Dynamics of Peritoneal Dialysis Associated Peritonitis

描述（由申请人提供）： 这项多学科试点应用的重点是腹膜透析相关腹膜炎（PDAP）背景下细菌生长动态与最佳细菌清除之间的相互作用。在拟议的工作中，我们将1）使用体外模型来定义腹膜透析液（PDF）中液相细菌生长和腹膜透析诱导的细菌杀灭的动力学和营养依赖性; 2）开发和验证PDF中细菌生长和杀灭的数学模型，作为时间、生长速率和营养可用性的函数; 3）开发腹膜透析期间细菌清除（抗生素和非抗生素相关）的数学模型。腹膜炎期间细菌清除的动力学引导优化将减少这些透析患者及其细菌植物群的抗生素暴露“负担”。此外，这项工作可能提供有关细菌生长动力学和抗生素敏感性的初步数据，在其他“压力”环境中有单一或多种营养素缺乏症。在腹膜透析中，腹腔间歇地充满允许停留在腹膜腔中的液体（PDF）。在此停留时间期间，废物、过量的盐和水扩散到PDF中。PDF随后被排出;携带着积聚的废物和水，并且腹膜腔被重新填充。新鲜PDF中的细菌代表了饥饿的群体，随之而来的是细菌分裂的严重抑制;饥饿的S。金黄色葡萄球菌可能需要2-2.5小时在提供足够的营养物后恢复活跃的细胞分裂。由于腹膜透析中常用的停留时间在4-6小时范围内，因此生长开始的延迟可能具有临床意义，因为它可以提供一种增强非抗生素介导的细菌清除（“冲洗”腹膜腔）的方法，并且因为减缓或停止细菌生长可能会降低常用抗生素的抗菌活性。此外，由于腹膜透析液中的非生理环境导致宿主腹膜防御功能显著受损，因此非宿主因素（如抗生素疗效和透析处方）在清除腹膜感染方面更为重要。宿主防御受损所需的延长抗生素治疗疗程可能使透析人群成为耐药微生物的有效“孵化器”。

DESCRIPTION (provided by applicant): 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.