Carbapenem-Resistant Enterobacteriaceae

Carbapenem-resistant Enterobacteriaceae (CRE) are Gram-negative gut bacteria, such as Klebsiella pneumoniae and Escherichia coli, that resist carbapenems, the broad-spectrum beta-lactams long held in reserve for severe and multidrug-resistant infections. Because carbapenems are frequently the agents of last resort against resistant Enterobacteriaceae, CRE are among the most serious antimicrobial-resistance threats and are designated a critical-priority pathogen group.

Definition

Carbapenem-resistant Enterobacteriaceae are Enterobacteriaceae that are non-susceptible to one or more carbapenem antibiotics, whether through production of carbapenem-hydrolysing enzymes (carbapenemases) or through combinations of other beta-lactamases with reduced membrane permeability.

Scope

The entry covers the mechanisms of carbapenem resistance, the distinction between carbapenemase production and other routes, the major carbapenemase enzyme families, and the epidemiologic and infection-control significance of CRE. It is descriptive reference material and does not provide antimicrobial selection or dosing advice.

Core questions

• By what mechanisms do Enterobacteriaceae become resistant to carbapenems?
• How do carbapenemase-producing and non-carbapenemase routes to resistance differ?
• Which carbapenemase enzyme families drive the global spread of CRE?

Key concepts

• Carbapenemase enzymes
• Klebsiella pneumoniae carbapenemase (KPC)
• Metallo-beta-lactamases (NDM, VIM, IMP)
• OXA-48-type carbapenemases
• Porin loss with ESBL or AmpC co-production
• Last-resort antibiotics
• Plasmid-mediated horizontal spread

Mechanisms

Carbapenem resistance in Enterobacteriaceae arises principally from carbapenemases, enzymes that hydrolyse carbapenems; the major families are Klebsiella pneumoniae carbapenemase (KPC, a serine enzyme), the metallo-beta-lactamases NDM, VIM, and IMP, and the OXA-48-type enzymes. Resistance can also occur without a carbapenemase when an organism combining an extended-spectrum or AmpC beta-lactamase with loss of outer-membrane porins reduces drug entry enough to raise carbapenem minimum inhibitory concentrations. Many carbapenemase genes reside on plasmids alongside other resistance determinants, enabling horizontal spread and accumulation of multidrug resistance.

Clinical relevance

CRE cause bloodstream, urinary, intra-abdominal, and respiratory infections, often in critically ill or device-exposed patients, and because carbapenems are a reserve class their loss leaves few reliable options, which is why CRE are a focus of infection prevention, surveillance, and stewardship. This entry characterizes the resistance mechanisms for educational reference and is not a guide to individual patient management.

Epidemiology

Carbapenemase-producing Enterobacteriaceae have spread globally with regional variation in dominant enzymes, including KPC, NDM, and OXA-48-type, frequently linked to healthcare exposure and international patient transfer. CRE are classified as a critical-priority pathogen group on international lists because of their limited treatment options and transmissibility.

History

Plasmid-mediated carbapenemases emerged and spread from around the turn of the twenty-first century, with KPC enzymes recognized in Klebsiella pneumoniae and subsequently disseminating internationally, followed by the global expansion of NDM and OXA-48-type enzymes, transforming carbapenem resistance from a rarity into a worldwide concern.

Debates

Should surveillance target carbapenem resistance or carbapenemase production?

Defining and detecting CRE by phenotypic carbapenem resistance versus by molecular carbapenemase production affects which isolates are captured for infection control, and the two approaches do not always overlap.

Seminal works

• nordmann-2009
• tacconelli-2018

Frequently asked questions

Is every carbapenem-resistant Enterobacteriaceae a carbapenemase producer?

No. Most CRE produce a carbapenemase, but resistance can also result from combining other beta-lactamases with loss of outer-membrane porins that reduce drug entry, without any carbapenem-hydrolysing enzyme.

Why are CRE considered an especially serious resistance threat?

Carbapenems are a broad-spectrum reserve class used against otherwise resistant Gram-negative infections, so resistance to them removes a critical option and is associated with limited alternatives, which is why CRE are ranked as critical priority.