Lipid emulsion composition as a determinant of fungal biofilm formation and incidence of candidemia

脂质乳液组合物作为真菌生物膜形成和念珠菌血症发病率的决定因素

• 批准号: 10213517
• 负责人: Brian M Peters
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213517
• 关键词: Acids; Adopted; Affect; Amino Acids; Antifungal Agents; Antifungal Therapy; Automobile Driving; Biology; Candida; Candida albicans; Candidiasis; Catheter-related bloodstream infection; Catheters; Cessation of life; Childhood; Clinical; Clinical Practice Guideline; Colon Carcinoma; Complex; Complication; Critical Illness; Data; Databases; Development; Disease; Disseminated candidiasis; Dose; Emulsions; Epidemiology; Ethanol; Event; Excision; Exhibits; Fat emulsion; Fatty Acids; Fatty acid glycerol esters; Filament; Focal Infection; Follow-Up Studies; Force of Gravity; Formulation; Frequencies; Genetic; Gold; Growth; Health Care Costs; Health Information System; Hospitals; Human; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Intervention; Link; Lipids; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Medical Device; Medium chain fatty acid; Metabolic Diseases; Micafungin; Microbe; Microbial Biofilms; Morbidity - disease rate; Mycoses; Outcome; Parenteral Nutrition; Pathogenicity; Pharmaceutical Preparations; Phenocopy; Phenotype; Population; Predisposition; Prophylactic treatment; Proteins; Recommendation; Rectal Cancer; Renal carcinoma; Repression; Research; Resistance; Risk Factors; Selection for Treatments; Sepsis; Septicemia; Short Bowel Syndrome; Source; Sterility; Structure; Surface; System; Systemic Therapy; Systemic infection; Testing; Thick; Time; Total Parenteral Nutrition; Translating; Treatment Failure; United States; Venous; Yeasts; analog; antimicrobial; antimicrobial tolerance; candidemia; clinically relevant; fungus; high risk; improved; malignant breast neoplasm; mortality; neonate; novel; pathogenic fungus; patient population; pediatric patients; sugar; transcriptomics

The Candida species remain significant causes of morbidity and mortality in the immunocompromised and critically ill population, despite timely and appropriate antifungal therapy. Hospitalized individuals often require catheter lines to facilitate delivery of medications and other needs, which can become colonized by antimicrobial tolerant fungal biofilms serving as nidi of systemic spread. Pediatric patients, especially those with short bowel syndrome or other metabolic disorders, are especially vulnerable to such infections as they require long-term catheter use to deliver parenteral nutrition (PN), containing sugars, proteins, and fats (lipid emulsions) needed for sustenance. In fact, receipt of PN remains an independent risk factor for candidemia. Lipid emulsions vary in their fatty acid (FA) composition. While Intralipid (⍵-6 FAs) has been the gold standard, newly marketed products, including Smoflipid (primarily medium chain and ⍵-3 FA) have been clinically adopted. How fungal growth of the Candida species differs across lipid emulsions remains incompletely defined. Our preliminary data demonstrates that C. albicans forms robust biofilms in Intralipid but only does so moderately in Smoflipid. The mechanism responsible for reduced biofilm growth in Smoflipid is driven by the medium chain FA capric acid via repression of elongated hyphal growth (a step required for mature biofilm formation in this species). However, this biofilm growth phenotype is not conserved in the non-albicans Candida (NAC) species Therefore, the objective of this proposal is to determine the impact of clinical lipid emulsions on fungal biofilm- mediated central venous catheter (CVC) line infections. These aims will test our central hypothesis that clinical lipid emulsions disparately contribute to biofilm formation across the Candida species and that this translates to alterations in catheter lock efficacy and relative clinical incidence of fungal central line infection. Under the first aim, we will determine whether NAC species form biofilm similarly in various lipid emulsions, if lipid growth reduces susceptibility to common catheter prophylaxis approaches, and delineate genetic mechanisms that govern Candida hyphal growth in lipid emulsions. In the second aim, using the PHIS database we will conduct a retrospective analysis of pediatric patients with candidemia who also received PN, in order to determine if the overall incidence of systemic candidiasis has decreased or if the species composition has changed with Smoflipid use. The outcomes of this project will identify whether the landscape of PN-related fungal infections are shifting toward more NAC species dominance and if so, provide a mechanistic understanding of this event. As these species are often resistant to first-line antifungals, results would inform rationale antifungal selection depending on lipid product use. Uncovering mechanisms used by fungi to grow in lipid emulsions will be leveraged to identify novel intervention points to limit fungal growth at the catheter interface.

念珠菌属仍然是免疫功能低下和免疫缺陷患者发病率和死亡率的重要原因。 重症人群，尽管及时和适当的抗真菌治疗。住院患者通常需要 导管管路，以便于输送药物和其他需求，这些管路可能被抗菌剂定植 耐受真菌生物膜作为系统传播的NDI。儿科患者，尤其是短肠患者 综合征或其他代谢紊乱，特别容易受到这种感染，因为它们需要长期 导管用于输送所需的肠外营养（PN），含糖、蛋白质和脂肪（脂肪乳剂） 来维持生计事实上，接受PN仍然是念珠菌血症的独立风险因素。 脂肪乳剂的脂肪酸（FA）组成各不相同。虽然Intraperoid（β-6 FAs）一直是黄金标准， 新上市的产品，包括Smoflipid（主要是中链和β-3 FA）已被临床采用。 脂肪乳剂中念珠菌属真菌生长的差异仍不完全明确。我们 初步数据表明，C.白色念珠菌在Intraperoid中形成坚固的生物膜，但在Intraperoid中仅适度地形成生物膜。 Smoflipid。Smoflipid中生物膜生长减少的机制是由中链FA驱动的， 癸酸通过抑制伸长的菌丝生长（在本发明中成熟生物膜形成所需的步骤 物种）。然而，这种生物膜生长表型在非白色念珠菌（NAC）种属中并不保守 因此，本提案的目的是确定临床脂肪乳剂对真菌生物膜的影响- 介导的中心静脉导管（CVC）管路感染。这些目标将检验我们的中心假设，即临床 脂肪乳剂间接促进念珠菌属生物膜的形成， 导管锁定效力和真菌中心线感染的相对临床发生率的改变。根据第一项 目的是，我们将确定NAC物质是否在各种脂肪乳剂中类似地形成生物膜，如果脂质生长， 降低对常见导管预防方法的易感性，并描述遗传机制， 控制脂肪乳剂中念珠菌菌丝生长。在第二个目标中，我们将利用公共卫生信息系统数据库， 对同时接受PN的念珠菌血症儿科患者进行回顾性分析，以确定 系统性念珠菌病的总体发病率下降，或者如果种属组成发生变化， 使用Smoflipid。该项目的结果将确定PN相关真菌感染的景观是否 正在向更多的NAC物种优势转变，如果是这样，请提供对该事件的机械理解。 由于这些菌种通常对一线抗真菌药物具有耐药性，因此结果将为抗真菌药物的选择提供依据 这取决于脂质产品的使用。揭示真菌在脂肪乳剂中生长的机制， 用于确定新的干预点，以限制导管接口处的真菌生长。