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: 10388392
• 负责人: Brian M Peters
• 金额: $ 19万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388392
• 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.

假丝酵母菌仍然是免疫受损和死亡的主要原因 尽管进行了及时和适当的抗真菌治疗，但仍存在危重人群。住院的个人通常需要 导管线路，以方便药物输送和其他需求，这些需求可能会被抗菌剂定植 耐受性真菌生物膜是全身传播的诱因。儿科病人，尤其是那些肠道短小的病人 综合症或其他代谢紊乱，特别容易受到这种感染，因为他们需要长期 使用导管提供肠外营养(PN)，其中包含所需的糖、蛋白质和脂肪(脂肪乳剂) 为了维持生计。事实上，接受PN仍然是念珠菌血症的独立危险因素。 脂肪乳剂的脂肪酸(FA)组成各不相同。虽然Intralipid(⍵-6 FA)一直是黄金标准， 新上市的产品，包括斯莫夫脂(主要是中链和⍵-3 FA)已被临床采用。 不同脂肪乳剂中念珠菌的真菌生长如何不同仍未完全确定。我们的 初步数据显示，白色念珠菌在Intralipid中形成了强大的生物膜，但只在Intralipid中温和地形成了生物膜 斯莫夫利特。导致生物膜生长减少的机制是由中链FA驱动的 通过抑制细长的菌丝生长(这是形成成熟的生物膜所需的步骤 物种)。然而，这种生物膜生长表型在非白念珠菌(NAC)物种中并不保守 因此，这项建议的目的是确定临床脂肪乳剂对真菌生物膜的影响。 中心静脉导管(CVC)介导性感染。这些目标将检验我们的核心假设，即临床 脂肪乳剂对假丝酵母菌生物膜的形成有不同的贡献，这转化为 导管锁定效果的改变和真菌中心线感染的相对临床发生率。在第一个下 目的：我们将确定NAC物种是否在不同的脂肪乳剂中形成类似的生物膜，如果脂肪生长 降低对普通导管预防方法的易感性，并描述 控制脂肪乳剂中念珠菌的菌丝生长。在第二个目标中，我们将使用PHIS数据库进行 对同时接受PN治疗的念珠菌血症患儿的临床资料进行回顾性分析，以确定其治疗效果是否良好。 系统性念珠菌病的总体发病率有所下降，或者如果物种构成发生了变化 斯莫弗利特的使用。该项目的结果将确定与PN相关的真菌感染的情况 正在向更多的NAC物种优势转变，如果是这样的话，请提供对这一事件的机械性理解。 由于这些物种通常对一线抗真菌药物具有抗药性，结果将为抗真菌药物的选择提供理论依据。 取决于脂肪产品的使用情况。揭示真菌在脂肪乳剂中生长的机制将是 用来确定新的干预点，以限制导管界面上的真菌生长。

项目成果

How Broad Should Gram-Negative Coverage Be for Febrile Parenteral Nutrition Dependent Short Bowel Syndrome Patients?

• DOI: 10.1097/mpg.0000000000003382
• 发表时间: 2022-06-01
• 期刊: JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION
• 影响因子: 2.9
• 作者: Stultz, Jeremy S.;Fly, James H.;Bagga, Bindiya;Arnold, Sandra R.;Algotar, Anushree;Lee, Kelley R.
• 通讯作者: Lee, Kelley R.

Comparison of catheter-related bloodstream infection rates in pediatric patients receiving parenteral nutrition with soybean oil-based intravenous fat emulsion versus a mixed oil fat emulsion.

• DOI: 10.1002/phar.2740
• 发表时间: 2022-12
• 期刊: Pharmacotherapy
• 影响因子: 4.1

Disparate Candida albicans Biofilm Formation in Clinical Lipid Emulsions Due to Capric Acid-Mediated Inhibition.

由于癸酸介导的抑制作用，临床脂质乳剂中不同的白色念珠菌生物膜形成。

• DOI: 10.1128/aac.01394-19
• 发表时间: 2019
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Willems,HubertineME;Stultz,JeremyS;Coltrane,MollyE;Fortwendel,JabezP;Peters,BrianM
• 通讯作者: Peters,BrianM

Updates in the Pharmacologic Prophylaxis and Treatment of Invasive Candidiasis in the Pediatric and Neonatal Intensive Care Units: Updates in the Pharmacologic Prophylaxis.

• DOI: 10.1007/s40506-022-00258-z
• 发表时间: 2022-06
• 期刊: Current treatment options in infectious diseases
• 影响因子: 2
• 作者: Fly, James Hunter;Kapoor, Seerat;Bobo, Kelly;Stultz, Jeremy S
• 通讯作者: Stultz, Jeremy S