Emily Larkin

The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation

ABSTRACT Candida auris, a new multidrug-resistant Candida spp. which is associated with invasive infection and high rates of mortality, has recently emerged. Here, we determined the virulence factors (germination, adherence, biofilm formation, phospholipase and proteinase production) of 16 C. auris isolates and their susceptibilities to 11 drugs belonging to different antifungal classes, including a novel orally bioavailable 1,3-β-d-glucan synthesis inhibitor (SCY-078). We also examined the effect of SCY-078 on the growth, ultrastructure, and biofilm-forming abilities of C. auris. Our data showed that while the tested strains did not germinate, they did produce phospholipase and proteinase in a strain-dependent manner and had a significantly reduced ability to adhere and form biofilms compared to that of Candida albicans (P = 0.01). C. auris isolates demonstrated reduced susceptibility to fluconazole and amphotericin B, while, in general, they were susceptible to the remaining drugs tested. SCY-078 had an MIC90 of 1 mg/liter against C. auris and caused complete inhibition of the growth of C. auris and C. albicans. Scanning electron microscopy analysis showed that SCY-078 interrupted C. auris cell division, with the organism forming abnormal fused fungal cells. Additionally, SCY-078 possessed potent antibiofilm activity, wherein treated biofilms demonstrated significantly reduced metabolic activity and a significantly reduced thickness compared to the untreated control (P < 0.05 for both comparisons). Our study shows that C. auris expresses several virulence determinants (albeit to a lesser extent than C. albicans) and is resistant to fluconazole and amphotericin B. SCY-078, the new orally bioavailable antifungal, had potent antifungal/antibiofilm activity against C. auris, indicating that further evaluation of this antifungal is warranted.

Effectiveness of disinfectants against candida auris and other candida species

Contaminated surfaces are a suspected source for dissemination of the globally emerging pathogen Candida auris. In laboratory testing, sporicidal and improved hydrogen peroxide disinfectants were highly effective against C. auris, C. glabrata, and C. albicans. The widely used quaternary ammonium disinfectants exhibited relatively poor activity against all of the Candida species. Infect Control Hosp Epidemiol 2017;38:1240-1243.

In Vitro and In Vivo Evaluation of the Antifungal Activity of APX001A/APX001 against Candida auris

ABSTRACT Candida auris is an emerging multidrug-resistant yeast that has been responsible for invasive infections associated with high morbidity and mortality. C. auris strains often demonstrate high fluconazole and amphotericin B MIC values, and some strains are resistant to all three major antifungal classes. We evaluated the susceptibility of 16 C. auris clinical strains, isolated from a wide geographical area, to 10 antifungal agents, including APX001A, a novel agent that inhibits the fungal protein Gwt1 (glycosylphosphatidylinositol-anchored wall transfer protein 1). APX001A demonstrated significantly lower MIC50 and MIC90 values (0.004 and 0.031 μg/ml, respectively) than all other agents tested. The efficacy of the prodrug APX001 was evaluated in an immunocompromised murine model of disseminated C. auris infection. Significant efficacy (80 to 100% survival) was observed in all three APX001 treatment groups versus 50% survival for the anidulafungin treatment group. In addition, APX001 showed a significant log reduction in CFU counts in kidney, lung, and brain tissue (1.03 to 1.83) versus the vehicle control. Anidulafungin also showed a significant log reduction in CFU in the kidneys and lungs (1.5 and 1.62, respectively) but did not impact brain CFU. These data support further clinical evaluation of this new antifungal agent.

Relative Resistance of the Emerging Fungal Pathogen Candida auris and Other Candida Species to Killing by Ultraviolet Light

Mobile ultraviolet-C (UV-C) light room decontamination devices are frequently used as an adjunct to standard cleaning in healthcare facilities, but their efficacy in killing Candida species is not clear. In laboratory testing, the emerging multidrug-resistant Candida auris and 2 other Candida species were significantly less susceptible to killing by UV-C than methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol 2018;39:94-96.

Evaluation of the efficacy of rezafungin, a novel echinocandin, in the treatment of disseminated Candida auris infection using an immunocompromised mouse model

Abstract Background Multiple cases of Candida auris infection have been reported with high mortality rates owing to its MDR nature. Rezafungin (previously CD101) is a novel echinocandin with enhanced stability and pharmacokinetics that achieves high plasma drug exposure and allows for once weekly dose administration. Objectives Evaluate the efficacy of rezafungin in the treatment of disseminated C. auris infection using a mouse model of disseminated candidiasis. Methods Mice were immunosuppressed 3 days prior to infection and 1 day post-infection. On the day of infection, mice were inoculated with 3 × 107C. auris blastospores via the tail vein. Mice were randomized into four groups (n = 20): rezafungin at 20 mg/kg, amphotericin B at 0.3 mg/kg, micafungin at 5 mg/kg and a vehicle control. Treatments were administered 2 h post-infection. Rezafungin was given additionally on days 3 and 6 for a total of three doses, while the remaining groups were treated every day for a total of seven doses. Five mice from each group were sacrificed on days 1, 4, 7 and 10 of the study. Kidneys were removed from each mouse to determine the number of cfu for each respective day. Results Rezafungin had significantly lower average log10 cfu/g of tissue compared with amphotericin B- and vehicle-treated mice on all days when kidneys were harvested. Additionally, rezafungin-treated mice had significantly lower average log10 cfu/g of tissue compared with micafungin-treated mice on day 10. Conclusions Our findings show that rezafungin possesses potent antifungal activity against C. auris in a disseminated model of candidiasis.

Biofilms and beyond: expanding echinocandin utility

Echinocandins have been in use for over 15 years, starting with the first approval in 2001. Current trends, such as increasing resistance to fluconazole and shifts toward non-albicans spp. of Candida, suggest a growing role for echinocandins, as reflected by recent (2016) updates to guidelines that recommend echinocandins as first-line treatment for candidaemia. The efficacy, tolerability, and safety of echinocandins and their target site of action (1,3-β-d-glucan synthesis) have prompted research into potential new uses, such as for treatment of biofilm infections, MDR Candida auris and dermatophytes. Moreover, new mycobiome discoveries linking inflammatory bowel disease (IBD; for instance Crohns disease) to fungi have led to preliminary but encouraging data regarding echinocandin therapy and treatment of IBD. In this article, we will review the available evidence and potential utility of echinocandins and 1,3-β-d-glucan synthesis inhibition in these areas of emerging interest.

Evaluation of the In Vitro and In Vivo Antifungal Activity of APX001A/APX001 Against Candida auris

Abstract Background Candida auris, an emerging multidrug-resistant yeast, causes deadly invasive infections with high mortality. C. auris strains often show high MICs to fluconazole and amphotericin B, and some are resistant to all 3 major antifungal classes, limiting treatment options. We tested 16 C. auris strains from a wide geographical area (Germany, Japan, S. Korea, and India) against 10 antifungals including APX001A (APXA), an antifungal with a novel mechanism of action (inhibition of the Gwt1 fungal enzyme). The prodrug APX001 (APX) is in clinical development and its efficacy was evaluated in an immunocompromised murine model of disseminated C. auris. Methods MICs were determined by CLSI M27-A3 method. Mice were immunocompromised for the study. Treatment was initiated 2 hours post challenge. IP treatment groups included a vehicle control, APX 78mg/kg (mpk) BID, 78mpk TID, and 104mpk BID, and anidulafungin (AFG) 10mpk BID. Survival was monitored for 16d post inoculation. Results Susceptibility. APXA had significantly lower MIC50 and MIC90 values (concentration that inhibits 50 and 90% of the tested isolates, respectively) than the other tested antifungals with a MIC90 of 0.031 µg/mL (Table 1). Survival. 100% mortality in the vehicle-treated control group occurred by 6d. Significant efficacy was observed in all APX treatment groups with 90, 100, and 80% survival observed respectively for APX 78 mpk BID; 78 mpk TID and 104 mpk BID. AFG treatment resulted in 50% survival at 16d. Mice in all of the APX treated groups had a significantly higher % survival compared with the AFG and vehicle groups. Conclusion APXA was the most active antifungal agent in vitro. The prodrug APX resulted in significantly better survival than AFG in a C. auris disseminated infection model. Thus APX may be a viable treatment for C. auris infections. Table 1: Susceptibility of 16 C. auris isolates against antifungals Disclosures K. J. Shaw, Amplyx Pharmaceuticals Inc.: Employee, Salary; M. Ghannoum, Amplyx Pharmaceuticals: Consultant, Research Contractor and Scientific Advisor, Consulting fee and Research grant; Cidara Therapeutics: Consultant and Research Contractor, Consulting fee and Research grant