Thomas Morrow, MD

Most people reading this will never have heard of a scientist by the name of Koichi Tanaka who in 1987 demonstrated that a matrix-laser device could ionize a protein with the proper wavelength of light. This process was named matrix-assisted laser desorption/ionization (MALDI).

In fact, most readers would think: So what!

It had been known for some time that lasers could ionize smaller molecules, but proteins, being much more complex, posed difficulties. The 2002 Nobel Prize in chemistry was awarded, in part, to Tanaka for this discovery. Further development took the pairing of MALDI with a mass spectrometer to rapidly identify proteins. For those who did not train to be a chemist, a mass spectrometer measures the mass-to-charge ratios of molecules after ionizing a sample chemical to generate a charged molecule. It can actually determine the elemental composition of the sample.

A quarter of a century later, in late August of this year, the FDA allowed marketing of a system using this process to rapidly, inexpensively, and accurately identify bacteria and yeast known to cause illness in humans.

Vitek MS by bioMerieux

Vitek MS by bioMerieux

By the way, the FDA did not approve this technology in the same way that it awards approval for a drug; it allowed marketing of it through a de novo regulatory pathway that allows novel low-to-moderate-risk medical devices to come to market that were “not substantially equivalent to an already legally marketed device.”

The identification of illness-causing organisms is routinely done in physician offices and hospitals across the country. There are numerous methods to do this and some, such as a rapid strep test for strep throat, are able to determine a diagnosis in a matter of minutes. But rapid tests are not available for many organisms. Identifying organisms typically starts with a rather fast but crude test, the Gram stain, developed in 1884. This test utilizes a stain and (to use a metaphor) can get a physician into the correct city, but more accurate tests are needed to get the physician into the ball park or to the correct seat to determine the proper treatment. These additional tests take time, and sometimes a lot of time.

In fact, for most serious infections, delays of many hours or days can occur before some organisms are identified, because routine testing uses rather slow techniques such as culture and growth characteristics; all dependent upon the growth cycle of the bacteria. Delays in accurately diagnosing the exact organism can have significant consequences, including:

  • Delays in proper treatment
  • Use of broad-spectrum antibiotics while waiting for an accurate diagnosis
  • Wasted hospital days
  • Potential risk to the patient’s health

This new process with a rather complex name — matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) — can eliminate the Gram stain and it can, in an automated fashion, generate, interpret, and report test results for 193 different organisms within minutes.

The system, named VITEK MS, manufactured by bioMerieux in Durham N.C., can identify such bacteria as Clostridium, Haemophilus influenzae, Staphylococcaceae, Streptococcaceae, Enterobacteriaceae, Pseudomonadaceae, and Bacteroidaceae families, to name a few. These organisms are associated with skin infections, pneumonia, meningitis, sepsis, and other serious, life-threatening infections.

The device can also identify yeasts such as the Candida, Cryptococcus and Malassezia groups, something that typically takes considerable time.

Many of these infections are particularly dangerous and common in patients suffering from cystic fibrosis, cancer, and immune suppression for autoimmune diseases.

They are also found in patients on anti­rejection drugs post organ transplant.

The process is rather novel as it uses spectra (think light waves) obtained from the sample (which can be blood, cerebral spinal fluid, wound drainage, stool, biopsy, or pus that is placed directly on a matrix-containing plate) and creates mathematical models of their spectra bands. It compares these to a known library of spectra. Basically it matches complex patterns from an unknown to a known in the library to make the identification — similar to how fingerprints are used for identification.

The FDA based its approval on a study involving 7,068 microorganisms. MALDI-TOF MS correctly matched 93.6 % of the organisms with the scientific group and family. The comparator for the study was genetic sequencing and biochemical testing, the current time-consuming “gold standards.” MALDI-TOF MS provided no identification for 3.2 % of samples, and an additional 2.4% were deemed of low discrimination. Only 0.8% were mistakenly identified.

Since antibiotic resistance is associated with different bands of spectra, MALDI-TOF MS can determine methicillin-resistant Staph aureus within minutes. Also important is that the MALDI-TOF MS process will be able to identify some rare anaerobic organisms that have been very difficult to identify: Current methods often result in ambiguous or even incorrect identification. This device and process will allow infectious disease specialists to actually discover new organisms that cause human disease as many of the organisms the MALDI-TOF MS process is able to identify are often underestimated in infections of orthopedic prosthesis and brain abscess.

Managed care implications

The company that developed the process and received FDA approval sells the machinery. It does not do the testing, so it does not set the price. Each independent lab that performs the test will bill for it. The cost may vary widely, but several sources used the terms “inexpensive” and “efficient” and “cost effective” to describe this breakthrough technology. One even went on to suggest that widespread use will drive the price down even further. Obviously, much of this testing will be done in hospitals where the cost of the test is much lower than the actual therapy and hospital-day costs, potentially saving money as well as reducing medical risk to the patient because of a delay in diagnosis. Also, many health plans contract on a “per diem” basis where this will just be included in the daily charge.

MALDI-TOF MS will take on a great deal of importance as we fight rising antibiotic resistance. It is likely that the use of MALDI-TOF MS will decrease the tendency to use multiple or wide-spectrum antibiotics, implicated in antibiotic resistance. MALDI-TOF MS is also another great example of how yesterday’s rather obscure and humble scientists have led to dramatic improvement in Tomorrow’s Medicine.

Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. Contact him at TMorrow@ManagedCareMag.com.

The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.

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