Defining Antimicrobial Resistant Organisms: The Meaning of the Classification

Defining and classifying organisms with specific labels such as Methicillin-Resistant Staphylococcus aureus (MRSA), Multidrug-Resistant (MDR), and Difficult-to-Treat (DTR) must be purposeful, intentional, and meaningful. These classifications must prompt actions and responses by the microbiology laboratory, treating physicians, pharmacists, and infection prevention teams.

The purpose of these classifications goes beyond simply labeling an organism. For example, calling Enterobacterales "MDR" without clear criteria does not provide useful information. An E. coli resistant to one agent in three classes (e.g., ampicillin/sulbactam, cefazolin, and ciprofloxacin) may be common and does not necessarily confer any therapeutic insight, whereas ESBL or CRE classifications are more specific for signaling resistance against extended spectrum cephalosporins and carbapenems respectively.

AMR classification is about driving purposeful decisions in patient care and public health. Intentional and meaningful definitions ensure that clinicians are equipped with the right information to make informed choices, optimize treatment plans, and implement effective infection control measures. Each classification should trigger specific, actionable responses that ultimately improve patient outcomes and reduce the spread of resistant organisms.

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Defining Criteria

The first step is to clearly indicate the significance of the classification. For example, defining Vancomycin-Resistant Enterococcus (VRE) along with the organism's name—E. faecalis VRE—communicates to providers and pharmacists that vancomycin must not be used and indicates to infection prevention teams that this patient should be under contact precautions. As for E. fecalis, penicillin or ampicillin may be an appropriate therapeutic option even when VRE (review your local antibiogram).

The definition and criteria are based on the organism's prevalence, cumulative antimicrobial data, resistance rates, first, second, and even third treatment options, and whether resistance is acquired or intrinsic. Here is an example of defining criteria and classifying A. baumannii complex as "Difficult-to-Treat" (DTR) as per our Antimicrobial Stewardship (ASP) team.

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Antimicrobial Treatment?

Ampicillin/sulbactam is our first line of treatment against A. baumannii complex. When evaluating its performance, up to 67% of all isolates were susceptible, leaving the remaining 33% resistant group as the target of interest for AMR classification. When evaluating other agents in the ampicillin/sulbactam-resistant group, no other beta-lactam was found to be susceptible, and only a few antimicrobials from other classes were potent. This means that ampicillin/sulbactam resistance is a reliable indicator that other first- and second-line beta-lactams should be avoided.

Reevaluating the ampicillin/sulbactam-susceptible group (67%), meropenem was the second beta-lactam with the best performance after ampicillin/sulbactam, with 54% of isolates being susceptible. To build the criteria and classification from a specific multidrug approach, isolates of A. baumannii complex resistant to both ampicillin/sulbactam and meropenem are classified as DTR. This labeling trigger two significant actions:

• Automatic AST Reflex: Additional antimicrobial testing will be performed without a prior request from providers. This action ensures standardization and rapid antimicrobial results for the third line of treatment. This protocol must be agreed upon and approved by the ASP.
• Antimicrobial Escalation: Accessing and evaluating historical cumulative data for third-line antimicrobials prompts physicians and pharmacists to escalate to an appropriate agent 24 hours before in-vitro results are available.

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Infection Prevention?

In this case, the infection prevention action is clear. A patient with an infection caused by A. baumannii classified as DTR, which is resistant to almost all first- and second-line antimicrobials, must be placed under contact isolation. However, before reaching this level of resistance, these isolates must have been resistant to one agent in three active classes, or MDR. This is why we have two different classifications for this organism: a microbiological, therapeutic, and preventive one (reflex testing, escalation, and contact isolation) for DTR; and a preventive one, MDR for infection prevention, which does not trigger additional laboratory testing or escalation, but contact isolation.

The reason behind this distinction is that A. baumannii complex MDR isolates are still susceptible to ampicillin/sulbactam and/or meropenem, along with other agents. From an Antimicrobial Stewardship perspective, these MDR isolates do not commonly require escalation to third-line antimicrobials. This MDR label is used solely by the infection prevention team for isolation purposes.

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Why Not Carbapenem-Resistant or CRAB??

In our A. baumannii complex population, the percentage of CRAB (43%) falls between the highly sensitive MDR (49%) and the most specific DTR (33%). Using MDR as the classification (where CRABs are included) for driving contact isolation ensures that significant and evolving resistant strains are contained as soon as they are identified. Targeting CRAB would let a group of MDR strains evade contact precautions.

The other consideration with the CRAB definition is the fact that carbapenem resistant in non-fermenters may be mediated by porin restrictions and/or efflux pumps. These intrinsic mechanisms, may express in an isolate as carbapenem resistance without an acquired component. This is why MDR have a better role as defining the presence of MDR mechanisms.

Third-Line Testing and Treatment?

As described above, the DTR classification not only triggers contact isolation but also internal lab testing. All DTR isolates are tested against the next two better beta-lactams available against A. baumannii, sulbactam/durlobactam and cefiderocol. Additionally, to complement the activity of beta-lactams with a different antimicrobial class, eravacycline is also tested.

Automatically performing these tests triggered by the DTR label allows the laboratory to provide rapid, optimized, and actionable clinical results to providers and pharmacists, avoiding delays or requiring a direct call to the lab. This additional testing also guarantees comprehensive clinical information for different scenarios.

Based on the narrow and specific spectrum of sulbactam/durlobactam, the addition of cefiderocol testing provides a broader-spectrum agent in case of polymicrobial infection, especially other MDR isolates.

The addition of eravacycline provides access to a third-generation tetracycline as a synergistic agent. Since minocycline susceptibility is only 46% in DTR, eravacycline MIC ≤ 1 is 79% in DTR isolates.

This automatic testing of DTR isolates provides collection of comprehensive in-vitro data, enabling clinicians to use historical cumulative data for rapid escalation while awaiting additional susceptibility results for third-line agents. This approach reduces the time to appropriate therapy by 24 hours.

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These are the meanings of the classifications:?

• A. baumannii MDR: Contact isolation required. Ampicillin/sulbactam, meropenem, and other agents such as minocycline are still active. Treatment is based on the isolate’s susceptibility panel reported. Additional susceptibility testing is performed only upon request.
• A. baumannii DTR: Contact isolation required. This isolate is resistant to all beta-lactams and most agents. Cumulative data show that 97%, 76%, and 79% of DTR isolates are susceptible to sulbactam/durlobactam, cefiderocol, and eravacycline (MIC ≤ 1) respectively. Escalation is strongly recommended while additional susceptibility testing is being performed.

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This approach allows for meaningful classification of AMR organisms, in agreement with the Antimicrobial Stewardship program and infection prevention practices, while optimizing laboratory workflow, promoting appropriate use of resources, expediting antimicrobial results, optimizing treatment, and ensuring the safety of our patients and staff.

CDC Antimicrobial Resistance Threat Report, 2019

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