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.

念珠菌物种仍然是免疫功能低下的发病率和死亡率的重大原因， 重病人群，期望及时且适当的抗真菌疗法。住院的人通常需要 促进药物和其他需求的导管线，可以通过抗菌剂定植 耐受的真菌生物膜作为全身传播的NIDI。小儿患者，尤其是肠子短的患者 综合征或其他代谢疾病，特别容易受到这些需要长期感染的影响 可用于提供父母营养（PN），含糖，蛋白质和脂肪（脂质乳液） 寄托。实际上，PN的收到仍然是候选血症的独立危险因素。 脂质乳液的脂肪酸（FA）组成不同。虽然静脉内（⍵-6 FAS）已成为黄金标准，但 新销售的产品，包括Smoflipid（主要是中链和⍵-3 FA），已在临床上采用。 念珠菌物种的真菌生长如何在脂质乳液中差异不完全定义。我们的 初步数据表明，白色念珠菌在内颌骨中形成强大的生物膜，但仅在 Smoflipid。中型链FA驱动了导致Smoflipid生物膜生长降低的机制 通过表达伸长菌丝生长的表达（在此成熟生物膜形成所需的步骤） 物种）。但是，这种生物膜生长表型在非阿尔比克念珠菌（NAC）物种中并不保守 因此，该提案的目的是确定临床脂质乳液对真菌生物膜的影响 介导的中央静脉导管（CVC）线感染。这些目标将检验我们的临床中心假设 脂质乳液不同时促进整个念珠菌物种的生物膜形成，这转化为 真菌中央线感染的导管锁有效性和相对临床入射的改变。在第一个 目的，我们将在各种脂质乳液中确定NAC物种是否同样形成生物膜，如果脂质生长 降低了对常见导管预防方法的敏感性，并描述了遗传机制 控制脂质乳液中的念珠菌生长。在第二个目标中，使用PHIS数据库，我们将进行一个 回顾性分析也接受PN的小儿念珠菌患者，以确定是否是否 全身性念珠菌病的总体事件已减少，或者是否随着物种成分的变化而随着 Smoflipid使用。该项目的结果将确定与PN相关真菌感染的景观是否 正在转向更大的NAC物种优势，如果是这样，请对此事件提供机械理解。 由于这些物种通常对一线抗真菌性具有抵抗力，因此结果将为抗真菌抗真菌的选择提供信息 取决于脂质产品的使用。发现真菌在脂质乳液中生长的机制将是 杠杆以识别新的干预点以限制导管界面处的真菌生长。