Language matters: CRE vs. CPE; SDD vs. I; and MDR, XDR, PDR, UDR vs. DTR

Note: See also these related newsletters: 13 Jan 2019 (link) on DTR as part of the language of resistance and 7 June 2020 (link) on using DTR to estimate antibiotic value. There is also a 5-minute DTR explainer on YouTube that you might find useful.

Dear All (wonk-ish note alert!),

Three technical points for your consideration today. All focus on the subtleties of language, something I always find fascinating

First, and from the pen of David Livermore and colleagues, we have ‘CRE, CRO, CPE and CPO’: terminology past its ‘sell-by-date’ in an era of new antibiotics and regional carbapenemase epidemiology that is just out in Clinical Infectious Diseases (link).

• In brief, the authors argue that CRE and CRO (carbapenem-resistant Enterobacterales/Organisms) are ambiguous in important ways.
  • For example, does CRE/CRO include porin-deficient Enterobacterales that are resistant to ertapenem but not other carbapenems?
• The authors further argue that CPE/CPO (carbapenemase-producing Enterobacterales/Organisms) is better but still flawed in that the precise type of carbapenemase really matters when choosing treatment for a given patient.
  • CRE with OXA-48 or KPC carbapenemases generally are susceptible some of the new agents; those with metallo-beta-lactamases remain resistant and will require a very different approach. 

The authors conclude that at the very least we should stop using the terms CRE/CRO and instead speak of CPE/CPO. Even more specific descriptions would be better but will be challenging to find, particularly if we want simple shorthand.

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Second, Mel Weinstein and Jim Lewis bring us The Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing: Background, Organization, Functions, and Processes in Journal of Clinical Microbiology (link). The paper provides a good compare-contrast between CLSI and EUCAST, but I would especially draw your eye to the discussion (page 5 of the paper) of the interpretive breakpoint categories of “SDD” (Susceptible Dose-Dependent) and “I” (Intermediate). There is something very subtle going on here!

The background is that interpretations of susceptibility test results are easy for very high and very low MICs — we use the interpretive categories  Susceptible and Resistant without difficulty. But, MICs in the middle are confusing — is the MIC really different or is this just the natural variation of MICs? No matter how careful you are, the MIC for any given bug-drug combination shifts around a bit day-to-day! Or, is the MIC accurate? If so, and if the MIC is only slightly higher than a (S)usceptible MIC, would more drug work?

There’s never been a clear and universally agreed way to describe these in-between MICs. The microbiology community has experimented with ideas such as MS (moderately susceptible) and MR (moderately resistant) but ultimately settled on “I” for this Intermediate space. Confusingly, the letter “I” easily becomes ambiguous and can be seen meaning anything from Intermediate to (my spin on it) “Indeterminate”, “I don’t know what ‘I’ means,” and “I’d rather use a different drug.”

So we now get to the point about language: The two major global committees that work to define methods and interpretive breakpoints (CLSI in the US and EUCAST in the EU) have now chosen to solve this thorny problem in two different ways. And, you need to understand both systems! Thus, we now have these interpretive categories and ideas:

• Increasing drug dose is a plausible strategy to achieve clinical efficacy based on all available data:
  • CLSI: The interpretive category is SDD, for “Susceptible, Dose-Dependent” (see paper cited just above)
  • EUCAST: The interpretive category is I, for “Susceptible, increased exposure” (link, there is also a video tutorial here!)
• The MIC’s meaning is hard to easily summarize:
  • CLSI: I, for intermediate, but with at least two meanings: (i) more drug might be better but the data are limited, but also (ii) for the idea of technically indeterminate
  • EUCAST: ATU, for Area of Technical Uncertainty. Critically, and unlike S, I, SDD, and R, ATU is NOT an interpretive category … rather it is an warning to the laboratory that the test result is in an area where interpretation is not straightforward (most commonly because the breakpoint in a difficult place) and that it would be worthwhile to consider doing something to confirm the result (go here for a paper and here for a PowerPoint on these ideas). The lab has to decide how to communicate this to the clinician, but some options are (i) to confirm the result with an alternative test, (ii) to report with a comment, (iii) leave blank with a comment, or (Iv) downgrade the interpretive susceptibility category.

Each solution has strengths and weaknesses (and for transparency, I have long been an advocate of SDD). The EUCAST approach retains a single-letter description (helpful in some settings) and is completely unambiguous (once you understand it) but is easily misunderstood due to the many years of the letter I being vague. The CLSI approach creates a very clear message with SDD (the acronym tells you what to do) but retains the inherent ambiguity around the letter I and also requires a 3-letter abbreviation in any report. Representatives from the two committees wrote a great point-counterpoint on this that came out a few months ago in Journal of Clinical Microbiology (link). 

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Finally, we round off today’s language tour with a discussion of categories of resistance. Based on expert consensus, CDC and ECDC gave us the widely used ideas of MDR, XDR, and PDR in 2012 (link), McDonnell et al. proposed UDR in 2016 (link, I am part of the et al.), and Kadri et al. proposed DTR in 2018 (link):

• MDR (Multi-Drug Resistance) was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories.
• XDR (eXtensive Drug Resistance) was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories).
• PDR (Pan Drug Resistance) was defined as non-susceptibility to all agents in all antimicrobial categories.
• UDR (Usual Drug Resistance) describes isolates that aren’t fully susceptible wild-type strains but that can nonetheless be readily treated with standard therapies. 
• DTR (Difficult-to-Treat Resistance) is resistance to all of the typical first-line, lower toxicity agents.

I really like the idea of DTR and wrote about it in a prior newsletter (link). As we begin to have new antibiotics to treat resistant pathogens, terms that convey both the essence of a thing (resistance!) and its public health implications (not just resistance, but DIFFICULT resistance!) are important.

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Apologies if all this makes your head spin! But, the language we use really does matter and these sorts of spirited debates are key to improving our mutual understanding. Patty Bradford graciously reviewed a draft of this newsletter and said that these ideas made her think of these classic quotes:

• ”What’s in a name? That which we call a rose by any other name would smell as sweet” … or like a dirty, rotten, carbapenem-resistant bug!
• “I don’t care what you call me, as long as you don’t call me late for dinner” … names are arbitrary, as long as the bug gets flagged as being problematic
• And in the immortal words of Bill Craig (link), “It’s the susceptibility test, stupid!”

All of this makes me think of Francis Picabia, a madcap artist of early 20th century Modernism and a huge fan of perpetual change, whose oft-quoted comment was “Our head is round so our thoughts can change direction” (link and link). It’s great to see our use of language evolve!

Happy wordsmithing, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/