hope the promising performance and FDA clearance of these tests will encourage continued investment, research, and development in this area of pressing medical need,” write the authors led by M. Hong Nguyen, M.D., from University of Pittsburgh in Pennsylvania. “Now that performance characteristics … have been established in multicenter clinical trials, a top priority is to define their precise roles in clinical practice and their effect on patient outcomes.”

The multisite study assessed the diagnostic performance of the T2Bacteria Panel, compared to paired blood cultures, in 1,427 adults (median patient age, 56 years) treated at 11 hospitals. T2 Biosystems provided financial support for the study.

Both aerobic and anaerobic blood cultures (one bottle each, the “companion blood cultures”) and three whole blood samples for T2Bacteria testing were collected in that sequence from the same anatomical site. T2Bacteria results were not available to health care teams caring for study patients and were not incorporated into clinical decision making. Arbitration of incongruent case results was based on whether the same organism was recovered from clinical blood culture specimens unrelated to study samples or from cultures at nonblood sites (e.g., urine or respiratory tract).

The researchers found that blood culture results were positive for the five targeted bacteria in 3 percent of patients (39 of 1,427) and T2Bacteria in 13 percent of patients (181 of 1,427). Companion blood cultures detected a total of 85 organisms, including 39 of 82 with organisms included in the T2Bacteria panel plus additional species (Coagulase-negative staphylococci, diphtheroids, and Corynebacterium species) in 23 of 82 positive blood cultures.

Blood culture and T2Bacteria results were concordant in 90 percent of samples. Per patient sensitivity and specificity for T2Bacteria for proven BSIs (concordant results) were both 90 percent. The negative predictive value was 99.7 percent.

The rate of negative blood cultures with a positive T2Bacteria result was 10 percent (n = 146), of which 62 results were probable (defined as a negative blood culture but a positive T2Bacteria result which yielded isolation of a T2Bacteria-detected organism within 21 days from a clinical blood culture or specimen) and 26 were possible (defined as a negative blood culture but a positive T2Bacteria result in the absence of supporting culture data) BSIs. If probable BSIs were assumed to be true positives (missed by blood culture), specificity of the panel increased to 94 percent. The specificity increased to 96 percent if both probable and possible BSIs were assumed to be true positives. Specificities for specific T2Bacteria-targeted organisms ranged from 96 percent for E coli to 98 percent or higher for other species.

Time to identification of pathogens was shorter for T2Bacteria (4 to 8 hours depending on how many samples were loaded for testing) versus 39 to 72 hours for blood cultures.

“The initial commercial experience appears to be aligned with the strong results demonstrated in the pivotal study, as several customers have shared case studies of the T2Bacteria Panel providing actionable test results that improved patient care and several have developed and implemented patient selection criteria for the intensive care unit, oncology units, and the emergency department,” said Sandy Estrada, vice president of medical affairs at T2 Biosystems, in a statement. “We continue to engage with clinicians, stewardship teams, and laboratory personnel at hospitals as they expand utilization of the T2Bacteria Panel and develop independent data examining its clinical and cost-savings benefits, similar to what we have already seen with the T2Candida Panel.”

However, in an accompanying editorial, published in the Annals of Internal Medicine, David A. Weinrib, M.D., from Atrium Health–Carolinas Medical Center (Charlotte, N.C.) advises caution saying that the published study is not clear how the panels add “value” to the clinical management of patients with suspected BSI or sepsis.

“In this era of increasing cost consciousness and ‘lean operations,’ clinicians and laboratories need to be good stewards of health care resources and make careful determinations of cost, utility, and benefit to the patient before adopting a new assay,” writes Weinrib. “As with many other culture-independent diagnostic tests, incorporation of the T2Bacteria Panel would be additive. … Personnel, space, and efficiency are important issues that must be addressed, especially when adding testing that does not have proven clinical benefit is being considered.”

Data Emerging for T2 Panels’ Cost Effectiveness

T2 Biosystems also recently published two papers, one in PLOS ONE and one in Diagnostic Microbiology and Infectious Disease, highlighting the potential of the T2Bacteria and T2Candida panels to improve outcomes and be cost-effective for several clinical scenarios, including adults presenting in the emergency department or the medical intensive care unit with severe sepsis or septic shock.

Models evaluated the cost-effectiveness of using two blood culture sets in conjunction with the T2Bacteria and T2Candida rapid molecular diagnostic assays (the bundle approach) versus blood culture alone. In both studies the bundle approach was cost effective when considering cost savings for deaths and in cases that the length of hospital stay differs by four days between patients receiving appropriate and inappropriate antimicrobial therapy.

“This is aligned with the real-world results reported by our customers, which includes actionable results in as little as 3 [to] 5 hours, allowing for appropriate adjustment of antibiotic therapy, or de-escalation of therapy in patients with a negative result,” said T2 Biosystem’s CEO, John McDonough, in a statement. “This rapid result uniquely provided by our products and benefits patient care can lead to cost-savings and supports improved antimicrobial stewardship.”

Takeaway: T2 Biosystem’s recently cleared panel may be a promising way to cost-effectively speed time to results for identification of pathogens responsible for BSIs.