SUMMARY/ABSTRACT Finding novel strategies to reduce healthcare-associated infections (HAIs), and Clostridium difficile infections (CDI) specifically, is a primary focus of the US DHHS and AHRQ. Improved terminal cleaning of hospital rooms is a critical imperative to interrupting transmission of HAIs. Unfortunately, the quality of terminal room cleaning achieved with standard hospital protocols is highly variable and inadequate. More reliable, intense disinfection has great potential to improve standard terminal room cleaning as a method to reduce HAIs. HyperDRYMist is a novel disinfectant device that creates a submicron, liquid particle mist of an EPA- approved, sporicidal, hydrogen peroxide-based, silver ion-impregnated disinfectant, which is dispersed across all air-exposed surfaces. After an EPA-compliant dwell period, the mist settles and the air in the room clears below EPA standards for particle safety, leaving all impacted surfaces dry to the touch. The entire process takes 20-30 minutes. In contrast, hydrogen-peroxide vapor technology, in which the active agent is in gaseous form and is not a liquid particulate mist, requires 2-3 hours to safely turn around a room. No patient or staff safety concerns of the misting process were identified despite months of use at multiple hospitals. Most importantly, in a 6 month, pilot, cross-over study, use of HyperDRYMist reduced the incidence of CDI from 4.2% to 0.6%; after cessation, CDI rates rose back up to 4.7% (prelim data). Thus HyperDRYMist has strong preliminary evidence. We propose to conduct a multi-centered trial to: 1. Define the impact of HyperDRYMist on HAI rates. Los Angeles County+University of Southern California, Harbor-UCLA, and Olive View Medical Centers are public hospitals in LA that provide care for AHRQ priority populations. A 12 month lead-in period will be used to establish baseline HAI rates and study infrastructure, and to ship, test, prepare, deploy and train personnel on the equipment. During the 24-month, prospective, active-controlled intervention, single occupancy rooms in the hospitals will undergo normal terminal cleaning by EVS with (intervention) vs. without (control) the HyperDRYMist device. After the intervention, the relative change from baseline in the rate of facility-onset, CDC-defined CDI between intervention and control rooms will be the primary outcome measure; secondary outcome measures will evaluate other forms of MDRO infection; a direct medical cost-benefit analysis will also be conducted. 2. Define the impact of HyperDRYMist on microbiome ecology and densities in key areas of hospital rooms. Microbial ecology on high touch surfaces in hospital rooms will be compared between interventional vs. control rooms to determine the impact of HyperDRYMist disinfection. This study will determine the potential for a novel method to routinely, more effectively disinfect many more surfaces in a hospital room than is achieved with standard cleaning. The availability of a simple, effective, terminal room-cleaning technology that reduces HAIs will tremendously benefit US healthcare.