The World Health Organization (WHO) currently classifies carbapenem-resistant Enterobacterales (CRE) as one of the top three most dangerous multidrug-resistant pathogens. With the incidence of infections from CRE increasing dramatically since the first reported case in 1996, it is considered a significant public health threat. The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae 2 (CRACKLE-2) Study was designed to provide additional observational data to help design future randomized clinical trials on both therapeutics and diagnostics for multi-drug resistant organism (MDRO) infections.
The multi-center study conducted in in 42 U.S. hospitals collected clinical and epidemiological data on patients with MDRO isolated from clinical cultures during hospitalization. The study’s primary outcome measure was desirability of outcome ranking (DOOR) at 30 days after index culture. Study personnel also recorded epidemiological information on patients that included identifying potential clinical trial enrollment barriers as well as data on the patient outcomes resulting from various antimicrobial treatment regimens.
Study researchers further detailed information on MDRO species, strain type, and mechanism of carbapenem resistance. Since not all diagnostics detect and not all therapeutics are active against the same mechanism of carbapenem resistence, this understanding of the molecular characteristics of carbapenem resistance of the causative CRE will further inform upcoming clinical trial design.
Initially, study personnel expected the study data would show two subsets of CRE, carbapenemase-producing Enterobacterales and non-carbapenamase-producing Enterobacterales. However, a novel subset of CRE was identified comprised of Centers for Disease Control (CDC) defined CRE. It consisted of unconfirmed CRE initially reported as CRE but susceptible to carbapenems in two central laboratories. Unexpectedly, clinical outcomes were similar between patients with all three subsets of CRE.
Carbapenemase-producing Enterobacterales have been the focus of most anti-CRE dedicated efforts. This is primarily based on their extensive resistance profile and the ability of these resistance mechanisms to spread from one bacterium to the other and from one patient to the other.
The unexpected finding that outcomes were similar among patients infected with any of these subsets illustrates that any patient diagnosed with CDC-defined CRE is at risk for poor outcomes. Overall, 24% of infected patients died within 30 days of first positive culture for CRE. Of patients who survived and were discharged, almost half were readmitted to the hospital within 90 days. This illustrates that CRE that do not produce carbapenemases are also clinically important. They are a more genetically diverse group and any intervention targeting the spread of these organisms would likely be more general. Examples of such interventions may include antimicrobial stewardship and improved hand hygiene.
The sites that participated in CRACKLE-2 are now part of ARLG’s international MDRO Network dedicated to studying antimicrobial resistance. Work is underway with similar studies on carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Pseudomonas aeruginosa. In addition, the first manuscript describing the CRE epidemic in the U.S. compared to other parts of the world is in progress. Next the MDRO Network will implement follow-up clinical trials based on CRACKLE-2 therapeutics and diagnostic data.
Review this tool to interact with the summary data from CRACKLE-II.
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