Carbapenem-Resistant Enterobacteriaceae: A Formidable Opponent in the Fight against Multidrug Resistance

bacteria picIt is no longer news that after several decades of antibiotic treatment of bacterial infections, a recurring pattern of antibiotic resistance continues to persist among several bacterial pathogens. Such antibiotic resistance generally originates from severely ill hospitalized patients. Initial discoveries of antibiotic-resistant bacteria were usually localized to a specific geographic origin. However, subsequent spread of resistant bacterial strains to other regions has led to global pandemics.  This pattern has been observed with several resistant bacterial strains, which have now become “household names” such as methicillin-resistant Staphylococcus aureus and penicillin-resistant Staphyloccoccus aureus.

Common pathogens in humans include gram-negative bacteria from the Enterobacteriaceae family. This family of bacteria is responsible for several infections ranging from cystitis to meningitis [1]. In the past, a wide range of antibiotics could be used to successfully treat infections caused by this family of bacteria. Alas! Our false sense of security has been dashed with the recent rise of multidrug resistance among several bacterial strains in the Entrobacteriaceae family. This seemingly boundless resistance occurs through acquired genes that code for Extended Spectrum Betalactamases (ESBLs) [1]. Until recently, the most effective antibiotic utilized for the treatment of broad-spectrum resistance was carbapenem. This class of antibiotics has been referred to as the “agents of last resort” due to their efficiency in the decimation of multidrug-resistant bacteria. The recent emergence of carbapenem-resistant Enterobacteriaceae (CRE) makes the future look bleak. It insinuates that there is no longer an effective antibiotic option for the treatment of infections caused by gram-negative Enterobacteriaceae.

The development of CRE occurs due to the hydrolysis and inactivation of the carbapenem antibiotic by enzymes known as carbapenemases. The most common carbapenemases are the serine β-lactamase KPC and the metallo-β-lactamase VIM [1,2]. Resistance is mediated through the transfer of plasmids that have acquired various resistant genes for beta-lactamases. These mobile elements are able to spread quite easily between members of the Enterobacteriaceae family as well as other bacteria species. Although carbapenem resistant strains were rare, reports of several cases associated with health care facilities have recently surfaced and continue to surface in various parts of the world. The spread of resistance is particularly difficult to curb because gram-negative Enterobacteriaceae are a natural part of the human intestinal flora [1]. Humans who serve as reservoirs for these organisms are susceptible to long-term infections under the right conditions. CRE pose a serious threat to global public health due to the limited treatment options available and the high mortality rate associated with their infection. Major problems with these organisms are associated with their ever-increasing prevalence in health care facilities that provide long-term care.

The most common carbapenem-resistant bacterium in the U.S. is the Klebesiella pneumoniae. It was first reported in a clinical specimen from a patient in North Carolina in 2001 [3]. Subsequent outbreaks were then reported in the northeastern parts of the U.S. As of December 2010, Klebsiella pneumoniae carbapenemase-producing isolates have been identified in 36 U.S. states and Washington, D.C. [1]. Other incidences of KPC-producing Enterobacteriaceae have been reported in several parts of the world. In 2007, 27 hospitals in Israel were blind-sided by a clonal outbreak of carpabenem-resistant K. pneumoniae with 1,275 patients affected [4]. The isolated KPC-3 gene believed to be responsible for this outbreak was previously implicated in multiple outbreaks in United States health care facilities. Mortality rate due to this outbreak was estimated at 44% [1].

The uniting fact among several reported cases of CRE outbreaks is their association with patients in long-term acute care hospitals. Therefore, long-term acute care facilities are important reservoirs in the transmission and spread of CRE. An example of this situation occurred in 2011 at the United States National Institutes of Health (NIH) clinical center. An outbreak of carbapenem-resistant K. pneumoniae resulted in the infection of 18 patients and the eventual death of 11 of those patients [5]. A more aggressive incentive for action may have developed with the recent emergence of CRE among children. Hospital-acquired infections due to carbapenem resistance have been observed in a diverse pediatric population ranging from newborns to teenagers in five countries and four continents [6]. In most cases, children were located in intensive care units (ICUs), pediatric wards, and surgical wards; all locations are utilized for long-term patient care. Most infected children had underlying medical conditions such as pulmonary disease, leukemia, and tumors that led to decreased immunity. Although mortality rates in children due to CRE infections are lower than observed in adults, attempts at effective therapy have been less successful.

Can mankind hold on to a thread of hope? There is no doubt that CRE pose a serious danger to public health. In order to achieve successful and effective control of CRE, a nationwide intervention that targets the control of transmission and infection especially in long-term acute care facilities needs to be implemented. Decelerating the spread of CRE in locations where infection is still uncommon will decrease the impact of these organisms. Technology that enhances laboratory detection of CRE is an initial step in the right direction towards the containment of infections. Recently, the NIH utilized a system that combines whole genome sequencing with epidemiological data to track an outbreak in their clinical center. The system of whole genome sequencing has become the gold standard in the process of bacteria typing [5]. Its ability to track the spread of an epidemic in a reasonable time frame has made this system an attractive option in deciphering the route and mode of transmission of CRE between patients. Through gene sequencing, similarities, differences, and mutations among isolates of CRE can be discovered. The use of surveillance cultures from patients with an epidemiological link to CRE-colonized patients can also be used to monitor transmission [2].

Further national intervention should also involve successful implementation and enforcement of nationwide guidelines for infection control and containment by health authorities. Standard precautions such as proper contact isolation and hand hygiene for colonized patients should not be taken for granted. Health policies that specifically address the increasing outbreak of CRE can also help to bolster commitment to curb the transmission of CRE. Broadening preventative methods to include all types of health facilities that may treat infected patients will increase awareness and communication. Although humans have become increasingly effective in identifying and controlling infections caused by CRE, there is no doubt that additional research must be carried out so that our thread of hope can grow stronger.


[1] Schwaber M.J. and Carmeli Yehuda. 2008.  Carbapenem-Resistant Enterobacteriaceae:A Potential Threat. Journal of American Medical Association 300(24).

[2] Queenan AM, Bush K. 2007. Carbapenemases: the versatile beta-lactamases. Clinical Microbiology Review 20(3): 440-458.

[3] Gupta N., Limbago B.M., Patel J.B., Kallen J. A. 2011. Carbapenem- Resistant Enterobacteriaceae: Epidemiology and Prevention. Healthcare Epidemiology 53: 60-63

[4] Schwaber MJ, Lev B, Israeli A. 2011. Containment of a countrywide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention. Clinical Infectious Disease 52:848–855

[5] Snitkin ES, Zelazny AM, Thomas PJ, Stock F, Henderson DK, Palmore TN, Segre JA. 2012. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Science Translational Medicine 4: 48ra116.

[6] Logan LK. 2012. Carbapenem-resistant Enterobacteriaceae: an emerging problem in children. Clinical Infectious Disease 55:852–859

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[1] Retrieved April 16, 2014, from:


Aishat Mustapha is a senior at The George Washington University (GWU) majoring in Biological Sciences. She is interested in epidemiology and global public health and plans to pursue a degree in public health upon her graduation from GWU. Follow The Triple Helix Online on Twitter and join us on Facebook.