By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: Patient mortality rates were high among patients from whom carbapenem-resistant Enterobacterales (CRE) were cultured, regardless of whether the organism was causing infection or was a only a colonizer. In addition, mortality was similar regardless of whether a carbapenemase gene was present. Finally, not all “CRE” were truly CRE.

SOURCE: van Duin D, Arias CA, Komarow L, et al; Multi-Drug Resistant Organism Network Investigators. Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): A prospective cohort study. Lancet Infect Dis 2020 Mar 6. doi: 10.1016/S1473-3099(19)30755-8. [Epub ahead of print].

Van Duin and colleagues in the Multi-Drug Resistant Organism Network Investigators group examined the clinical and molecular aspects of carbapenem-resistant Enterobacterales (CRE) in the CRACKLE-2 study. They prospectively examined CRE isolates from 1,040 patients from 49 hospitals in 15 states between April 2016 and August 2017. They used the 2015 Centers for Disease Control and Prevention (CDC) definition of CRE, which includes isolates with resistance to any carbapenem, including ertapenem. The rate of hospital admissions with CDC-defined CRE was 57 per 100,000. Urine isolates accounted for 39% of the total, followed by respiratory, blood, and wound isolates in 26%, 13%, and 13%, respectively. Forty-three percent were the cause of infection, while 57% were colonizers.

The investigators classified the Enterobacterales isolates into three groups: 618 (59%) that proved to have carbapenemase genes (CPE); 194 (19%) confirmed as CRE but without a carbapenemase gene; and 228 (22%) that had been identified as CRE at local laboratories but that did not contain such a gene and that could not be confirmed as carbapenem-resistant in two central laboratories (unconfirmed CRE). Of the 593 Klebsiella pneumoniae isolates identified by local laboratories as CRE, 493 (83%) were CPE, while this was true for 46 (24%) of 192 Enterobacter species, and 38 (31%) of 122 Escherichia coli. The most frequently identified carbapenemase genes were blaKPC-3, blaNDM, and blaOXA-48-like, which were detected in 51%, 41%, and 3%, respectively. In addition, extended-spectrum β-lactamase (ESBL) genes also were detected frequently in CPE: blaSHV in 35% and blaCTX-M in 20%; the latter was detected more frequently in CRE without a carbapenemase (30%). Carriage of blaAmpC was detected in 58% of non-CPE CRE and in 62% of unconfirmed CRE, while mutations of outer membrane porin (OmpK35, OMPk36) protein genes were present in 62% and 21% of these, respectively.

Among those with infection due to CDC-defined CRE, the 30-day mortality did not differ significantly by organism classification, ranging from 22% to 25%, while the 30-day mortality in those who were colonized was only 19%. Ninety-day readmission rates for those discharged were 46% for those infected and 40% for those only colonized.


Resistance of Enterobacterales to carbapenems generally is the result of either the production of carbapenemase or a combination of alterations of outer membrane proteins resulting in impaired ingress of the antibiotic together with hyperproduction of an ESBL or ampC cephalosporinase.

This study provides an important overview of CRE in the United States. Some of the results are of particular interest. Thus, although the mortality rates were high, there was no significant difference between infections due to CRE with or without a detectable carbapenemase — a result that differs from the one previously reported in a small, single-center study.

Also of interest was that infections for which the CDC definition of CRE could not be confirmed by two central laboratories also were not associated with a significant comparative difference in mortality. Finally, there was little difference in mortality or readmission rates in patients who were infected or only colonized with CRE. The latter indicates that the detection of CRE is an indicator of the fact that a patient is at high risk of a poor outcome for reasons over and above the presence of the organism.

One in five isolates labeled as carbapenem-resistant by local laboratories could not be confirmed to be resistant to any of the carbapenems, including ertapenem. This has important implications regarding the use of in-hospital isolation as well as of appropriate antibiotic therapy.