The T2Bacteria Panel does not replace the need for blood culture and antibiotic susceptibility testing. In addition, an infection identified by the T2Bacteria Panel may be resistant. But despite these limitations, the T2Bacteria Panel can still realize substantial clinical value. (i) The vast majority of bacteremia episodes are correctly treated after a positive species identification, without initial assessment of susceptibility results, and (ii) physicians acknowledge the value of a species ID, even without susceptibility results.

In a study of blood culture species identification and susceptibility, 94.5% (362/383) of U.S. patients with a positive blood culture were found to be on an appropriate therapy after species identification but before antibiotic susceptibility testing – results are available. (1). In contrast, a meta-analysis of 70 studies found the proportion of patients on an appropriate empiric therapy (i.e., without diagnostic data) was 53.5% (2). Similarly, a study of 364 patients in Belgium found empiric therapy was appropriate in 63% of patients but increased to 94% after Gram staining (3). An additional study from the Netherlands found that in 93 patients with blood culture positive results, empiric treatment was correct in 63% of patients, and the addition of species ID increased the correct therapy proportion to 100%, without the impact of susceptibility results (4). Data confirms that the value of the T2Bacteria Panel is clear – and reduces the time required to increase the probability of appropriate therapy from ~55% to 95%.

Second, these gains in appropriate therapy will be realized because clinicians are supportive of rapid diagnostics that only provide species identification. A 2014 blinded survey inquired about clinical impressions of a hypothetical direct-from-blood bacteremia test from 242 infectious disease practitioners (94% MD physicians), where 31% practiced in Germany and 69% practiced in the United States (8). The survey found that the time to result after blood draw must be no longer than 4.7 ± 2.2 hrs. (mean ± SD) to provide clinical value – a time that is achieved by the T2Bacteria Panel. In addition, across a spectrum of common infectious bacteria, 60 to 85% practitioners indicated they would change empiric therapy based on species identification alone, which increased to 77 to 87% with species identification and antibiotic susceptibility data. By comparing the mean of these ranges, we find that species identification is responsible for 88% of changes to empiric therapy, highlight the positive impact species identification influences clinical decisions and improves patient management.

Overall, while the T2Bacteria Panel will not influence all clinical decisions, the above data supports that infectious disease practitioners are receptive to changing empiric therapy based on species ID, and that the T2Bacteria Panel will increase the proportion of patients on appropriate therapy in 3 to 5 hours from 55 to 75%, which represents a substantial clinical improvement.

DNA is the genetic material that makes species unique. The T2Bacteria Panel exploits this fact and uses cell-associated DNA to specifically identify bacterial pathogens. But a key difference compared to other diagnostic platforms is how the T2Bacteria Panel detects bacterial DNA. In particular, all other FDA cleared diagnostics for bacteremia require blood culture before species identification. Therefore, the T2Bacteria Panel identifies bacteria in several novel ways relative to all other FDA cleared bacteremia tests:

1. New FDA Product Code – Upon clearance of the T2Bacteria Panel, the FDA issued a new, unique product code (QBX, NSU for a “Direct Blood Bacterial Nucleic Acid Detection System”). This reflects that the mechanism of action for the T2Bacteria Panel is novel and new.

2. No cell growth – The T2Bacteria Panel is independent of biological growth rate and does not require waiting 1 to 5 days for sufficient cell doublings (9). The T2Bacteria Panel requires no growth and identifies species in 3 to 5 hours direct from blood.

3. No interference from antibiotics – The T2Bacteria Panel detects cell-associated DNA regardless of whether or not the cells can grow in vitro. Antibiotics are a well-known interferent in blood culture dependent methods. For instance, a recent study of 1364 clinical blood cultures found a 60% lower odds of bacterial detection with prior antibiotic administration compared to no prior antibiotic administration (10). In contrast, the T2Bacteria Panel shows no interference from antibiotics and can still identify cell-associated DNA in the presence of antibiotics (11).

4. No competitive growth – In blood culture bottles, one species can grow faster than other species and mask the true presence of a polymicrobial infection. For example, in a study of 687 positive blood cultures, compared to monomicrobial infection, polymicrobial infections showed 8.1% lower sensitivity (12). In addition, polymicrobial infections are difficult to treat. A study in the emergency department found that relative to monomicrobial infections, polymicrobial infections showed a 2.5-times higher rate of inappropriate therapy and a 2-times higher mortality rate (13). In contrast, the culture-independent T2Bacteria Panel shows no interference from polymicrobial species and can sensitively and specifically detect multiple species simultaneously (11).

5. Direct detection – The T2Bacteria Panel detects DNA from pathogens causing disease. In contrast, blood culture dependent methods detect DNA from progeny cells after many doublings. Similarly, other technologies depend on microbiological methods and require other hardware and consumables, often from third parties. The T2Bacteria Panel does not have these dependencies.

6. Detection Mechanism – T2MR uses magnetic resonance coupled with breakthroughs in nanotechnology to detect pathogens via DNA.

Taken together, while the T2Bacteria Panel does identify species with DNA, the differences from direct and independent detection, lack of growth, and lack of interference from antibiotics and competitive growth relative to all other FDA cleared diagnostics distinguishes the T2Bacteria Panel as a novel technology.

In treatment of bacteremia, the key determinant of length of stay and mortality is time to effective therapy. Each infectious species responds differently to therapy – some therapies are simply ineffective against certain species but effective against others – and thus hospitals maintain antibiograms to track the effectiveness of their antibiotic treatments. Since administering an effective therapy requires knowledge of the infectious species, reducing the time to species identification reduces time to effective therapy.

Several studies have shown the benefits of effective therapy on patient outcomes, which includes multiple-day reduction in length of stay based on improvement in specific identification:

1. In blood culture positive patients, relative to standard of care, the use of post-blood culture species identification using MALDI-TOF shortened by 1.2 days the time to effective therapy by 1.2 days, which was associated with a 2.8 day reduction in mean length of stay (14).

2. In blood culture positive patients with a Gram negative organism, the use of post-blood culture species identification with MALDI-TOF reduce time to species ID by 1.1 days, producing a 2.6 day reduction in mean length of stay (15).

3. In blood culture positive patients with a resistant Gram negative organism, the use of post-blood culture species identification with MALDI-TOF reduced time to effective therapy by 2.4 days, producing an 8.0 day reduction in mean length of stay (16).

Taken together, in these studies, the observed ratio of reduced length of stay to time to effective therapy or species ID is 2.7 ± 0.5. In other words, for every hour reduction in time to effective therapy or species ID, the length of stay decreased by 2.7 hours. Notably, these studies all employed post-culture diagnostics and required time for culture growth, and thus culture-independent assays may produce a stronger effect by identifying the infection earlier in the progression of disease. Recent data from a direct-from-sample meningitis panel to detect bacteria directly in cerebrospinal fluid (i.e., no culture) found a 1.5 day reduction in length of stay that the authors attributed to the faster time to species ID (17). Hence, a rapid direct-from-blood diagnostic like the T2Bacteria Panel should also produce substantial reductions in length of stay.

One of the best predictors of mortality due to bacteremia and sepsis is time to effective therapy. This has been demonstrated in multiple publications:

1. In 2,731 septic shock patients, during the first 6 hours of hospital care, every hour delaying effective antimicrobial therapy reduced survival by 7.6% (18).

2. In 111,816 patients given a New York state-mandated sepsis bundle, every hour delaying appropriate antibiotic therapy increased odds of death by 4.0% (19).

3. In a meta-analysis of 70 studies, compared to patients given an appropriate empiric antibiotic therapy, patients given inappropriate empiric antibiotics showed over two-times higher odds of death (2).

These studies support that rapid and targeted therapy to treat bacteremia and sepsis saves lives.

In a 2016 study of 165,593 blood cultures from 13 acute care hospitals in the United States, the median time to species identification was 44.0 hrs. By species, the medians ranged from 36.0 to 90.2 hrs (9).

In the 2014 T2Candida Pivotal study, the mean time to species identification for blood culture dependent methods was 129.9 ± 26.3 hrs. In contrast, for the T2Candida Panel, the mean time to species identification was 4.4 ± 1.0 hrs. The mean difference in time to species identification between blood culture dependent methods and the T2Candida Panel was 125.5 hrs. or 5.2 days (20).

In the 2017 T2Bacteria Pivotal study, the mean time to species identification for blood culture dependent methods was 71.7 ± 39.3 hrs. In contrast, for the T2Bacteria Panel, the mean time to species identification depended on the number of samples loaded, and ranged from 3.61 ± 0.2 hrs. for 1 sample loaded to 7.70 ± 1.38 hrs. for a full load of 7 samples. Comparing against a full load of 7 samples, the mean difference in time to species identification between blood culture dependent methods and the T2Bacteria Panel was 64.0 hrs. or 2.7 days (21).

In patients suspected of bloodstream infection, despite a 10% blood culture positivity (9), empiric therapy treatment rates range from 50 to 70% (22-24). In patients treated with empiric therapy, across 70 studies, the proportion of patients where the empiric therapy was not appropriate was 46.5% (2). Therefore, there is a substantial over-prescription of antibiotics, and an opportunity to place patients on the correct therapy faster.

Depending on the patient population and hospital ward, the T2Bacteria Panel will cover 50 to 70% of all bacteremia (5, 6). Notably, the panel covers 90% of bacteremia by ESKAPE pathogens (5-7), which are pathogens at particularly high risk of resisting broad spectrum antibiotics and could benefit from a species-directed change in therapy (7). So the value of the T2Bacteria Panel is accelerating the time to species directed therapy adjustments for 50 to 70% of all bacteremia and 90% of ESKAPE bacteremia to just 3 to 5 hours.

In a study of 559 septic ICU patients, prior administration of antibiotics resulted in a 60% lower odds of a blood culture positive (25). Similarly, in a study of 25,686 emergency department patients, prior administration of antibiotics for as little as 2 hours reduced blood culture positivity by over 50% (26). Therefore, prior administration of antibiotics can be a major source of reduced positivity in blood culture methods.

In contrast, since T2 assays do not require cell growth, the assays show no interference from antimicrobials even at supraphysiological levels (11, 27).