Cornelius (Neil) J. Clancy, MD, has been awarded funding in the amount of $461,686 for a two-year grant by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) entitled, “Polyclonality of carbapenem resistant Enterobacteriaceae bloodstream infections.” This proposal was submitted in response to the competitive funding opportunity entitled NIH Exploratory/Developmental Research Grant Program (Parent R21) under funding opportunity number PA-19-053.
Carbapenem resistant Klebsiella (CRK) species, in particular carbapenem resistant Klebsiella pneumoniae (CRKP), are recognized as “urgent threat” pathogens globally. Bloodstream and other serious Klebsiella infections, including those due to CRK, usually are caused by a strain that colonizes the gastrointestinal (GI) tract. Emerging whole genome sequence (WGS) data show that the GI tract is colonized by clonal bacterial populations, in which genetic diversity develops over time. It is unknown how often bloodstream infections are caused by clonal but genetically diverse strains of a given bacterium, since clinical and research laboratories generally characterize a single colony from positive cultures.
The objectives of the project are to characterize the genetic and phenotypic diversity of bloodstream CRK strains recovered from baseline and longitudinal blood cultures of inpatients, and to implicate specific genes, plasmids and mutations in antibiotic responses and virulence. Results will affirm the extent and type of genetic diversity in CRK-positive blood cultures and identify novel genetic determinants of antibiotic treatment failure and virulence. Insights will provide the foundation for laboratory studies of mechanisms by which CRK genes dampen antibiotic responses and promote pathogenesis, and for follow-up clinical studies to define genetic diversity during other types of CRK infections or infections by other bacteria, and correlations between genetic diversity and outcomes in patients.