Surveillance for antimicrobial resistance in C. difficile in the VA Healthcare System

Background and Innovation: Clostridioides difficile is the most common pathogen causing healthcare-associated infections in the United States. Recent reports have raised concern that C. difficile strains with reduced susceptibility to the primary treatments for C. difficile infection (CDI) (i.e., fidaxomicin and vancomycin) are emerging. However, the extent of the problem is uncertain as surveillance for antimicrobial resistance in C. difficile is very limited in the United States. To address this unmet need, we will conduct a 3-year multicenter surveillance study for emergence of reduced susceptibility to vancomycin or fidaxomicin in the VA Healthcare System. The study will be conducted in 7 VA facilities in collaboration with VA co-investigators with expertise in C. difficile (5 sites) and with the Veterans Affairs Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD) biorepository (2 sites). Several aspects of our approach will be innovative, including correlation of susceptibility results with clinical outcomes, timely processing of specimens providing the ability to act on emerging resistance trends in real-time, use of state-of-the-art molecular studies to identify genes or mutations associated with reduced susceptibility, and use of an established mouse model to determine if reduced susceptibility to fidaxomicin or vancomycin impacts the ability of C. difficile isolates to colonize the intestinal tract and/or reduces the response to treatment with these agents. Significance and Impact to Veterans Healthcare: CDI is a substantial cause of morbidity and mortality in the VA Healthcare System, particularly among older Veterans and those in VA community-living centers. Emergence of C. difficile isolates with reduced susceptibility to CDI treatments could have a significant adverse impact on the care of Veterans. At the Cleveland VA, we have recovered C. difficile isolates with reduced susceptibility to fidaxomicin from 6% of CDI patients who failed to respond to fidaxomicin or had recurrent infections after fidaxomicin. This proposal will address the unmet need for surveillance for antimicrobial resistance in C. difficile in the VA Healthcare System and will provide evidence that can be used to inform treatment. Path to translation/implementation: The work proposed will establish a 3-year state-of-the-art multicenter surveillance program for detection of antimicrobial resistance in C. difficile in the VA Healthcare System. The findings will provide high-quality data on current trends in C. difficile susceptibility to vancomycin and fidaxomicin and will clarify whether reduced susceptibility impacts the effectiveness of these agents for CDI treatment. The information gained will be used to inform treatment algorithms for CDI in the VA and in non-VA healthcare settings. The results will be significant because CDI is an important clinical challenge and there is an urgent need for improved surveillance for emergence of resistance. Project Number: 1I01BX006885-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Curtis Donskey | Institution: LOUIS STOKES CLEVELAND VA MEDICAL CENTER, CLEVELAND, OH | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 INFB-K (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11183293