NEW YORK (GenomeWeb) – Selecting among tests that identify pathogens with the potential to cause sepsis can pose multiple challenges for laboratory directors, who must evaluate multiple criteria including speed, ease of use, and diagnostic accuracy and cost.
Adding to the complexity of making that decision, selecting an appropriate system is frequently done in the context of varying requirements, ranging from the severity of a condition to the types of pathogens and infections being detected.
"Rapid identification methods may have multiple positive impacts on patient outcomes including reductions in mortality, morbidity, hospital lengths of stay, and antibiotic use," Donna Wolk, system director of clinical and molecular microbiology at Geisinger, an integrated health service organization, told GenomeWeb. "Speed in providing test results and accuracy of the test are among the primary requirements," she added, "but all of the considered criteria fall within the umbrella of seeking actionable results. If you can't trust accuracy, no one will escalate or de-escalate treatment of antibiotics. There's a growing body of literature that says speed does matter — speed plus the action of the pharmacy."
Sepsis, the body's severe inflammatory response to an infection, is most commonly caused by bacteria, but it can also be caused by fungi, viruses, or parasites. Bacteremia or fungemia, for example, are frequent causes of sepsis, which contributes to more than 1.6 million hospital visits annually in the US and is the most common cause of death in the intensive care unit.
In identifying and treating for sepsis, laboratory directors have an array of tests and systems from which they can select. Around 20,000 identification and antimicrobial susceptibility test placements are in operation globally, according to Accelerate Diagnostics, an in vitro diagnostics company that provides diagnostic test solutions for antibiotic resistance and hospital acquired infections.
Some diagnostics firms are betting on a well-established approach to diagnosing sepsis — measuring patient levels of procalcitonin (PCT), a peptide precursor of the hormone calcitonin. Within the past month, the US Food and Drug Administration has granted 510(k) clearances to PCT assays from Roche and BioMérieux to test for the risk of severe sepsis or septic shock.
Also within this past month, Accelerate Diagnostics came a step closer to selling an automated system and test kit in the US as a clinical diagnostic that can be used for identification and antimicrobial susceptibility testing of pathogens that lead to bacteremia and fungemia.
The firm submitted a de novo request for evaluation of Automatic Class III Designation to the US Food and Drug Administration for its Accelerate Pheno system and Accelerate PhenoTest BC kit for positive blood culture samples.
In preliminary clinical trial results, according to the firm, the total time to identification from presentation of a patient sample averaged 1 hour and 23 minutes, while the total time to an antimicrobial susceptibility result averaged 6 hours and 41 minutes. Additionally, in recent marketing studies, the system and kit saved more than 40 hours compared to the standard of care, according to the firm.
If the results of the FDA review are favorable, the company may be able to launch its tests in the US towards the end of the third quarter. Both the system and initial kit for positive blood cultures are available in Europe and commercial activities are already underway.
Shares of T2 Biosystems, a maker of a non-culture-based diagnostic assay that uses magnetic resonance technology, tumbled more than 20 percent July 8th after the company disclosed that it had secured fewer commitments for its T2Candida sepsis test than expected, that it has encountered problems with test results from T2Candida cartridges, and that it has had to delay plans to submit its upcoming T2Bacteria bacterial sepsis test to US regulators.
Industry participants are closely watching the progress of the Accelerate and T2 Biosystems diagnostic tests. The T2 Biosystems test for Candida looks promising because it is done directly from blood without a pre-incubation, Wolk said. It is FDA cleared, and there is some literature that suggests it may have impact, she added. "There really needs to be more evidence-based literature on both of those technologies to understand how we can truly best use the capabilities in an actionable and cost-effective way."
OpGen has been working recently to improve the visibility of its QuickFISH diagnostic for sepsis by publishing the results of a study in The American Journal of Clinical Pathology that elaborated on the benefits of using its molecular test at Winter Haven Hospital in Florida.
QuickFISH is a molecular diagnostic system based on patented PNA-FISH technology. The assay uses fluorescent in situ hybridization by incorporating peptide nucleic acids. The study demonstrated that when incorporating QuickFISH testing for Staphylococcus into its antimicrobial stewardship program, the hospital achieved annual savings of more than $760,000 through a 30 percent reduction in length of stay, Kevin Krenitsky, president of OpGen, told GenomeWeb.
"Our QuickFISH product is the fastest sepsis test on the market right now and it's FDA approved," Krenitsky said.
Additional systems on the market capable of identifying bloodstream infections that could lead to sepsis include Abbott's Iridica, Nanosphere's Verigene, Bruker's Biotyper, Becton Dickinson's Phoenix, and Cepheid's Xpert. In addition, BioMerieux supplies the Biofire FilmArray diagnostic test as well as the Vitek 2.
Using standard methods to get identification and antimicrobial susceptibility test results for the microorganisms causing blood stream infections can take 48 hours or longer to obtain, Wolk wrote in a paper she co-authored with colleagues that described a systematic review and meta-analysis of laboratory medicine best practices in the context of increasing timeliness and providing targeted therapy for patients with bloodstream infections.
According to the paper, rapid molecular testing with direct communication significantly improves timeliness compared to standard testing and yielded a significant and homogeneous reduction in mortality.
Wolk, working with Stephanie Buehler, a principal research scientist at Battelle Memorial Institute, and others reported using a variety of different phenotypic and molecular techniques in studies they conducted to provide the laboratory medicine best practice review. The group described use of a single PNA-FISH test process used with different PNA probes and found that the test was less expensive and simpler to perform than a number of PCR procedures. Additionally, the PNA-FISH and PCR methods provided 95 percent or greater sensitivity and specificity for detection of genetic targets.
While the broad range of available systems for sepsis testing provide multiple advantages, they also pose complex questions for the lab director. Despite the array of tests available, some lab directors are still seeking broader functionalities and capabilities from the systems they purchase.
"Most laboratories would prefer not to be required to have multiple tests on hand," Natalie Whitfield, director of laboratory and technical operations at OpGen, told GenomeWeb. "We do the best we can with what we have. … A few companies out there are doing a good job of expanding their menus very quickly, and as a lab director you try to maintain a relationship with those companies so that they keep you abreast of what's in the pipeline for the next year or two. You can try to project that you are not purchasing a one-trick pony, but sometimes because a company's strategic goals change, things do not always work out as planned."
Prior to joining OpGen, Whitfield worked as an administrator and later as a lab director at the University of Arizona Medical Center, which is now part of Banner Health in Phoenix, Arizona.
"In most cases, laboratories are using multiple different assays, reagents, and kits," she said. "Sepsis is a good example because most laboratories may be using a couple of different tests together to get you the answer. The test you use comes down to speed and how serious an infection it is, and how that's going to impact treatment. For something like sepsis, we know that for every hour that you delay the most accurate and targeted treatment, you increase the chances for mortality."
In addition to speed and accuracy, ease of use as well and cost of a test were also cited as key criteria by multiple sources.
"Sepsis is a disease area with one of the highest mortality rates that generates some of the highest costs in healthcare today," Wolk said. "This is a 24/7, 365-day operation, so if the test is not easy enough to perform at 3 am, 10 pm, and 8 am among other tasks at the laboratory, then it's not going to be easily adopted to help people.”
The test sometimes has to be performed by people who are not microbiologists, so it must display only moderate complexity, she said, and many laboratories are cross-training now in a broader way than ever before, because the lab workforce shortage is increasing.
The perspective of a lab director about test selection criteria can also be quite different depending on the type of laboratory involved.
"In a primary care center, clinical need and speed of result for the patient treatment and treatment decision are among the primary considerations," Whitfield said. "The clinical need plays a key role especially in terms of decisions around requirements for cost and speed. However, if there is a clinical need for a test and it's one that normally is sent out, you might also need to consider the volume of that test and whether to do the test in-house. For someone who works at a large reference laboratory, the clinical part could be less important."
Because labs are sometimes constrained by available space, construction work may be needed to accommodate the desired tests, and the associated capital expenditures might not be in line with the institution's administrative goals.
Although molecular tests have emerged with the promise of greater speed and accuracy than competitive offerings, Whitfield expressed concern that some molecular tests can be too specific in what they can test, leaving the lab director needing to purchase additional capabilities.
"You can bring the test in, but it may be applicable to one type of infection or one type of clinical syndrome — there may not be a lot of breadth to it," Whitfield said. "That really impacts your cost and things of that nature. As molecular diagnostics expand, speed is becoming the important go-to for everything. Whether or not it is going to greatly impact the clinical decision, it is all about speed and how quickly we can get the result."
Test volume should come into play as well in the decision around which system to use in a given situation, she noted. "If speed is not going to impact a clinical decision, it's okay for the test to take longer. … Some people are willing to give up some of that speed, if they can get more accuracy, sensitivity, and information.”