This multidisciplinary pilot application focuses on interactions between dynamics of bacterial growth and optimal bacterial clearance in the setting of peritoneal dialysis associated peritonitis (PDAP). In the proposed work, we will 1) use in vitro models to define the dynamics and nutrient dependence of fluid phase bacterial growth and antibiotic-induced bacterial killing in peritoneal dialysate (PDF); 2) develop and validate mathematical models of bacterial growth and killing in PDF as functions of time, growth rate, and nutrient availability; 3) Develop mathematical models of bacterial clearance (antibiotic and non-antibiotic related) during peritoneal dialysis. Dynamics guided optimization of bacterial clearance during peritonitis will allow reduction in the antibiotic exposure """"""""burden"""""""" for these dialysis patients and their bacterial flora. In addition, this work may provide preliminary data regarding bacterial growth dynamics and antibiotic susceptibility in other """"""""stressful"""""""" environments having single or multiple nutrient deficiencies. In peritoneal dialysis, the abdominal cavity is intermittently filled with a fluid (PDF) that is allowed to dwell in the peritoneal cavity. During this dwell time, waste products, excess salts, and water diffuse into the PDF. The PDF is subsequently drained; carrying with it the accumulated waste products and water, and the peritoneal cavity is refilled. Bacteria in fresh PDF represent a starved population, with consequent and profound suppression of bacterial division; starved S. aureus may require 2-2.5 hours to resume active cell division following provision of adequate nutrients. As the dwell times commonly used in peritoneal dialysis are in the 4-6 hour range, this delay in growth onset could be clinically significant, both because it may offer a means to augment non-antibiotic-mediated bacterial clearance (""""""""flushing out"""""""" the peritoneal cavity), and because slowing or halting bacterial growth may decrease the antibacterial activity of commonly used antibiotics. Moreover, the significant impairment of host peritoneal defenses due to the non-physiologic milieu in PD fluid renders non-host factors, such as antibiotic efficacy and dialysis prescription, more important in clearing peritoneal infection. Prolonged courses of antibiotic therapy required by compromised host defenses may render the dialysis population an effective """"""""incubator"""""""" for drug resistant microorganisms.
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