Development and Evaluation of an Experimental Model of Invasive Candidiasis caused by Candida auris
Morressier, 2017
Online
unknown
Development and Evaluation of an Experimental Model of Invasive Candidiasis caused by Candida auris Nathan P. Wiederhold, Laura K. Najvar, Rosie Jaramillo, Marcos Olivo, Jason Pizzini, Gabriel Catano, Thomas F. PattersonUT Health San Antonio, South Texas Veterans Health Care SystemObjectives: Candida auris is an emerging cause of invasive candidiasis, with a high rate of antifungal resistance, including multi-drug resistance. Animal models of invasive disease are needed to evaluate novel therapeutic strategies. We report our experience with a murine model of C. auris invasive candidiasis.Methods: Immunocompetent and neutropenic ICR mice were used. Mice were rendered neutropenic by 5-fluorouracil (150 mg/kg IV x1) 1 day prior to inoculation via the lateral tail vein. The virulence of two clinical bloodstream isolates of C. auris (UTHSCSA DI16-46 and DI16-47) was assessed over a range of inocula. To assess response to therapy, mice infected with DI16-46 were treated with fluconazole (10 mg/kg orally BID; MIC >64 mg/L) or caspofungin (1 mg/kg by intraperitoneal injection QD; MIC 0.25 mg/L), and therapy was initiated 1 day post-inoculation. Outcome measures included survival and changes in kidney and brain tissue fungal burden. Multiple experiments were conducted to evaluate the reproducibility of the results. Results: Immunocompetent mice were relatively resistant to C. auris, as survival was 100% at day 14 post-challenge at inocula ranging between 5 x 104 to 4.5 x 106 cells/mouse. Mortality was observed with the highest inoculum (4.1 x 107 cells/mouse) but was not uniformly lethal. Fungal burden increased with higher inocula. In neutropenic mice, virulence differed between the two isolates. In mice infected with DI16-47, mortality range between 40% to 70% over an inocula range of 2.6 x 106 to 2.5 x 107 cells/mouse. In contrast, in mice infected with DI16-46, mortality was rapid (median survival 2-3 days) and approached 100% with higher inocula (4.1-8.6 x 107 cells/mouse). In mice infected with the higher inoculum of DI16-46, fluconazole and caspofungin did not improve survival (0% & 15%, respectively) or reduce kidney fungal burden (log10 CFU/g 7.79 & 7.15 vs. 8.09 for placebo). However, when infection was established using a lower inoculum (1 to 5 x 106 cells/mouse), fungal burden was significantly reduced in mice treated with caspofungin (mean range 2.68 - 3.53 log10 CFU/g) compared to controls after 7 days of therapy (mean range 6.27 - 6.58 log10 CFU/g; p < 0.001). Infection also disseminated to the brain in mice infected with C. auris. However, treatment with caspofungin did not result in significant reductions in brain tissue burden.Conclusions: Immunocompetent mice were relatively resistant to infection. However, C. auris was able to cause lethal disease in neutropenic mice, and a standard dose of fluconazole was ineffective. Treatment with caspofungin did improve outcomes, but this was inoculum dependent. This neutropenic model may be useful in evaluating new treatment strategies against this emerging pathogen.
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Development and Evaluation of an Experimental Model of Invasive Candidiasis caused by Candida auris
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Autor/in / Beteiligte Person: | Wiederhold, Nathan |
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Veröffentlichung: | Morressier, 2017 |
Medientyp: | unknown |
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