earn free cme credit
Earn CME credit by reading this article and completing the posttest.
CME Author: Zeena Nackerdien
Study Authors: M. Hong Nguyen, Cornelius J. Clancy, et al.; David A. Weinrib, Gerald A. Capraro
Target Audience and Goal Statement: Infectious disease specialists, hematologists, intensivists, hospitalists, primary care physicians
The goal was to assess the performance of a qualitative test that combined PCR amplification and T2 magnetic resonance (T2MR) in a closed system for the rapid and accurate diagnosis of bloodstream infections (BSIs) or sepsis caused by five common bacteria.
- How did the T2Bacteria (T2B) panel perform in terms of detecting specific BSIs in adults?
Synopsis and Perspective:
Bacteria may be transient in the blood or persist to cause serious infections which, if left untreated, could lead to sepsis. Almost 50% of all deaths of U.S. hospitalized patients are caused by sepsis.
- Using data from more than 1,400 patients, researchers validated the first direct-from-blood, non-culture test for the rapid detection of the five most common bacterial blood stream infections that are the leading cause of hospital infections worldwide, with mean times to species identification ranging from 3.61 to 7.76 hours.
- Realize that future studies are called for to aid in understanding the novel assay’s role in modern antibiotic stewardship and care — including whether it can reduce time to appropriate therapy compared with multiplex PCR on positive blood cultures, its effect on hospital stay and survival, and potential for inappropriate antibiotic use.
Blood culture is considered to be the gold standard for diagnosing BSIs, but it is limited by suboptimal sensitivity ranging from 10% in suspected bacteremia to 50% in septic shock and a slow turnaround time of several days.
“With a blood culture, it typically takes days to cultivate organisms to learn if a patient has bacteremia and, if so, what bacteria is causing the infection. Additionally, blood cultures are not always sensitive enough to pick up the presence of bacteria in the bloodstream, such as when the patient has already been started on antibiotics,” co-author M. Hong Nguyen, MD, University of Pittsburgh Department of Medicine, said in a statement. A proprietary, FDA-cleared assay rapidly and accurately diagnosed common BSIs, the team reported in Annals of Internal Medicine.
T2B tests for the five most common and deadly bacteria that cause sepsis — Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Together with Acinetobacter baumannii, this group — better known as ESKAPE pathogens — of bacteria are the leading cause of nosocomial infections throughout the world. According to the manufacturer, “studies have shown that the mortality rate for BSIs can be reduced significantly with appropriate targeted therapy within 12 hours.”
In a multicenter, diagnostic accuracy study funded by the test’s manufacturer (T2 Biosystems), 1,427 hospitalized patients (median age 56 years; 63% white; 57% men) for whom blood cultures had been ordered also had samples collected for the T2B panel.
Pre-specified clinical/microbiological criteria were used to arrive at definitions for proven, probable, and possible BSIs.
Comparison between the T2B panel and blood culture showed detection of targeted bacteria in 13% and 3% of patients, respectively. Mean time to species identification with the T2B panel ranged, on average, from 3.6 hours to 7.7 hours, depending on the number of samples tested. By contrast, average times from the start of blood culture incubation to positivity and species identification were 38.5 hours and 71.7 hours, respectively. Both per-patient specificity and sensitivity for proven BSIs associated with the targeted bacteria were 90%. Negative predictive value of the diagnostic test was 99.7%.
T2B results were positive in roughly 10% (146 of 1,427) of patients with negative blood cultures for targeted bacteria. These results were associated with probable (n=62) or possible (n=26) BSIs. Based on the assumption that probable and possible BSIs were true positives that were missed by blood culture, Nguyen and colleagues calculated the per-patient specificity of T2B to be 94% and 96%, respectively.
Study limitations included the low prevalence of positive blood cultures, collection of only one set of culture specimens, and inability of T2B to detect non-targeted pathogens.
Source Reference: Annals of Internal Medicine 2019; DOI: 10.7326/M18-2772
Editorial: Annals of Internal Medicine 2019; DOI: 10.7326/M19-0971
Study Highlights: Explanation of Findings
T2B showed sensitivity and specificity of 90% in identifying BSIs caused by five common bacterial pathogens, noted Nguyen’s group. Crucially, they account for about 50% of organisms recovered from positive blood cultures and are noted for their propensity for resistance to multiple antibiotics, the team added.
Sensitivity and specificity of the novel assay for targeted organisms were both 90%. “Specificity increased to 94% if probable BSIs were considered as true positives that were not identified by companion blood cultures and to 96% if both probable and possible BSIs were considered as true positives,” the researchers wrote. Predictive value for ruling out the presence of the targeted bacteria approached 100%. Depending on the number of samples processed, the shortest average interval from starting tests to diagnosing targeted pathogens was nearly four hours for the T2B panel versus nearly 39 hours for blood culture.
Only 0.4% (4 of 1,427) of samples had a positive blood culture and negative T2B results. But for two of these cases, T2B showed positive results using a backup sample. The team also raised the possibility that low circulating bacterial DNA concentrations in false-negative T2B samples were below the limit of detection of the assay. Nguyen and colleagues stated that there was room for improving the sensitivity of T2B by collecting additional samples.
“T2Bacteria and its companion test, T2Candida, are the first FDA-cleared diagnostic tests for bacterial and fungal causes of bloodstream infection that do not require cultivation of microbes in blood cultures. By avoiding the need for blood cultures, the tests can shorten time to diagnoses and antimicrobial treatment, and identify cases that may be missed by cultures,” explained Nguyen in a related report.
“The T2Bacteria Panel’s rapid results and high sensitivity make it a valuable tool for the diagnosis and management of suspected bloodstream infections,” W. Frank Peacock, MD, of Baylor College of Medicine, said in a statement.
“This is an important breakthrough as bacterial infections are a major cause of poor patient outcomes and high hospital costs,” said Peacock, who was not involved with the study. “This is a game-changer.”
In an accompanying editorial, David A. Weinrib, MD, and Gerald A. Capraro, PhD, both of Atrium Health in Charlotte, North Carolina, cautioned that the clinical benefit of the novel assay was still uncertain. The editorialists suggested possible goals for future outcome studies to aid the understanding of T2B’s role in modern antibiotic stewardship and care. These suggestions were posed as questions/comments:
- Can studies demonstrate better outcomes, such as significantly shorter time to appropriate therapy, compared with use of multiplex PCR on positive blood cultures and other standards of care?
- Does the test improve 30-day survival, decrease length of stay, or reduce the number of days of antibiotic therapy per 1,000 patient-days?
- Is there a potential for inappropriate antibiotic use (with concomitant complications — e.g., Clostridium difficile diarrhea), given that putative false-positives were observed with negative blood culture and positive T2B results?
Cost and laboratory time were additional considerations raised by the editorialists.
Nguyen’s group concurred that a critical next step would be to define the precise role of T2B in clinical practice and the effect of results derived from the molecular diagnostic test on patient outcomes. However, they emphasized the success of the first step — i.e., validation of a test able to identify or exclude common bacterial pathogens that are often multidrug resistant.
T2B will most likely be useful if it is used in conjunction with blood and non-blood cultures and results are interpreted with careful consideration of patients’ clinical status and antibiotic use, the team concluded.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco