FAQs about Choosing and Implementing a CRE Definition
Carbapenem resistance among Enterobacteriaceae is complex; unlike methicillin resistance among Staphylococcus aureus which, for the most part, represents one resistance mechanism in one species of bacteria, Enterobacteriaceae include more than 70 different genera and many different mechanisms can lead to carbapenem resistance. All carbapenem-resistant Enterobacteriaceae (CRE), regardless of the mechanism underlying the carbapenem resistance, are likely multidrug-resistant organisms for which interventions might be required in healthcare settings to prevent transmission. However, carbapenemase-producing CRE (CP-CRE) are currently believed to be primarily responsible for the increasing spread of CRE in the United States and have therefore been targeted for aggressive prevention. A reliable way to differentiate CP-CRE from non-CP-CRE might help guide such targeting by identifying the organisms of greatest epidemiologic interest. Because mechanism testing is not recommended for guiding therapeutic decisions, this testing is not routinely performed in many U.S. clinical laboratories, so phenotypic definitions, based on the bacteria’s antibiotic susceptibility pattern, are the primary way clinical laboratories and infection prevention teams attempt to identify CP-CRE; although no phenotypic definition will perform perfectly in distinguishing between CP-CRE and non-CP-CRE.
The previous CDC CRE definition (nonsusceptible to imipenem, meropenem, or doripenem, AND resistant to all third generation cephalosporins tested) was designed to be more specific for CP-CRE; however, it has proven to be complicated, difficult to implement, and has been found to miss some CP-CRE. In January 2015, The Centers for Disease Control and Prevention (CDC) modified its surveillance definition for CRE to the current definition (resistant to imipenem, meropenem, doripenem, or ertapenem OR documentation that the isolate possess a carbapenemase). The following document provides answers to frequently asked questions from healthcare facilities and laboratories about choosing and implementing a CRE definition.
CRE are Enterobacteriaceae that are nonsusceptible to carbapenem antibiotics. This is a phenotypic definition (i.e., based on the antibiotic susceptibility pattern of the organism) and it includes bacteria that are not susceptible to carbapenems via more than one type of mechanism. In general, these carbapenem resistance mechanisms include:
- The production of carbapenemases (called CP-CRE), enzymes that break down carbapenems and related antimicrobials making them ineffective. This includes enzymes like Klebsiella pneumoniae carbapenemase (KPC)
- The combination of mechanisms other than carbapenemase production (called non-CP-CRE), most commonly the production of beta-lactamases (e.g., AmpC) in combination with alterations in the bacteria’s cell membrane (e.g., porin mutations).
Therefore, CP-CRE are a subset of all CRE. CP-CRE have been targeted for prevention because much of the recent increase in CRE in the United States appears to have been driven by the spread of CP-CRE strains and experience from both the United States and from other parts of the world suggests that these organisms have the ability to spread rapidly and can cause infections that are associated with high mortality rates. U.S. phenotypic CRE definitions have attempted to target CP-CRE for both surveillance and prevention; however, no phenotypic CRE definition is perfect and some non-CP-CRE can also meet these definitions. At this time, mechanism testing that might readily differentiate CP-CRE from non-CP-CRE is not widely used and phenotypic definitions are the only available option for many facilities to target CRE prevention efforts.
Yes, CRE that do not produce carbapenemase are generally still resistant to multiple antibiotics (i.e., multidrug-resistant organisms) and likely warrant use of infection control interventions such as use of contact precautions when patients with these organisms are being cared for in acute care healthcare settings. However, more aggressive interventions like the implementation of screening cultures of contacts and patient and staff cohorting could be reserved for CP-CRE which are believed to have greater potential for spread.
Understanding the scope of a problem is important for prevention. Surveillance helps identify the extent of a problem and some of its characteristics (e.g., risk factors). Using standardized surveillance definitions is a basic surveillance principle allowing multiple sites to capture the same information and for information to be captured consistently over time. Surveillance definitions allow for valid “apples to apples” comparisons to be made across multiple sites, making surveillance data richer and more generalizable. CRE are a national public health priority; understanding the prevalence and epidemiology of the organisms by employing surveillance definitions can help better define and target prevention.
When choosing a surveillance definition, facilities should identify if CRE reporting is required in their state and, if so, should use that definition. Although attempts are being made to standardized the definitions states use for CRE surveillance, at this time, most states’ CRE definitions vary slightly with respect to the breakpoints used or the antimicrobials included. If your state does not have a required definition, you should consider the CDC definition because it has been evaluated, its attributes have been characterized, it is the basis for current CDC prevention recommendations, and is specifically designed to identify CP-CRE which appear to be the organisms of greatest public health concern at this time.
The previous CDC CRE definition (nonsusceptible to imipenem, meropenem, or doripenem, AND resistant to all third generation cephalosporins tested) was originally based on input from experts. This definition has proven confusing, and has been difficult for facilities to implement due to the multiple antimicrobials included and the inclusion of different criteria for carbapenems (nonsusceptibility) and cephalosporins (resistance). Further, the carbapenem ertapenem, was originally not included in the definition due to concerns over its low breakpoint for nonsusceptibility (nonsusceptible ≥1 mcg/ml). However, concern began to develop that this definition might miss some CP-CRE. CDC began to identify CRE that were positive for the KPC gene and were resistant to ertapenem but susceptible to the other carbapenems. A small validation study conducted by CDC identified that a portion of KPC-producing Klebsiella species could be missed by excluding ertapenem from the definition. Further, if a laboratory routinely tested only ertapenem, CRE could not be detected using the prior definition. Finally, CRE producing OXA-48-type carbapenemases might not exhibit resistance to third-generation cephalosporins and might not be captured by the previous definition. In light of this evidence, CDC elected to modify the CRE surveillance definition in January 2015 (resistant to imipenem, meropenem, doripenem, or ertapenem OR documentation that the isolate possess a carbapenemase) to make it simpler and to improve its ability to detect CP-CRE strains. No phenotypic definition is perfect; however, until mechanism testing is more widely available many facilities will need to rely on phenotypic CRE definitions to guide their prevention efforts.
The requirement that CRE be resistant to all third generation cephalosporins tested was removed from the current CDC CRE definition (1) to simplify the definition to make it easier to apply, (2) to accommodate the emergence of OXA-48-type-producing CRE which might not be resistant to this class of antimicrobials, and (3) because data from a CDC evaluation of multiple definitions suggested that the addition of the cephalosporins did not substantially improve the ability of these definitions to differentiate between CP-CRE and non-CP-CRE.
Some Enterobacteriaceae (e.g., Proteus spp., Morganella spp., Providencia spp.) have intrinsic elevated MICs to imipenem and therefore results for meropenem, doripenem, and ertapenem should be used for these organisms to determine if these organisms meet the CRE definition. Imipenem resistance alone (i.e., without resistance to at least one other carbapenem) does not allow these organisms to meet the CRE surveillance definition.
Organisms that are resistant to a carbapenem, regardless of the underlying mechanism, are likely to be multidrug-resistant and should warrant the use of infection control interventions in healthcare settings to limit transmission. Facilities may choose to target the most intensive interventions to CP-CRE as these organisms appear to have been the main contributor to recent increases in CRE seen in the United States and in other parts of the world.
For example, if a facility identifies an isolate that meets the 2015 CDC CRE definition (resistant to imipenem, meropenem, doripenem, or ertapenem OR documentation that the isolate possess a carbapenemase), consideration should be given to screening the isolate for carbapenemase (e.g., use of modified Hodge test, polymerase chain reaction, CarbaNP). If the isolate is found to NOT produce a carbapenemase, facilities may choose to use basic infection control interventions to control further spread including interventions like placing the patient in contact precautions while admitted and use of hand hygiene by healthcare personnel caring for the patient. If the isolate is found to possess a carbapenemase, facilities should consider the addition of more intensive interventions such as performing screening cultures of patient contacts of the patient and cohorting of patients and staff if more than one CP-CRE colonized or infected patient is present in the facility. If a facility chooses not to perform carbapenemase testing on isolates meeting the 2015 CDC CRE definition, the isolate should be considered to be a CP-CRE, and both basic and more intensive interventions should be implemented. Choosing to do carbapenemase testing on isolates meeting the 2015 CRE definition has the potential to limit the number of patients requiring more CRE interventions at the cost of additional laboratory testing at the facility. For more information about CRE specific interventions please consult the CDC CRE Toolkit (https://www.cdc.gov/hai/organisms/cre/cre-toolkit/index.html).
Carbapenemase mechanism testing is not required to identify CRE or for CRE prevention. However, the addition of this testing will allow facilities to better understand the epidemiology of CRE in their facility and region, and to better target different interventions to different types of CRE. If facilities wish to limit the amount of mechanism testing being done, consideration could be given to limiting this testing to situations in which the pre-test probability that an organism is a carbapenemase-producer is lower and therefore for which the testing might be more likely to lead to changes in the infection control interventions that are instituted. This might include CR-E. coli and CR-Enterobacter species, CRE isolates in areas where CP-CRE are less common (i.e., low prevalence areas), and isolates for which multiple carbapenems are tested but the isolate is resistant to only one.
Carbapenem susceptibility results should be reported as tested along with the appropriate interpretation. Results from tests that detect carbapenemase-production should not be used to change the interpretation of a carbapenem susceptibility result. A carbapenemase test result should be reported to infection control and those requesting epidemiological information (e.g., state-based surveillance programs).
If a facility decides to switch from the previous to the 2015 CDC CRE definition will the measured rates of CRE go up? Switching from the previous CDC CRE definition (nonsusceptible to imipenem, meropenem, or doripenem, AND resistant to all third generation cephalosporins tested) to the 2015 CDC CRE definition (resistant to imipenem, meropenem, doripenem, or ertapenem OR documentation that the isolate possess a carbapenemase) will increase measured CRE prevalence due to the fact that a larger number of non-CP-CRE will meet the current definition. The magnitude of the increase will likely vary based on the baseline prevalence of non-CP-CRE in a facility or region.
As the use of mechanism testing increases with the development and dissemination of new technologies, and as the epidemiology of CRE is better defined, CDC will re-evaluate the definition to ensure it is still performing as intended.