AST breakpoints: a case of not aging gracefully

Dr. Humphries promises more webinars, as well as feedback through PT write-ups, which highlight every suspected use of an obsolete breakpoint. CLSI webinars and newsletters, both current and past, are another useful source of information, she says.

Smaller labs may feel like they’re at a disadvantage when it comes to updating breakpoints, says Dr. Martin, who is a member of the CAP Microbiology Committee. That might be especially true for community hospitals, she says, “where you don’t have a dedicated microbiologist or even a dedicated microbiology supervisor. You have people who are more a Jack- and Jill-of-all-trades, who are very good at what they do, but it becomes a little more challenging to keep up with some of these nuances.”

Nevertheless, “It can be broken down into manageable pieces,” she says, offering her own experiences at Dartmouth as evidence.

She and her lab colleagues recognized that their breakpoints weren’t current, but they, like many labs, faced chronic staff shortages as well as competing priorities within the lab. Little wonder updating breakpoints kept getting moved to the back burner.

In 2016–2017, the lab selected new panels to validate for new carbapenem and cephalosporin breakpoints. “It took us a year to do the validation and get everything built into our LIS,” says Dr. Martin.

At the same time, the laboratory was adopting MALDI-TOF, so it wasn’t until 2019 that the lab went live with its new panel and lower breakpoints.

Unfortunately, that wasn’t the end of the story. That same year the breakpoints for fluoroquinolones were lowered. “As it turned out, our new panels did not have dilutions that were low enough for the new breakpoints,” Dr. Martin says.

That’s why the lab has yet to adopt those breakpoints. For now, Dr. Martin says, the lab will use the old breakpoints but report results with a comment to inform clinicians that ciprofloxacin and levofloxacin should be used with caution in critically ill patients.

That approach isn’t foolproof. “That’s always the worry with adopting a ‘solution’ where you’re depending on a clinician to read a comment,” Dr. Martin says. “I think there’s a lot of misunderstanding about susceptibility testing on the part of many clinicians.” She considers her lab to be fortunate, since their infectious disease colleagues at Dartmouth-Hitchcock are well versed in the nuances of testing and actively seek out discussions with her. “But for the broader population of clinical providers, there’s a need to educate.”

One unintended consequence of changing breakpoints: In changing the panels, “we lost a drug or two from our old panels,” says Dr. Martin, a change that was especially concerning to urologist colleagues. “We hadn’t anticipated all the ramifications of what the new panels would mean, even though we had vetted those panels with our antimicrobial stewardship and infectious disease colleagues.”

She also points to another consideration: “If we’re lowering breakpoints for the carbapenems, we start to have more isolates that test as carbapenem resistant,” Dr. Martin says. That requires follow-up, “which means an increased volume of tests for carbapenemase production.” They’re in a low-prevalence area, so they currently send those to their state public health laboratory for further evaluation.

Updating breakpoints, clearly, is necessary, doable, yet complicated. Dr. Humphries is sympathetic to those who feel intimidated and offers this bit of reassurance: “Susceptibility testing is not a chemistry test,” she says. “You’re dealing with living organisms, and like any living organism, the bacteria can misbehave a little bit sometimes.

“One of the biggest things I hear—and I continue to hear it—is people expect perfect when they do these transitions, and that’s just not the reality,” Dr. Humphries continues. “So labs need to be thoughtful about understanding what are the most important drugs being used at your institution.” In short, that means “just using some common sense, and discussing with the clinicians and pharmacy how these tests are being used.”

“If we expect perfect performance,” she says,” it’s never going to happen.”

Given that no one actually embraces the use of obsolete breakpoints, curious minds might wonder: Why has it been so hard to spur change? Why does every action seem to trigger an equal and opposite inaction, to misquote Newton?

As is so often the case, a little history is instructive.

In late 2016, president Barack Obama signed the 21st Century Cures Act into law, which allowed the FDA to be more nimble in updating breakpoints, explains Dr. Humphries.

Prior to that, the FDA didn’t have a mechanism to recognize CLSI breakpoints, says Dr. Humphries, who works with CLSI staff to write rationale documents. Breakpoints were included in the drug prescribing information, and whenever CLSI updated a breakpoint, the FDA had to do its own due diligence, research, and evaluation to see if the drug sponsor would be willing to update the breakpoint. The Act removed breakpoints from the drug labeling and put them on the FDA website, which allowed the FDA to do a couple of things, says Dr. Humphries.

“First, it allowed them to not be so beholden to the pharmaceutical companies when they make updates,” she says.

Second, the FDA could now distinguish between a drug’s approval for treatment, “and what makes sense for susceptibility testing. That distinction is important because many drugs are used off-label,” says Dr. Humphries, yet still have CLSI breakpoints.

Another historical chapter involves the pace of breakpoint revisions. In addition to the changes in 2019 and 2020, there’s been an uptick since 2010. For many antimicrobials still in use, the first breakpoints were published in the 1980s and 1990s, Dr. Martin says. Matters were fairly quiet in the early aughts, as she puts it, and then since 2010 there have been “tweaks to various breakpoints every year or two.”

In some cases, revisions occur when a new antimicrobial mechanism is recognized. Prior to 2010, says Dr. Simner, there were very few carbapenem-resistant Enterobacterales. When that began to change, the previous breakpoints were set quite high and thus could not identify some carbapenemase producers. “It would look like you had a carbapenem-susceptible organism, despite it having a carbapenemase enzyme.”

In other cases, breakpoints are revised when new pharmacokinetic and pharmacodynamic data indicate a current breakpoint is too high or too low. That’s what happened in 2019, when the breakpoints for the fluoroquinolones needed to be lowered.

The data used to inform a change in breakpoints send a sobering message about drug resistance, Dr. Humphries notes. “The whole reason the breakpoints are updated is because of a very high mortality signal” associated with older breakpoints. “If you have an isolate that has an MIC of, let’s say, 4, to a carbapenem, that would be susceptible by the old breakpoints and resistant by the new breakpoints. The mortality for that patient is in the 80s,” compared to an MIC of 1—the new susceptible breakpoint—where the mortality drops down to the 20s, Dr. Humphries says.

While the gaps between CLSI and FDA have slowly narrowed, some remain frustrated by the gaps that can still occur between laboratories and commercial AST manufacturers.

To be clear, Dr. Humphries says, some manufacturers “have stepped up to the plate—some are totally up to date with everything.”

And companies are in a tough position, Dr. Humphries says, even as she and others continue to press for updated breakpoints. “They’re in a difficult situation,” she says. On the one hand, they want to update breakpoints—it is, after all, the right thing to do for patient care.

On the other hand, manufacturers have competing priorities, just like labs do. Resources need to be aimed at developing new, cutting-edge tests, as well as updating tests already on the market.

Jean Patel, PhD, D(ABMM), has seen firsthand the pressures on both labs and manufacturers. Formerly with the CDC’s Antimicrobial Resistance Laboratory Network and the Office of Antimicrobial Resistance, she also formerly chaired the CLSI AST subcommittee. The refrain was familiar—those who updated breakpoints wanted them implemented ASAP, given that patient safety was at stake, and didn’t understand why it took so long.

Her move to Beckman Coulter, where she is principal scientist, gave her “a whole new perspective on how challenging it is for AST device manufacturers to translate a decision made by CLSI or FDA or EUCAST [European Committee on Antimicrobial Susceptibility Testing] into a product.” Manufacturers are always watching the breakpoint-setting process, she says. Once an update occurs, “The clock starts ticking. There’s an expectation that as soon as that decision’s made, we’ll have a product for customers. And that’s unrealistic.”

“It takes a lot of time. It takes a lot of planning,” she says, as well as “a lot of money.”

When manufacturers know a new breakpoint will be recommended, they typically conduct a clinical trial to collect data. “It’s not something we can do on the fly,” Dr. Patel says. Planning and conducting the study takes about a year; the data then need to be analyzed and submitted to the FDA, tacking on several more months.

Once the FDA responds, manufacturers have to implement the data into their product. Sometimes—but not always—that means designing new panels, Dr. Patel says. It also requires software updates to implement the new breakpoint.

She’d like to see the standards development organizations lay out multiyear agendas for updating breakpoints. “That helps us in industry plan.”

“For a long time we talked at CLSI about having a plan to solicit information from outside groups,” she says, to anticipate concerns about breakpoints, new drugs, and the need for new drug point classifications. Such transparency would help “harvest all the issues and then prioritize them,” she says.

It’s helpful, Dr. Patel notes, that industry representatives are allowed to participate in CLSI meetings (including as a voting member of the subcommittee), which enables manufacturers “to anticipate what changes are coming, to some extent.” EUCAST, on the other hand, bars industry from participating in its meetings. “We get surprised a lot by EUCAST decisions.”

Like labs, manufacturers are faced with decisions of whether to respond to a breakpoint that’s supported by either CLSI or FDA but not both. The stakes are higher for industry, Dr. Patel says. “It’s a huge challenge from a business perspective—it does not make sense to start developing toward a CLSI breakpoint for the U.S. market unless you’re pretty sure the FDA is going to take it up.” Even though the gap between CLSI and FDA breakpoints has narrowed, she says, “industry is unable to predict when FDA will adopt a breakpoint.”

Dr. Patel also echoes others in noting the difficulties labs face in updating breakpoints even when all the other pieces are in place. “One place where we’ve seen a little bit of a struggle is customers who don’t want to switch to a new panel with a new breakpoint. It’s a lot of work. They have to go through a validation process. It takes time.”

In those cases, manufacturers do have a lever they can pull: They can start to obsolete the breakpoints, removing panels from the inventory. It’s a step they take gradually, she says, “because that is a lot of upheaval for the customer.”

Still, says Dr. Patel, a more severe upheaval appears to lie in wait. “Antimicrobial resistance is a health problem that’s going to get worse before it gets better,” she predicts. The likely source of trouble: carbapenem-resistant Enterobacteriaceae and other gram-negatives in which metallo-beta-lactamases occur.

“Almost all of the new drugs coming to market for treating those infections aren’t active against bacteria that carry those metallo-beta-lactamases,” Dr. Patel warns. “And the number of bacteria that are carrying those enzymes is increasing—they’re actually the most common type of CRE worldwide.”

Unfortunately, she continues, the drug pipeline is not robust. Nothing is happening quickly enough “to predict a savior drug,” she says. In fact, there’s only one effective drug on the near horizon that covers all CRE infections. “And having only one drug that’s effective in treating an infection is a bad plan.”

A bad plan is the last thing the world needs. “We’re worried about bacteria spreading faster than drugs are being developed,” she says. “That does not bode well for the general public.” Already such infections are spreading inside hospitals. “And that’s bad,” Dr. Patel says. “But what’s worse is when they start causing community-associated infections.”

Detecting resistance is key. That’s the simple, hard truth—she barely needs to draw a parallel to COVID-19. “If you can’t detect it, you can’t prevent it,” she says. “And breakpoints are how you detect it.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.