Characterization and suppression of resistance to new CRE agents

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ABSTRACT I am an infectious diseases pharmacist who aspires to pursue an academic career devoted to translating scientific discoveries into safe and effective antimicrobial strategies to prevent and treat infections caused by drug-resistant pathogens. I have recently been promoted to Associate Professor of Medicine at the University of Pittsburgh, where I have trained in the labs of Drs. Neil Clancy, Hong Nguyen, and Raman Venkataramanan to study antimicrobial resistance and the pharmacokinetics-pharmacodynamics of antibacterial drugs. In doing so, I have learned basic and advanced laboratory techniques and pursued NIH career development funding. As a K08 award recipient, I am now submitting an application for R03 funding to provide new preliminary data and hypotheses in support of a subsequent R01 application. The goals of the proposed project are to 1) understand the frequency and mechanisms by which KPC- producing Klebsiella pneumoniae (KPC-Kp) clinical isolates develop resistance to newly-approved antibiotics, ceftazidime-avibactam (CAZ-AVI) and meropenem-vaborbactam (MER-VAB), and 2) identify strategies that effectively suppress the emergence of resistance. KPC-Kp infections continue to be a major cause of morbidity and mortality among patients. The recent availability of ceftazidime-avibactam treatment has improved outcomes among KPC-Kp infected patients, but has come at the cost of the emergence of resistance in some cases. We anticipate that resistance emerges through distinct molecular mechanisms for CAZ-AVI and MER- VAB based upon the genetic characteristics of isolates. The central hypothesis of this proposal is that combination regimens of CAZ-AVI or MER-VAB with synergistic antibiotics will suppress the emergence of resistance seen following exposures to either agent alone. To test this hypothesis, we will compare the KPC-Kp mutational frequency rates against CAZ-AVI and MER- VAB, and determine mechanisms mediating the emergence of resistance. We will screen antibiotic combinations by time-kill analysis using antibiotics that may have synergistic mechanisms of action with CAZ- AVI and/or MER-VAB (aim 1). Next, we will validate effective combinations for their ability to eradicate KPC-Kp and suppress the emergence of resistance over a 10-day treatment course in an in vitro hollow-fiber infection model that accurately simulates humanized exposures of antibiotics (aim 2). The model features site-specific exposures that are achieved at sites of infection, from which we will develop mathematical models to define the best combinations. Through these objectives, we will generate timely, clinically-relevant data that cannot be obtained through other approaches, and will open new lines of investigation for future grant applications. I am well-positioned to carry out the proposed aims within a medical center that has accumulated much of the world's experience with CAZ-AVI and a research environment that has allowed me to develop the advanced laboratory and analytical skills needed to study antimicrobial resistance.