MALDI-TOF MS: An Evolving Tool in Clinical Diagnostics
Advances in MALDI-TOF MS have significantly expanded its use in high-throughput diagnostic labs
Jake Moskowitz, DVM, PhD is a postdoctoral scientist in the Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai Medical Center, and a freelance consultant/science writer with expertise in microbiome-based therapeutics.
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Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has become a well-established tool for the identification of pathogens in a variety of patient samples. Though this technology has been used for bacterial identification for many years now, newer generations of MALDI-TOF MS are quickly expanding the capabilities of this technology in a high-volume clinical setting.
The latest iterations of MALDI-TOF MS instruments can detect a wider range of biomolecules, have expanded pathogen ID capabilities, and improve processing efficiency for high-throughput diagnostics. These improvements directly facilitate more rapid turnaround from diagnostics to treatment and further guide therapeutic strategies through novel antimicrobial sensitivity testing methods. The continued evolution of MALDI-TOF MS has cemented this technology as a key component of diagnostic laboratories.
Using MALDI-TOF MS for applications beyond bacterial identification
With the rising prevalence of antimicrobial-resistant bacterial infections, the appropriate use of antibiotics is critical to prevent the development of new resistant pathogens that can evade current treatment options. Classic microbiology techniques can provide antimicrobial susceptibility testing (AST) profiles by determining minimum inhibitory concentrations for pathogens of interest, but this approach requires up to 72 hours to produce results. In critical cases, this relatively slow turnaround time is a significant hindrance to timely treatment for the patient in need and may force health care providers to prescribe antibiotics with unknown efficacy for the pathogen at hand.
"MALDI-TOF MS has been used to generate proteomic “fingerprints” that facilitate classification of Staphyloccoccus aureus based on resistance profiles. "
MALDI-TOF MS uses novel detection methods to determine AST without the need for time- and labor-intensive growth assays, providing susceptibility profiles faster than the traditional standard. Led by Dr. Karsten Becker, a group from the Institute of Medical Microbiology in Muenster, Germany, reportedly used MALDI-TOF MS to determine AST with up to 100 percent sensitivity and specificity in four to five hours, depending on the pathogen of interest. Becker’s team successfully determined AST profiles for strains of Klebsiella and Pseudomonas by comparing spectral intensities during growth in microdroplets of media containing antimicrobials. Spectral shifts in the presence of antimicrobial-spiked media predictably indicated strain resistance.
In other instances, MALDI-TOF MS has been adapted to detect proteins that confer antibiotic resistance due to the presence of known resistance genes in bacteria. For example, some strains of pathogenic Bacteroides fragilis harbor a gene encoding metallo-beta-lactamase, conferring resistance against nearly all beta-lactam drugs. Using MALDI-TOF MS, specific spectral shifts can determine the presence of this resistance factor, thereby guiding health professionals toward alternative therapeutic options.
Moreover, MALDI-TOF MS has been used to generate proteomic “fingerprints” that facilitate classification of Staphylococcus aureus based on resistance profiles. Given the prevalence of methicillin-resistant S. aureus (MRSA) as a problematic antibiotic-resistant infection that causes approximately 20,000 deaths per year in the US, efficient identification of an outbreak is critical to improving health outcomes. Thus, the use of MALDI-TOF MS for AST profiling demonstrates a promising application for this technology beyond standard pathogen identification.
The evolving commercial landscape of MALDI-TOF MS
The release of new generations of MALDI-TOF MS instruments reflects the advancement of applied MALDI-TOF MS technology in clinical diagnostics. The global diagnostic company bioMerieux recently announced 510(k) clearance from the FDA for their latest iteration of MALDI-TOF MS, VITEK MS PRIME. This clearance follows the product’s CE-marking in April 2021, enabling market availability in the United States, Europe, and other regions around the world. VITEK MS PRIME demonstrates many of the recent updates to this technology that are specifically designed for more streamlined diagnostics. New features enable continuous sample loading without disruption to current processing and allows sample prioritization for critical cases that need an immediate diagnosis. Additionally, VITEK MS PRIME’s pathogen identification system can be integrated with bioMerieux’s MALDI-TOF technology for AST testing, providing efficient diagnosis and therapeutic guidance.
"New features enable continuous sample loading without disruption to current processing and allows sample prioritization for critical cases that need an immediate diagnosis."
Shimadzu Scientific Instruments also recently released their latest MALDI-8030, which significantly enhances detection capabilities from earlier models. The MALDI-8030 specifically reflects the need to broaden the classes of biomolecules that can be analyzed by MALDI-TOF MS, and in turn expand pathogen identification. Shimadzu’s model analyzes both positive and negative ions (dual polarity), which facilitates improved detection of a wider range of molecules, including peptides, oligonucleotides, lipids, glycans, polymers, and small molecules. The ability to detect different classes of molecules may expand the database of identifiable organisms and ideally allows more complete phenotypic characterization of known pathogens. As a primary example, more thorough molecular fingerprints will provide better AST profiling for detected pathogens, and ultimately, facilitate more effective treatment strategies while limiting antibiotic resistance.
Applying MALDI-TOF MS to the COVID-19 pandemic
The COVID-19 pandemic caused by SARS-CoV-2 continues to spawn global widespread infections as new pathogenic variants emerge. SARS-CoV-2 is typically diagnosed via RT-PCR using primer/probe combinations that bind viral nucleotide sequences that are then amplified for detection. However, the latest SARS-CoV-2 variants are of cause for concern because novel mutations may prevent primer/probe binding to viral sequences, leaving many of the commonly used RT-PCR techniques prone to false negative results.
A group led by Dr. Alberto Paniz-Mondolfi from the Icahn School of Medicine at Mount Sinai, New York, recently combined the use of MALDI-TOF MS with RT-PCR to improve the detection of different SARS-CoV-2 variants. Paniz-Mondolfi’s team combined the two technologies to reliably detect five different targets across two viral genes. Notably, the addition of MALDI-TOF MS facilitated the detection of viral genes that were not detected by RT-PCR alone due to mutations of viral sequences. Paniz-Mondolfi’s work further illustrates the wide-ranging capabilities of the latest MALDI-TOF MS technology.
Advancing clinical diagnostics
As diagnostic laboratories evolve to accommodate higher sample loads and more sophisticated diagnostic capabilities, advances in MALDI-TOF MS demonstrate that this technology is here to stay. MALDI-TOF has already been established as a standard for pathogen identification, but more recent updates have significantly improved the range of identifiable organisms and expanded the technology’s functionality to include antimicrobial sensitivity profiling. In doing so, MALDI-TOF not only provides efficient diagnostics, but also facilitates more effective treatment plans. Moreover, the latest MALDI-TOF MS instruments are specifically tailored to facilitate high-throughput sample processing with the ability to seamlessly prioritize urgent samples. Together, these features establish MALDI-TOF MS as a key component of diagnostic laboratories that aim to provide high-volume diagnostics with evidence-based therapeutic guidance.
