Labs enter a MALDI-TOF state of mind

When MALDI-TOF arrives in the lab, observers talk about witnessing the loss of classic microbiology—shades of the former Prince Hal, now Henry IV of England, telling Falstaff, “I know thee not, old man.”

At Penn, says Dr. Alby, “Now we have techs and students who have no idea about anything [related to] the biochemical reactions or classic techniques. Which is fine—except for the occasions when the MALDI-TOF is down. It’s an instrument; it’s not always working.” Though Dr. Alby is not advocating a return to days of yore, his point is clear: Biochemical tubes always worked. “You’re not going to have downtime with your isolates.”

Dr. Alby’s laboratory uses a protocol that relies on classical methods “to get us through our work, because if the MALDI is down for two days, we can’t not do microbiology—as much as I think our techs would like that,” he jokes.

“But what we’re finding is now we have techs who didn’t work the benches before MALDI was around,” Dr. Alby continues. “They don’t have the intrinsic knowledge about what’s PYR positive and what’s PYR negative, and things like that.”

At this transitional point, the laboratory still has technologists who know the classical techniques, but it won’t for much longer, as retirement looms for most of them. “So that’s probably our biggest concern: How do we maintain the knowledge?” Dr. Alby asks.

Adam Barker, PhD, assistant professor, Department of Pathology, and medical director, AFB laboratory, ARUP Laboratories, also bemoans this fading knowledge. “Most laboratories have completely lost the ability to read molds. And most laboratories have completely lost the ability to ID rapid-growing mycobacterium,” apart from TB, he says. He blames budget cuts and current lack of expertise in the field.

Add to that the aforementioned concern that MALDI-TOF is not accurate 100 percent of the time. Dr. Alby worries about the ability of less-experienced technologists to identify such errors. Will they spot the red flags that indicate when a result doesn’t make sense, the way more experienced technologists can when, say, the colony morphology doesn’t match a MALDI result? “Much to my dismay,” Dr. Alby says with a laugh, “the MALDI is probably right more than it’s wrong when I challenge it. But occasionally I’m smarter than the MALDI.”

Just as technologists have had to make adjustments to their work, the laboratory as a whole has had to reconsider how MALDI-TOF fits in. Simply adding an expensive piece of equipment into the lab, much like the Yankees have added high-priced free agents over the years, is no guarantee of success.

Dr. Alby says he and his colleagues failed to anticipate its impact on workflow. At Penn, the instrument didn’t save time, at least not initially. At the blood culture bench, for example, the laboratory did plate readings on all three shifts but implemented MALDI only on the first shift. That created a different workflow and delayed results slightly.

For those considering MALDI-TOF, Dr. Alby advises paying close attention to fit. “You can’t just drop this in like it’s a regular biochemical analyzer,” he says. “You need to adjust your workflow around the technology, and maybe not the other way around.”

Dr. Alby notes that one of the biggest considerations is how to pay for MALDI-TOF. “For most labs, this is probably the single largest purchase for microbiology they have ever made,” apart from total lab automation.

It takes considerable cost analysis to convince administrators inside the laboratory and out that spending hundreds of thousands of dollars on equipment in the microbiology lab is a smart move. Academic centers and larger community hospitals have the volumes to help justify the cost, Dr. Alby says, since the savings comes primarily from reagents.

But as Dr. Barker points out, with staff cuts and disappearing expertise, even smaller labs might be able to make an argument for adding MALDI-TOF to their armamentarium as a way to reduce sendouts. “You buy one instrument; you get really good IDs of yeast and bacteria—and maybe 85 percent calls on acid-fast bacteria.” In economic terms, that’s 85 percent of cases labs wouldn’t need to send to ARUP or another reference lab, says Dr. Barker, who is also associate clinical director of the ARUP Institute for Clinical & Experimental Pathology.

Almost any laboratory that does full-service microbiology should consider MALDI-TOF, Dr. Branda suggests. Large, complex labs are unquestionably interested, he says, because of the obvious opportunity to expand their capabilities and to rely less on reference labs. But small hospital labs can benefit as well, he says. It can improve turnaround time substantially as well as provide highly accurate identifications in a lab staffed by technologists with more general, rather than specialized, expertise.

MALDI-TOF also allows laboratories to identify rare species. That can be a blessing and curse financially as well as clinically.

Once labs start using MALDI-TOF, Dr. Alby says, it’s possible to see a sharp rise in reports of rare species causing infections. It’s not that rare species are necessarily taking off. “We just didn’t know what they were before,” he says.

In the pre-MALDI days, says Dr. Alby, hard-to-differentiate specimens, such as Gram-positive rods, created a dilemma, since they were difficult to differentiate without sequencing. Now, instead of describing them all as diphtheroid-like rods, the lab can provide genus- and species-level identifications.

“That’s useful, but it’s also potentially harmful,” Dr. Alby says. “We’re changing how we report things to the clinical staff.” Now that the laboratory is providing identification of Corynebacterium species, the requests for susceptibility testing have risen. Because MALDI-TOF enables the laboratory to add a species name, the inference among clinicians is that the test results are more significant.

In some cases, the additional information can be helpful. In cases involving a prosthetic joint infection, for example, being able to identify Gram-positive rods on three different tissue samples is helpful—it tells clinicians the likely causative agent in the infection, Dr. Alby says. There’s a similar scenario with enterococcal bacteremia. MALDI-TOF can differentiate between Enterococcus faecium and Enterococcus faecalis, which has treatment implications.

But it’s difficult, at least right now, to parse out the cost savings attributable to better therapeutic interventions. “It’s hard for us to dive into that,” Dr. Alby says, pointing to changing volumes resulting from mergers with other health systems and shifts in outreach business. Studies that look at extrapolating cost per isolate might be of more use in helping to justify a MALDI-TOF purchase, he adds.

His laboratory has attempted to study MALDI-TOF outcomes related to bacteremia, by defining patient characteristics and analyzing antibody use. The data haven’t been all that helpful. “Depending on your baseline, you may or may not see improvement in utilization [although that was the case with enterococcal bacteremia, as noted] or length of stay, because we still don’t have susceptibility information.”

One pleasant surprise, says Dr. Alby, has been the ability to identify interesting organisms. “You find trends with bacteria or fungi that might be associated with an outbreak. You see the same species over and over, and it may be a species that you never saw before.” It’s also been helpful in tackling organisms like nonfermenting Gram-negative rods and Gram-positive rods that are more difficult to identify by traditional methods.

The laboratory also sees organisms it wouldn’t have known were there. “Some of the veterinary coagulase-positive Staphylococcus, the Staph intermedius group, for example—we would call it Staph aureus. Every now and then they’ll pop up, and it’s interesting to see how it plays into the clinical story,” Dr. Alby says. “Those are always fun to find.”

It has also, Dr. Alby observes, enhanced the lab’s standing in some quarters. “The infectious disease group definitely have an appreciation for our ability to merely pronounce the names of these different bacteria,” he says. Occasionally even the lab will have to turn to the textbooks to figure out exactly what it’s dealing with.

Next month: Dr. Lau and Dr. Barker talk about MALDI-TOF
databases, acid-fast bacteria and mold identification, nomenclature, results reporting, and more.

Dr. Barker reports a similar response from some of his clinical colleagues at the University of Utah. “We get calls on the urine bench especially,” he says. “We used to just gross ID, and now we’re giving out names that none of us have ever heard of.”

And as Dr. Lau notes, “The beauty of mass spec is that it is giving us a level of detail in fungal identification that we just didn’t have before.”

Fungal identifications are challenging because of look-alike organisms, she explains. A mold that looks like a common variety such as Aspergillus fumigatus may turn out to be something completely different once it’s undergone analysis via MALDI-TOF mass spec. “You’ll find that it may be one of the organisms within the Aspergillus fumigatus complex, such as Aspergillus lentulus,” says Dr. Lau. “There’ve been quite a few publications that show that these cryptic species, or look-alike species, are either more pathogenic, more virulent, or they’re more resistant to antifungals. And so mass spec is really giving us now a level of identification to improve clinical care, at the level of specificity associated with that.”

Even Falstaff might drink to that.
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Karen Titus is CAP TODAY contributing editor and co-managing editor.