Rat Indwelling Urinary Catheter Model of Candida albicans Biofilm Infection 2 3 4

ABSTRACT 24 Indwelling urinary catheters are commonly used in the management of 25 hospitalized patients. Candida can adhere to the device surface and propagate 26 as a biofilm. These communities differ from free-floating Candida, exhibiting high 27 tolerance to antifungal therapy. The significance of catheter-associated 28 candiduria is often unclear and treatment may be problematic considering the 29 biofilm drug resistant phenotype. Here we describe a rodent model for study of 30 urinary catheter-associated Candida albicans biofilm infection that mimics this 31 common process in patients. In the setting of a functioning, indwelling urinary 32 catheter in a rat, Candida proliferated as a biofilm on the device surface

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.U01 TR002625 - NCATS NIH HHS; MOP-133636 - CIHR; U19 AI110818 - NIAID NIH HHS; R35 GM118173 - NIGMS NIH HHS; FDN-154288 - CIHR; R01 AI141202 - NIAID NIH HHS; R01 AI073289 - NIAID NIH HHSPublished versio

β-1, 3 glucan as a test for central venous catheter biofilm infection.

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Role of Fks1p and Matrix Glucan in Candida albicans Biofilm Resistance to an Echinocandin, Pyrimidine, and Polyene▿

Candida infections frequently involve drug-resistant biofilm growth on device surfaces. Glucan synthase gene FKS1 has been linked to triazole resistance in Candida biofilms. We tested the impact of FKS1 modulation on susceptibility to additional antifungal classes. Reduction of FKS1 expression rendered biofilms more susceptible to amphotericin B, anidulafungin, and flucytosine. Increased resistance to anidulafungin and amphotericin B was observed for biofilms overexpressing FKS1. These findings suggest that Candida biofilm glucan sequestration is a multidrug resistance mechanism

Development and Validation of an In Vivo Candida albicans Biofilm Denture Model▿

The most common form of oral candidiasis, denture-associated stomatitis, involves biofilm growth on an oral prosthetic surface. Cells in this unique environment are equipped to withstand host defenses and survive antifungal therapy. Studies of the biofilm process on dentures have primarily been limited to in vitro models. We developed a rodent acrylic denture model and characterized the Candida albicans and mixed oral bacterial flora biofilm formation, architecture, and drug resistance in vivo, using time course quantitative culture experiments, confocal microscopy, scanning electron microscopy, and antifungal susceptibility assays. We also examined the utility of the model for measurement of C. albicans gene expression and tested the impact of a specific gene product (Bcr1p) on biofilm formation. Finally, we assessed the mucosal host response to the denture biofilm and found the mucosal histopathology to be consistent with that of acute human denture stomatitis, demonstrating fungal invasion and neutrophil infiltration. This current oral denture model mimics human denture stomatitis and should be useful for testing the impact of gene disruption on biofilm formation, studying the impact of anti-infectives, examining the biology of mixed Candida-oral bacterial flora biofilm infections, and characterizing the host immunologic response to this disease process