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T2Bacteria Panel: What you need to know
In this guest editorial, Diane C. Halstead, PhD, DABMM, FAAM, who has over 35 years of experience as a clinical infectious disease laboratory director, discusses current data supporting T2 Biosystems’ T2Bacteria Panel, which patients should be tested using the technology, its potential economic benefits for both labs and hospitals, and how the test fits into a larger strategy to curb the use of inappropriate antibiotics.
T2 Biosystems is the first company to receive FDA-clearance for their T2Candida Panel and, more recently, their T2Bacteria Panel (the focus of this publication) to identify sepsis-causing organisms directly from whole blood. The panels are run on a fully automated, tabletop T2Dx platform combining magnetic resonance (MR) with nanotechnology. Using what some consider third-generation technology, T2MR identification does not rely on growth-dependent blood cultures (BCs) like other identification systems currently available. Whereas the pathway to identification of a positive BC can take approximately 1 to 3 days for results, T2MR results are available in approximately 6 hours.
Principle of T2Dx
Briefly, the automated procedural steps for running the molecular T2Bacteria Panel include detergent lysis of blood cells in ethylenediaminetetraacetic acid (EDTA)-whole blood samples; concentration of cellular debris and intact bacterial cells that are then lysed by bead beating; and amplification of bacterial DNA in concentrated sample matrix using a reagent pack that contains an internal control, thermostable polymerase and primer pairs, each specific for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli. Separate detection channels arise from the T2Dx automatic splitting of amplified product into separate wells, each containing a unique set of superparamagnetic particles with attached probes specific for one of the five detected species or internal control. The species-specific probes enable amplicon-induced clustering of the superparamagnetic particles within a channel to yield a positive or negative result for each pathogen or internal control. Qualitative results for single pathogens and coinfections are available within approximately 6 hours of collecting a 3- to 4- mL tube of blood. The T2Dx instrument is designed to run six samples plus a stat sample, allowing the user to run both Candida panels and bacteria panels at the same time. As the menu expands, this may take on even greater importance.
Sensitivity and specificity of T2Dx
Using prospectively paired samples, the T2Bacteria Panel compared with BCs had a reported sensitivity and specificity of 81.3% to 100% (overall 90%, 35/39) and 95% to 99.4% (overall 98%, 8,416/8,588), respectively, which varied with the target detected. With a lower limit of detection of 2 to 11 colony-forming units (CFU)/mL of blood, there was an increased likelihood of organism detection using T2MR compared with BCs that required incubation for amplification and detection of organisms. The T2Bacteria Panel also has the capability of identifying at least 90% of samples, giving negative results within approximately 6 hours. Low-risk patients may be spared therapy using a watchful eye, rather than waiting 5 days for a final negative BC report. Because there have been instances of BC-positive/T2-negative cases, and the panel is not comprehensive, clinicians may be reluctant to discontinue empiric therapy. In some patient populations, they may withhold vancomycin while waiting for the BC result. As more published data become available, clinicians may consider using negative T2 results to rule out bacteremia and de-escalate therapy in low-risk individuals.
So how does T2 technology impact patient care? Sepsis, one of the leading causes of death in the United States and an equal opportunity killer, requires timely diagnosis and administration of appropriate antibiotics. The frequently cited study by Kumar and colleagues highlights the importance of getting the right antibiotic(s), at the right time, to the right patient for survival. A 24-hour delay in appropriate treatment can contribute to doubling the mortality rate, yet up to 40% of patients with bacteremia have been reported to receive ineffective empiric therapy. The importance of providing results in a timely fashion cannot be overstated. The results from paired T2 and BC samples from 1,427 patients in a pivotal trial conducted at 11 U.S. hospitals showed that T2Dx provided faster results by at least 2.5 days compared with BC-dependent tests. Rapid identification allows for greater likelihood of providing targeted therapy, de-escalating antibiotics and decreasing resistance, costs, potential toxicity and side effects. As part of a lab’s quality improvement initiatives, turnaround time to results and de-escalation of antibiotics need to be monitored to ensure they are getting the “best bang for their buck.”
Are T2-positive/BC-negative results false-positive findings? A false-positive rate of 11% has been reported based on T2-positive/BC-negative results. Potential explanations for these discordant results include prior treatment with antibiotics, poor antibiotic management, presence of a localized infection with undetectable BC CFU levels, or transient bacteremia, as evidenced by a positive BC collected at another time. As with other molecular tests, contamination is always a consideration. Following an early T2Bacteria clinical study resulting in prospective discordant results with no evidence of infection, an investigation revealed reagent contamination as the likely source. Measures were taken to correct reagent methods. Certainly, careful manipulation of samples and thorough cleaning around the area of testing is always a prudent policy even though T2Dx is a closed system with built-in safety measures to avoid contamination.
Currently, BCs are considered the gold standard, even though many will agree that they are suboptimal at best, with reports of sensitivity around 50% to 70%, depending on the organism and the volume of blood cultured. In the pivotal T2 clinical trial, BCs missed 59% of cases that were clinically infected but correctly identified by T2 based on criteria used to define true infections (eg, clinical findings consistent with infection, recovery by culture in sites other than blood or in BCs collected at another time, or sequencing results from an archived sample collected at the same time as the paired T2 and BC samples). Even if some discordant positives represented nonviable organisms, a T2-positive sample may represent a bacteremic event requiring further monitoring, particularly if pretest clinical and laboratory signals are present. We only need to look at other examples in which cultures were considered to be the gold standard — such as Chlamydia trachomatis, Neisseria gonorrhoeae and Bordetella pertussis — only to find that PCR results were accurate and reflected the clinical condition of patients. I suspect that the same will occur in the near future to explain the discordance between T2 and BC results.
Who should be tested by T2Dx?
A cost-related concern has surfaced related to who should be tested. Many labs are now making changes in what tests should be offered and how they are performed and ordered. Some of the trends affecting these decisions are related to a shift from fee- to value-based testing. Economic justification is an absolute necessity when trying to bring in a new lab test, although lab costs must be balanced by clinical need and hospital costs. For example, sepsis-related expenditures, averaging $18,000 in the U.S., are at the top of the scale for inpatient care. Interestingly, CMS and insurance companies, in their attempt to avoid paying for health care-associated infections, have spurred the interest of some hospitals to consider molecular testing for rapid identification of infections to support early effective therapy and reduce mortality, length of stay, pharmacy and lab costs. The National Physicians Alliance is promoting good stewardship in medicine through the “Choosing Wisely” campaign. The charge for labs today is to provide accurate and rapid, clinically meaningful results for patient care that support antimicrobial stewardship programs.
Lab stewardship teams can help in the effort to select appropriate technology while addressing shrinking lab budgets, overall costs per patient health care encounter and improved patient outcomes. To that point, a reasonable approach might be to selectively use the T2Bacterial Panel, ie, only for high-risk, hypotensive patients with signs and symptoms of sepsis that are seen by first responders in the ED and on critical care floors. As an alternative, hospitals might well develop a testing algorithm, starting with patients exhibiting hypotension and a positive qSOFA score, followed by a positive lactate, procalcitonin and/or C-reactive protein and elevated white blood cell count. Only patients meeting these criteria would be tested using the T2Bacteria Panel.
T2Bacteria Panel coverage
The panel targets five sepsis-causing pathogens that account for identification of approximately 50% of bloodstream infections and several ESKAPE organisms associated with multidrug resistance (eg, E. faecium, S. aureus, K. pneumoniae, P. aeruginosa) in the pivotal clinical trial, and 86% to 91% in another study. With the heightened sensitivity of T2 compared with the significant percentage of ‘false’-negative BCs, the panel coverage may be an excellent rapid adjunct to culture. There are seven channels available on the current T2Dx instrument, allowing the incorporation of a universal gene for detection of bacteremia in one of the channels. Currently, T2 testing would not be appropriate for patients with community-acquired pneumonia due to the absence of Streptococcus pneumoniae on the panel. A welcome addition to a future expansion of the panel would be to include this organism, as well as invasive streptococci. The lack of testing for resistant genes is a concern that precludes discussion at this point, although the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) is funding the development of T2Dx-based panels for over 25 species and resistance targets, including comprehensive coverage of gram-negative extended-spectrum beta-lactamase and carbapenemase genes. The T2Bacteria Panel was not designed to be a standalone test but rather was designed to provide rapid confirmation of a physician’s clinical assessment of bacteremia in their patients, along with a species-specific identification.
The 2018 surviving sepsis campaign bundle update now recommends “hour-1 bundle” rather than a 3- or 6-hour bundle, to address sepsis as a medical emergency. This change has been adopted by the National Quality Forum, New York State Department of Health and the CMS. The recommendation now states that empiric broad-spectrum antimicrobials to cover all likely pathogens should be given immediately to patients presenting with sepsis or septic shock. Antimicrobials should then be de-escalated on receipt of specific lab results. That said, data reported from two studies showed that 66.7% of patients with strong evidence of infection and T2-positive/BC-negative results were inappropriately treated when the T2 results were available. Additional clinical studies may well support the use of T2 results for empiric broad-spectrum therapy, if not targeted therapy, based on the hospital’s antibiogram so they can be administered with confidence.
Justification
As we see the effects of decreasing reimbursement on lab testing, shrinking budgets and increased demand for value-related results that are available in a timely manner, labs are forced to make some pretty significant changes. Despite significant advances in BC instruments over the past years, actionable results generally take at least 1 to 3 days, too long to allow physicians to make early decisions related to targeted therapy. The BC process is still impacted by time from sample collection to loading bottles on an instrument, amplification for organism detection, gram stain performance, growth in subculture, followed by identification and antimicrobial susceptibility testing. BCs are also subject to antibiotic inhibition, fastidious or slow-growing bacteria, contamination and volume of blood collected, thus extending the time to detection or preventing detection all together. In contrast to growth-independent technology that can provide a negative result in approximately 6 hours, negative BCs take 5 days to final results. Physicians may therefore consider discontinuing therapy based on receipt of a negative T2 result for patients not exhibiting signs and symptoms of bacteremia or other significant epidemiologic or lab data, thus avoiding unnecessary exposure to side effects of antibiotics.
As good as many of the newer FDA-cleared molecular platforms are in providing rapid results with good sensitivity and specificity, they still rely on BCs with the inherent time delay and other potential issues listed above. On the other hand, the T2Bacteria Panel, based on direct sample-to-result technology, bypasses all these issues. For patients placed on broad-spectrum antibiotics within 1 hour of presentation based on the 2018 updated guidelines, positive T2 results could potentially be used to de-escalate therapy using the hospital’s antibiogram as a guide for therapy in institutions with a low level of antimicrobial resistance.
Successful implementation and realization of the true benefits of any new technology or service requires both communication and collaboration with stakeholders in other departments. Members of the lab stewardship program have a vested interest in determining the clinical and operational impact of bringing in new technology to the lab, as well as the potential savings outside of the lab. Preparation of a brief and concise PowerPoint presentation for lab administration and the C-suite may help to drive home the value of the instrument and service for improved patient care. Some of the information needed may in fact already be available through colleagues who have already “been there and done that.” That said, doing your homework to justify how a new system like T2MR will improve patient care and impact positively on the hospital’s bottom line are crucial.
Conclusion
Over a quarter million individuals die from sepsis in the U.S. each year. The average hospitalization cost to treat a septic patient runs over $18,000 — at least double the average cost per stay of most other conditions. With the emphasis on value-based tests, agencies are advocating the introduction of technology to provide rapid, accurate results that will impact positively on patient care. Improving rates of early appropriate antibiotic therapy based on the Surviving Sepsis Campaign have relied on prompt treatment with broad empiric coverage, followed by de-escalation once culture and antimicrobial susceptibility testing results are available. However, delays in generating culture results underscore the need for implementing rapid, direct-from-blood assays, preferably with real-time identification of the offending pathogen(s) and, ideally, resistance genes.
One of the goals of the National Action Plan for Combating Antibiotic-resistant Bacteria is to advance the development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria. CARB-X is donating millions of dollars to companies to develop rapid technology to improve patient care and outcomes related to sepsis. T2MR has been positioned to do just that. This breakthrough technology has the potential to provide economic savings for hospitals by decreasing sepsis-related morbidity and mortality and supporting their antimicrobial stewardship programs. We need to work with our C-suite administrators to gain recognition for the value the lab brings to the table so they will be prepared to look outside of the lab silo when making decisions to support new equipment that potentially can revolutionize the way the lab supports their hospital’s mission.
The next major landmark event will be inclusion of direct sample-to-identification technology in hospital sepsis protocols. T2MR provides a promising new approach to sepsis diagnosis. Rapid diagnostic results will likely expand to include more pathogens and resistance markers — two limitations of T2MR — but based on the T2 Biosystem’s pipeline, labs and antimicrobial stewardship teams will have opportunities to collaborate in providing actionable results for treatment earlier than ever before possible. Hospitals and health care systems who have adopted this technology are encouraged to report their strategies for implementing this new technology, how it has supported their current or emerging sepsis protocol and antimicrobial stewardship program and the evidence-based clinical and economic benefits realized.
For more information:
Diane C. Halstead, PhD, DABMM, FAAM, can be reached at Diane.Halstead@live.com.
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Disclosure: Halstead is a consultant for Merck and T2 Biosystems.