SBIR-STTR Award

Intravascular (IV) catheters in the hospital setting are associated with a high rate of bacterial colonization, resulting in >20,000 deaths annually in the U.S. from catheter related blood stream infections (CR-BSIs). Newer commercial catheters pre-loaded with silver or antibiotics within their walls have failed to dramatically reduce this very significant problem. A variety of catheter lock solutions (catheters that are filled with these solutions when not in use) containing antibiotics, ethanol and other antimicrobials are currently employed in hospitals around the world. However none of the antimicrobial agents used in existing lock solutions are able to diffuse through the walls of the catheters and prevent infection and biofilm formation on the outer surfaces of the catheters. Further, microbial biofilm commonly formed on catheter surfaces is particularly resistant to antibiotic treatment owing to the inability of the antibiotics to penetrate the protective polysaccharide matrix associated with biofilm. Nitric oxide (NO) is an endogenous antimicrobial agent that kills planktonic bacteria as well as those microbes within a biofilm. Recent research has demonstrated that NO release from catheters surfaces using NO donors incorporated into the walls of the catheters is quite effective in preventing bacterial colonization. However, the use of exogenous NO donors within the walls of catheters will likely face significant FDA hurdles associated with ensuring the safety of the specific NO donors utilized. To move NO release catheters more quickly into clinical use, NOTA plans to create a simple NO release IV catheter lock solution that will be reconstituted from a dry powder state (in vial) by hospital personnel immediately before use, and then loaded into the IV catheter using a syringe. The solution will contain a proprietary mixture of S-nitrosogutathione (GSNO), a known carrier of NO within the human body, along with S-glutathione and/or ascorbate (vitamin C) as accelerants to control the rate of NO release from GSNO over many hours (in physiological saline solution). Phase I will focus on 1) optimizing the GSNO/additive formulation’s NO release kinetics and examining dry-state storage stability over 8 months of different recipes; 2) determining the duration and magnitude of NO release for different concentrations of lock solution reagents when loaded within the lumen of catheters made of different polymeric materials; and 3) assess the antimicrobial activity of different catheter tubing loaded with fresh GSNO/additive lock solutions (replaced daily) over 7 d periods against S. aureus and P. aeruginosa using a CDC bioreactor model. Given the known presence of GSNO in blood, the proposed use of antimicrobial GSNO-based catheter lock solutions should be a very safe, effective, and inexpensive new approach to greatly reduce the rates of CR-BSIs.

Public Health Relevance Statement:
NARRATIVE Intravascular (IV) catheter associated bloodstream infections are a very major problem in the hospital setting, causing >20,000 deaths annually in the U.S. alone, and also significantly increasing healthcare costs. Efforts to develop silver and antibiotic impregnated catheters have, to date, not resolved the high infection rates associated with IV catheters. NOTA Laboratories now plans to develop a new product line of various dry reagent formulations containing S-nitrosoglutathione (GSNO), along with appropriate additives in a saline background, that can be reconstituted with pure water at the patient’s bedside for use as completely new and much more effective antimicrobial lock solutions in the hospital setting. The NO gas generated within the lock solution from the GSNO confined within the lumen(s) of catheters will be capable of preventing bacterial colonization on both the inner and outer surfaces of the catheter owing to NO’s ability to readily permeate the walls of the catheter (not possible with antibiotics) and serve as localized bactericidal agent and also prevent/disperse microbial biofilm.

Project Terms:
Adhesions; Amber; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; antimicrobial; antimicrobial drug; Antiplatelet Drugs; ascorbate; Ascorbic Acid; Bacteria; Bacterial Counts; bactericide; base; Bicarbonates; Bioreactors; Blood; Blood Vessels; Catheter-related bloodstream infection; Catheters; Cell Count; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Citrates; Clinical; Clinical Trials; Collaborations; controlled release; cost; Devices; Diffuse; Distal; Edetic Acid; Electrolytes; Ensure; Epithelial Cells; Ethanol; experimental study; Face; Fluorescent Dyes; Formulation; Gases; Glutathione; Health Care Costs; Heparin; Hospital Personnel; Hospitals; Hour; Human; Human body; imaging modality; Infection; Infection prevention; Inflammatory; Ions; Kinetics; Laboratories; Life; Longevity; Michigan; Microbe; Microbial Biofilms; microorganism; Modeling; Nature; new technology; Nitric Oxide; Nitric Oxide Donors; novel; novel strategies; Patient Care; Patients; Permeability; Phase; Physiological; Polymers; Polysaccharides; Polyurethanes; Powder dose form; prevent; Pseudomonas aeruginosa; Reagent; Recipe; reconstitution; Research; Risk; S-Nitrosoglutathione; Safety; Saline; Sepsis; Signaling Molecule; Silicone Elastomers; Silicones; Silver; Sinus; Stains; Staphylococcus aureus; Stream; Surface; Syringes; Tablets; Temperature; Testing; Thrombus; Toxic effect; Trace metal; Vial device;