Role of immune system in prophylaxis antibiotic's surgical site infection control

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Role of immune system in prophylaxis antibiotic’s surgical site infection control Despite many advances in infection control practices – including improved operating room ventilation, barriers, sterilization methods, improved surgical techniques, surgical site infection (SSI) remains a significant cause of morbidity, prolonged hospitalization, and death with an estimated annual cost of $3.5 to $10 billion in healthcare expenditures in the US alone. Administration of prophylaxis antibiotics in the perioperative period (~1h prior to surgery) is the standard of care for most surgical procedures. However, even short-term antibiotic use is associated with the emergence of antibiotic resistance, as well as, increased risk for Clostridium difficile infection, and immunological and neurological diseases, many of which have been attributed to dysbiosis in the gut flora due to antibiotics. Novel approaches (preferably antibiotic-free) are urgently needed to address SSI. Surgical site infection is considerably worse in immunocompromised patients where prophylaxis antibiotics are considerably much less effective, even in the case where the infective pathogen is sensitive to the administered antibiotics. Whether or not immune system plays a direct role in boosting prophylaxis antibiotics effectiveness or prophylaxis antibiotics functioning in heightening immune system has not been studied. Rather, reduced antibiotic effectiveness in immunocompromised patients has been blamed on factors, such as therapy-induced neutropenia, or disregulated innate immune responses, and/or impaired neutrophil functions. Driven by our preliminary data, we hypothesize that bacterial killing by prophylaxis antibiotics at the site of infection results in immune system activation which in turn directly boosts the effectiveness of antibiotics by mobilizing immune leukocytes to the site of infection. In aim 1 of this proposal, we will assess the molecular mechanism(s) that couple innate immune system with prophylaxis antibiotics. In aim 2, we will test our hypothesis that immunomodulators -- that can mobilize and activate immune system at the site of infection -- will be effective in controlling surgical site infections even in the absence of prophylaxis antibiotics. We will use an implant and a wound animal models for surgical site infection to evaluate the effectiveness of immunomodulator-based therapies (single vs. in combination with antibiotics) as compared to prophylaxis antibiotics alone in controlling local and systemic infections. We will also assess the possible deleterious side- effects of immunomodulator-based approaches on animal health and normal physiological processes. These comprehensive studies will tackle surgical site infection which is an important public health concern. They will address critical knowledge gaps in our understanding of the direct role that immune system plays in boosting infection control by prophylaxis antibiotics. And they will lay the groundwork for the development of novel immunomodulator-based approaches to control surgical site infections.