Clinical Outcomes of CDC-Defined CRE in the United States

Carbapenem-resistant Enterobacteriaceae (CRE) are difficult to treat and have become a global threat to public health. In December 2019 CRE were featured in the US Centers for Disease Control and Prevention (CDC) “Biggest Threats” report on antibiotic resistance.

The investigators behind CRACKLE-2 study results published in The Lancet Infectious Diseases have described the clinical characteristics of CDC-defined CRE in the United States. They found that CDC-defined CRE represent a myriad of bacteria whose spread may not respond to efforts focused solely on carbapenemase-producing Enterobacteriaceae.

The CDC initially defined CRE by non-susceptibility to imipenem, meropenem, or doripenem and resistance to extended spectrum cephalosporins in 2012. The definition was updated in 2015 to include in-vitro resistance to one more carbapenems, with the cephalosporin resistance requirement removed.

Information was gathered as part of CRACKLE-2, a prospective, multicenter, cohort study concerning CREs in the United States. The study population included patients from 49 US hospitals with clinical cultures positive for CDC-defined CRE from April 30, 2016 through August 31, 2017.

The study team assessed cases with a desirability of outcome ranking (DOOR) at 30 days after index culture. CDC-defined CRE were broken into 3 subset categories: carbapenemase-producing, non-carbapenemase-producing, and unconfirmed CRE.

Unconfirmed CREs were pathogens reported as CRE but found susceptible to carbapenems in 2 central laboratories. The need for this category was itself a major finding of the study, as these made up 22% of isolates.

"We were fully expecting to see carbapenemase-producing CRE and non-carbapenemase-producing CRE. What we had not expected was that there would be a significant subset of CRE that when we brought them back to our research labs would not be resistant to carbapenems at all in that setting," investigator David van Duin, MD, PhD, Associate Professor of Medicine at the UNC School of Medicine, told Contagion®.

A total of 1040 patients with unique isolates were included in the analysis, 449 with infection and 591 with colonization. CRE admission was 57 per 100,000 admissions (95% Confidence interval [CI] 45-71).

Carbapenemase-producing CRE made up 618 of 1040 isolates, or 59%. Non-carbapenemase-producing CRE made up 194 isolates (19%). The unconfirmed CRE constituted 228 (22%) of the isolates.

The most common carbapenemase-producing CRE was clonal group 258 Klebsiella pneumoniae. K pneumoniae belonging to clonal group 307 appeared to be increasing in prevalence.

Interestingly, DOOR outcomes were not significantly different between the 3 subsets. At 30 days, 107 (24%, 95% CI 20—28) patients with infection had died. At 90 days, mortality was 137 (31%, 95% CI 26–35).

“CPE [carbapenemase-producing Enterobacteriaceae] are generally considered of the greatest epidemiological interest for their association with poor outcomes and ability to spread rapidly throughout health-care systems. However, in this cohort, 41% of isolates that met CDC guidelines did not carry carbapenemase genes, and 22% were not carbapenem resistant upon centralized laboratory retesting,” study authors wrote.

It is noteworthy that DOOR outcomes were similar between groups. The authors suggest that CDC criteria may identify patients who are at high risk of mortality and readmission regardless of the underlying mechanism of carbapenem resistance.

"While the CDC definition is quite broad and includes this very heterogeneous group of organisms, it does seem to accurately identify those bacteria that

result in a high risk for poor outcomes," van Duin said.