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Association of Molecular Pathology Report Looks at Emerging Uses for MALDI in Clinical Microbiology


NEW YORK (GenomeWeb) – In recent years, clinical microbiologists have widely adopted MALDI-TOF systems like Bruker's MALDI Biotyper and BioMérieux's Vitek MS as part of their bacterial identification workflows. Offering the possibility of more rapid, less expensive identifications and improved patient outcomes, MALDI-based methods have become standard practice in many hospitals across the US and Europe.

As this market has matured, vendors and clinicians have begun looking ahead to new uses for the technology. In a paper published last month in the Journal of Molecular Diagnostics, researchers from the Association of Molecular Pathology detailed a number of emerging applications, describing their potential benefits and limitations.

The report focused on three areas: identification of filamentous fungi, identification of mycobacteria, and testing for resistance and susceptibility to antibiotics.

Of these, applications for identification of mycobacteria like tuberculosis are perhaps the closest to readiness for the clinic, Susan Butler-Wu, director of medical microbiology at Los Angeles County-USC Medical Center and an author on the report, told GenomeWeb.

"I think mycobacteria is almost there," she said, noting that data from several studies indicates MALDI's usefulness in this area. Most recently, in 2014 Butler-Wu and colleagues at the University of Washington (where she was then a researcher), published a study in the Journal of Clinical Microbiology evaluating the ability of the Biotyper and Vitek MS to identify mycobacteria infections.

In an analysis of 198 clinical isolates spanning 18 species, they found that the Vitek correctly identified 94.4 percent of isolates to the species level, while the Biotyper using Bruker's Mycobacteria v2.0 library correctly identified 79.3 percent, and the Biotyper using the v2.0 library augmented with a custom database developed in-house by the UW team correctly identified 94.9 percent of isolates.

In the recent JMD paper, the authors noted that the lower performance of the Biotyper in this study might have stemmed from the fact that the researchers used a different extraction protocol than that used to generate the Bruker mycobacteria database. Even so, they noted, it managed a variety of clinically significant identifications, including distinguishing between Mycobacterium chelonae and M. abscessus and identifying 100 percent of M. tuberculosis strains to the complex level.

The authors added that Bruker last year expanded the number of species in its mycobacterial database, but that no studies have yet evaluated the performance of this larger library.

Speaking of MALDI for identification of filamentous fungi, Butler-Wu suggested that this application was also likely to make its way into the clinic in the relative near term, though not as quickly as mycobacteria assays.

"We're not quite there with fungi, in my opinion," she said. "I think we'll be there soon, but we're not quite there right now."

"Filamentous fungi is remarkably complex," she said, noting that, for instance spores can produce different spectra than fungal hyphae and that spectra can change from subculture to subculture.

This complexity also makes fungi challenging and time consuming to identify via conventional methods.

"The expertise [and] competency that you need to maintain for looking at these very specialized reproductive structures and being able to know which mold it is, it's very challenging," Butler-Wu said.

Turnaround time is also an issue for conventional methods, as clinicians must wait for isolates to grow enough to display their distinguishing characteristics.

"There are two advantages, really, [to MALDI-based methods] which are, the improved turnaround time and the potential for improved accuracy with respect to species identification," Butler-Wu said. "That's the power of this technology for these organisms."

According to the AMP report, there have been only two studies evaluating the Biotyper's filamentous fungi capabilities. In one, the system correctly identified only 16.2 percent of isolates to the species level and left 48.4 percent of isolates unidentified.

In a more recent study, the system correctly identified 72 percent of isolates to the species level. It left 16.5 percent unidentified, which compared unfavorably to a 4 percent rate for conventional identification methods.

Data from the Vitek MS appears more promising, the AMP report noted. Abstracts presented on fungal ID using a not-yet-available updated version of BioMérieux's US Food and Drug Administration-cleared database "reported species identification rates of 83.3 percent to 97.8 percent for routine clinical isolates, with no misidentifications," the authors wrote.

"The initial data on the Vitek MS looked very positive," Butler-Wu said. "And I'm looking forward to there being more data available on that."

She also noted work by researchers at the National Institutes of Health, who have built one of the most extensive MALDI-TOF mold databases and use the method for routine identification of mold. The database has shown excellent performance in-house at NIH but has performed less well in the hands of different labs, Butler-Wu said.

The AMP report also addressed MALDI's usefulness for antibiotic resistance and susceptibility testing, where, Butler-Wu said, the technology has potential but will require further development before its value can be fully evaluated.

"I think MALDI has had some great potential, but how it fits in and what will be the advantages and disadvantages versus some other technologies, we will have to see," she said.

Researchers and vendors have taken a variety of approaches to applying MALDI to resistance and susceptibility testing. For instance, Bruker has developed a research-use-only method on the MALDI Biotyper for detection of carbapenem-resistant strains of Bacteroides fragilis and Staphylococcus aureus by detecting the presence of, respectively, the cfiA gene and the mecA cassette expressing the protein PSM.

The company also this year released its MBT STAR-BL assay, which detects antibiotic resistance in Gram-negative bacteria by looking for products generated when these antibiotics are degraded by carbapenemases.

Several research teams have also published studies on using MALDI to measure the pKpQIL_p019 protein as a proxy for Klebsiella pneumoniae carbapenemase (KPC) protein, which can confer resistance to carbapenems. The genes for p019 and KPC are frequently expressed on the same plasmid, meaning that p019 can be used to detect the presence of KPC.

Ideally, clinicians would also be able to use MALDI for antibiotic susceptibility testing, which would allow them to identify the antibiotics that will be effective for treating a particular infection. In a 2014 JCM paper, Bruker researchers demonstrated the ability of the MALDI Biotyper to measure the growth of K. pneumoniae isolates in the presence of meropenem, thereby testing their susceptibility to this agent.

Butler-Wu said, though, that currently such methods might be too complicated for broad clinical use.

"These publications on using MALDI for susceptibility testing or for detection of resistance, these are really research assays," she said. "The big part that I'm not clear on, and that I'm sure the manufacturers are working on, is, how scalable is it? I think we have to wait and see."