This Small Business Innovation Research (SBIR) Phase I project is aimed at the development of antimicrobial sutures containing an active agent that displays broad activity against pathogens associated with surgical site infections (SSIs) and, via its unique mechanism of action, possesses a low potential for resistance development. SSIs are the third most common nosocomial infection. We have developed a series of non-peptidic analogues of antimicrobial peptides, important members of the innate immune system, that are broadly antimicrobial, have enhanced stability, are economical to synthesize and their physical properties can be optimization of potency and safety. One class of these analogues, based on vinyl polymers, appears to be well-suited for development as the active agent in antimicrobial sutures.
The broader/commercial impacts of this research include the development of new antimicrobial sutures, as one example of a new medical-material that limits or prevents associated bacterial colonization. The overall incidence of SSI is 2.8%, which translates into >750,000 SSIs in the US/year, using 3.7 million extra hospital days and costing >$1.6 billion in excess hospital charges/year. Because >60% of SSIs are confined to the incision, the use of sutures coated with antibacterial agent will reduce infection rates. Once successful, this technology can be applied to other wound closure devices to augment infection control. The goal is to develop a foundational technology platform that provides clinicians additional resources to reduce SSIs. This technology can be expanded to the surfaces of other medical devices, such as catheters and implants.
Surgical site infections (SSIs) are the third most common nosocomial infection and most SSIs (66%) are localized to the incision. A number of systematic procedures have been recommended by the CDC to help control SSIs and recently, an antimicrobial suture was approved by the FDA that is now being used in surgeries. While there are certain advantages of the current antimicrobial sutures (Vicryl Plus Antibacterial Suture®, ETHICON), the active agent in the suture, triclosan, has specific limitations and liabilities including limited coverage for Gram-negative SSI pathogens, the potential for resistance and its ubiquitous use in consumer products. Therefore, substitution of more appropriate active agents in antimicrobial sutures is highly warranted. Silver nitrate is another active agent that has been tested for antimicrobial suture applications but potential safety concerns and slow cell killing have limited its use. We have developed small nonpeptidic mimics of host defense proteins (HDP) as antimicrobial agents. The HDP mimics offer several advantages including broad and rapid bactericidal activity, reduced risk for the development of resistance and ease of synthesis. Importantly, the HDP mimics act by disrupting the integrity of the bacterial membrane which leads to rapid cell death. Furthermore, in contrast to most antibiotics that act on specific molecular targets in the bacteria, this mechanism of action is associated with a low risk for the development of resistance. We have examined the suitability of these mimics versus triclosan and silver nitrate as active agents for antimicrobial sutures. The goals of this proposal were to characterize the anti-bacterial activities of the HDP mimics, evaluate their superiority over triclosan and silver nitrate, and demonstrate antimicrobial activity when the HDP mimics are incorporated into suture material. We found that the HDP mimics are active against a broad number of bacterial pathogens commonly associated with surgical wounds and several of the mimics were active against a greater number of pathogens than triclosan. Furthermore, the HDP mimics killed bacteria more rapidly than either triclosan or silver nitrate. Rapid killing is important because it prevents bacteria from establishing a foothold at the infection site which, once it occurs, makes the infection more difficult to treat. Resistance to any of the HDP mimics was not observed after extended treatment times, whereas significant resistance to triclosan occurred very shortly after treatment was initiated. The potential usefulness of the HDP mimics for creating antimicrobial sutures was demonstrated by adding several different mimics into suture materials. Suture preparations containing one mimic showed rapid and significant bacterial killing at the suture surface and other suture preparations containing a different HDP mimic showed rapid and significant bacterial killing at the suture surface and in the surrounding area. Importantly, killing was much more rapid with suture materials containing the HDP mimics than those with triclosan. These studies demonstrate clear superiority of the HDP mimics over triclosan or silver nitrate as active agents for production of antimicrobial sutures. The goals of Phase 2 will be to manufacture antimicrobial sutures containing an HDP mimic and demonstrate their ability to prevent surgical site infections in an animal without causing any unwanted toxic responses.
