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

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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.