POR Program on Genomic Prediction of Antimicrobial Resistance in VRE

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ABSTRACT My major goal through this mid-career development award (K24) is to increase my ability to conduct patient oriented research (POR) on antibiotic resistance and mentor a new generation of clinicians as to how to approach this important public health threat. The emergence of antibiotic resistant bacteria is one of the greatest threats to human health in the 21st century and vancomycin-resistant enterococci (VRE) are some of the most challenging organisms in clinical settings. Indeed, vancomycin-resistant Enterococcus faecium have been designated by the Infectious Diseases Society of America and CDC as a serious threat and one of the “super- bugs” against which new therapies are urgently needed. My current NIH funding is directed to the investigation of the genetic and mechanistic bases of daptomycin (DAP) resistance in VRE. During the course of our investigations, we have provided compelling data that the emergence of DAP resistance results from the accumulation of specific gene mutations and demonstrated that some of the genetic changes do not often correlate with changes in in vitro susceptibility of the organisms (as defined by standard MIC breakpoint) leading to therapeutic failure. Based on major advances in sequencing technologies, I hypothesize that a genetic platform will predict antibiotic susceptibilities in a more accurate manner and that such an approach is feasible and may be better equipped to predict therapeutic success than standard MIC determination in critically ill patients. This hypothesis is supported by robust data suggesting that MIC is not an accurate tool to predict clinical outcomes and the fact that sequencing technologies are likely to be widely implemented in clinical laboratories in the near future. During the course of this award, I plan to use VRE as the model organism to develop a whole genome platform for antibiotic susceptibility with the aim of testing this platform in a cohort of patients with VRE bacteremia. Additionally, I plan to develop a robust mentoring program that integrates the molecular and genetic bases of resistance into clinical practice and seeks to engage young clinicians in a new and expanding area of infectious diseases. The specific aims of this program include, i) development of a genomic antimicrobial susceptibility profile (GASP) to predict antibiotic resistances in enterococci, and ii) prediction of clinical outcomes in a cohort of patients with VRE bacteremia treated with DAP (both retrospectively and prospectively) using GASP. The POR program will be developed at The University of Texas Health Science Center at Houston (UTHealth) taking advantage of the strong clinical research facilities and resources (including one of the original NIH CTSAs) and the numerous training programs at UTHealth and UT MD Anderson Cancer Center with collaborations at Memorial Sloan Kettering Cancer Center and Detroit Medical Center (Henry Ford Hospital). Additionally, this application also has an important international component based on the multiple previous collaborations and an additional research site established by the candidate in Colombia (South America).