Candida auris, a recently recognized, often multidrug-resistant yeast, has become a significant fungal pathogen due to its ability to cause invasive infections and outbreaks in healthcare facilities which have been difficult to control and treat. The extraordinary abilities of C. auris to easily contaminate the environment around colonized patients and persist for long periods have recently resulted in major outbreaks in many countries. C. auris resists elimination by robust cleaning and other decontamination procedures, likely due to the formation of ‘dry’ biofilms. Susceptible hospitalized patients, particularly those with multiple comorbidities in intensive care settings, acquire C. auris rather easily from close contact with C. auris-infected patients, their environment, or the equipment used on colonized patients, often with fatal consequences. This review highlights the lessons learned from recent studies on the epidemiology, diagnosis, pathogenesis, susceptibility, and molecular basis of resistance to antifungal drugs and infection control measures to combat the spread of C. auris infections in healthcare facilities. Particular emphasis is given to interventions aiming to prevent new infections in healthcare facilities, including the screening of susceptible patients for colonization; the cleaning and decontamination of the environment, equipment, and colonized patients; and successful approaches to identify and treat infected patients, particularly during outbreaks.

Candida auris: Epidemiology, Diagnosis, Pathogenesis, Antifungal Susceptibility, and Infection Control Measures to Combat the Spread of Infections in Healthcare Facilities

Candida auris is globally recognized as an opportunistic fungal pathogen of high concern, due to its extensive multidrug resistance (MDR) Still, molecular mechanisms of MDR are largely unexplored This is the first account of genome-wide evolution of MDR in C auris obtained through serial in vitro exposure to azoles, polyenes, and echinocandins We show the stepwise accumulation of copy number variations and novel mutations in genes both known and unknown in antifungal drug resistance Echinocandin resistance was accompanied by a codon deletion in FKS1 hot spot 1 and a substitution in FKS1 “novel” hot spot 3 Mutations in ERG3 and CIS2 further increased the echinocandin MIC Decreased azole susceptibility was linked to a mutation in transcription factor TAC1b and overexpression of the drug efflux pump Cdr1, a segmental duplication of chromosome 1 containing ERG11, and a whole chromosome 5 duplication, which contains TAC1b The latter was associated with increased expression of ERG11, TAC1b, and CDR2 but not CDR1 The simultaneous emergence of nonsense mutations in ERG3 and ERG11 was shown to decrease amphotericin B susceptibility, accompanied with fluconazole cross-resistance A mutation in MEC3, a gene mainly known for its role in DNA damage homeostasis, further increased the polyene MIC Overall, this study shows the alarming potential for and diversity of MDR development in C auris, even in a clade until now not associated with MDR (clade II), stressing its clinical importance and the urge for future research IMPORTANCECandida auris is a recently discovered human fungal pathogen and has shown an alarming potential for developing multi- and pan-resistance toward all classes of antifungals most commonly used in the clinic Currently, C auris has been globally recognized as a nosocomial pathogen of high concern due to this evolutionary potential So far, this is the first study in which the stepwise progression of multidrug resistance (MDR) in C auris is monitored in vitro Multiple novel mutations in known resistance genes and genes previously not or vaguely associated with drug resistance reveal rapid MDR evolution in a C auris clade II isolate Additionally, this study shows that in vitro experimental evolution can be a powerful tool to discover new drug resistance mechanisms, although it has its limitations

Genome-Wide Analysis of Experimentally Evolved Candida auris Reveals Multiple Novel Mechanisms of Multidrug Resistance.

Candida auris is an emerging MDR pathogen raising major concerns worldwide. In Italy, it was first and only identified in July 2019 in our hospital (San Martino Hospital, Genoa), where infection or colonization cases have been increasingly recognized during the following months. To gain insights into the introduction, transmission dynamics, and resistance traits of this fungal pathogen, consecutive C. auris isolates collected from July 2019 to May 2020 (n = 10) were subjected to whole-genome sequencing (WGS) and antifungal susceptibility testing (AST); patients' clinical and trace data were also collected. WGS resolved all isolates within the genetic clade I (South Asian) and showed that all but one were part of a cluster likely stemming from the index case. Phylogenetic molecular clock analyses predicted a recent introduction (May 2019) in the hospital setting and suggested that most transmissions were associated with a ward converted to a COVID-19-dedicated ICU during the pandemic. All isolates were resistant to amphotericin B, voriconazole, and fluconazole at high-level, owing to mutations in ERG11(K143R) and TACB1(A640V). Present data demonstrated that the introduction of MDR C. auris in Italy was a recent event and suggested that its spread could have been facilitated by the COVID-19 pandemic. Continued efforts to implement stringent infection prevention and control strategies are warranted to limit the spread of this emerging pathogen within the healthcare system.

https://www.mdpi.com/2309-608X/7/2/140/pdf

Molecular Epidemiological Investigation of a Nosocomial Cluster of C. auris : Evidence of Recent Emergence in Italy and Ease of Transmission during the COVID-19 Pandemic.

Fungal pathogens cause more than a billion human infections every year, resulting in more than 1.6 million deaths annually. Understanding the natural history and evolutionary ecology of fungi is helping us understand how disease-relevant traits have repeatedly evolved. Different types and mechanisms of genetic variation have contributed to the evolution of fungal pathogenicity and specific genetic differences distinguish pathogens from non-pathogens. Insights into the traits, genetic elements, and genetic and ecological mechanisms that contribute to the evolution of fungal pathogenicity are crucial for developing strategies to both predict emergence of fungal pathogens and develop drugs to combat them. Understanding the mechanisms and evolution of pathogenicity in fungi will bring us a step closer to reducing the annual toll of 1.6 million deaths from fungal disease. 

https://www.nature.com/articles/s41564-022-01112-0.pdf

Evolution of the human pathogenic lifestyle in fungi

Human activities have significantly impacted the environment and are changing our climate in ways that will have major consequences for ourselves, and endanger animal, plant and microbial life on Earth. Rising global temperatures and pollution have been highlighted as potential drivers for increases in infectious diseases. Although infrequently highlighted, fungi are amongst the leading causes of infectious disease mortality, resulting in more than 1.5 million deaths every year. In this review we evaluate the evidence linking anthropomorphic impacts with changing epidemiology of fungal disease. We highlight how the geographic footprint of endemic mycosis has expanded, how populations susceptible to fungal infection and fungal allergy may increase and how climate change may select for pathogenic traits and indirectly contribute to the emergence of drug resistance.

The Consequences of Our Changing Environment on Life Threatening and Debilitating Fungal Diseases in Humans

Candida auris is a multidrug resistant pathogen that presents a serious global threat to human health. As C. auris is a newly emerged pathogen, several questions regarding its ecological niche remain unexplored. While species closely related to C. auris have been detected in different environmental habitats, little is known about the natural habitat(s) of C. auris. Here, we explored the virgin habitats around the very isolated Andaman Islands in the Indian Ocean for evidence of C. auris. We sampled coastal wetlands, including rocky shores, sandy beaches, tidal marshes, and mangrove swamps, around the Andaman group of the Andaman & Nicobar Islands, Union Territory, in India. Forty-eight samples of sediment soil and seawater were collected from eight sampling sites representing the heterogeneity of intertidal habitats across the east and west coast of South Andaman district. C. auris was isolated from two of the eight sampling sites, a salt marsh and a sandy beach. Interestingly, both multidrug-susceptible and multidrug-resistant C. auris isolates were found in the sample. Whole-genome sequencing analysis clustered the C. auris isolates into clade I, showing close similarity to other isolates from South Asia. Isolation of C. auris from the tropical coastal environment suggests its association with the marine ecosystem. The fact that viable C. auris was detected in the marine habitat confirms C. auris survival in harsh wetlands. However, the ecological significance of C. auris in salt marsh wetland and sandy beaches to human infections remains to be explored. IMPORTANCECandida auris is a recently emerged multidrug-resistant fungal pathogen capable of causing severe infections in hospitalized patients. Despite its recognition as a human pathogen a decade ago, so far the natural ecological niche(s) of C. auris remains enigmatic. A previous hypothesis suggested that C. auris might be native to wetlands, that its emergence as a human pathogen might have been linked to global warming effects on wetlands, and that its enrichment in that ecological niche was favored by the ability of C. auris for thermal tolerance and salinity tolerance. To understand the mystery of environmental niches of C. auris, we explored the coastal wetland habitat around the very isolated Andaman Islands in the Indian Ocean. C. auris was isolated from the virgin habitats of salt marsh area with no human activity and from a sandy beach. C. auris isolation from the marine wetlands suggests that prior to its recognition as a human pathogen, it existed as an environmental fungus.

https://journals.asm.org/doi/pdf/10.1128/mBio.03181-20

Environmental Isolation of Candida auris from the Coastal Wetlands of Andaman Islands, India

Candida auris is a nosocomial pathogen responsible for an expanding global public health threat. This ascomycete yeast has been frequently isolated from hospital environments, representing a significant reservoir for transmission in healthcare settings. Here, we investigated the relationships among C. auris isolates from patients with chronic respiratory diseases admitted in a chest hospital and from their fomites, using whole-genome sequencing (WGS) and multilocus microsatellite genotyping. Overall, 37.5% (n = 12/32) patients developed colonisation by C. auris including 9.3% of the screened patients that were colonised at the time of admission and 75% remained colonised till discharge. Furthermore, 10% of fomite samples contained C. auris in rooms about 8.5 days after C. auris colonised patients were admitted. WGS and microsatellite typing revealed that multiple strains contaminated the fomites and colonised different body sites of patients. Notably, 37% of C. auris isolates were resistant to amphotericin B and a novel amino acid substitution, G145D in ERG2 gene, was detected in all amphotericin B resistant isolates. In addition, 55% of C. auris isolates had two copies of the MDR1 gene. Our results suggest significant genetic and ecological diversities of C. auris in healthcare setting. The WGS and microsatellite genotyping methods provided complementary results in genotype identification.

Colonisation and Transmission Dynamics of Candida auris among Chronic Respiratory Diseases Patients Hospitalised in a Chest Hospital, Delhi, India: A Comparative Analysis of Whole Genome Sequencing and Microsatellite Typing.

Yue Wang

Papers

Environmental Isolation of Candida auris from the Coastal Wetlands of Andaman Islands, India

Colonisation and Transmission Dynamics of Candida auris among Chronic Respiratory Diseases Patients Hospitalised in a Chest Hospital, Delhi, India: A Comparative Analysis of Whole Genome Sequencing and Microsatellite Typing.