Dataset Information

Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses.

ABSTRACT:

Background

Candida auris, a multidrug-resistant yeast that causes invasive infections, was first described in 2009 in Japan and has since been reported from several countries.

Methods

To understand the global emergence and epidemiology of C. auris, we obtained isolates from 54 patients with C. auris infection from Pakistan, India, South Africa, and Venezuela during 2012-2015 and the type specimen from Japan. Patient information was available for 41 of the isolates. We conducted antifungal susceptibility testing and whole-genome sequencing (WGS).

Results

Available clinical information revealed that 41% of patients had diabetes mellitus, 51% had undergone recent surgery, 73% had a central venous catheter, and 41% were receiving systemic antifungal therapy when C. auris was isolated. The median time from admission to infection was 19 days (interquartile range, 9-36 days), 61% of patients had bloodstream infection, and 59% died. Using stringent break points, 93% of isolates were resistant to fluconazole, 35% to amphotericin B, and 7% to echinocandins; 41% were resistant to 2 antifungal classes and 4% were resistant to 3 classes. WGS demonstrated that isolates were grouped into unique clades by geographic region. Clades were separated by thousands of single-nucleotide polymorphisms, but within each clade isolates were clonal. Different mutations in ERG11 were associated with azole resistance in each geographic clade.

Conclusions

C. auris is an emerging healthcare-associated pathogen associated with high mortality. Treatment options are limited, due to antifungal resistance. WGS analysis suggests nearly simultaneous, and recent, independent emergence of different clonal populations on 3 continents. Risk factors and transmission mechanisms need to be elucidated to guide control measures.

SUBMITTER: Lockhart SR

PROVIDER: S-EPMC5215215 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTransmission of multidrug-resistant Candida auris infection has been reported in the USA. To better understand its emergence and transmission dynamics and to guide clinical and public health responses, we did a molecular epidemiological investigation of C auris cases in the USA.MethodsIn this molecular epidemiological survey, we used whole-genome sequencing to assess the genetic similarity between isolates collected from patients in ten US states (California, Connecticut, Florida, Illinois, Indiana, Maryland, Massachusetts, New Jersey, New York, and Oklahoma) and those identified in several other countries (Colombia, India, Japan, Pakistan, South Africa, South Korea, and Venezuela). We worked with state health departments, who provided us with isolates for sequencing. These isolates of C auris were collected during the normal course of clinical care (clinical cases) or as part of contact investigations or point prevalence surveys (screening cases). We integrated data from standardised case report forms and contact investigations, including travel history and epidemiological links (ie, patients that had shared a room or ward with a patient with C auris). Genetic diversity of C auris within a patient, a facility, and a state were evaluated by pairwise differences in single-nucleotide polymorphisms (SNPs).FindingsFrom May 11, 2013, to Aug 31, 2017, isolates that corresponded to 133 cases (73 clinical cases and 60 screening cases) were collected. Of 73 clinical cases, 66 (90%) cases involved isolates related to south Asian isolates, five (7%) cases were related to South American isolates, one (1%) case to African isolates, and one (1%) case to east Asian isolates. Most (60 [82%]) clinical cases were identified in New York and New Jersey; these isolates, although related to south Asian isolates, were genetically distinct. Genomic data corroborated five (7%) clinical cases in which patients probably acquired C auris through health-care exposures abroad. Among clinical and screening cases, the genetic diversity of C auris isolates within a person was similar to that within a facility during an outbreak (median SNP difference three SNPs, range 0-12).InterpretationIsolates of C auris in the USA were genetically related to those from four global regions, suggesting that C auris was introduced into the USA several times. The five travel-related cases are examples of how introductions can occur. Genetic diversity among isolates from the same patients, health-care facilities, and states indicates that there is local and ongoing transmission.FundingUS Centers for Disease Control and Prevention.

Project description:Candida auris is a recently described pathogenic fungus that is causing invasive outbreaks on all continents. The fungus is of high concern given the numbers of multidrug-resistant strains that have been isolated in distinct sites across the globe. The fact that its diagnosis is still problematic suggests that the spreading of the pathogen remains underestimated. Notably, the molecular mechanisms of virulence and antifungal resistance employed by this new species are largely unknown. In the present work, we compared two clinical isolates of C. auris with distinct drug susceptibility profiles and a Candida albicans reference strain using a multi-omics approach. Our results show that, despite the distinct drug resistance profile, both C. auris isolates appear to be very similar, albeit with a few notable differences. However, compared to C. albicans both C. auris isolates have major differences regarding their carbon utilization and downstream lipid and protein content, suggesting a multifactorial mechanism of drug resistance. The molecular profile displayed by C. auris helps to explain the antifungal resistance and virulence phenotypes of this new emerging pathogen.IMPORTANCECandida auris was first described in Japan in 2009 and has now been the cause of significant outbreaks across the globe. The high number of isolates that are resistant to one or more antifungals, as well as the high mortality rates from patients with bloodstream infections, has attracted the attention of the medical mycology, infectious disease, and public health communities to this pathogenic fungus. In the current work, we performed a broad multi-omics approach on two clinical isolates isolated in New York, the most affected area in the United States and found that the omic profile of C. auris differs significantly from C. albicans In addition to our insights into C. auris carbon utilization and lipid and protein content, we believe that the availability of these data will enhance our ability to combat this rapidly emerging pathogenic yeast.

Project description:Candida auris, initially identified in 2009, has rapidly become a critical concern due to its antifungal resistance and significant mortality rates in healthcare-associated outbreaks. To date, whole-genome sequencing (WGS) has identified five unique clades of C. auris, with some strains displaying resistance to all primary antifungal drug classes. In this study, we presented the first WGS analysis of C. auris from Bangladesh, describing its origins, transmission dynamics, and antifungal susceptibility testing (AFST) profile. Ten C. auris isolates collected from hospital settings in Bangladesh were initially identified by CHROMagar Candida Plus, followed by VITEK2 system, and later sequenced using Illumina NextSeq 550 system. Reference-based phylogenetic analysis and variant calling pipelines were used to classify the isolates in different clades. All isolates aligned ~90% with the Clade I C. auris B11205 reference genome. Of the 10 isolates, 8 were clustered with Clade I isolates, highlighting a South Asian lineage prevalent in Bangladesh. Remarkably, the remaining two isolates formed a distinct cluster, exhibiting >42,447 single-nucleotide polymorphism differences compared to their closest Clade IV counterparts. This significant variation corroborates the emergence of a sixth clade (Clade VI) of C. auris in Bangladesh, with potential for international transmission. AFST results showed that 80% of the C. auris isolates were resistant to fluconazole and voriconazole, whereas Clade VI isolates were susceptible to azoles, echinocandins, and pyrimidine analogue. Genomic sequencing revealed ERG11_Y132F mutation conferring azole resistance while FCY1_S70R mutation found inconsequential in describing 5-flucytosine resistance. Our study underscores the pressing need for comprehensive genomic surveillance in Bangladesh to better understand the emergence, transmission dynamics, and resistance profiles of C. auris infections. Unveiling the discovery of a sixth clade (Clade VI) accentuates the indispensable role of advanced sequencing methodologies.IMPORTANCECandida auris is a nosocomial fungal pathogen that is commonly misidentified as other Candida species. Since its emergence in 2009, this multidrug-resistant fungus has become one of the five urgent antimicrobial threats by 2019. Whole-genome sequencing (WGS) has proven to be the most accurate identification technique of C. auris which also played a crucial role in the initial discovery of this pathogen. WGS analysis of C. auris has revealed five distinct clades where isolates of each clade differ among themselves based on pathogenicity, colonization, infection mechanism, as well as other phenotypic characteristics. In Bangladesh, C. auris was first reported in 2019 from clinical samples of a large hospital in Dhaka city. To understand the origin, transmission dynamics, and antifungal-resistance profile of C. auris isolates circulating in Bangladesh, we conducted a WGS-based surveillance study on two of the largest hospital settings in Dhaka, Bangladesh.