Carbapenem Resistance

The Enterobacteriaceae are a large family of gram-negative bacilli that includes Escherichia coli, Klebsiella species, and Enterobacter species. They are normal inhabitants of the gastrointestinal tract of humans and animals and a common cause of community-acquired and health-care–acquired infections.  They have gradually developed resistance to broad spectrum antibiotics. In the United States, these resistant strains have been treated with carbapenem antibiotics including imipenem, meropenem, doripenem, and ertapenem.  However, new classes of enzymes that hydrolyze and inactivate the carbapenems are being detected in the United States. These carbapenemases are usually plasmid-mediated, which facilitates transfer between bacteria.

Carbapenem-resistant Enterobacteriaceae (CRE) were uncommon in the United States before 2000, but have increased in hospitals over the past 16 years. Invasive bloodstream infections with CRE have mortality rates as high as 50%. Therefore, they have become a serious infection control concern.

The most common carpabenemase to date is found in Klebsiella pneumoniae, and is hence referred to as KPC. This carbapenemase is plasmid-mediated, which facilitates transfer between bacteria. Other enteric bacteria in which this type of plamid mediated carbapenemase has been reported include E. coli, K. oxytoca, S. marcescens, E. cloacae, E. aerogenes, C. freundii, and Salmonella. Klebsiella pneumoniae carbapenemase (KPC) is encoded by a highly transmissible gene that has now spread widely throughout the United States and around the world. In addition to KPC, other carbapenemases have emerged among Enterobacteriaceae outside the United States.

The best known example is the New Delhi metallo-betalactamase (NDM). The unfortunate clinical significance of these carbapenemase-producing organisms is that they are usually resistant to most other anti-microbials, including all classes of beta lactam agents, and often aminoglycosides and quinolones as well.

More recently, other mechanisms besides carbapenemase enzymes that may render Enterobacteriaceae resistant to carbapenems have been recognized. Most commonly this would include production of AmpC beta-lactamase in combination with porin mutations of the bacterial cell membrane.

Due to recognition of multiple types of carbapenem resistance, the CDC recently revised its definition of CRE to include any Enterobacteriaceae that is resistant to imipenem, doripenem, meropenem, or ertapenem OR is found to produce a carbapenemase.

Centers for Disease Control (CDC) & Clinical Laboratory Standards Insitute (CLSI) have issued recommendations for the detection of carpabenemases. Some gram-negative organisms producing this enzyme may fall within the susceptible range for carbapenems by automated test systems, but will exhibit an elevated MIC to carbapenems. When these organisms are also resistant to a 3rd-generation cephalosporin, such as ceftriaxone, additional testing for carbapenemase production should be performed. This confirmatory testing is called the Modified Hodge Test. Organisms tested by this method are reported as positive or negative for carbapenemase production. All carbapenems are reported as resistant when an organism tests positive.

Current CRE prevention strategies are based on the identification of patients colonized or infected with CRE.  Contact precautions are implemented for those patients harboring CRE.

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