Delayed Onset of Biofilm Formation and CAUTI with Superhydrophobic Catheters

描述（由申请人提供）：导尿管相关性尿路感染（CAUTI）发生在21-50%的留置导尿管患者中，每年仅在美国就花费惊人的4.21 - 4.51亿美元用于医疗干预、抗菌治疗和频繁的导尿管更换。患者创伤的增加不容忽视：当CAUTI发作出现症状时，由此产生的后遗症可从轻微（发烧、尿道炎和膀胱炎）到严重（急性肾盂肾炎、肾瘢痕、结石形成和菌血症）不等。导致CAUTI的生物通过两种方式之一进入：通过导管的外部管腔或通过内部管腔。减轻CAUTIs的尝试，已显示出体外比腔内更好的疗效，已针对在导管表面开发抗菌作用：(i)银合金导尿管容易产生抗菌药物耐药性；（ii）使用几种药物/药物组合的抗菌浸渍导管引发了对其疗效的信心。根本原因在于污染发生的早期，细菌粘附到导管表面引发了一系列事件（蛋白质合成等），导致抗生素耐药性的发展和厚生物膜的形成。必须认识到两个重要的后果：1)抗生素耐药细菌渗入膀胱可引起严重感染；Ii)试图通过表面的抗菌作用来控制细菌增殖将不断被证明是无效的（如所观察到的）。美国每年报告的CAUTI病例超过100万例，声称这是一个高度关注的医学领域并不牵强。因此，有必要引入一种新的导管技术，这种技术有可能引起可持续的范式转变，克服当前最先进技术的局限性。拟议的第一阶段SBIR工作专门用于解决上述挑战。为此，我们提出了一种新的超疏水导管技术。普遍的假设是，与其试图控制粘附的耐药细菌，内表面具有超疏水性的导尿管应该允许尿液自然流动，有效地冲洗掉任何粘附的细菌，并对新的定植细菌表现出最小的适应性，从而延缓细菌增殖、生物膜的形成和随后的并发症。在这个一期项目中，我们的总体目标是通过追求一系列具体目标来证明生物膜形成延迟的概念验证，即：(I)尿路病原体不适宜的导管内腔；（ii）优化涂层强度和稳定性；（iii）改善导管功能寿命改善导管功能寿命。这些具体目标的成功完成将充分证明该导管技术平台的可行性，并使我们能够规划更全面的技术开发和商业化，以及在后续的II期工作中探索其他应用模型。

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.