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:10213517
- 负责人:
- 金额:$ 22.8万
- 依托单位:
- 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 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAdoptedAffectAmino AcidsAntifungal AgentsAntifungal TherapyAutomobile DrivingBiologyCandidaCandida albicansCandidiasisCatheter-related bloodstream infectionCathetersCessation of lifeChildhoodClinicalClinical Practice GuidelineColon CarcinomaComplexComplicationCritical IllnessDataDatabasesDevelopmentDiseaseDisseminated candidiasisDoseEmulsionsEpidemiologyEthanolEventExcisionExhibitsFat emulsionFatty AcidsFatty acid glycerol estersFilamentFocal InfectionFollow-Up StudiesForce of GravityFormulationFrequenciesGeneticGoldGrowthHealth Care CostsHealth Information SystemHospitalsHumanImmunocompromised HostIn VitroIncidenceIndividualInfectionInterventionLinkLipidsMalignant neoplasm of pancreasMalignant neoplasm of prostateMediatingMedical DeviceMedium chain fatty acidMetabolic DiseasesMicafunginMicrobeMicrobial BiofilmsMorbidity - disease rateMycosesOutcomeParenteral NutritionPathogenicityPharmaceutical PreparationsPhenocopyPhenotypePopulationPredispositionProphylactic treatmentProteinsRecommendationRectal CancerRenal carcinomaRepressionResearchResistanceRisk FactorsSelection for TreatmentsSepsisSepticemiaShort Bowel SyndromeSourceSterilityStructureSurfaceSystemSystemic TherapySystemic infectionTestingThickTimeTotal Parenteral NutritionTranslatingTreatment FailureUnited StatesVenousYeastsanalogantimicrobialantimicrobial tolerancecandidemiaclinically relevantfungushigh riskimprovedmalignant breast neoplasmmortalityneonatenovelpathogenic funguspatient populationpediatric patientssugartranscriptomics
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
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Brian M Peters其他文献
Brian M Peters的其他文献
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{{ truncateString('Brian M Peters', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 22.8万 - 项目类别:
Candidalysin: a key mediator of Candida vaginitis immunopathology
念珠菌溶素:念珠菌阴道炎免疫病理学的关键介质
- 批准号:
10229531 - 财政年份:2018
- 资助金额:
$ 22.8万 - 项目类别:
Candidalysin: a key mediator of Candida vaginitis immunopathology
念珠菌溶素:念珠菌阴道炎免疫病理学的关键介质
- 批准号:
9767658 - 财政年份:2018
- 资助金额:
$ 22.8万 - 项目类别:
Candidalysin: a key mediator of Candida vaginitis immunopathology
念珠菌溶素:念珠菌阴道炎免疫病理学的关键介质
- 批准号:
9594689 - 财政年份:2018
- 资助金额:
$ 22.8万 - 项目类别:
A novel role for the inflammasome in the immunopathogenesis of Candida vaginitis
炎症小体在念珠菌阴道炎免疫发病机制中的新作用
- 批准号:
9206120 - 财政年份:2016
- 资助金额:
$ 22.8万 - 项目类别:
A novel role for the inflammasome in the immunopathogenesis of Candida vaginitis
炎症小体在念珠菌阴道炎免疫发病机制中的新作用
- 批准号:
8820695 - 财政年份:2016
- 资助金额:
$ 22.8万 - 项目类别:
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