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.
This project studies the frequency and mechanisms of resistance to newly-approved antibiotics, ceftazidime- avibactam and meropenem-vaborbactam, against a well-recognized hospital superbug, KPC-producing Klebsiella pneumoniae (KPC-Kp). We will identify and validate antibiotic combination regimens that effectively treat KPC-Kp infections, and suppress the emergence of drug resistance. A key aspect of this study is the mechanistic approach to understand drug resistance mechanisms in order to define strategies to overcome resistance. This has the potential to improve public health because KPC-Kp infections lead to high rates of patient morbidity and mortality, and the optimal treatment strategies are undefined.
