Friday, May 3, 2024
5/3/2024
Although oral vancomycin (VAN) treatment failures in Clostridioides difficile infection (CDI) are common, antibiotic susceptibility testing is not conducted in the clinical setting. This has resulted in, and is in part due to, the lack of established susceptibility measure(s) corresponding with clinical outcomes. Our long-term goal is to develop clinically relevant microbiologic susceptibility measures that are predictive of patient outcomes in patients with CDI. The objective of this proposal is to determine if VAN inhibitory or bactericidal concentrations against C. difficile isolates are predictive of sustained clinical cure. The central hypothesis is that bactericidal concentrations will be more discriminatory and clinically significant than inhibitory concentrations in predicting outcomes. The rationale underlying this proposal is well supported by CDI pathophysiology, VAN drug characteristics, and preliminary data. As CDI is a toxin-mediated disease, ongoing production of toxins worsens clinical outcomes. Toxins are predominately produced during the stationary growth phase in which cell wall synthesis slows, thereby decreasing VAN effectiveness and allowing for continued toxin production at concentrations around the MIC. VAN MICs are also relatively non-discriminatory and generally cluster between 0.5-2 µg/mL. Isolates with the most common resistance mechanism, vanG-mediated resistance, are also known to have disproportionately increased MBCs compared to MICs. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the variance of VAN bactericidal concentrations stratified by C. difficile MICs; 2) Determine if VAN bactericidal measures or MIC better predicts sustained clinical cure in hospitalized patients given VAN for CDI. This project will prove innovative through challenging the current clinical practice paradigm that VAN susceptibility testing is not needed for patients with CDI, through the expansion of our valuable biobank of 600 patients with CDI that will enable future in-depth mechanistic studies, and development of a high-throughput ATP assay to perform bactericidal concentration testing for future studies. The proposed research is significant as CDI is the most common healthcare-acquire infection and VAN is the most common antibiotic used to treat it; a VAN susceptibility measure corresponding with outcomes is critical to ensuring optimal VAN use and desirable patient outcomes. The expected outcome will provide valuable preliminary data allowing for a future stream of research into molecular diagnostics and point-of-care susceptibility tests incorporate VAN susceptibility. Compared to the CLSI-recommended but labor-intensive broth microdilution MBC method, the high-throughput ATP bioluminescence MBC assays will enable future research studies and implementation into clinical microbiology labs. These studies also lay the foundation for the PI to further expand into CDI translational research and become an independent researcher.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
