Sooner, smarter—new strategies against sepsis

While the rapid turnaround times did not come as a surprise to Dr. Schifman, he says the study did turn up several unexpected findings about the use of technology to monitor blood cultures. “There were 64 laboratories in the Q-Probes study, and every one of them used a continuous-monitoring blood culture system,” Dr. Schifman says. “Based on the labs that participated, it seems this technology has more or less penetrated the lab community, which is a good thing because these systems have been shown to be very reliable and much faster in terms of detecting bacteremia with greater productivity than some of the other systems out there.”

While 100 percent of the labs used continuous-monitoring systems, the study found that almost a third of the labs did not make full use of the technology. “With these systems, you can get a positive signal anytime during a 24-hour period. But some of the laboratories—more than I expected—were not sufficiently staffed on evenings during the week or nights on the weekend to process that blood culture when it first signaled as positive,” Dr. Schifman says.

As a result, several hours might pass before the positive culture is removed from the machine and subjected to Gram staining. That delay lengthened the overall median turnaround time for those labs to two hours, compared with just 37 minutes for labs that provided around-the-clock coverage. “That’s an area for improvement,” Dr. Schifman says. “Laboratories that are not processing blood cultures on a continuous basis might need to revisit this issue and see if there’s some way they might make that happen.” Labs might find it difficult to follow this recommendation in the face of tough financial pressures, he adds, but the authors encourage labs to be resourceful. Telepathology, for example, might help overcome the challenges of understaffing or lack of expertise during certain times of day.
Interestingly, the study found no differences between the accuracy of Gram stain results when a nonspecialist versus specialist microbiologist processed the positive blood culture samples. In fact, among more than 5,000 blood cultures, the authors found a very low (1.2 percent) rate of discordance between the results of preliminary Gram staining and the final blood culture results.

“Most of the discordances were mixed cultures,” says Q-Probes coauthor Frederick A. Meier, MD, senior staff pathologist at Henry Ford Hospital in Detroit and director of regional laboratory services, Henry Ford Health System. “It’s not that nonspecialists were misinterpreting Gram stains.”

For laboratories to maintain such high Gram stain interpretation quality, the authors recommend that laboratories track the accuracy of their initial blood culture Gram stain results. The Q-Probes study also highlighted the value to laboratories of setting and monitoring turnaround time goals for processing and reporting, and of monitoring the efficiency of their efforts to report preliminary blood culture Gram stain results as critical values. “Of our 64 participating institutions, laboratories that set goals reached better levels of performance than those who didn’t,” Dr. Meier says.

He adds, “A lab that monitors blood culture incubators 24/7, sets itself goals for rapid Gram stain performance and reporting, and monitors the correlation between the Gram stain and the final diagnosis is doing its part to maintain quality in positive blood culture initial detection, characterization, and reporting.”

After the preliminary blood culture results are reported, laboratories work quickly to identify the pathogen and determine its antibiotic susceptibility profile.

“When you have something that’s positive in the continuous-monitoring blood culture system, you have several options,” says Vincent LaBombardi, PhD, director of microbiology at New York Hospital-Queens, Flushing, NY. Various technologies—existing ones and those to come—aim to provide more information in a shorter time with less complexity compared with previous methods.

Newer technologies tend to channel the power of multiplex PCR, which generally provides more targets in a shorter time compared with nonmultiplex assays. “Instead of one target per test, we now have many targets per test in the same amount of time—and in some cases less time—than it took to perform the manual or singleplex methods,” Dr. Wolk says. Nanosphere’s Verigene Gram-Positive Blood Culture Test, for example, is an automated multiplex test capable of detecting nine species of gram-positive bacteria commonly associated with bloodstream infections, as well as four genera and three antibiotic resistance genes within about 2.5 hours of obtaining a positive blood culture test. A Gram-Negative Blood Culture Test, also FDA-approved, detects five species, four genera, and six resistance genes in less than two hours. And in June, the FDA cleared BioFire’s blood culture ID panel for the FilmArray instrument, which relies on multiplex PCR to test for 24 pathogens and four resistance genes in about one hour.

AdvanDx’s PNA FISH testing algorithm was among the first FDA-cleared systems for the rapid detection of bacteria and yeast from blood culture bottles. The PNA FISH assay uses fluorescent probes to illuminate species-specific rRNA sequences in whole cells within 90 minutes.

Other technologies have not been FDA cleared but are available for research use only. Europe and Canada have approved the use of Bruker’s IVD MALDI Biotyper for the rapid identification of microorganisms via MALDI-TOF analysis, for example.
Still other technologies are in prototype form and have yet to hit the clinical arena. Accelerate Diagnostics, of Tucson, Ariz., is working on a prototype of an instrument called the BACcel, designed to identify organisms and provide susceptibility testing directly from a positive blood culture in a two- to six-hour window.

Though these technologies are rapid and informative, most lack the ability to assess antibiotic susceptibility, and those that have this ability often require up to 24 hours to yield results. Dr. LaBombardi considers the VITEK 2 by bioMérieux among the fastest systems to combine pathogen identification with antibiotic susceptibility profiling. “Some of the other growth-based systems have to incubate overnight, so essentially it doesn’t make a difference when you set them up because you’re not going to get a result until the following day.”

By streamlining the VITEK 2 workflow, Dr. LaBombardi’s group at a hospital he was with previously greatly reduced the time needed to transition patients to targeted antibiotic therapies. In particular, his group began placing primary plates or subcultures into the machine continually throughout the day, rather than batch loading at the end of each shift.

To expedite the reporting of results, particularly with regard to drug-resistant organisms, Dr. LaBombardi initiated a feature he calls autoposting. As soon as an isolate is identified and susceptibility tests are complete, the results go through an advanced expert system to confirm that the isolate identification is consistent with the organism’s susceptibility profile. Results that pass this internal screen are automatically sent across the interface and posted to the lab and hospital information systems. Contradictory results are held back for manual review.

“As soon as I can see the results, our clinicians can see the results,” Dr. LaBombardi says. “So instead of having a result the following morning, by the time the technologists get around to reading the result and sending it across the interface, the results are now available the same afternoon the isolate is set up.”

Dr. LaBombardi’s group further customized the machine to flag some of the antibiotic resistance mechanisms commonly reported in New York. “If I have an organism producing a carbapenemase, for example, I don’t want to hold that back for review. I want that sent across right away, because for us that’s quite common. If you’re somewhere else in the country, it might not be that commonplace and you might want to look at it beforehand. But in this case, we need to trust the instrument.”

These relatively simple changes in workflow brought dramatic results at his former hospital. “Before we started autoposting, 36 percent of our isolates of Klebsiella pneumoniae produced carbapenemase,” Dr. LaBombardi estimates. “One year after implementation, we were down to 23 percent. And the year after that, we were down to 21 percent. We made a significant decrease in our rates of resistant isolates because the patients could be placed in context precautions right away.”

Physicians quickly latched onto the efficiency of autoposting, Dr. LaBombardi recalls. “Clinicians would comment to me that they became used to looking for results in the afternoons. So when they were around the computer, they knew to check and see what was new. We changed their whole way of doing business.”

Innovative technologies and workflows continue to change the landscape of clinical pathology, Dr. Wolk says, but with them comes greater responsibility. Dr. Wolk uses the term “interventional diagnostics” to describe the recent push to monitor the effects of new technologies on patient outcomes, such as might result from shortening the time to when a patient receives targeted antimicrobial therapy. This information can, in turn, be used to generate evidence-based clinical microbiology practices. “These practices will drastically improve the way we assess new technology, moving from a model where we assess accuracy with no metrics to prove patient benefit, to a model in which patient benefit metrics become the norm.”

Those metrics involve tracking morbidity, mortality, health care cost, length of hospital stay, duration of antibiotic or antiviral treatment, and other factors before and after the technology is implemented, she explains. “It’s a statistical approach—rather than presuming, ‘We have this new technology so we should test for all of these microbes just because we have the tools,’ maybe we should rapidly and critically examine the impact to patient care.”

From where Dr. Wolk stands, the future of pathology and laboratory medicine will call for greater ownership of the postanalytical impact of laboratory tests, ranging from improvements in patient care to reductions in health care costs and increased adoption of antibiotic stewardship. “Laboratories spend a lot of time and effort examining analytical and preanalytical phases of testing,” Dr. Wolk notes. “But from my perspective, the larger impact will come from our postanalytical footprint—it’s in this phase that we can prove these new laboratory tests are actually worth what we’re paying for them.”

In her lifetime, she hopes, “we’ll have an ability to prove the laboratory impact in ways we never could before.”

Ann Griswold is a writer in Annapolis, Md.