Carbapenem-Resistant Enterobacteriaceae

by Charles Poli, GCSOM, MBS 2019
Mentor: Kimberly Miller, PharmD.

The Centers for Disease Control and Prevention (CDC) has classified carbapenem-resistant Enterobacteriaceae (CRE) as an urgent public health threat. Infections that are linked to CRE organisms are difficult to treat and have mortality rates as high as 40-50%. CRE infections mostly affect patients that are in acute or long-term healthcare settings and patients who have compromised immune systems. Some common CRE infections include urinary tract infections, respiratory infection, wound infections, and blood infections.

Enterobacteriaceae is a family of bacteria that are Gram-negative rods. This means that the organisms have a thin cell wall that is made up of a thin layer of peptidoglycan, a substance that consists of sugars and amino acids. Some of the most common members of this family of organisms are E. coli and K. pneumoniae. Both of these organisms are found inside the human gastrointestinal tract and assist in digestion and defense from different pathogens by competing for resources to survive. These two organisms can cause serious infections if they travel outside of their normal locations in the body.

 In 1928, the first antibiotic, penicillin, was discovered by Sir Alexander Fleming. Once penicillin gained popularity, it was often seen as a cure-all to many illnesses. As time progressed, bacteria were able to alter their genes in order to fight off the penicillin. To counteract this, more and more antibiotics were produced, and similarly the bacteria evolved to become resistant to these medications as well. As time progressed, the bacteria were able to alter their genes to be able to produce enzymes, such as beta-lactamase, extended spectrum beta-lactamase and carbapenemase. These enzymes are proteins that have the ability to breakdown antibiotics and are a hallmark of CRE.

CRE produce an enzyme called carbapenemase. This enzyme breaks down antibiotics, such as carbapenems, cephalosporins, penicillins, and drug combinations with beta-lactamase inhibitors. The enzyme produced by these organisms can be classified into classes A, B, or D based off of their chemical makeup. Due to the wide range of resistance, infections caused by CRE are often times difficult to treat. Depending on the severity of the infection, physicians may choose a cocktail of antibiotics to treat it.
The carbapenemase enzyme is produced by genes found within the organism. The gene may be found either on the organism’s main chromosome, which houses all of the organism’s genetic make-up, or it can be found on a transferable plasmid. A plasmid is a small, circular loop of DNA that can be used to make molecules for the organisms, independent of the main chromosome. Researchers have sequenced the genetic code of plasmids that cause the production of carbapenemase and discovered that the production is caused by very minor changes in the genetic sequence of plasmids that do not produce the enzyme.
 
Since the threat of CRE is on the rise, it is important to be able to easily detect these organisms, simply read the results, and implement easy-to-follow techniques in a clinical laboratory. Although genetic testing is the most thorough way to detect CRE, it often times not practical in a hospital laboratory. One type of genetic testing, called Polymerase Chain Reaction (PCR) using Xpert® Carba-R assay, has been endorsed by the FDA due to its rapid screening in a hospital setting. Other techniques look at the physical characteristics of the organisms, such as their ability to continue to grow in the presence of carbapenem antibiotics.
The most prevalent CRE infections are caused by K. pneumoniae. From a study conducted in China from 2012-2015, it was determined that there was a statistically significant increase in prevalence from 1.8% to 3.6%. Also, the organisms in this study showed a wide range of resistance to many different antibiotics. A study that was conducted in long-term acute care hospitals in the United States over 15 months showed a prevalence of 24.6% for infections caused by K. pneumoniae. The second most prevalent cause of CRE infections is E. coli. From a study that was conducted in China, carbapenem-resistant E. coli caused 17.5% of the CRE infections, which was second to K. pneumoniae (52.9%). Likewise, carbapenem-resistant E. coli also show wide varieties of resistance to carbapenems, cephalosporins, penicillins, and other classes of antibiotics.

 CRE are a public health risk, according to the CDC. These organisms have gained the ability to be resistant to a large variety of antibiotics due to slight changes in their genomic sequence. Currently, CRE infections are mostly prominent in hospital-acquire infections. Like many multidrug resistant organisms in the past, CRE organisms may one day move from being mainly hospital-acquired and become more prevalent in community-acquired infections.