Multiple introductions and subsequent transmission of multidrug-resistant Candida auris in the USA: a molecular epidemiological survey

Chow, Nancy A.; Gade, Lalitha; Tsay, Sharon; Forsberg, Kaitlin; Greenko, Jane; Southwick, K; Barrett, Patricia; Kerins, Janna L.; Lockhart, Shawn R.; Chiller, Tom; Litvintseva, Anastasia P.; Adams, Eleanor; Barton, Kerri; Beer, Karlyn D.; Bentz, Meghan L.; Berkow, Elizabeth L.; Black, Stéphanie; Bradley, Kristy; Brooks, Richard; Chaturvedi, Sudha; Clegg, Whitney J; Cumming, Melissa; DeMaria, Alfred; Dotson, Nychie; Epson, Erin; Fernández, Rafael; Fulton, Tara; Greeley, Rebecca; Jackson, Brendan R; Kallen, Alexander J.; Kemble, Sarah K.; Klevens, Monina; Kuykendall, Randy; Le, Ngoc H; Leung, Vivian; Lutterloh, Emily; McAteer, Jarred B.; Pacilli, Massimo; Peterson, Joyce; Quinn, Monica; Ross, Kathleen; Rozwadowski, Faye; Shannon, D.J.; Skrobarcek, Kimberly A.; Vallabhaneni, Snigdha; Welsh, Rory M.; Zhu, Yan

doi:10.1016/s1473-3099(18)30597-8

Cited by 235 publications

(257 citation statements)

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“…The phylogenetic data using ITS and D1/D2 regions of the ribosomal genes revealed that the South Asia clade I was the major genotype and the East Asia clade II was a minor genotype of the C. auris outbreak in NY. These results are consistent with whole genome sequencing results reported for NY strains (25). The distinct separation of South and East Asia clades by ribosomal gene sequencing in the present study is encouraging as next generation sequencing technologies are not in widespread use by clinical, public, and commercial laboratories for fungal pathogens.…”

Section: Discussionsupporting

confidence: 92%

Laboratory Analysis of an Outbreak of Candida auris in New York from 2016 to 2018-Impact and Lessons Learned

Zhu

O’Brien

Leach

et al. 2019

Preprint

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Candida auris is a multidrug-resistant yeast which has emerged in healthcare facilities worldwide, however little is known about identification methods, patient colonization, spread, environmental survival, and drug resistance. Colonization on both biotic and abiotic surfaces, along with travel, appear to be the major factors for the spread of this pathogen across the globe.In this investigation, we present laboratory findings from an ongoing C. auris outbreak in NY from August 2016 through 2018. A total of 540 clinical isolates, 11,035 patient surveillance specimens, and 3,672 environmental surveillance samples were analyzed. Laboratory methods included matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for yeast isolate identification, real-time PCR for rapid surveillance sample screening, culture on selective/non-selective media for recovery of C. auris and other yeasts from surveillance samples, antifungal susceptibility testing to determine the C. auris resistance profile, and Sanger sequencing of ribosomal genes for C. auris genotyping. Results included: a) identification and confirmation of C. auris in 413 clinical isolates and 931 patient surveillance isolates, as well as identification of 277 clinical cases and 350 colonized cases from 151 healthcare facilities including 59 hospitals, 92 nursing homes, 1 long-term acute care hospital (LTACH), and 2 hospices, b) successful utilization of an in-house developed C. auris real-time PCR assay for the rapid screening of patient and environmental surveillance samples, c) demonstration of relatively heavier colonization of C. auris in nares compared to the axilla/groin, and d) predominance of the South Asia Clade I with intrinsic resistance to fluconazole and elevated minimum inhibitory concentration (MIC) to voriconazole (81%), amphotericin B

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Section: Discussionsupporting

confidence: 92%

Laboratory Analysis of an Outbreak of Candida auris in New York from 2016 to 2018-Impact and Lessons Learned

Zhu

O’Brien

Leach

et al. 2019

Preprint

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“…Initial genomic analysis of the outbreak identified four major genetic groups corresponding to these geographic regions or Clades I, II, III, and IV (8). Clades I, III, and IV are responsible for the ongoing and difficult to control outbreaks in healthcare facilities worldwide (9). Clade II, also termed the East Asia clade, is predominantly associated with cases of ear infection and appears to be less resistant to antifungals than other clades (10).…”

Section: Observationmentioning

confidence: 99%

Chromosomal rearrangements and loss of subtelomeric adhesins linked to clade-specific phenotypes in Candida auris

Muñoz

Welsh

Shea

et al. 2019

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11Candida auris is an emerging fungal pathogen of rising concern due to its increasing incidence, 12 its ability to cause healthcare-associated outbreaks and antifungal resistance. Genomic analysis 13 revealed that early cases of C. auris that were detected contemporaneously were 14 geographically stratified into four major clades. Clade II, also termed East Asian clade, consists 15 of the initial isolates described from cases of ear infection, is less frequently resistant to 16 antifungal drugs and to date, the isolates from this group have not been associated with 17 outbreaks. Here, we generate nearly complete genomes ("telomere-to-telomere") of an isolate 18 of this clade and of the more widespread Clade IV. By comparing these to genome assemblies 19 of the other two clades, we find that the Clade II genome appears highly rearranged, with 2 20 inversions and 9 translocations resulting in a substantially different karyotype. In addition, large 21 subtelomeric regions have been lost from 10 of 14 chromosome ends in the Clade II genomes. 22We find that shorter telomeres and genome instability might be a consequence of a naturally 23 occurring loss-of-function mutation in DCC1 exclusively found in Clade II isolates, resulting in a 24 hypermutator phenotype. We also determine that deleted subtelomeric regions might be linked 25 to clade-specific adaptation as these regions are enriched in Hyr/Iff-like cell surface proteins, 26 novel candidate cell surface proteins, and an ALS-like adhesin. The presence of these cell 27 surface proteins in the clades responsible for global outbreaks causing invasive infections 28 suggests an explanation for the different phenotypes observed between clades.29 30 IMPORTANCE 31Candida auris was unknown prior to 2009 and since then it has quickly spread around the world, 32 causing outbreaks in healthcare facilities and representing a high fraction of candidemia cases 33 in some regions. The emergence of C. auris is a major concern, since it is often multidrug-34 resistant, easily spread between patients, and causes invasive infections. While isolates from 102 103 Depleted Hyr/Iff and species-specific cell-wall protein families in C. auris Clade II 104The subtelomeric regions deleted in Clade II likely contribute to the phenotypic differences of 105 this clade, most notably by the loss of fourteen candidate adhesins present in Clades I, III and 106 IV. These include two sets of genes that contain predicted GPI anchors and secretion signals, 107 one set sharing sequence similarity to C. albicans adhesins from the Hyr/Iff family and a second 108 set of clustered genes only found in C. auris and the closely related species C. haemulonii and 109 C. duobushaemulonii (Figure 2a; Supplementary Table 2). The Hyr/Iff gene family was 110 previously noted to be the most highly enriched family in pathogenic Candida species and has 111 been associated with pathogenicity and virulence (15). Six of eight Hyr/Iff proteins found in C. 112auris contain intergenic tandem repeats, which modulate adhesion ...

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“…Subsequently, WGS study of C. auris isolates from various hospitals within the USA demonstrated the presence of all four genetically diverse clades suggesting that US patients acquired isolates and or infections from three continents. (18) This spread of C. auris in USA demonstrates that travel and or migration plays an important role in spreading this disease.…”

Section: Introductionmentioning

confidence: 97%

Development of Candida auris microsatellite typing and its application on a global collection of isolates

Groot

Puts

Berrío

et al. 2019

Preprint

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22Candida auris is a pathogenic yeast that causes invasive infections with high mortality. Infections 23 most often occur in intensive care units of healthcare facilities. It is crucial to trace the source and 24 prevent further spread of C. auris during an outbreak setting, therefore, genotyping of C. auris is 25 required. To enable fast and cost-effective genotyping, we developed a microsatellite typing assay 26 for C. auris. 27 Short tandem repeats (STRs) in C. auris were identified, and a novel STR typing assay for C. auris was 28 developed using 4 panels of three multiplex PCRs. Having shown that the microsatellite typing assay 29 was highly reproducible and specific, a robust set of 444 C. auris isolates was investigated to identify 30 genotypic diversity. In concordance with whole-genome sequencing (WGS) analysis we identified five 31 major different C. auris clusters, namely, South-America, South-Asia, Africa, East-Asia and Iran. 32Overall, a total of 40 distinct genotypes were identified, with the largest variety in the East Asian 33clade. Comparison with WGS demonstrated that isolates with <20 SNPs are mostly not differentiated 34 by STR analysis, while isolates with 30 or more SNPs usually have differences in one or more STR 35 markers. 36Altogether, a highly reproducible and specific microsatellite typing assay for C. auris was developed, 37 which distinguishes the five different C. auris clades in identical fashion to WGS, while most isolates 38 differing >20 SNPs, as determined via WGS, are also separated. This new C. auris specific genotyping 39 technique is a rapid, reliable, cost-effective alternative to WGS analysis to speedily investigate 40 outbreaks. 41 Importance 42Candida auris is an emerging fungal pathogen now recognized as a threat to public health. The 43 pathogen has spread worldwide and mainly causes hospital associated outbreaks. To track and trace 44 outbreaks and to relate them to new introductions from elsewhere, whole genome sequencing and 45 amplified fragment length polymorphism (AFLP) have been used for molecular typing. While the 46 former is costly and only available in few centers, AFLP is a complicated technique and 47 standardization is not possible. We describe a novel simple microsatellite genotyping technique 48 based on small tandem repeats in the C. auris genome. Further we show that this microsatellite 49 based genotyping technique has been proven comparable to WGS. Overall, this work provides a 50 novel, rapid, reliable and cost-effective method of molecular outbreaks investigations of C. auris. 51

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Multiple introductions and subsequent transmission of multidrug-resistant Candida auris in the USA: a molecular epidemiological survey

Cited by 235 publications

References 19 publications

Laboratory Analysis of an Outbreak of Candida auris in New York from 2016 to 2018-Impact and Lessons Learned

Laboratory Analysis of an Outbreak of Candida auris in New York from 2016 to 2018-Impact and Lessons Learned

Chromosomal rearrangements and loss of subtelomeric adhesins linked to clade-specific phenotypes in Candida auris

Development of Candida auris microsatellite typing and its application on a global collection of isolates

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