Delayed Onset of Biofilm Formation and CAUTI with Superhydrophobic Catheters

描述（由申请人提供）：导管相关性尿路感染（CITTI）发生在21-50%接受留置导管的患者中的> 40%，仅在美国，每年花费惊人的4.21 - 4.51亿美元用于医疗干预，抗菌治疗和频繁的导管更换。患者创伤的增加不容忽视：当尿路感染发作出现症状时，所产生的后遗症可能从轻度（发热、尿道炎和膀胱炎）到重度（急性肾盂肾炎、肾瘢痕形成、结石形成和菌血症）不等。导致CAUTI的生物体通过两种方式之一进入：通过导管的外腔或通过内腔。减轻尿道炎的尝试（其在管腔外比管腔内显示出更好的功效）已经针对在导管表面上产生抗菌作用：（i）银合金导尿管易于产生抗菌剂耐药性;（ii）使用几种药物/药物组合的抗菌剂浸渍导管引起对其功效的尚未建立的信心。根本原因在于污染的早期发生，其中细菌粘附到导管表面引发级联事件（蛋白质合成等）。导致抗生素抗性的发展和厚生物膜的形成。必须认识到两个重要的后果：i）抗生素抗性细菌浸出到膀胱中会引起严重的感染，以及; ii）通过表面的抗微生物作用来控制细菌增殖的尝试将不断证明是无效的（如观察到的）。在美国，每年有超过100万例的急性呼吸道感染病例报告，声称这是一个高度医学关注的领域并不牵强。因此，有必要引入一种新的导管技术，该技术有可能引起可持续的范式转变，克服当前最新技术水平的局限性。这一拟议的第一阶段SBIR工作是专门为应对上述挑战而设计的。在这项工作中，我们提出了一种新的超疏水导管技术。流行的假设是，具有超疏水内表面的导管应该允许尿液的自然流动以有效地洗掉任何粘附的细菌，并对新的定殖细菌表现出最小的适应性，从而延迟细菌增殖、生物膜形成和随后的并发症，而不是无意义的尝试来控制粘附的耐药性细菌。在该I期项目期间，我们的总体目标是通过追求一系列特定目标来证明生物膜形成的概念验证延迟发作，即：（i）不适合泌尿病原体的导管内腔;（ii）优化的涂层强度和稳定性;以及（iii）改善的导管功能寿命。这些具体目标的成功完成应证明该导管技术平台具有充分的可行性，并应使我们能够计划更全面的技术开发和商业化目标，以及在后续II期工作中探索其他应用模型。 公共卫生相关性：我们建议生成并验证一种导管技术，该技术表现出预防优于治疗：涂层配方和机制，可防止细菌粘附到具有抗菌表面的最先进导管表面，最终产生抗生素耐药性并导致严重感染。所产生的益处应降低医疗保健成本，降低感染率和死亡率，并改善患者的整体生活质量。

DESCRIPTION (provided by applicant): Catheter-associated urinary tract infections (CAUTI) occur in >40& of the 21-50% patients that are administered indwelling catheters, annually costing a staggering $421-$451 million in medical intervention, antimicrobial treatments and frequent catheter replacements in the US alone. Increased patient trauma cannot be overlooked: when a CAUTI episode becomes symptomatic, the resulting sequelae can range from mild (fever, urethritis and cystitis) to severe (acute pyelonephritis, renal scarring, calculu formation and bacteremia). Organisms that lead to a CAUTI gain access in one of two ways: through the external lumen of the catheter or through the internal lumen. Attempts at mitigating CAUTIs, which have shown better efficacy extraluminally than intraluminally, have been directed at developing antimicrobial action on the catheter surface: (i) silver alloy urinary catheters are prone to antimicrobial resistance development; (ii) antimicrobial- impregnated catheters using several drugs/drug combinations elicit yet-to-be-established confidence in their efficacy. The root cause lies in the early onset of contamination where adhesion of bacteria to the catheter surface initiates a cascade of events (protein syntheses, etc.) leading to development of antibiotic resistance and the formation of thick biofilms. Two important consequences must be recognized: i) leaching of antibiotic- resistant bacterial into the bladder can cause serious infections, and; ii) attempts to control bacterial proliferation by means of antimicrobial action o the surface will constantly prove to be ineffective (as observed). With over 1 million cases of CAUTI reported in the United States annually, the claim that this is an area of high medical concern is not far-fetched. Therefore, the introduction of a new catheter technology with the potential to induce a sustainable paradigm shift that overcomes the limitations of the current state-of-the-art is warranted. This proposed Phase I SBIR effort is specifically designed to address the above challenge. In this effort, we propose a new superhydrophobic catheter technology. The prevalent hypothesis is that instead of moot attempts to control adhered, drug-resistant bacteria, catheters with super-hydrophobic internal surface should allow natural flow of urine to efficiently wash-off any adhered bacteria and exhibit minimal accommodation to new colonizing bacteria, thereby delaying bacterial proliferation, bio-film formation and subsequent complications. During this Phase I project, our overall goal is to demonstrate proof-of-concept delayed onset of bio-film formation by pursuing a series of specific aims, namely: (i) a uropathogen-inhospitable catheter internal lumen; (ii) optimized coating strength and stability, and; (iii) improved catheter functional lifetime Improved catheter functional lifetime. Successful completion of these specific aims should demonstrate ample feasibility of this catheter technology platform and should allow us to plan more comprehensive technology development and commercialization thrusts, in addition to exploration of other applied models in a follow-on Phase II effort. PUBLIC HEALTH RELEVANCE: We propose to generate and validate a catheter technology that exhibits prevention over cure: a coating formulation and mechanism that prevents adhesion of bacteria, which eventually develop antibiotic resistance and cause severe infections, to the catheter surface over state-of-the-art catheters with antimicrobial surfaces. Benefits derived should decrease healthcare costs, decrease infection and mortality rates and improve overall patient quality-of-life.