Triple play in lab’s MALDI-TOF efforts

“The pharmacy has been incredibly supportive,” Dr. Ledeboer says. It helped, he says, that the lab devoted plenty of time to educate everyone about the new process prior to launch. He and his colleagues talked about the test’s advantages and limitations, what it could and couldn’t identify, and how they would report the results. “There are so many players whose hands touch a positive blood culture,” he says: critical care, ID, pharmacy, and hospitalists. The lab had to make them all comfortable.

Like Methodist, the lab is also exploring other uses for MALDI-TOF. It recently submitted a paper to the Journal of Clinical Microbiology describing a new database and a new extraction method for identifying Mycobacterium species. The data were presented at the 2012 ICAAC meeting.

Methodist is now studying how well its three-pronged approach will work in its other four system hospitals, which gets to the heart of an important question: Is it realistic for smaller facilities to start thinking about rapid testing and antimicrobial stewardship? “If one is a stand-alone 300-bed, largely community hospital with a different patient profile, this may not have as dramatic an impact,” Dr. Musser says.

One obvious difference is that not all facilities enjoy the luxury of an ID pharmacist, Dr. Septimus notes—less than 10 percent of community hospitals can support one, he says. But, he hastens to add, clinical pharmacists can fill the role if they’re given additional training in infectious diseases.

For a program like this to work elsewhere, it also requires a physician champion, Dr. Septimus says. In some places, the pharmacist-clinician relationship is rock solid. In others, physicians don’t take kindly to a pharmacist telling them what to do. In such places, a physician will need to step in. “Because ultimately, stewardship is about physician behavior. And sometimes you have to deal with a difficult physician. We all have them,” says Dr. Septimus, who is also an adult infectious diseases physician and hospital epidemiologist. The best person to talk to physicians is often a fellow physician, albeit one who can talk to them collegially. “Stewardship is a big team sport,” says Dr. Septimus, who, being from Texas, should know.

Real results have persuasive powers of their own, says Dr. Perez. “When you call physicians with objective data, it’s very difficult for them to turn their heads away.”

For his part, Dr. Musser says he encountered almost no resistance to the lab’s bold proposal. When the vastly improved speeds became clear only a few patients into the study, in fact, “There was zero push­back.” If anything, he says, he was met with incredulity from clinicians who were stunned by the speedy TATs. In one instance an intensivist said, “We don’t believe they can do it this fast. Can they really do it this fast?” Adds Dr. Musser: “Seriously. I’m not making this up.”

Smaller hospitals might also blanch at the price tag. MALDI-TOF is expensive—about $200,000. “It’s like a new car,” Dr. Musser says. ”You get a bit of a sticker shock at first, but the downstream cost savings are tremendous. We can no longer do cost accounting with blinders on in the pathology department.”

Sandra Richter, MD, and her colleagues at Cleveland Clinic have been doing clinical trial work using both of the MALDI-TOF mass spec instruments on the market, Bruker’s Biotyper and bioMérieux’s Vitek MS. “It seems like a no-brainer to bring this technology into the clinical lab,” says Dr. Richter, director of bacteriology in the departments of Clinical Pathology and Molecular Pathology. Based on her work with both systems in the research lab, as well as what has been reported in the literature, “It’s clear that this is a giant step forward in the accuracy and speed of organism identification routinely reported by the lab. Both systems provide reliable results that compare quite well to either reference biochemicals or molecular sequencing identification.”

Dr. Richter finds it reasonable to look beyond the purchase price. The data she’s seen suggest large institutions could recoup their costs within two years (Neville SA, et al. J Clin Microbiol. 2011;49:2980–2984; Gaillot O, et al. J Clin Microbiol. 2011;49:4412). Even the initial price doesn’t leave her deeply unsettled. “Compared to, say, a chemistry analyzer, it doesn’t seem expensive.”

For now, the technology is for research use only. “We need some FDA-approved applications for MALDI so we can start billing,” Dr. Ledeboer says.

Both bioMérieux and Bruker planned to submit their systems to the FDA in early 2013 and anticipate clearance during the year.

The companies are refreshingly understated when they talk about the future of MALDI-TOF.

Bruker’s George Goedesky, executive director, MALDI Biotyper for the Americas, says laboratories will need to consider not only accuracy but also ease of use and throughput. “All technologies—sequencing, mass spec, NAT—will have a place,” he says. “The issue is, what questions will best be answered by each of these technologies?”

When MALDI-TOF does become available for clinical use, it won’t be as if the FDA has waved a magic wand over the technology, immediately freeing it for the masses. What labs may not fully appreciate, says bioMérieux’s Nedal Safwat, PhD, is that the RUO and IVD databases will be treated differently. The MALDI-TOF database is a growing component, and new organisms or updates to existing organisms will be in the RUO database format, he says, while the IVD database (still in clinical trials) will reflect the new additions once FDA clearance is granted. The RUO database will be used more for research, and the database will grow in research settings. (Dr. Safwat says the regulation of both databases is under discussion now.) This is no small consideration if, as some predict, labs first run samples on the IVD database, and, if they can’t make an identification, potentially turn to the RUO database. The biggest implications would be for smaller institutions.

“Not every institution would be able to access both databases. RUO databases are meant for larger institutions where they can conduct research with an open architecture where new data can be archived for database research and development,” says Dr. Safwat, the company’s director of product marketing, U.S. Clinical Microbiology.

Asked about how MALDI-TOF mass spec might fit into the community setting, Dr. Safwat says that he’s seeing “big hype in the market about getting MALDI,” in part because of the prestige it might confer on the institution. “It’s image perception,” he says.

MALDI-TOF might not be a good fit for every hospital right now, he allows, unless they have high volumes and a diversity of organisms. For slow-growing organisms—filamentous fungi, mycobacteria, molds, yeast—MALDI-TOF is a superior technology, he says. But for routine isolates, it might be harder to justify its use. “And the hospital has to enable the physician to act on the results as soon as they’re available and have antibiotic susceptibility results shortly after to target therapy further,” Dr. Safwat says.

While many are actively exploring applications for strain typing and resistance testing, Dr. Safwat speaks cautiously. “It’s premature to say that it’s going to be able to do either. We see some major challenges.” He sees next-generation mass spec focusing on proteomic analysis, enzyme markers for resistance, and even drug metabolism.

As even the vendors make clear, MALDI-TOF isn’t the only player on stage (and MALDI may not even be the final form of mass spec in the lab). Next-generation sequencing is quickly moving on the scene and can address limitations found in current MALDI-TOF and NAT technologies. Each approach, like a poem, has its strengths and mysteries.

Regardless of the specific characters and their roles, the unfolding story will be one of transformation for the microbiology laboratory, says Dr. Ledeboer.

Ask ID physicians today if they would like automatic typing in their next-generation identification system, says Dr. Ledeboer, and “They’ll say it would be nice, but they won’t rank it high on their list.”

Ask the question differently, and the response will be far more enthusiastic, he predicts. “What if instead of typing being confirmatory of an outbreak, it could identify outbreaks early?” he says. If the lab used a technology like mass spec or next-gen sequencing, and included bioinformatics in the identification scheme, “We could actually look for sequences of enterococcus, sequences of staph, in real time, on a unit-by-unit basis.”

“It’s going to change the value of microbiology’s data,” Dr. Ledeboer says. “It’s also going to change how microbiology does its work, in that we’re going to depend a lot more on software, a lot more on bioinformatics.”

That will shift the science of microbiology. Until now, microbiology has largely been a confirmatory science, for a very good reason: “We have to culture everything,” he says. But now, he says, microbiology has the potential to become a prospective science.

Karen Titus is CAP TODAY contributing editor and co-managing editor.