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 am an Assistant Professor at the University of Pittsburgh, where I have trained in the labs of Drs. Neil Clancy and Hong Nguyen to characterize echinocandin (EC) resistance among Candida species. In doing so, I have learned basic laboratory techniques and pursued clinical research training through the University's KL2 program. I am now submitting my revised K08 application to obtain advanced laboratory and translational research skills necessary for long-term success as an independent pharmacist-scientist. The goals of the proposed project are to validate specific Candida glabrata FKS hot spot mutations as causes of EC resistance, and to use site-specific pharmacokinetic-pharmacodynamic (PK-PD) parameters to determine optimal EC regimens for treating intra-abdominal candidiasis (IAC) due to FKS wild-type and hot spot mutant C. glabrata, and preventing the emergence of new or higher-level drug resistance. IAC is an under-recognized, poorly studied disease that is common at many centers, for which optimal treatment strategies are undefined. My preliminary data indicate that EC failures, breakthrough infections, and the presence of FKS mutant Candida are as common in IAC as candidemia. The central hypothesis of this proposal is that standard EC doses used for candidemia result in suboptimal concentrations within the peritoneal cavity that lead to treatment failures and emergence of EC resistance mediated by FKS mutations. To test my hypothesis, I will use my clinical database and biorepository to identify clinically-relevant FKS mutations that I will introduce into C. glabrata strain BG2 (standard laboratory strain) by site-directed mutagenesis (aim 1a). Mutagenesis strains will be tested for EC susceptibility, FKS expression, and glucan synthase enzyme kinetics and compared to clinical strains with the same mutation (aim 1b). Next, I will derive site-specific EC PK parameters at intra-abdominal sites using a C. glabrata IAC mouse model developed by my mentors (aim 2a). These data will be modeled to simulate 14-day EC treatment courses in a hollow-fiber infection model to identify regimens that eradicate wild-type and FKS mutant C. glabrata and suppress the emergence of new or high-level resistance (aim 2b). To validate optimized regimens, I will test standard and optimized EC doses in mice for the ability to decrease fungal burdens and suppress resistance (aim 3). To augment my proposed research and previous training, I developed an individualized career development plan that incorporates mentoring, advanced laboratory training, and structured educational activities. My mentors and I have assembled a team of senior investigators with experience in mentoring young scientists, whose expertise is well-aligned with my training goals. I will use the K08 award to generate preliminary data and further publications that will support proposals for independent funding and my long-term career goals.
This project studies the pharmacokinetic and pharmacodynamic effects of the front-line antifungal drug caspofungin, during intra-abdominal candidiasis (IAC), a prevalent form of invasive candidiasis that is not well-studied. An important aspect of this study is the mechanistic approach to understanding antifungal drug resistance mechanisms against Candida (a type of fungus that causes infection in humans). This has the potential to improve public health because optimal treatment regimens for IAC are undefined, especially when infection is caused to drug-resistant pathogens. Thus, the goal of the proposed research is to determine appropriate dosing strategies for caspofungin to effectively treat IAC and suppress the emergence of drug resistance.
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