scholarly journals Cellular and Extracellular Vesicle RNA Analysis in the Global Threat Fungus Candida auris

2021 ◽  
Author(s):  
Isadora F. Munhoz da Rocha ◽  
Sharon T. Martins ◽  
Rafaela F. Amatuzzi ◽  
Daniel Zamith-Miranda ◽  
Joshua D. Nosanchuk ◽  
...  
Keyword(s):  
High Frequency ◽  
Extracellular Vesicle ◽  
Global Public Health ◽  
Candida Auris ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Rna Analysis ◽  
Extremely High Frequency ◽  
Rapid Spread ◽  
Global Threat

Candida auris , a relevant emerging human-pathogenic yeast, is the first fungus to be called a global public health threat by the WHO. This is because of its rapid spread on all inhabited continents, together with its extremely high frequency of drug and multidrug resistance.

scholarly journals Insights into the Unique Nature of the East Asian Clade of the Emerging Pathogenic Yeast Candida auris

2019 ◽  
Vol 57 (4) ◽  
Author(s):  
Rory M. Welsh ◽  
D. Joseph Sexton ◽  
Kaitlin Forsberg ◽  
Snigdha Vallabhaneni ◽  
Anastasia Litvintseva
Keyword(s):  
Large Scale ◽  
East Asian ◽  
Candida Auris ◽  
Pathogenic Yeast ◽  
Content Type ◽  
New Information ◽  
Asian Clade ◽  
Single Region ◽  
Invasive Infections ◽  
Unique Nature

ABSTRACT The emerging yeast Candida auris can be highly drug resistant, causing invasive infections, and large outbreaks. C. auris went from an unknown pathogen a decade ago to being reported in over thirty countries on six continents. C. auris consists of four discrete clades, based on where the first isolates of the clade were reported, South Asian (clade I), East Asian (clade II), African (clade III), and South American (clade IV). These clades have unique genetic and biochemical characteristics that are important to understand and inform the global response to C. auris. Clade II has been underrepresented in the literature despite being the first one discovered. In this issue of the Journal of Clinical Microbiology, Y. J. Kwon et al. (J Clin Microbiol 57:e01624-18, 2019, https://doi.org/10.1128/JCM.01624-18) describe the largest collection of clinical isolates from Clade II, which is also the longest-running span of clinical cases, 20 years, from any single region to date. Clade II appears to have a propensity for the ear that is uncharacteristic of the other clades, which typically cause invasive infections and large-scale outbreaks. This study provides new information on an understudied lineage of C. auris and has important implications for future surveillance.

scholarly journals A Zinc Cluster Transcription Factor Contributes to the Intrinsic Fluconazole Resistance of Candida auris

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Eva-Maria Mayr ◽  
Bernardo Ramírez-Zavala ◽  
Ines Krüger ◽  
Joachim Morschhäuser
Keyword(s):  
Transcription Factor ◽  
Efflux Pumps ◽  
Azole Resistance ◽  
Drug Resistant ◽  
Candida Auris ◽  
Pathogenic Yeast ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Zinc Cluster ◽  
Genes Encoding

ABSTRACT The recently emerged pathogenic yeast Candida auris is a major concern for human health, because it is easily transmissible, difficult to eradicate from hospitals, and highly drug resistant. Most C. auris isolates are resistant to the widely used antifungal drug fluconazole due to mutations in the target enzyme Erg11 and high activity of efflux pumps, such as Cdr1. In the well-studied, distantly related yeast Candida albicans, overexpression of drug efflux pumps also is a major mechanism of acquired fluconazole resistance and caused by gain-of-function mutations in the zinc cluster transcription factors Mrr1 and Tac1. In this study, we investigated a possible involvement of related transcription factors in efflux pump expression and fluconazole resistance of C. auris. The C. auris genome contains three genes encoding Mrr1 homologs and two genes encoding Tac1 homologs, and we generated deletion mutants lacking these genes in two fluconazole-resistant strains from clade III and clade IV. Deletion of TAC1b decreased the resistance to fluconazole and voriconazole in both strain backgrounds, demonstrating that the encoded transcription factor contributes to azole resistance in C. auris strains from different clades. CDR1 expression was not or only minimally affected in the mutants, indicating that Tac1b can confer increased azole resistance by a CDR1-independent mechanism. IMPORTANCE Candida auris is a recently emerged pathogenic yeast that within a few years after its initial description has spread all over the globe. C. auris is a major concern for human health, because it can cause life-threatening systemic infections, is easily transmissible, and is difficult to eradicate from hospital environments. Furthermore, C. auris is highly drug resistant, especially against the widely used antifungal drug fluconazole. Mutations in the drug target and high activity of efflux pumps are associated with azole resistance, but it is not known how drug resistance genes are regulated in C. auris. We have investigated the potential role of several candidate transcriptional regulators in the intrinsic fluconazole resistance of C. auris and identified a transcription factor that contributes to the high resistance to fluconazole and voriconazole of two C. auris strains from different genetic clades, thereby providing insight into the molecular basis of drug resistance of this medically important yeast.

scholarly journals Impact of Candida auris Infection in a Neutropenic Murine Model

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Steven R. Torres ◽  
Amber Pichowicz ◽  
Fernando Torres-Velez ◽  
Renjie Song ◽  
Navjot Singh ◽  
...  
Keyword(s):  
Public Health ◽  
Innate Immunity ◽  
Monoclonal Antibodies ◽  
Multidrug Resistance ◽  
Murine Models ◽  
Global Public Health ◽  
Candida Auris ◽  
Innate And Adaptive Immunity ◽  
Content Type ◽  
Public Health Threat

ABSTRACT Candida auris has become a global public health threat due to its multidrug resistance and persistence. Currently, there are limited murine models to study C. auris infection. Those models use a combination of cyclophosphamide and cortisone acetate, suppressing both innate and adaptive immunity. Here, we compare C. auris infection in two neutrophil-depleted murine models in which innate immunity is targeted using the monoclonal antibodies 1A8 and RB6-8C5.

scholarly journals In Vitro Evaluation of Antifungal Drug Combinations against Multidrug-Resistant Candida auris Isolates from New York Outbreak

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Brittany O’Brien ◽  
Sudha Chaturvedi ◽  
Vishnu Chaturvedi
Keyword(s):  
New York ◽  
Drug Combination ◽  
Multidrug Resistant ◽  
Drug Combinations ◽  
Health Care Facilities ◽  
Antifungal Drugs ◽  
Candida Auris ◽  
Pathogenic Yeast ◽  
Content Type

ABSTRACT Since 2016, New York hospitals and health care facilities have faced an unprecedented outbreak of the pathogenic yeast Candida auris. We tested over 1,000 C. auris isolates from affected facilities and found high resistance to fluconazole (MIC > 256 mg/liter) and variable resistance to other antifungal drugs. Therefore, we tested if two-drug combinations are effective in vitro against multidrug-resistant C. auris. Broth microdilution antifungal combination plates were custom manufactured by TREK Diagnostic System. We used 100% inhibition endpoints for the drug combination as reported earlier for the intra- and interlaboratory agreements against Candida species. The results were derived from 12,960 readings, for 15 C. auris isolates tested against 864 two-drug antifungal combinations for nine antifungal drugs. Flucytosine (5FC) at 1.0 mg/liter potentiated the most combinations. For nine C. auris isolates resistant to amphotericin B (AMB; MIC ≥ 2.0 mg/liter), AMB-5FC (0.25/1.0 mg/liter) yielded 100% inhibition. Six C. auris isolates resistant to three echinocandins (anidulafungin [AFG], MIC ≥ 4.0 mg/liter; caspofungin [CAS], MIC ≥ 2.0 mg/liter; and micafungin [MFG], MIC ≥ 4.0 mg/liter) were 100% inhibited by AFG-5FC and CAS-5FC (0.0078/1 mg/liter) and MFG-5FC (0.12/1 mg/liter). None of the combinations were effective for C. auris 18-1 and 18-13 (fluconazole [FLC] > 256 mg/liter, 5FC > 32 mg/liter) except MFG-5FC (0.1/0.06 mg/liter). Thirteen isolates with a high voriconazole (VRC) MIC (>2 mg/liter) were 100% inhibited by the VRC-5FC (0.015/1 mg/liter). The simplified two-drug combination susceptibility test format would permit laboratories to provide clinicians and public health experts with additional data to manage multidrug-resistant C. auris.

scholarly journals Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Karen J. Shaw ◽  
Rosie Jaramillo ◽  
Hoja Patterson ◽  
...  
Keyword(s):  
Murine Model ◽  
Invasive Candidiasis ◽  
Pathogenic Fungi ◽  
Candida Auris ◽  
Pathogenic Yeast ◽  
Once Daily ◽  
Content Type ◽  
Fungal Burden ◽  
Fluconazole Resistant

ABSTRACT The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal agent manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris. Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole-resistant clinical isolate of C. auris. Twenty-four hours postinoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg of body weight by intraperitoneal injection three times daily, or intraperitoneal 260 mg/kg twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (intraperitoneal 10 mg/kg once daily) and continued for 7 days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole-resistant C. auris even when therapy is delayed.

scholarly journals Survival, Persistence, and Isolation of the Emerging Multidrug-Resistant Pathogenic Yeast Candida auris on a Plastic Health Care Surface

2017 ◽  
Vol 55 (10) ◽  
pp. 2996-3005 ◽  
Author(s):  
Rory M. Welsh ◽  
Meghan L. Bentz ◽  
Alicia Shams ◽  
Hollis Houston ◽  
Amanda Lyons ◽  
...  
Keyword(s):  
Health Care ◽  
Multidrug Resistant ◽  
Health Care Facilities ◽  
Candida Auris ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Health Care Settings ◽  
Care Facilities ◽  
Enrichment Protocol ◽  
Plastic Surfaces

ABSTRACTThe emerging multidrug-resistant pathogenic yeastCandida aurisrepresents a serious threat to global health. Unlike most otherCandidaspecies, this organism appears to be commonly transmitted within health care facilities and causes health care-associated outbreaks. To better understand the epidemiology of this emerging pathogen, we investigated the ability ofC. auristo persist on plastic surfaces common in health care settings compared with that ofCandida parapsilosis, a species known to colonize the skin and plastics. Specifically, we compiled comparative and quantitative data essential to understanding the vehicles of spread and the ability of both species to survive and persist on plastic surfaces under controlled conditions (25°C and 57% relative humidity), such as those found in health care settings. When a test suspension of 104cells was applied and dried on plastic surfaces,C. aurisremained viable for at least 14 days andC. parapsilosisfor at least 28 days, as measured by CFU. However, survival measured by esterase activity was higher forC. auristhanC. parapsilosisthroughout the 28-day study. Given the notable length of timeCandidaspecies survive and persist outside their host, we developed methods to more effectively cultureC. aurisfrom patients and their environment. Using our enrichment protocol, public health laboratories and researchers can now readily isolateC. aurisfrom complex microbial communities (such as patient skin, nasopharynx, and stool) as well as environmental biofilms, in order to better understand and preventC. auriscolonization and transmission.

scholarly journals Combined Antifungal Resistance and Biofilm Tolerance: the Global Threat of Candida auris

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Ryan Kean ◽  
Gordon Ramage
Keyword(s):  
Clinical Importance ◽  
Multidrug Resistant ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Medical Mycology ◽  
Candida Auris ◽  
Content Type ◽  
Echinocandin Resistance ◽  
Global Threat ◽  
The Impact

ABSTRACT The enigmatic yeast Candida auris has emerged over the last decade and rapidly penetrated our consciousness. The global threat from this multidrug-resistant yeast has generated a call to arms from within the medical mycology community. Over the past decade, our understanding of how this yeast has spread globally, its clinical importance, and how it tolerates and resists antifungal agents has expanded. This review highlights the clinical importance of antifungal resistance in C. auris and explores our current understanding of the mechanisms associated with azole, polyene, and echinocandin resistance. We also discuss the impact of phenotypic tolerance, with particular emphasis on biofilm-mediated resistance, and present new pipelines of antifungal drugs that promise new hope in the management of C. auris infection.

scholarly journals Experimental Mouse Models of Disseminated Candida auris Infection

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Hong Xin ◽  
Farhan Mohiuddin ◽  
Jensen Tran ◽  
Abby Adams ◽  
Karen Eberle
Keyword(s):  
Mouse Model ◽  
Fungal Pathogen ◽  
The United States ◽  
Multidrug Resistant ◽  
Host Responses ◽  
High Dose ◽  
Invasive Infection ◽  
Global Public Health ◽  
Candida Auris ◽  
Content Type

ABSTRACT Disseminated candidiasis is a life-threatening disease and remains the most common bloodstream infection in hospitalized patients in the United States. Despite the availability of modern antifungal therapy, crude mortality in the last decade has remained unacceptably high. In particular, Candida auris is a multidrug-resistant, health care-associated fungal pathogen and has recently emerged as the first fungal pathogen to cause a global public health threat. A reliable animal model for disseminated C. auris candidiasis is therefore needed to study the unique aspects of this little-known host-pathogen interaction. In this study, we established an inbred A/J intravenous model as an appropriate model for human disseminated C. auris infection. We found that C5 deficiency in A/J mice results in a complex phenotype characterized by rapid fungal proliferation in target organs and the development of a unique and rapidly fatal response. In contrast, C57BL/6J mice and mice deficient in neutrophil elastase (NE−/−) survived high-dose C. auris intravenous challenge, even with cyclophosphamide (CY)-induced immunosuppression. Our study is the first to provide insight into the role of C5 in the host responses to C. auris invasive infection and establishes an inbred A/J mouse model of systemic C. auris infection without CY-induced immunosuppression. IMPORTANCE In the last decade, Candida auris has emerged globally as a multidrug‐resistant fungal pathogen. Although C. auris was initially isolated from the external ear canal, it can cause outbreaks of invasive infections with very high mortality and comorbidities. Recent reports highlight the ongoing challenges due to organism misidentification, high rates of multifungal drug resistance, and unacceptably high patient mortality. The assessment of C. auris virulence in a specific genetic deficiency mouse model of invasive C. auris infection in this study contributes to the little knowledge of host defense to C. auris infection, which holds promise as a model for investigating the pathogenesis of C. auris invasive infection, exploring the immune responses elicited by the fungus, evaluating the possible induction of immunity to the infection, and targeting candidates for an antifungal vaccine.

scholarly journals Characterization of the Differential Pathogenicity of Candida auris in a Galleria mellonella Infection Model

2021 ◽  
Author(s):  
Victor Garcia-Bustos ◽  
Amparo Ruiz-Saurí ◽  
Alba Ruiz-Gaitán ◽  
Ignacio Antonio Sigona-Giangreco ◽  
Marta Dafne Cabañero-Navalon ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Galleria Mellonella ◽  
Infection Model ◽  
Host Pathogen Interactions ◽  
Candida Auris ◽  
Content Type ◽  
Host Pathogen ◽  
Global Threat

Candida auris is an emergent fungus that has become a global threat due to its multidrug resistance, mortality, and transmissibility. These unique features make it different from other Candida species, but we still do not fully know the degree of virulence and, especially, the host-pathogen interactions.

scholarly journals Tracking a Global Threat: a New Genotyping Method for Candida auris

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Christina A. Cuomo ◽  
Alexandre Alanio
Keyword(s):  
Genetic Relationships ◽  
Whole Genome ◽  
Inexpensive Method ◽  
Candida Auris ◽  
Content Type ◽  
The Past ◽  
Genotyping Method ◽  
The World ◽  
Ear Infections ◽  
Global Threat

ABSTRACT Over the past decade, Candida auris has emerged as an urgent threat to public health. Initially reported from cases of ear infections in Japan and Korea, C. auris has since been detected around the world. While whole-genome sequencing has been extensively used to trace the genetic relationships of the global emergence and local outbreaks, a recent report in mBio describes a targeted genotyping method as a rapid and inexpensive method for classifying C. auris isolates (T. de Groot, Y. Puts, I. Berrio, A. Chowdhary, and J. F. Meis, mBio 11:e02971-19, https://doi.org/10.1128/mBio.02971-19, 2020).

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