CRE Technical Information

For public health, labs, healthcare facilities, and clinicians.

Carbapenem-resistant Enterobacterales (CRE) are multidrug-resistant organisms that that can cause serious infections and require interventions in healthcare settings to prevent spread. The information below is intended for healthcare, laboratory, and public health professionals and provides answers to frequently asked questions about CRE, including types of CRE, identification, and epidemiology and prevention strategies.

Types of CRE

How does CDC define CRE?

Enterobacterales that test resistant to at least one of the carbapenem antibiotics (ertapenem, meropenem, doripenem, or imipenem) or produce a carbapenemase (an enzyme that can make them resistant to carbapenem antibiotics) are called CRE.

Some Enterobacterales (e.g., Proteus spp., Morganella spp., Providencia spp.) have intrinsic elevated minimum inhibitory concentrations (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.

How do Enterobacterales become resistant to carbapenems?

Many different mechanisms can lead to carbapenem resistance in Enterobacterales.

Carbapenemase-producing CRE make enzymes called carbapenemases that inactivate carbapenems and other β-lactam antibiotics, including penicillins and cephalosporins. The presence of a carbapenemase is usually sufficient to cause carbapenem resistance. Many carbapenemase genes are on mobile genetic elements that can be transmitted from one bacterium to another, thereby spreading resistance. One carbapenemase, the Klebsiella pneumoniae carbapenemase (KPC), was first identified in the United States in 2001. Since then, KPC-producing bacteria have spread widely across the country. In addition to KPC, there are a number of other carbapenemases associated with mobile genetic elements, including

• New Delhi Metallo-beta-lactamase (NDM)
• Verona Integron-Encoded Metallo-beta-lactamase (VIM)
• Imipenemase (IMP)
• Oxacillinase-48 (OXA-48)

Although non-KPC carbapenemases have historically been associated with exposure to healthcare outside the United States, they have now been identified in many states across the country and in patients who did not receive healthcare abroad.

CRE can also become resistant to carbapenems through a combination of chromosomal mutations and acquired non-carbapenemase resistance mechanisms (e.g., a chromosomal mutation in a porin gene that limits the ability of carbapenems to get into the bacteria combined with acquisition or upregulation of a beta-lactamase). CRE without carbapenemases are called non-carbapenemase-producing CRE.

Some Enterobacterales, such as Morganella morganii, Proteus species, and Providencia species, always have elevated minimum inhibitory concentrations (MICs) to the carbapenem imipenem but have also been found to harbor carbapenemase genes.

What is the difference between CRE and CP-CRE?

CRE are Enterobacterales that are resistant to carbapenem antibiotics. This is a phenotypic definition (i.e., based on the antibiotic susceptibility pattern of the organism). There are many different mechanisms (i.e., genotypes) that can result in carbapenem resistance. CRE that produce carbapenemases, enzymes that break down carbapenems and related antimicrobials making them ineffective, are called carbapenemase-producing CRE (CP-CRE). CP-CRE are therefore a subset of all CRE.

How common are carbapenemases?

In the United States, CRE are generally associated with healthcare settings, and approximately 30% of CRE carry a carbapenemase. These carbapenemase genes are often on mobile genetic elements, which can be easily shared between bacteria, leading to the rapid spread of resistance.

How common are metallo-beta-lactamase genes, like NDM and VIM, in CRE in the United States?

NDM, VIM, and IMP are less commonly identified in CRE in the United States relative to KPC. Since the AR Lab Network began testing in 2017, only about 10% of carbapenemases identified have been metallo-β-lactamases (MBLs). Preventing the spread of these carbapenemases is critical, because they are resistant to some newer antibiotics that are effective against KPC-producing CRE.

The 2018 Sanford Guide to Antimicrobial Therapy recommends the combination therapy ceftazidime-avibactam + aztreonam for treatment of serious infections caused by MBL-producing CRE. Talk to your HAI coordinator about testing MBL-producing CRE isolates against this combination therapy through the AR Lab Network.

CRE and Carbapenemase Identification

Why is carbapenemase testing important?

Carbapenemase mechanism testing is important for CRE prevention because it identifies CP-CRE for which a public health response is recommended and enables healthcare facilities and public health departments to better target different interventions to different types of CRE. For more information about CRE specific interventions for healthcare facilities, consult the CDC CRE Toolkit pdf icon[PDF – 1 page].

How can a laboratory determine if a CRE is carbapenemase-producing?

Clinical laboratories can perform phenotypic tests for carbapenemase production (e.g., CarbaNP, mCIM, and mCIM with eCIM) or molecular assays for the presence of a carbapenemase gene (CLSI, M100, S29).

Carbapenemase testing is available through the AR Lab Network. This testing includes phenotypic testing for carbapenemase activity and molecular identification of the five carbapenemases most frequently identified in CRE: KPC, NDM, VIM, OXA-48-type, and IMP.

Note that 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, a case notification should be sent to the National Notifiable Diseases Surveillance System (NNDSS) and those requiring or requesting epidemiological information should be notified (e.g., state or local public health programs).

CRE Epidemiology and Prevention

How are CRE transmitted?

In healthcare settings, CRE are transmitted from person to person, often via the hands of healthcare personnel or through contaminated medical equipment. Additionally, sink drains and toilets are increasingly recognized as an environmental reservoir and CRE transmission source. Preventing CRE transmission requires meticulous hand hygiene, appropriate use of transmission-based precautions (i.e., use of Contact Precautions or Enhanced Barrier Precautions depending on setting and organism), environmental cleaning, and adherence to sink and toilet hygiene practices.

Which patients are at increased risk for CRE acquisition?

The main risk factors for CRE acquisition in the United States include exposure to healthcare and exposure to antibiotics. Healthcare-related risk factors include requiring help with most activities of daily living, like toileting and bathing, exposure to an intensive care unit, and mechanical ventilation. Several antibiotics have been associated with getting CRE, including carbapenems, cephalosporins, fluoroquinolones, and vancomycin.

Exposure to antibiotics can disrupt the community of bacteria living on and in a person’s body (microbiome). This can make it easier for someone without CRE to acquire it. For patients with CRE colonizing their digestive tract, taking antibiotics can increase the amount of CRE in the body and the chances of developing an infection or spreading CRE to other patients. Several antibiotics have been associated with getting CRE, including carbapenems, cephalosporins, fluoroquinolones, and vancomycin.

What infections do CRE cause?

CRE can cause infections in almost any body part, including urinary tract infections, bloodstream infections, ventilator-associated pneumonia, and intra-abdominal abscesses.

What is the difference between CRE colonization and infection?

Infection occurs when a pathogen such as CRE invades a body site and causes signs and symptoms of disease. Colonization means that the organism is found in or on the body but it is not causing any symptoms or disease. Individuals colonized with CRE can develop CRE infections and can spread CRE to other patients; therefore, CRE prevention practices include both colonized and infected individuals.

CRE most frequently colonizes the digestive tract. Screening certain high-risk individuals for CRE colonization is a CDC-recommended intervention that can help stop the spread of CP-CRE. These high-risk individuals include patients or residents who shared some of the same risk factors as a newly identified CP-CRE-colonized individual (e.g., hospitalized on same unit) and patients who have been hospitalized outside the United States in the prior 6 months. The AR Lab Network offers free colonization screening.

What are the recommendations to prevent the spread of CP-CRE?

Most of the increase in carbapenem resistance in Enterobacterales in the United States and worldwide is attributed to the spread of carbapenemase genes. These genes can be transferred between bacteria, amplifying the spread of carbapenem resistance. Therefore, CP-CRE are targeted for intensive prevention efforts. CDC recommends a coordinated public health response to identification of even single cases of unusual carbapenemases, with assessment of infection control practices and assessment for potential transmission through colonization screening.

Because CP-CRE are spread through contact, meticulous adherence to core infection control practices prevents person to person transmission. This includes:

• use of Contact Precautions for known CRE-infected or colonized individuals in acute care
• Enhanced Barrier Precautions for CRE-infected or colonized individuals in post-acute care
• adherence to hand hygiene and environmental cleaning and disinfection

For more information on facility-level prevention strategies, see the CRE toolkit and Information for Healthcare Facilities about CRE.

What are the recommendations to prevent the spread of CRE that don’t produce carbapenemases?

CRE that do not produce carbapenemases are generally still resistant to multiple antibiotics (i.e., multidrug-resistant organisms) and likely warrant use of targeted infection control interventions (e.g., Contact Precautions in acute care settings) in healthcare settings to limit transmission. However, more aggressive interventions like screening contacts for colonization are generally reserved for CP-CRE, which have greater potential for spread.

Resources

• AR Laboratory Network
• Expanded Antimicrobial Susceptibility Testing for Hard-to-Treat Infections (ExAST) pdf icon[PDF – 1 page]

• Facility Guidance for Control of Carbapenem-resistant Enterobacterales (CRE)
• National Notifiable Diseases Surveillance System (NNDSS): Carbapenemase Producing Carbapenem-Resistant Enterobacteriaceae (CP-CRE)
• New carbapenem-resistant Enterobacteriaceae warrant additional action by healthcare providers