M.C. Parker, S. Kumar, I. Martinez, V.D. Pinon, M. Lancaster, C. Schmiedt, B. Brainard, E.J. Brisbois, H. Handa
University of Georgia,
United States
Keywords: nitric oxide, catheter model, in vivo, clinical translation
Summary:
Biofilm-associated infections on medical devices contribute to treatment failure and antibiotic resistance due to impaired drug penetration and persistent bacterial communities. Biofilm-associated Central venous catheters and urinary catheters are widely used in hospital settings, however, the implantation of these devices is often accompanied by complications. About 65% of nosocomial infections are linked to biofilms. Biofilms are complex structures of bacterial organisms that adhere to surfaces, surrounded by an extracellular polymeric substance, allowing them to persist in the host. Commonly associated with catheter infections, the crossing of the skin barrier in both venous and urinary catheters allows contaminants to travel along the catheter, potentially leading to fatal complications. Bloodstream and urinary tract-related infections urge the need for novel developments to prevent and treat biofilm infections. Antibiotic-impregnated catheters have been utilized previously due to their low toxicity and ability to decrease bacterial colonization; however, they are limited in their practical clinical application due to their inability to disrupt a preformed biofilm and ineffectiveness against antibiotic-resistant bacterial strains. The greatest concern with antibiotic-impregnated catheters is the emergence of drug-resistant organisms. It is critical to combat biofilms in a dual-action method, capitalizing on multiple prevention and biocidal effects. Innovative solutions are required to combat these persistent infections. Combination therapy is a promising treatment option that allows for two or more active agents to be locally delivered to the surrounding tissue and area. The combination release of nitric oxide and antibiotics has been widely studied for their vast synergistic antibacterial and antibiofilm approach but there has been limited translation into the clinical setting. This work demonstrates the effective development and incorporation of a novel NO-releasing Ciprofloxacin-SNAP conjugate and its translation into a catheter in vivo model. Ciprofloxacin, a fluoroquinolone antibiotic, is active against Gram-negative bacteria; however, it has limited effect against Gram-positive bacteria and biofilm infections. Nitric oxide is a small gasotransmitter molecule, identified as an important signaling molecule involved in biofilm dispersal. It is particularly recognized for its broad-spectrum antibacterial properties, showing affecting biocidal activity against both gram-positive and gram-negative bacteria. Due to the short half-life of NO and the multiple killing mechanisms, bacterial cells have a difficult time developing resistance to the potent bactericidal agent. However, considering its short half-life, the NO release often depends on the depth of the reservoir or the longevity of the NO donor. The incorporation of SNAP_CIP with a silicone-based catheter resulted in NO release for 14 days, while remaining cytocompatible and hemocompatible. Furthermore, the in vitro antibiofilm properties were assessed through a 14-day CDC bioreactor, resulting in >85% reduction in adhered S. aureus. Furthermore, approx. 1.1 log reduction in bacterial adhesion was demonstrated in a 14-day in vivo infectious catheter rabbit model, while reducing clot area by >84%. To assess the migration of bacteria across a skin barrier, a skin translocation model was performed, showing no migration of bacteria on SNAP_CIP catheters. Overall, SNAP_CIP catheters provide combination technology that both disrupt the biofilm and kill the dispersed bacteria of both Gram-positive and Gram-negative bacterial strains.