Leaving behind outdated AST breakpoints

Karen Titus

May 2022—Among the countless interruptions COVID-19 has inflicted on the medical community, one of the most obvious has been conversational. In the face of a global pandemic, other topics can seem unworthy of discussion.

But as some post-pandemic normalcy creeps back in, so does the focus on topics of equal, if less dramatic, importance.

Two years ago, experts were just digging into data collected through a voluntary supplemental questionnaire, distributed with a 2019 CAP Bacteriology Survey, about antimicrobial susceptibility testing breakpoints. The information, shared with Surveys participants, “was a bit of a teaser,” recalls Trish Simner, PhD, D(ABMM), associate professor of pathology and medicine, Johns Hopkins University School of Medicine, and director of the medical bacteriology and infectious disease sequencing laboratories, Johns Hopkins Hospital. She and others involved in the work called the results striking but couldn’t say more, at least not publicly, at the time.

Now comes the big reveal, in the form of a February publication in Open Forum Infectious Diseases (Simner PJ, et al. Open Forum Infect Dis. 2022;9[3]:ofac007). That article, together with a new requirement in the 2021 edition of the CAP accreditation microbiology checklist, should be the revving engine that drives laboratories to adopt up-to-date breakpoints.

The new requirement, MIC.11385, says laboratories subject to U.S. regulations must, by Jan. 1, 2024, use current breakpoints for antimicrobial susceptibility test interpretation. By that date, at minimum, laboratories will need to employ breakpoints that have been updated within three years of official publication by the FDA, though the laboratory may use currently accepted breakpoints from other standards development organizations (for example, CLSI) with validation to support use.

The February publication points out what’s at stake—not only how labs are falling short, but the cost to patients.

Recipients of the 2019 questionnaire (sent to 2,296 labs, with a 60 percent response rate) were asked if they were applying current breakpoints for seven so-called drug-bug combinations—combinations with breakpoints that the FDA or CLSI had updated relatively recently (since 2010). Those who weren’t using them, or were unsure which breakpoints they used, were asked why they weren’t up to date.

Depending on the organism/antimicrobial agent, between 40 to 70 percent of U.S. labs were still using breakpoints now considered obsolete. (For international labs, the range was 20 to 40 percent, “which really drives home the point that this is a larger issue within the United States,” Dr. Simner says.) The results reflected when the breakpoint changes occurred, she says—essentially, whether automated AST manufacturers and clinical labs have had sufficient time to devise strategies for updating the breakpoints. The number of labs using current breakpoints for the cephalosporins and carbapenems (updated around 2010) was greater than the number of labs using current breakpoints for the fluoroquinolones (updated in 2019).

Of the labs that were still applying outdated breakpoints, roughly 50 percent reported they recognized the problem and planned to update them. The other half had diminished ambitions, saying they either didn’t intend to update their breakpoints or had no current plans to do so.

“When we further asked why they’re using the outdated breakpoints,” Dr. Simner says, “the largest response we received, about half, was manufacturer related.” More than 90 percent of labs in the United States use automated antimicrobial susceptibility testing for their methodology to determine AST results; if a manufacturer’s panel and software aren’t updated, labs are left in the lurch. (In the current regulatory environment, when a manufacturer submits a susceptibility testing panel to the FDA to obtain clearance, it must apply the FDA breakpoints in place at that time. However, the manufacturer is not required to update those breakpoints if and when they change after FDA clearance.)

Another 20 percent of labs cited lack of internal resources to perform the validation of new AST breakpoints, Dr. Simner continues, including being short of staff, money, and perhaps expertise. In addition to lack of time and other resources, “it comes down to the cost of doing a validation,” Dr. Simner says. Unless an institution’s upper management sees the need to make this a lab priority, outdated breakpoints will remain in force.

“There are so many competing demands,” Dr. Simner observes. “Hospitals are finding it a challenge to prioritize this.” Or they may not understand the need to update breakpoints, she says, or the impact of using outdated breakpoints.

Interestingly (or perhaps unnervingly), another slice—13 percent—of respondents reported being unaware of breakpoint changes or the need to update them. Or, as Dr. Simner puts it: We had no clue this was an issue.

That clarifies the mission for Dr. Simner and colleagues: to increase awareness among labs of all sizes, given the patient safety and public health repercussions of using outdated breakpoints. If labs can’t detect critical and urgent threats, she says, “then we’re not going to be good at containing or preventing the further spread of these resistant bugs.” Standard AST methods are the primary methods used globally to detect antimicrobial resistance, she adds. When detection fails, “we’re actually perpetuating the further spread of these bugs.”

The February publication is crucial, says coauthor Carol Rauch, MD, PhD, adjunct associate professor of pathology, microbiology, and immunology, Vanderbilt University School of Medicine, and formerly with the CDC’s Antibiotic Resistance Laboratory Network. “We can have an opinion, and we can say there’s a problem, but it’s very different once something’s in the published literature. These data provide a focal point to have the discussion.”

She agrees with Dr. Simner and other colleagues about the urgency. In her role with the AR Laboratory Network, she says she had concerns that the “front line of this program, where resistance is initially detected in clinical laboratories, isn’t functioning as well as we all need.” Not only are there patient care consequences, Dr. Rauch says, but “these initial results from clinical labs are what feeds into the public health infrastructure. From any viewpoint,” she adds, “we cannot afford to miss resistant pathogens.”

AST breakpoints for each bug-drug combination are set initially based on three categories of data, says Isabella Martin, MD, D(ABMM), medical director of microbiology, Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center. Standards development organizations such as the FDA and CLSI look at the following: the distribution of minimum inhibitory concentration values in hundreds of wild type bacterial isolates versus those with known acquired resistance mechanisms; pharmacokinetic/pharmacodynamic data for the antimicrobial agent in question; and clinical outcomes data, whenever possible. Breakpoints subsequently change when new data come to light in one of those three categories.

“Specific studies detailing the overall effect on patient outcomes from widespread use of outdated breakpoints do not currently exist. However,” Dr. Martin says, “we know that those breakpoints were updated for a reason and that continued use of outdated breakpoints puts patients at risk for being treated with ineffective therapy.”

“At the end of the day,” says Dr. Martin, a coauthor on the Open Forum publication, “most of us will need an antimicrobial at some point in our lives to treat an infection. It’s important we are able to accurately assess the effectiveness of common antimicrobial agents in our laboratories.”

The labs that aren’t aware that breakpoints have changed may be misclassifying a particular organism as susceptible, whereas a current breakpoint might identify that same organism as resistant. Says Dr. Rauch, “If we’re going to be tracking rates of resistance, we had better make that determination accurately.”

She says she found it fascinating to read through the hundreds of notes from respondents explaining why they weren’t using current breakpoints. The reasons are predictable: lack of resources, including expert personnel. Others noted that they awaited the green light from corporate, as in, Corporate has to tell us. “Who’s corporate?” Dr. Rauch asks. “Corporate probably doesn’t include a microbiologist.”

It’s clear that laboratories need to act—but so do others. How can regulatory agencies, accrediting organizations, clinical labs, and manufacturers come together to solve the problem?

All share a common goal—patient safety—but each group faces a different barrier, Dr. Simner says. “So how can we make this better without pointing fingers?”

It’s a subtle dance. “The CAP has taken a difficult but necessary step,” Dr. Rauch says of the new checklist requirement. In some ways, the logistics are the least of the problems.

As she and others worked to bring about changes, Dr. Rauch recalls, they spent untold hours trying to strike the right tone. “We don’t want anyone to come to this in anger or frustration.”

“This is big enough that we should all want to pay attention.”

She explains further: “You want to say that it’s a patient safety issue, and it is. That’s totally legitimate. What we don’t want is for people to overreact.” And given that every party has different constraints, “we want to communicate this in a positive and responsible way.”

Choosing a deadline showed how this challenge played out, says Dr. Rauch. “We wanted to pick a time off in the future, because we recognize labs have work to do to prepare.”

“We also had to lay out a path for how to get from here to there,” she continues. “We want to be deliberate and rational and calm and serious. We can’t ignore this, and we don’t want labs to be panicky. We don’t want people worried that they’re giving out a bad result without any clue what to do about it. So we need to give them support in the form of guidance and resources.”

There’s another delicate issue at play: the comfort level between a manufacturer and the lab. A lab might have been using a particular commercial system for years and, as with any relationship, change is hard. So even if the manufacturer hasn’t updated its breakpoints, no one’s necessarily agitating to break up.

In those cases, says Dr. Rauch, “we are asking them [labs] to either switch to a newer panel that applies current breakpoints, or to do a little bit of what is technically off-label work. And CAP does not enter into a recommendation like that lightly.” She calls the CAP conservative, careful to protect laboratories, and bent on “staying within every regulatory guideline we can think of.” But with AST, “we unfortunately don’t have a regulatory environment that has kept up with the resistant bugs. We have carbapenem-resistant organisms out there. Sometimes they’re called ‘the nightmare bacteria.’ We don’t like to use inflammatory language like that, especially with patients. But if we miss one,” the impact can be huge—for individuals, hospitals, and communities.

As she identifies the gaps between the key players, Dr. Rauch could be describing a Jane Austen plot. “There are insufficient relationships between and among all these partners.”

And even if a manufacturer’s breakpoints were sufficient at one point, they may not be now. Lead pipes were deemed sufficient for municipal water supplies at one point, too. The organisms are evolving in real time; the regulatory environment supporting revised breakpoints is not.

That leaves it to labs, at least for now, to “do some extra work that allows them to apply different interpretive criteria,” beyond what may have been established years ago when their commercial devices were cleared by the FDA.

Manufacturers, for their part, will cite the huge financial burden of updating breakpoints, as well as regulatory speed bumps along the way. Newer agents have a more streamlined process for this, but for older agents, it’s not simply a matter of providing data to the FDA for recognizing updated breakpoints. If the submission process for older agents could be similarly streamlined, Dr. Simner says, it would be much easier for manufacturers to update their panels and systems with current, FDA-cleared breakpoints.

Another complication: FDA and CLSI breakpoints aren’t always in agreement. The FDA’s breakpoints may be based on its initial approval for indicated organisms and dosing, which may differ from what happens in clinical practice. “When we revisit the breakpoints,” says Dr. Simner, “we’re generally applying the dosing that is used currently.”

If, for example, manufacturers want to update their carbapenem breakpoints—for, say, Enterobacterales—they might then lose the ability to address carbapenem breakpoints in other organisms.

Work has already been done to decouple breakpoints from prescribing information on the FDA STIC (susceptibility test interpretive criteria) website, although more work remains. “There’s got to be some sort of further lobbying, essentially, to get this changed,” Dr. Simner says. The FDA already recognizes CLSI as a standards development organization and can recognize its breakpoints. So why not apply it more broadly, she asks, and allow manufacturers to apply either group’s breakpoints for clearing their devices?