Precision coordination of therapeutic and prophylactic antibiotics to reduce infection, toxicity, and emergence of resistance following acute abdominal surgery

急性阑尾炎是世界上最常见的腹部外科急症，其终生风险为8.6% 男性为6.9%，女性为6.9%。在美国，急性阑尾炎影响> 280，000人，占1 每年有100万患者住院日。阑尾切除术后的手术部位感染（SSI）率 无并发症、无穿孔阑尾炎的发病率仍然高得令人无法接受。最近的一篇综述报道了盆腔脓肿 阑尾切除术后的发病率为9.4%。腹膜微生物污染的风险最高， 阑尾被横切的时候无论手术技术如何，保留的阑尾残端总是 使腹膜粘膜和腔细菌暴露于正常无菌的腹膜腔。因此，至关重要的是， 在该手术风险窗口期间发生最佳的抗生素组织暴露。 急性阑尾炎的抗生素干预是复杂的。治疗性抗生素是根据经验在 急诊科，通常在阑尾切除术前几个小时（通常等待4-18小时）。因此，在 在外科手术中，已经有治疗性抗生素，预防性抗生素的作用尚不清楚。 到目前为止，对于治疗性和预防性抗生素的混合使用尚未达成共识， 手术，在许多情况下，预防是不管理，因为治疗性抗生素已经 被管理。不幸的是，在这些情况下，抗生素组织水平可能低于最低水平 由于半衰期短和缺乏协议， 相对于手术切口的剂量定时。因此，阑尾，一个已知的微生物库， 在阑尾切除术中，结肠的管腔向腹膜开放，保证一定程度的组织， 手术期间腹膜微生物污染，增加SSI和脓肿形成的风险。一个更 急性阑尾炎患者的个性化抗生素给药方法可以降低SSI风险， 不必要的抗生素使用，减少过量的风险，并遏制抗生素耐药性的发展。 我们假设，基于阑尾切除术前时间的个性化抗生素剂量可以 优化手术部位的组织抗生素暴露，避免使用不必要的抗生素（选择性 抗生素耐药性压力），并降低毒性。因此，我们的具体目标是：1）描述 接受手术的患者中治疗性抗生素的血浆、组织和手术部位组织浓度 阑尾切除术; 2）设计治疗性β-内酰胺类抗生素的精确剂量列线图， 定量组织PK-PD建模和模拟，其将抗菌药物敏感性分布、患者 人口统计学和形态类型以及在阑尾切除术中实现最佳组织暴露的时机;以及 3)试验和评估精确混合抗生素治疗和预防诺模图的有效性 阑尾切除术，为将来外科质量合作者的大规模传播做准备。

Acute appendicitis is the most common abdominal surgical emergency in the world, with a lifetime risk of 8.6% in males and 6.9% in females. In the U.S., acute appendicitis affects > 280,000 individuals and contributes to 1 million patient days of admission each year. Surgical site infection (SSI) rates following appendectomy for uncomplicated, non-perforated appendicitis remain unacceptably high. A recent review reported pelvic abscess rates of 9.4% following appendectomy. The highest risks for microbial contamination of the peritoneum occur when the appendix is transected. Regardless of surgical technique, the retained appendiceal stump ALWAYS exposes appendiceal mucosa and luminal bacteria to the normally sterile peritoneal cavity. It is thus critical that optimal antibiotic tissue exposure occurs during this operative risk window. Antibiotic intervention for acute appendicitis is complex. Therapeutic antibiotics are initiated empirically in the emergency department, often hours before the appendectomy (usually a 4-18 hour wait). Thus, at the time of surgery, there are already therapeutic antibiotics on board, and the role of prophylactic antibiotics is unclear. To date, there has been no consensus on the blended use of therapeutic and prophylactic antibiotics for acute surgeries, and in many cases, prophylaxis is not administered because therapeutic antibiotics have already been administered. Unfortunately, in these instances antibiotic tissue levels are likely below the minimum inhibitory concentration at the time of appendiceal transection due to the short half-life and lack of protocoled dose timing relative to surgical incision. Consequently, the appendix, a known microbiome reservoir for the colon, has its lumen open to the peritoneum during appendectomy, guaranteeing some level of tissue and peritoneal microbial contamination during the surgery, increasing risk for SSI and abscess formation. A more personalized method of dosing antibiotics in patients with acute appendicitis could reduce SSI risk, limit unnecessary antibiotic use, reduce overdosing risks, and curb the development of antibiotic resistance. We hypothesize that personalized antibiotic dosing based on time to surgical appendectomy can optimize tissue antibiotic exposure at the surgical site, avoid use of unnecessary antibiotics (selective antibiotic resistance pressure), and reduce toxicity. Our Specific Aims are therefore to 1) characterize the plasma, tissue and surgical site tissue concentration of therapeutic antibiotics in patients undergoing appendectomy; 2) design a precision dosing nomogram for therapeutic beta-lactam antibiotics using quantitative tissue PK-PD modeling and simulation that factors antimicrobial susceptibility distributions, patient demographics and morphotypes as well as timing to achieve optimal tissue exposure at appendectomy; and 3) pilot and evaluate the effectiveness of a precision blended antibiotic treatment and prophylaxis nomogram for appendectomy in preparation for future large-scale dissemination by surgical quality collaboratives.