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 ap- proach 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 investi- gations, we have provided compelling data that the emergence of DAP resistance results from the accumula- tion 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 therapeu- tic 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 out- comes 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 ge- netic 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 antimicro- bial susceptibility profile (GASP) to predict antibiotic resistances in enterococci, and ii) prediction of clinical out- comes in a cohort of patients with VRE bacteremia treated with DAP (both retrospectively and prospec- tively) 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 Cen- ter 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 Amer- ica).
? PUBLIC HEALTH RELEVANCE Antibiotic resistance is one of the most critical public-health threats of the 21st century, a situation that has been highlighted by the World Health organization, US Congress, CDC, IDSA and the President?s Council of Science and Technology. Vancomycin-resistant enterococci (VRE) are one of the most important hospital-as- sociated multidrug-resistant organisms affecting critically ill patients and is considered a serious public health threat by the CDC. Treatment of VRE infections poses immense therapeutic dilemmas in clinical settings due to the lack of reliable antibiotic options, making these infections untreatable in certain scenarios. Due to the inherent complexities of antibiotic resistance, the management of patients infected with antibiotic-resistant bac- teria is challenging and a critical vacuum in knowledge exists among clinicians. This proposal seeks to develop a patient oriented research program (POR) on antibiotic resistance that fills this gap in expertise. The POR pro- gram is focused on VRE aiming to develop a robust mentoring program for clinicians and scientists dealing with antibiotic-resistant organisms and directed to apply genomic tools for the prediction of antibiotic suscepti- bilities in VRE that could potentially increase the ability to predict therapeutic outcomes in severe VRE infec- tions.
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