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MALDI Mass Spec Poised for Further Expansion into Clinical Microbiology Market Pending FDA Approvals

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MALDI mass spectrometry continues to make inroads into the microbiology market, with a growing number of researchers and clinicians adopting the technology for microbe identification.

With the space's two main players – Bruker and BioMérieux – in the process of submitting MALDI-based microbial ID platforms for US Food and Drug Administration approval, the field could see a significant burst of growth in the near future.

"So far what you've seen in clinical labs is that the early adopters have brought in or looked at [MALDI microbial ID platforms] and have either started running them or are just waiting on FDA approval to start running them," Nathan Ledeboer, medical director for the clinical microbiology and molecular diagnostics laboratories at Milwaukee's Froedtert Hospital, told ProteoMonitor.

Ledeboer said that he expects to see a second wave of adoption among clinicians if and when the Bruker and BioMérieux systems receive US FDA approval. He added that he had "heard [that] the comments have been fairly positive back from FDA to both companies" regarding their submissions, although neither has received clearance yet.

Both platforms, Bruker's MALDI Biotyper and BioMérieux's Vitek MS, identify microbes by matching protein profiles of sample organisms generated via MALDI mass spec to profiles contained in the companies' proprietary databases. According to Ledeboer, who is not affiliated with either firm, both systems sell for around $200,000 to $250,000, which includes the instrument, software, and training. Database updates are typically included as part of the device service packages, he said.

Compared to conventional biochemical methods of microbe detection, the MALDI-based platforms offer significant improvements in speed, price, and accuracy, Ledeboer said, noting that once the devices obtain FDA clearance he plans to transition fully to mass spec for microbe identification.

Some facilities have already transitioned to extensive use of the MALDI platforms in their clinical microbiology departments, he said, noting that the decision whether or not to do so in advance of FDA approval was dependent on each individual institution's compliance department.

"You do have hospitals that are using these [devices] before FDA approval," he said. "It's something that quite honestly each laboratory needs to review with their compliance officers. How have you done your verification studies? Are you using exclusively commercial databases or have you built your own? All of those factors will play into whether or not you can report results and whether or not you can bill for it."

One facility using a MALDI device in advance of FDA approval is Houston's Methodist Hospital. In a study published in December in the online edition of Archives of Pathology & Laboratory Medicine, clinicians there found that using Bruker's Biotyper as part of its antibiotic stewardship program reduced average patient stays by 2.6 days and average hospitalization costs from $45,709 to $26,162 per patient (PM 5/24/2013).

Calling the research an "incredibly interesting study," Ledeboer said that it provided evidence for what many clinical microbiologists already suspected – "that more rapid identification ... can result in very positive outcomes in terms of getting patients out of the hospital faster ... and can provide significant cost savings, as well."

Like Methodist, the Mayo Clinic's Infectious Diseases Research Laboratory is also currently using the Bruker Biotyper for clinical work. Robin Patel, director of the lab, echoed Ledeboer's assessment of the MALDI-based ID techniques, noting their ability to identify organisms in a matter of minutes, compared to hours for conventional biochemical methods, while also offering significant cost savings.

At Mayo, the Biotyper has become the primary method for "routine identification of bacteria and yeast and dermatophytes grown from clinical specimens," Patel told ProteoMonitor, adding that as part of establishing the platform for clinical use, she and her colleagues "have done extensive validation with hundreds and hundreds of organism."

"We're not just using [a database] that you can get from a vendor," she said. "We've built our own Mayo database" on top of that offered by Bruker.

Launched in 2006, Bruker's Biotyper was the first MALDI-based microbial ID system to market, with BioMérieux's Vitek MS arriving five years later in 2011. Both devices have received CE-IVD approval and are available for clinical use in Europe. Bruker's Biotyper is also approved for clinical use in Australia, New Zealand, Taiwan, and Japan, while BioMérieux's Vitek MS platform is approved for clinical use in China as well as a number of additional Asian and Latin American countries, the company said. There are roughly 800 Biotypers installed worldwide, versus around 400 Vitek MS units.

Currently, Bruker dominates the European clinical market, Ledeboer noted, but, he said, the US market will likely be more evenly split between the two devices.

Last week, BioMérieux announced an agreement with San Diego, Calif.-based lab services firm Ultimate Labs to offer microbial detection services using the Vitek MS system to its industrial and clinical customers.

Ultimate Labs CEO Kimberly Lim told ProteoMonitor that the Vitek MS system would allow the company to bring assay times down from as long as a day to the range of minutes and could cut costs down to one-third of that of the conventional biochemical assays currently in use.

Ultimate Labs is currently in the process of validating the MALDI methods and plans to offer the service to its customers starting August 1, Kim said.

In addition to Bruker and BioMérieux, French biotech firm AndroMas offers MALDI mass spec-based microbial detection, though it is a much smaller player that has confined itself primarily to the French market. Ledeboer noted that other mass spec vendors have expressed interest in potentially entering the microbe identification space, but, he said, it will be difficult for any late-entrants to take market share from the two entrenched firms.

"I think that for somebody who wants to enter the space next, they are really going to need to come up with the next kind of revolution [in the field], if you will," he said.

One potential advance that he suggested might fit that bill is improving mass spec-based detection of antimicrobial resistance.

"I think both Bruker and BioMérieux are struggling" in this area, Ledeboer said. "We can identify these organisms much faster using the mass spec, but no one has really developed a good method to date for detecting antimicrobial resistance factors that can be put into full-scale clinical production."

That being the case, a vendor that offered "a relatively simple assay that in addition to providing identification could provide some important rudimentary susceptibility information," could have success entering the market, he said.

Patel agreed that the inability of MALDI-MS methods to provide much in the way of resistance information "is a huge limitation."

"For patient care, the healthcare provider needs to know what the organism is and what to treat it with," she said. "In the majority of cases, physicians rely on antimicrobial susceptibility testing results. The [MALDI-based] identification platforms don't provide that."

Ledeboer noted that while the initial mass spec microbe ID platforms have been MALDI based, he didn't think the field will "necessarily be limited to MALDI" going forward.

"I think triple quads are a possibility. I think [Thermo Fisher Scientific's] Orbitraps are a possibility," he said. "Each of those systems certainly offers an advantage over MALDI in terms of the wider mass range they can detect."

However, he said, such systems require considerably more complicated sample prep than the Biotyper or Vitek MS platforms. He cited recent work using LC-MS/MS for identification, noting that while that system was able to identify organisms and detect resistance determinants, "the problem was that the [protein] digestion steps required were still quite extensive."

With their devices, by contrast, Bruker and BioMérieux "have done a really nice job of taking a complex process of mass spec and simplifying it to the point where it can be done easily in a clinical laboratory."

And, while the two vendors' platforms currently struggle to detect antimicrobial resistance, recent work suggests they may be able to improve upon their present capabilities.

For instance, at the 2013 Mass Spectrometry's Applications to the Clinical Lab meeting, Bruker presented data demonstrating the ability of the system to detect carbapenemase, or KPC – a factor that can confer resistance to certain anti-microbial agents – in blood culture bottles.

In December, the company licensed intellectual property from the Erasmus Medical Center for rapid testing on the Biotyper of beta-lactamase activity, a mechanism of antibiotic resistance. In May, it released the MALDI-Biotyper-Spectrum-Beta-Lactamase, MSBL, workflow, which allows researchers to perform functional beta-lactam antibiotic resistance testing for selected antibiotics.

In addition, Bruker is working on Biotyper-based methods that could address antibiotic resistance developed via mechanisms including efflux pumps and porin changes, George Goedesky, executive director of marketing and business development at Bruker, told ProteoMonitor.

BioMérieux is likewise researching the use of MALDI mass spec for detection of resistant pathogen, Nedal Safwat, the company's director of global marketing of microbiology, told ProteoMonitor. However, he said, "based on our studies, we don't believe that any current MALDI-TOF MS platform can deliver reliable, fast, and accurate resistance data."

"We continue to investigate MALDI-TOF MS for this purpose," he said, citing as current key hurdles "ease-of-use and sensitivity."

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