A study examining the clinical and molecular epidemiology of carbapenem-resistant Enterobacterales (CRE) in US hospital patients indicates there is greater diversity in CRE than previously thought, a finding that could have implications for how hospitals treat and control the pathogens.
The study, published late last week in The Lancet Infectious Diseases, looked at clinical and whole-genome sequencing data on a cohort of patients at 49 US hospitals in 15 states who were colonized or infected with CRE according to Center for Disease Control and Prevention (CDC) 2015 CRE guidelines. CRE are considered an urgent healthcare threat by the CDC because they are frequently multidrug resistant and can carry mobile resistance elements that are easily shared with other bacteria.
High death rate in CRE patients
For the study, CDC-defined CRE were Enterobacterales that were resistant to one or more carbapenems, including ertapenem, were documented to harbor a gene encoding a carbapenemase enzyme, or were positive for carbapenemase production. The primary clinical outcome was desirability of outcome ranking (DOOR), which assigns higher ranks to patients with better overall clinical outcomes, at 30 days after the index culture.
Of the 1,040 patients included in the study, 449 (43%) had an infection and 591 (57%) were colonized with CRE. The CDC-defined CRE admission rate was 57 per 100,000 admissions.
Analysis of the 1,040 isolates identified three mutually exclusive subsets of CRE: carbapenemase-producing Enterobacterales (CPE, 618 isolates, 59%), non-carbapenemase-producing Enterobacterales (non-CPE, 194, 19%), and unconfirmed CRE (228, 22%), which were initially reported as CRE but were later found to be susceptible to carbapenems at two central laboratories. Klebsiella pneumoniae accounted for 80% (493 of 618) of CPE isolates.
The most commonly identified carbapenemase genes among CPE were Klebsiella pneumoniae carbapenemases (93%), New Delhi metallo-beta-lactamases (3%), and oxacillinase-48-like beta-lactamases (3%).
Analysis of clinical outcomes showed that, of the 449 patients with infections, 24% were dead at 30 days, but 30-day mortality was not significantly different among the three subgroups after adjusting for possible confounding factors: 25% for CPE, 22% for non-CPE, and 23% for unconfirmed CRE.
Not all CRE are alike
The authors of the study, a team led by researchers from the University of North Carolina and the University of Health Sciences Center at Houston, say the finding that 41% of the CRE isolates did not carry carbapenemase genes, and that 22% were not carbapenem resistant upon further testing, is an important one because hospitals put a lot of focus on prevention of CPE, which are associated with poor outcomes and are known to spread rapidly in healthcare settings. But efforts to prevent and treat CPE in hospitals might not be as effective against other types of CRE, which are just as deadly, they argue.
"Correct identification of carbapenemase production at the patient, hospital, regional, and national levels is important for treatment selection, infection control, and prevention of spread," they wrote.
In an accompanying commentary, infectious disease experts from Washington University School of Medicine in St. Louis say the results underscore the need for more research into how different types of CRE emerge and spread, and how hospitals can combat them.
"First, the absence of difference in clinical outcomes among CRE groups warrant new evidence-based epidemiological health-care policies," they wrote. "Studies focusing on transmissibility and the effect of antibiotic exposure on the emergence and acquisition risk of various types of CRE are needed so that effective prevention strategies can be designed."
They also call for randomized controlled trials on effective antibiotics for all CRE infections, and enhanced guidance on identifying unconfirmed CRE.