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MALDI Facing Competition in Clinical Microbiology Space from Alternative Mass Spec Methods

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NEW YORK(GenomeWeb) – Where mass spec-based microbiology is concerned, MALDI has largely led the way, with commercial platforms from Bruker and BioMérieux in recent years receiving regulatory approvals and winning clinical customers around the world.

If the Mass Spectrometry Applications to the Clinical Laboratory annual meeting held last month inSan Diegois any indication, though, the clinical microbiology field is looking beyond MALDI for the next generation of mass spec-based tools.

For instance, said Susan Butler-Wu, associate director of the clinical microbiology laboratory at the University of Washington, in 2014 the meeting had three microbiology sessions, all of which focused primarily on MALDI-based microorganism identification.

By contrast, this year's meeting had five microbiology sessions, only one of which focused on MALDI-based identification, she noted. Instead, researchers presented on a variety of mass spec approaches, applying techniques like rapid evaporative ionization mass spectrometry (REIMS) and triple quad-based multiple-reaction monitoring for purposes including direct detection of bacteria from clinical samples and assessment of antibiotic resistance.

Clinical proteomics has arguably had its greatest success in the microbiology space with Bruker's MALDI Biotyper and BioMérieux's Vitek MS systems making significant inroads into the field. Both received US Food and Drug Administration 510(k) approval for their systems in 2013 and, with the FDA clearance this month of Bruker's expanded organism library, both systems allow for the identification of a variety of gram-negative bacteria, gram-positive bacteria, yeast, and anaerobes.

Both platforms identify microbes by matching the protein profiles of sample organisms generated via MALDI mass spec to profiles contained in proprietary databases. Compared to traditional biochemical methods of microbe detection, MALDI-based systems can offer significant improvements in speed, price, and accuracy.

These advantages are particularly attractive in their potential to translate into reductions in patient costs as well as improvements in antibiotic stewardship programs. For instance, a 2013 study by Houston's Methodist Hospital found that use of the Bruker MALDI Biotyper within the hospital's clinical microbiology department reduced average patient stays by 2.6 days and average hospitalization costs from $45,709 to $26,162 per patient.

Despite the advantages — both realized and potential — of MALDI-based microorganism ID, however, there remain a number of goals within the field that might prove better achieved by different modes of mass spec.

For instance, said Nathan Ledeboer, medical director for the clinical microbiology and molecular diagnostics laboratories at the Medical College of Wisconsin, while research into using MALDI for assessing antibiotic resistance is ongoing, "we have yet to see significant movement towards commercialization of a rapid resistance detection assay using MALDI."

In fact, BioMérieux presented research at MSACL for the second straight year looking at use of MRM-MS on a triple quadrupole instrument to detect analytes linked to antibiotic resistance. This year, researcher Tiphaine Cecchini presented a study in which the company used MRM to quantify expression levels of efflux pumps and β-lactamase, bacterial proteins both linked to resistance to a variety of antibiotics.

Perhaps at the top of the field's wish list, Ledeboer said, is the ability to detect organisms directly from a specimen without having to enrich it through culturing first, as is required by current MALDI methods and, essentially, all approaches in wide use in clinical practice.

Butler-Wu agreed, noting that "one of the things we are all talking about right now is direct identification of pathogens from clinical specimens using mass spec."

In that regard, work presented at MSACL by Imperial College London researcher Nicole Strittmatter on use of REIMS for detection of bacteria directly from human colorectal tissue samples drew significant attention at the conference.

Using REIMS to look at lipid profiles of microorganisms, Strittmatter and her colleagues were able to identify lipidomic markers for a number of bacteria at taxa levels ranging from phylum down to species.

Ledeboer noted that while evaluation of the technology has been limited outside that done by Strittmatter's group, which is led by Imperial College researcher and developer of the REIMS technology Zoltan Takats, the findings were exciting in that they suggested REIMS could allow researchers to do direct detection of bacteria without having to culture first.

Additionally, he said, the high specificity of lipids to various forms of bacteria made lipidomics a potentially attractive approach to bacterial ID.

REIMS's potential is also interesting from a commercial perspective in that it provides a route for Waters to join Bruker and BioMérieux in the mass spec-based clinical microbiology space.

Waters in July of last year acquired MediMass, owner of the REIMS technology, and is pursuing mass spec-based microbe ID using the platform. In an interview with GenomeWeb following the acquisition, Mike Morris, senior director of mass spec research at Waters, said the company had "some indications from preliminary work that we may be able to get an earlier [ID] using [the REIMS] approach [because] you may not need as long a culture time as the MALDI method currently does."

"We've undertaken work with a number of laboratories looking at the possibility of using this on bacterial cultures in a similar way to [MALDI], and it shows a fingerprint pattern similar to what MALDI does that we believe gives enough information" to make bacteria IDs, Morris added.

As Ledeboer and Butler-Wu suggested, though, the real prize is direct detection without the need for culturing. In addition to REIMS-based lipid profiling, a study presented by University of California, San Diego researcher Vanessa Phelan used tandem mass spec measurements of metabolites to identify Pseudomonas aeruginosa directly from the sputum of cystic fibrosis patients.

"CF sputum is a very complicated specimen with lots of different organisms present, so the fact that you could directly detect specific metabolites of Pseudomonas aeruginosa in there by mass spec was really amazing," said Butler-Wu.

Such demonstrations suggest the future feasibility of direct detection, but, Butler-Wu noted, significant work needs to be done to nail down what the relevant analytes are and at what levels they are present. That, she noted, will inform decisions regarding which mass spec approaches are required to measure them.

"This is really a nascent field where [researchers] are starting to really look at detecting metabolites and microbial lipids in vivo," she said. "Now, in order to address what you need from [mass spec] in terms of sensitivity, you have to assess how much of the analyte is there. And that will determine what amount of enrichment needs to be done" upfront of mass spec analysis.

Ledeboer cited the example of sepsis, noting that "if you want to look for patients that are septic directly using mass spec from a blood sample, that may be very difficult because of the relatively small amount of organism that is present. So is there a biomarker we can look for, a combination of markers, or do we need to look at an enhancement of sensitivity using a brief culture or something like that?" he said.

One challenge of enriching for mass spec analysis in microbiology as opposed to, for instance, disease biomarkers, is that the number of different analytes you might want to measure clinically would likely be much higher in the former given that you are trying to identify a single organism amidst a large group of potential candidates.

This, Ledeboer noted, presents a challenge for approaches like immunoenrichment, where clinicians would run into multiplexing limitations in trying to devise assays for bacterial ID.

That is an advantage that MALDI has today," he said. "The databases are so large."

Nonetheless, Ledeboer said, "MALDI is probably not the end of where the proteomic revolution is going in microbiology."

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