AST breakpoints: a case of not aging gracefully

Karen Titus

April 2020—When Romney Humphries, PhD, D(ABMM), was section chief for clinical microbiology at UCLA Medical Center, it wasn’t unusual for her to take calls from worried clinicians who were concerned about patients who’d been transferred to the hospital for a higher level of care. The accompanying laboratory reports would indicate the presence of an isolate that was susceptible to a particular drug. But when Dr. Humphries’ lab did its own testing, the results were strikingly different: The isolate was drug resistant.

When Dr. Humphries would call the first lab, the reason for the discrepancy became clear. “Sure enough, they were using old breakpoints,” says Dr. Humphries, who is now chief scientific officer, Accelerate Diagnostics, and professor of pathology, University of Arizona.

Unlike Bordeaux, antimicrobial susceptibility test breakpoints do not age well. Over time, they might no longer be clinically useful, even as they continue to be used clinically.

Dr. Humphries’ anecdote is, of course, just that—an anecdote. But the problem is hardly unique to Los Angeles. How about the whole state of California?

Here, too, Dr. Humphries has something to say. As part of a survey done in that state (Humphries RM, et al. Clin Infect Dis. 2018; 66[7]:1061–1067), “We phoned every single clinical lab in the state of California to find out what breakpoints they were using,” she says. The answer: Some 30 percent were using obsolete breakpoints.

The study did not address the number of beds served. “When we went back and looked, some of the biggest labs in the state were using obsolete breakpoints,” says Dr. Humphries, a member of the CAP Microbiology Committee. “Just because it was only 30 percent, that doesn’t mean it’s not the majority of patients being tested.”

More recently, data collected through CAP proficiency testing raised further concerns about the use of obsolete breakpoints. Dr. Humphries declines to offer specifics, pending publication, but says, “It’s pretty striking.”

Undoubtedly she doesn’t mean “striking” in a good way.

That’s why Dr. Humphries and others are amping up efforts to draw attention to obsolete breakpoints and urge laboratories and manufacturers of antimicrobial susceptibility testing devices to adopt current breakpoints.

Their work has gained more urgency recently with updates of several breakpoints in 2019 and 2020: ciprofloxacin, levofloxacin (Enterobacterales, Pseudomonas aeruginosa); daptomycin (Enterococcus spp.); ceftaroline (Staphylococcus aureus); and colistin (P. aeruginosa, Acinetobacter spp.).

Trish Simner, PhD, D(ABMM), minces no words when she explains the importance of keeping up to date. Breakpoints are revised to ensure patient care and safety, and to limit and reduce the spread of antimicrobial resistance, says Dr. Simner, director of the medical bacteriology laboratory, Johns Hopkins University School of Medicine, and associate professor, Department of Pathology. Case in point: A study in Southern California (Bartsch SM, et al. J Clin Microbiol. 2016;54[11]:2757–2762) found that for each year laboratories delayed updating their carbapenem breakpoints for Enterobacterales, an additional 6,000 patients were predicted to become colonized by carbapenem-resistant Enterobacterales.

The gravity of the situation is hardly news to labs, which have long been concerned about drug-resistant organisms. “The big problem is that many labs, and even institutional management, don’t understand that revisions to breakpoints have occurred,” says Dr. Simner, who is a member of the Clinical and Laboratory Standards Institute’s AST subcommittee as well as the CAP Microbiology Committee.

The other challenge is figuring out what to do once a breakpoint has been revised. “You can’t simply start using the updated breakpoint without validating or verifying that your current” AST device accurately uses a new breakpoint interpretation, says Dr. Simner.

Breakpoint revisions don’t happen overnight, though it may seem that way to those who are grappling with making the changes.

Dig a little deeper and it soon becomes evident that nearly every aspect of breakpoint revisions involves multiple steps that unfold over time. In the best of circumstances, that can mean thoughtful change. In other cases, it gives way to confusion and what might pass for torpor when it comes to updates. Who, exactly, is responsible for doing what?

Breakpoints in the United States are set by CLSI and FDA’s Center for Drug Evaluation and Research. When CLSI (which began publishing breakpoints in 1972) revises a breakpoint, it creates a rationale document to explain its reasoning. CLSI submits the document to the FDA, which reviews it and responds (usually within six months). “In general, they tend to agree,” says Dr. Simner. But not always. When the agency does agree, the new breakpoint is recognized on the FDA’s susceptibility testing interpretive criteria, or STIC, website (www.fda.gov/drugs/development-resources/antibacterial-​susceptibility-​test-​interpretive-criteria).

Once a breakpoint is revised by CLSI, FDA, or both, commercial AST device manufacturers decide how to respond. Changing breakpoints isn’t a simple task for manufacturers, any more than it is for laboratories, and some react more swiftly than others. In the best-case scenario, this can be a yearlong process.

In others, it’s been a decade.

“We know this based on our experience with the cephalosporin breakpoints that were changed in 2010 for the Enterobacterales,” says Dr. Simner. “There are still some commercial [AST] systems out there that have not updated to the current breakpoints.”

It may, in fact, surprise some to know that manufacturers aren’t required to update their breakpoints after their devices have received FDA clearance, says Dr. Simner, nor is there a push from an accreditation standpoint to ensure labs are using current breakpoints.

“The challenge we still face,” says Dr. Humphries, “is companies still haven’t updated all of their breakpoints. And we know there’s a huge, huge misunderstanding among clinical labs, where they think, If my test is FDA cleared, that must mean it’s using the most up-to-date breakpoints.”

That places the onus on labs to do verification and validation studies to update breakpoints manually on their devices, Dr. Humphries says. Whether that’s the best use of a lab’s resources is also open to discussion, she says. “They should be spending their time doing patient testing,” she argues.

But that might mean labs are using obsolete breakpoints. “We see time and time again in our proficiency testing Surveys, where it comes up as a challenge,” Dr. Humphries says. “It really sends the wrong message about susceptibility testing if things are being interpreted with breakpoints that are incorrect.”

Assumptions, like rumors, float easily in all directions. Just as labs might be taking it on faith that their AST devices use current breakpoints, clinicians are apt to make suppositions about test results. “A lot of our clinical colleagues rely on the lab to keep up to date with this,” says Dr. Simner, and for AST results “to reflect the updated breakpoints in the interpretations we apply in our reports.”

All of which “just creates the perfect storm,” Dr. Simner says. “Here we are 10 years after the carbapenem breakpoints were lowered, and a lot of labs still haven’t implemented those changes.”

Updating breakpoints might be laboratory medicine’s equivalent of sorting through one’s basement. Yes, it needs to be done. Someone needs to start, but who? And how? As Dr. Simner puts it, “There’s really no one pushing from any direction to make sure this happens.”

So where to begin? Each lab’s starting line might be different.

“You need to make sure you know what breakpoints you’re applying,” Dr. Simner says. While that may sound obvious, she acknowledges, “I can guarantee there are many labs that don’t. There are a lot of assumptions by laboratories at all levels,” says Dr. Simner, “from small community hospitals to large academic centers, that the breakpoints that their automated systems are applying are the most up to date.”

Finding that information may also sound straightforward, she continues, but that’s not always the case. “A lot of the time that information is hidden within the automated system and the expert rules.” Labs can either try to figure it out on their own system, Dr. Simner says, or call their commercial vendor.

Once the labs have that information, they should turn to the most recent CLSI M100 document (the 30th edition was released in February), which is available online, and free (https://j.mp/2UEHgtj). That wasn’t always the case, Dr. Simner says, “but now there should be no barrier to having the most up-to-date document.”

Labs should also look at the FDA’s STIC website. The most up-to-date breakpoint would be one that is recognized by both CLSI and FDA, says Dr. Simner. In most cases, CLSI leads the charge. Last year, she notes, CLSI updated the fluoroquinolone breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa about six months before FDA did. That’s not to say a laboratory needs to wait until a breakpoint appears on both sites. “For the most part, larger clinical labs will follow the M100 documents as they become available,” Dr. Simner says.

CLSI updates the M100 document annually, with changes listed at the beginning, and offers webinars to explain key revisions. The M100 document also provides additional information about media, incubation times, etc., Dr. Simner notes, while the FDA site simply provides interpretive criteria based on its evaluations of the new breakpoints.

If they’re not already doing so, labs should check the CLSI and FDA breakpoints annually “to help them prioritize what they might want to implement,” Dr. Simner recommends.

Once they’ve figured out the breakpoints they’re using, some labs may find they’re lagging a bit, to put it delicately. “These might be labs that haven’t done this since 2010,” Dr. Simner says.

“If they’re one of those labs,” she continues, “they need to work with institutional leadership and some of their clinical colleagues,” such as the antimicrobial stewardship team, infection disease specialists, pharmacists, or some other clinical champion to help them make the changes.

That’s key, she says, “because if labs have not kept up to date with this, the amount of work needed to update this could be quite overwhelming.” (The longer you’ve been avoiding those boxes in the basement . . . .)

Regardless of an institution’s size or breakpoint savvy, working with clinical colleagues is crucial. At Johns Hopkins, says Dr. Simner, she and her lab colleagues work with the infection control team as well as the antimicrobial stewardship team, among others. “It’s a close-knit group.”

In fact, she says, “Each lab should know or get to know their antimicrobial stewardship lead and have these conversations with them,” if they haven’t already. (The Joint Commission has mandated new antimicrobial stewardship standards in recent years.)

It’s helpful, she says, for labs to talk to their clinician and pharmacist colleagues and understand the importance of a particular breakpoint change. She says she speaks with her pharmacy colleagues regularly, updating them on upcoming breakpoint revisions and discussing how to implement them. The updated fluoroquinolone breakpoints were a high priority for her pharmacists, she says. Because hers is a large, high-volume lab, they decided it would be too resource-intensive to set up a disk or gradient diffusion method as an interim step; instead, they waited to obtain a commercial AST panel with updated breakpoints. “There’s always open communication between the two teams, prioritizing the changes and how to make them happen—what works for both pharmacy and the lab in terms of workflow and resources.”

Dr. Simner has also found it critical to let institutional leadership know that breakpoints are a patient safety issue, as a way to garner resources. Labs “can be stuck in a situation where it isn’t a high priority unless something big happens. Make them understand the implications of not using the proper breakpoints.” No one wants carbapenem-resistant gram-negative organisms to spread undetected within a facility.

The work involved in updating breakpoints is real but not insurmountable. The basic steps—knowing what breakpoints the lab is currently using, and then putting together a strategy for doing updates as needed—is half the battle, observers say. After that, resources are available, especially for labs that may not have a PhD or MD laboratory director to help guide the process.

As Isabella Martin, MD, puts it, “We’re trying to lower the activation energy required to implement these changes.”

The CDC offers an excellent resource in the free isolates, which can be ordered online through the CDC and FDA Antibiotic Resistance Isolate Bank (www.cdc.gov/drugresistance/resistance-bank/index.html; ARbank@cdc.gov). The California Department of Public Health website (www.cdph.ca.gov/Programs/CHCQ/HAI/Pages/Antibiotics.aspx) also offers resources, developed by Janet Hindler, MCLS, MT(ASCP), which include step-by-step instructions, worksheets, and troubleshooting instructions on how to perform a validation study. While designed for carbapenems and the Enterobacterales, the suite of tools can be further adapted for other breakpoint validations, says Dr. Simner.

In addition to the previously characterized CDC isolates, “You also want to make sure that you’re testing a good variety of isolates from your own local patient population, and know you’re comparing your new method with lower breakpoints to another reference platform,” says Dr. Martin, medical director of microbiology, Dartmouth-Hitchcock Medical Center, and assistant professor of pathology, Geisel School of Medicine, Dartmouth College.

Labs might find the work worrisome, Dr. Simner acknowledges. To validate a modified breakpoint on a system that’s used every day requires a minimum of 30 isolates and staggering the breakpoints. “You’re really looking at categorical agreement,” she says. For a new system, 30 isolates is again the minimum; it also requires spanning breakpoints, as well as looking at both categorical and essential agreements. Bringing in a new disk for disk diffusions, or a new gradient diffusion strip, requires less-intense verification.

“There are some nuances to validation and verification studies,” Dr. Simner says, and the guidance isn’t always clear. The CLSI M52 document is helpful, but some labs might find its open-endedness disconcerting. “That’s why we’re creating more resources—to remove the question marks and tell labs: Here’s the FDA isolate panel bank you should order; here’s how you need to approach your scenario; here’s what your results should look like; here is the exact validation outline you should pursue.”