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Multicenter Study
. 2024 Feb 14;229(2):588-598.
doi: 10.1093/infdis/jiad527.

Impact of Intravenous Fat Emulsion Choice on Candida Biofilm, Hyphal Growth, and Catheter-Related Bloodstream Infections in Pediatric Patients

Gustavo R Alvira-Arill  1   2   3 , Hubertine M E Willems  2 , Jabez P Fortwendel  2 , April Yarbrough  4 , Jessica Tansmore  5 , Caroline M Sierra  6 , Ferras Bashqoy  7 , Jeremy S Stultz  2   3 , Brian M Peters  2   8
Affiliations
Multicenter Study

Impact of Intravenous Fat Emulsion Choice on Candida Biofilm, Hyphal Growth, and Catheter-Related Bloodstream Infections in Pediatric Patients

Gustavo R Alvira-Arill et al. J Infect Dis. .

Abstract

Background: Use of mixed-oil (MO) intravenous fat emulsion (IFE) was shown to inhibit Candida albicans biofilm formation and overall rate of catheter-related bloodstream infections (CR-BSIs) compared with soybean-oil (SO) IFE). We aimed to delineate this inhibitory mechanism and impact of IFE choice on distribution of fungal CR-BSIs.

Methods: Transcriptional profiling was conducted on C. albicans grown in SO-IFE, MO-IFE, or SO-IFE with capric acid. Overexpression strains of shared down-regulated genes were constructed using a tetracycline-off system to assess hypha and biofilm formation in IFEs. A 5-year retrospective multicenter cohort study was performed to assess differences in CR-BSIs caused by Candida species based on the IFE formulation received in pediatric patients.

Results: Genes significantly down-regulated in MO-IFE and SO-IFE with capric acid included CDC11, HGC1, and UME6. Overexpression of HGC1 or UME6 enabled filamentation in capric acid and MO-IFE. Interestingly, only overexpression of UME6 was sufficient to rescue biofilm growth in MO-IFE. MO-IFE administration was associated with a higher proportion of non-albicans Candida versus C. albicans CR-BSIs (42% vs 33%; odds ratio, 1.22 [95% confidence interval, .46-3.26]).

Conclusions: MO-IFE affects C. albicans biofilm formation and hyphal growth via a UME6-dependent mechanism. A numerical but not statistically significant difference in distribution of Candida spp. among CR-BSIs was observed.

Keywords: Candida; biofilm; catheter-related infections; intravenous fat emulsions; parenteral nutrition.

Plain language summary

Delivery of carbohydrates, amino acids, and lipids via intravenous catheters is necessary for some patients to supply daily caloric needs. These nutrient-dense parenteral solutions can promote microbial biofilm growth on the catheter surface, which may seed subsequent catheter-related bloodstream infection (CR-BSI). In fact, receipt of parenteral nutrition is an established risk factor for CR-BSI caused by the polymorphic fungal pathogen Candida albicans. New intravenous fat emulsions (IFEs) have gained market share and IFEs containing capric acid (mixed-oil [MO] IFE) compared with those without (soybean-oil [SO] IFE) impair the C. albicans yeast-to-hypha switch—a trait strongly associated with pathogenicity and biofilm formation. In this study, we found that MO-IFE and capric acid reduced expression of a transcriptional regulator involved in hyphal extension (UME6) and down-regulated genes involved in cell partitioning (HGC1). Overexpression of these genes enabled hyphal growth in MO-IFE. Secondly, we sought to determine whether the type of IFE administered was associated with the clinical incidence of CR-BSIs caused by C. albicans or other common non-albicans Candida species. There was a nonsignificant numerical reduction in C. albicans infections in patients administered MO-IFE compared with SO-IFE. Collectively, this work shows that IFEs differentially affect Candida biology with potential infectious consequences for the patient.

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Conflict of interest statement

Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Biofilm formation by Candida spp. isolates in soybean-oil (SO) and mixed-oil (MO) intravenous fat emulsion (IFE). Reference or clinical isolates of Candida albicans, Candida parapsilosis, Candida tropicalis, Candida auris, and Candida glabrata were cultivated as biofilms for 24 hours in minimal medium supplemented with 10% SO-IFE or MO-IFE and biomass quantitated by crystal violet staining. Data are expressed as means with standard errors of the mean (n = 3 replicates). *P < .05 (1-way analysis of variance and Sidak multiple comparison posttest). Abbreviation: OD570, optical density at 570 nm.
Figure 2.
Figure 2.
Transcriptional profiling of Candida albicans treated with soybean-oil (SO) intravenous fat emulsion (IFE), mixed-oil (MO) IFE, or capric acid. C. albicans was cultivated in minimal medium (MM), MM + 10% SO-IFE, MM + 10% MO-IFE, or MM + 10% SO-IFE supplemented with 55.2 mmol/L capric acid. Transcriptional profiling was performed using RNA sequencing. A, Cluster analysis of differentially expressed genes in each growth condition. B, Number of unique or shared differentially expressed genes down-regulated or up-regulated during growth in MO-IFE or SO-IFE with capric acid (P < .05; false-discovery rate, <0.01). C, Ontological analysis of shared down-regulated or up-regulated genes from B. D, Illustration created with BioRender.com depicting repression of the UME6-HGC1-CDC11 septation and hyphal growth pathway in both MO-IFE (black text) and SO-IFE with capric acid (red text). Numerical values represent log2-fold changes as measured by RNA sequencing.
Figure 3.
Figure 3.
Overexpression of UME6 and HGC1 restores hyphae formation in capric acid. Candida albicans PrtetO overexpression or empty vector control strains were grown in buffered Roswell Park Memorial Institute 1640 medium for 4 hours in the absence or presence of capric acid (125 or 250 µmol/L) or doxycycline (1 µg/mL). Nonadjacent fields (n = 10) were captured by bright-field microscopy in 3 independent experiments. Scale bar denotes 20 µm. Representative images are depicted.
Figure 4.
Figure 4.
Overexpression of UME6 and HGC1 increases hyphal growth in mixed-oil (MO) intravenous fat emulsion (IFE). A, TT21 + green fluorescent protein (GFP), TUME6 + GFP, and THGC1 + GFP overexpression strains were cultivated for 4 hours in minimal medium supplemented with soybean-oil (SO) IFE or MO-IFE in the presence or absence of 10 µg/mL doxycycline. Nonadjacent fields (n = 10) were captured by fluorescence microscopy. Scale bar denotes 20 µm, and representative images from 3 independent experiments are depicted. B, Number of hyphae, expressed per the total number of cells per field. Data are presented as means with standard errors of the mean (n = 3 biological replicates of 10 random fields). **P < .01 (1-way analysis of variance and Sidak multiple comparisons posttest). Abbreviation: NS, not significant.
Figure 5.
Figure 5.
Overexpression of UME6, but not HGC1, is sufficient to rescue biofilm formation during growth in mixed-oil (MO) intravenous fat emulsion (IFE). Candida albicans TT21, TUME6, and THGC1 were cultivated as biofilms for 24 hours in minimal medium supplemented with 10% soybean oil (SO) IFE or MO-IFE in the presence or absence of 10 µg/mL doxycycline. Biomass was quantitated by crystal violet staining. Data are expressed as means with standard errors of the mean (n = 3 independent experiments). **P < .01 (1-way analysis of variance and Sidak multiple comparison posttest). Abbreviations: NS, not significant; OD570, optical density at 570 nm.
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