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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

基本信息

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
项目类别：
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

项目摘要

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.

念珠菌属物种仍然是免疫功能低下和人群发病和死亡的重要原因。尽管进行了及时和适当的抗真菌治疗，但仍存在危重症人群。住院患者通常需要用于促进药物和其他需求输送的导管线路，这些导管线路可能会被抗菌药物定殖耐受的真菌生物膜充当系统性传播的巢穴。儿童患者，尤其是短肠患者综合症或其他代谢紊乱，特别容易受到此类感染，因为它们需要长期用于输送肠外营养 (PN) 的导管，其中含有所需的糖、蛋白质和脂肪（脂质乳液）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。脂质乳液的脂肪酸 (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Smoflipid（主要是中链和⍵-3 FA）已进入临床。不同脂质乳剂中念珠菌属真菌生长的差异仍未完全确定。我们的初步数据表明，白色念珠菌在 Intralipid 中形成强大的生物膜，但在 Intralipid 中只能形成适度的生物膜。斯莫菲德。 Smoflipid 中减少生物膜生长的机制是由中链 FA 驱动的癸酸通过抑制拉长的菌丝生长（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) 物种中并不保守因此，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）线感染。这些目标将检验我们的中心假设：临床脂质乳剂对念珠菌属生物膜的形成有不同的贡献，这转化为导管锁功效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 物种是否在各种脂质乳液中形成类似的生物膜，如果脂质生长降低对常见导管预防方法的敏感性，并描述遗传机制控制脂肪乳剂中念珠菌菌丝的生长。在第二个目标中，我们将使用 PHIS 数据库进行对同时接受 PN 治疗的念珠菌血症儿科患者进行回顾性分析，以确定是否系统性念珠菌病的总体发病率已下降，或者物种组成发生了变化斯莫菲的使用。该项目的结果将确定 PN 相关真菌感染的情况是否正在转向更多的 NAC 物种优势，如果是这样，请提供对此事件的机械理解。由于这些物种通常对一线抗真菌药物具有抗药性，因此结果将为选择抗真菌药物提供依据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将是用于确定新的干预点，以限制导管接口处的真菌生长。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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.