# Characterization and suppression of resistance to new CRE agents > **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $78,250 ## Abstract 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 l... ## Key facts - **NIH application ID:** 9884732 - **Project number:** 5R03AI144636-02 - **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH - **Principal Investigator:** Ryan K Shields - **Activity code:** R03 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $78,250 - **Award type:** 5 - **Project period:** 2019-03-04 → 2022-02-28 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9884732 ## Citation > US National Institutes of Health, RePORTER application 9884732, Characterization and suppression of resistance to new CRE agents (5R03AI144636-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9884732. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*