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
01 May 2017-Antimicrobial Agents and Chemotherapy (American Society for Microbiology)-Vol. 61, Iss: 5
TL;DR: C. auris expresses several virulence determinants and is resistant to fluconazole and amphotericin B, and a novel orally bioavailable 1,3-β-d-glucan synthesis inhibitor (SCY-078) had potent antifungal/antibiofilm activity against C. Auris, indicating that further evaluation of this antIFungal is warranted.
Abstract: Candidaauris, 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.
Citations
More filters
TL;DR: Alarmingly, in a span of only 7 years, this yeast, which is difficult to treat and displays clonal interand intra-hospital transmission, has become widespread across several countries, causing a broad range of healthcare-associated invasive infections.
Abstract: Candidiasis, which includes both superficial infections and invasive disease, is the most common cause of fungal infection worldwide. Candida bloodstream infections (BSI) cause significant mortality and elicit a major threat to intensive care unit (ICU) patients [1]. The annual global burden of Candida spp. BSIs is about 400,000 cases, with most cases reported from the developed world. Although Candida albicans remains the most frequently isolated Candida species in the clinical setting, in some countries, a marked shift towards species of Candida that have increased resistance to azoles such as fluconazole (FLU), the standard antifungal drug of choice in many countries, and to the recently introduced antifungals known as echinocandins, is reported. Several species of non-albicans Candida, such as C. tropicalis, C. glabrata, and C. parapsilosis, are well-recognized pathogens in BSIs in different geographic locations. More recently, Candida auris, a multidrug-resistant (MDR) yeast that exhibits resistance to FLU and markedly variable susceptibility to other azoles, amphotericin B (AMB), and echinocandins, has globally emerged as a nosocomial pathogen (Fig 1) [2–20]. Alarmingly, in a span of only 7 years, this yeast, which is difficult to treat and displays clonal interand intra-hospital transmission, has become widespread across several countries, causing a broad range of healthcare-associated invasive infections [4, 5, 10, 12, 21, 22].
471 citations
418 citations
TL;DR: Genetic analysis indicates the simultaneous emergence of separate clades of this organism in different geographical locations, which will provide direction for further work in this field of Candida auris.
Abstract: The emerging pathogen Candida auris has been associated with nosocomial outbreaks on five continents. Genetic analysis indicates the simultaneous emergence of separate clades of this organism in different geographical locations. Invasive infection and colonization have been detected predominantly in patients in high-dependency settings and have garnered attention due to variable antifungal resistance profiles and transmission within units instituting a range of infection prevention and control measures. Issues with the identification of C. auris using both phenotypic and molecular techniques have raised concerns about detecting the true scale of the problem. This review considers the literature available on C. auris and highlights the key unknowns, which will provide direction for further work in this field.
341 citations
Cites background from "The Emerging Pathogen Candida auris..."
...auris biofilms in the presence of SCY-078 highlight the future potential of this new therapy (45)....
[...]
...auris isolates has been demonstrated in vitro, against all geographic clades, with exposed cells failing to divide (45, 63)....
[...]
TL;DR: The antifungal susceptibility of C. auris isolates from 10 hospitals in India collected over a period of 8 years was studied, finding that 25% and 13% of isolates were MDR and multi-azole resistant, respectively.
Abstract: Background: Candida auris has emerged globally as an MDR nosocomial pathogen in ICU patients. Objectives: We studied the antifungal susceptibility of C. auris isolates (n = 350) from 10 hospitals in India collected over a period of 8 years. To investigate azole resistance, ERG11 gene sequencing and expression profiling was conducted. In addition, echinocandin resistance linked to mutations in the C. auris FKS1 gene was analysed. Methods: CLSI antifungal susceptibility testing of six azoles, amphotericin B, three echinocandins, terbinafine, 5-flucytosine and nystatin was conducted. Screening for amino acid substitutions in ERG11 and FKS1 was performed. Results: Overall, 90% of C. auris were fluconazole resistant (MICs 32 to >/=64 mg/L) and 2% and 8% were resistant to echinocandins (>/=8 mg/L) and amphotericin B (>/=2 mg/L), respectively. ERG11 sequences of C. auris exhibited amino acid substitutions Y132 and K143 in 77% (n = 34/44) of strains that were fluconazole resistant whereas WT genotypes, i.e. without substitutions at these positions, were observed in isolates with low fluconazole MICs (1-2 mg/L) suggesting that these substitutions confer a phenotype of resistance to fluconazole similar to that described for Candida albicans. No significant expression of ERG11 was observed, although expression was inducible in vitro with fluconazole exposure. Echinocandin resistance was linked to a novel mutation S639F in FKS1 hot spot region I. Conclusions: Overall, 25% and 13% of isolates were MDR and multi-azole resistant, respectively. The most common resistance combination was azoles and 5-flucytosine in 14% followed by azoles and amphotericin B in 7% and azoles and echinocandins in 2% of isolates.
333 citations
TL;DR: Various investigational antifungals are currently in preclinical or clinical development, including several that have the potential to overcome resistance observed against the azoles and the echinocandins, including agents that also target ergosterol and b-glucan biosynthesis.
Abstract: Antifungal resistance represents a major clinical challenge to clinicians responsible for treating invasive fungal infections due to the limited arsenal of systemically available antifungal agents. In addition current drugs may be limited by drug-drug interactions and serious adverse effects/toxicities that prevent their prolonged use or dosage escalation. Fluconazole resistance is of particular concern in non-Candida albicans species due to the increased incidence of infections caused by these species in different geographic locations worldwide and the elevated prevalence of resistance to this commonly used azole in many institutions. C. glabrata resistance to the echinocandins has also been documented to be rising in several US institutions, and a higher percentage of these isolates may also be azole resistant. Azole resistance in Aspergillus fumigatus due to clinical and environmental exposure to this class of agents has also been found worldwide, and these isolates can cause invasive infections with high mortality rates. In addition, several species of Aspergillus, and other molds, including Scedosporium and Fusarium species, have reduced susceptibility or pan-resistance to clinically available antifungals. Various investigational antifungals are currently in preclinical or clinical development, including several of them that have the potential to overcome resistance observed against the azoles and the echinocandins. These include agents that also target ergosterol and b-glucan biosynthesis, as well as compounds with novel mechanisms of action that may also overcome the limitations of currently available antifungal classes, including both resistance and adverse effects/toxicity.
285 citations
Cites background from "The Emerging Pathogen Candida auris..."
...auris isolates, including inhibition of biofilm formation.(92,93) Thus, this orally available glucan synthase inhibitor may hold promise against this emerging pathogen....
[...]
References
More filters
Book•
01 Jan 2008
TL;DR: A method for testing the susceptibility of antifungal agents to yeast that cause invasive fungal infections, including Candida spp.
Abstract: Clinical and Laboratory Standards Institute document M27-A3—Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard—Third Edition describes a method for testing the susceptibility of antifungal agents to yeast that cause invasive fungal infections, including Candida spp. (and Candida glabrata), and Cryptococcus neoformans. Selection and preparation of antifungal agents, implementation and interpretation of test procedures, and the purpose and implementation of quality control procedures are discussed. A careful examination of the responsibilities of the manufacturer and the user in quality control is also presented. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard—Third Edition. CLSI document M27-A3 (ISBN 1-56238-666-2). Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2008. The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a document through two or more levels of review by the health care community, is an ongoing process. Users should expect revised editions of any given document. Because rapid changes in technology may affect the procedures, methods, and protocols in a standard or guideline, users should replace outdated editions with the current editions of CLSI/NCCLS documents. Current editions are listed in the CLSI catalog and posted on our website at www.clsi.org. If your organization is not a member and would like to become one, and to request a copy of the catalog, contact us at: Telephone: 610.688.0100; Fax: 610.688.0700; E-Mail: customerservice@clsi.org; Website: www.clsi.org
2,590 citations
University of Tartu1, University of Gothenburg2, American Museum of Natural History3, University of Aberdeen4, Centraalbureau voor Schimmelcultures5, Max Planck Society6, University of Oslo7, University of Copenhagen8, Finnish Forest Research Institute9, Manchester Metropolitan University10, Macaulay Institute11, University of Washington12
1,471 citations
"The Emerging Pathogen Candida auris..." refers methods in this paper
...Identification was performed using a BLAST algorithm search against the sequences in the UNITE database (32)....
[...]
Book•
01 Jan 1976
TL;DR: A guide to interpretation of direct microscopic examination of clinical specimens and a detailed description of filamentous bacteria Yeasts and yeastlike fungi in culture.
Abstract: Section 1: Guide Guide to interpretation of direct microscopic examination of clinical specimens Guide to identification of fungi in culture Section 2: Detailed Descriptions Filamentous bacteria Yeasts and yeastlike fungi Thermally dimorphic fungi Thermally monomorphic fungi Section 3: Laboratory Technique Laboratory procedures Staining methods Media Glossary Bibliography Index
855 citations
TL;DR: A single strain of a novel ascomycetous yeast species belonging to the genus Candida was isolated from the external ear canal of an inpatient in a Japanese hospital and indicated that this strain represents a new species with a close phylogenetic relationship to Candida ruelliae and Candida haemulonii in the Metschnikowiaceae clade.
Abstract: A single strain of a novel ascomycetous yeast species belonging to the genus Candida was isolated from the external ear canal of an inpatient in a Japanese hospital. Analyses of the 26S rDNA D1/D2 domain, nuclear ribosomal DNA ITS region sequences, and chemotaxonomic studies indicated that this strain represents a new species with a close phylogenetic relationship to Candida ruelliae and Candida haemulonii in the Metschnikowiaceae clade. This strain grew well at 40 degrees C, but showed slow and weak growth at 42 degrees C. The taxonomic description of Candida auris sp. nov. is proposed (type strain JCM15448T= CBS10913T= DSM21092T).
778 citations
"The Emerging Pathogen Candida auris..." refers background in this paper
...only strain isolated from a nonblood source (2)....
[...]
...Originally isolated in 2008 from a Japanese patient’s ear canal (2), C....
[...]
TL;DR: Data indicate that phospholipase B is essential for candidal virulence, and early data suggest that direct host cell damage and lysis are the main mechanisms contributing to fungal virulence.
Abstract: Microbial pathogens use a number of genetic strategies to invade the host and cause infection. These common themes are found throughout microbial systems. Secretion of enzymes, such as phospholipase, has been proposed as one of these themes that are used by bacteria, parasites, and pathogenic fungi. The role of extracellular phospholipase as a potential virulence factor in pathogenic fungi, including Candida albicans, Cryptococcus neoformans, and Aspergillus, has gained credence recently. In this review, data implicating phospholipase as a virulence factor in C. albicans, Candida glabrata, C. neoformans, and A. fumigatus are presented. A detailed description of the molecular and biochemical approaches used to more definitively delineate the role of phospholipase in the virulence of C. albicans is also covered. These approaches resulted in cloning of three genes encoding candidal phospholipases (caPLP1, caPLB2, and PLD). By using targeted gene disruption, C. albicans null mutants that failed to secrete phospholipase B, encoded by caPLB1, were constructed. When these isogenic strain pairs were tested in two clinically relevant murine models of candidiasis, deletion of caPLB1 was shown to lead to attenuation of candidal virulence. Importantly, immunogold electron microscopy studies showed that C. albicans secretes this enzyme during the infectious process. These data indicate that phospholipase B is essential for candidal virulence. Although the mechanism(s) through which phospholipase modulates fungal virulence is still under investigations, early data suggest that direct host cell damage and lysis are the main mechanisms contributing to fungal virulence. Since the importance of phospholipases in fungal virulence is already known, the next challenge will be to utilize these lytic enzymes as therapeutic and diagnostic targets.
744 citations