Project Grant R21DE032844

DEFINING THE MECHANISMS OF SURGICAL SITE INFECTION AFTER ORAL CANCER SURGERY USING PERI-OPERATIVE METAGENOMICS - PROJECT SUMMARY ORAL CAVITY RECONSTRUCTION (OCR), WHICH INVOLVES OPEN SURGICAL RESECTION OF ORAL CANCER WITH VASCULARIZED TISSUE FLAP RECONSTRUCTION, REMAINS A CENTRAL COMPONENT OF ONCOLOGIC MANAGEMENT. HOWEVER, A MAIN SOURCE OF PERI- OPERATIVE MORBIDITY AFTER SUCH SURGERIES IS SURGICAL SITE INFECTION (SSI), WHICH CONTINUES TO OCCUR IN AT LEAST 20% OF CASES NATIONWIDE. POST-OPERATIVE SSI LEADS TO SIGNIFICANT PHYSICAL, PSYCHOSOCIAL, AND FINANCIAL BURDENS ON PATIENTS AND MAY COMPROMISE CANCER CONTROL BY DELAYING NECESSARY POST-OPERATIVE RADIATION. IN OCR, THERE ARE MULTIPLE OPPORTUNITIES FOR BACTERIAL CONTAMINATION OF THE SURGICAL FIELD LEADING TO SSI. WHILE COMMON ORAL MICROBIOTA CAN CAUSE SSI, MOST INFECTIONS ARE DUE TO PATHOGENS NOT TYPICALLY FOUND AMONG THE HEALTHY ORAL MICROBIOME, SUCH AS STAPHYLOCOCCUS AND PSEUDOMONAS SPP. THE SOURCE OF THESE BACTERIA AND THEIR MECHANISM OF INFECTION HAVE NOT BEEN ESTABLISHED. TO REDUCE SSI AFTER OCR, AND THEREBY PREVENT PATIENT SUFFERING, LIMIT HEALTHCARE COSTS, AND AVOID DELAYS IN NECESSARY POST-OPERATIVE RADIATION, WE MUST ADDRESS THESE SIGNIFICANT GAPS IN CURRENT KNOWLEDGE. OUR PRELIMINARY STUDIES SUGGEST THAT THE ORAL ENVIRONMENT IS THE LIKELY SOURCE OF SUCH INFECTIONS AND THAT GENOMIC TECHNIQUES CAN BE USED TO TRACK BACTERIAL STRAINS ACROSS THE TREATMENT PERIOD. BUILDING ON OUR PRELIMINARY DATA, WE PROPOSE A STUDY WITH THE FOLLOWING SPECIFIC AIMS: AIM 1) IDENTIFY THE PERI-OPERATIVE SOURCE OF BACTERIA WHICH LEAD TO SSI AFTER OCR IN ORAL CANCER PATIENTS; AND AIM 2) DETERMINE THE MECHANISMS OF BACTERIAL ANTIBIOTIC RESISTANCE IN ORAL CANCER PATIENTS WHO DEVELOP SSI AFTER OCR. PATIENTS PLANNED FOR STANDARD OF CARE OCR WILL BE RECRUITED TO UNDERGO PERI-OPERATIVE BACTERIAL SAMPLING, INCLUDING SKIN, ORONASAL, AND PHARYNGOESOPHAGEAL SITES. FOR PATIENTS WHO EXPERIENCE SSI, THE PURULENCE FROM THE INFECTION WILL ALSO BE SAMPLED. IN AIM 1, WE WILL DETERMINE WHICH PERI-OPERATIVE SITES MAY BE THE SOURCE OF INFECTION. WE WILL ACCOMPLISH THIS FIRST BY TESTING PERI-OPERATIVE SAMPLES FOR THE PRESENCE OF BACTERIA KNOWN TO CAUSE SSI AFTER OCR. THEN, WE WILL MORE PRECISELY IDENTIFY THE SITE AND MECHANISM BY MATCHING THE GENOME SEQUENCE OF THE INFECTIOUS BACTERIA TO IDENTICAL STRAINS AMONG THE PERI-OPERATIVE MICROBIOTA. IN AIM 2, WE WILL INVESTIGATE THE MECHANISMS OF ANTIBIOTIC RESISTANCE. WE WILL DETERMINE IF INSUFFICIENT ANTIBIOTIC PENETRATION IS AN ETIOLOGY OF INFECTION BY QUANTIFYING AMPICILLIN/SULBACTAM CONCENTRATIONS IN BOTH TISSUE AND BLOOD DURING SURGERY. NEXT, WE WILL EXAMINE GENETIC RESISTANCE MECHANISMS BY IDENTIFYING AND TRACKING ANTIBIOTIC RESISTANCE GENES HARBORED BY INFECTIOUS ORGANISMS ACROSS THE TREATMENT PERIOD. THESE DATA WILL ILLUMINATE THE POTENTIAL SOURCE OF BACTERIA THAT LEAD TO SSI AFTER OCR AND WILL FURTHER DEVELOP THE MECHANISMS LEADING TO INFECTION. THIS WILL PROVIDE A STRONG FOUNDATION TO DESIGN PRECISION THERAPEUTICS IN FUTURE STUDIES TO BETTER PREVENT SSI AFTER OCR. THESE INTERVENTIONS MAY INCLUDE TARGETED ANTISEPTICS AND IMPROVED METHODS OF ANTIBIOTIC DELIVERY.