Candida auris - an update on a globally emerging pathogen

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1 Candida auris - an update on a globally emerging pathogen Dr Elizabeth M. Johnson Public Health England Mycology Reference Laboratory Bristol Scottish Microbiology and Virology Network Meeting 2017

2 Disclosures UK Government employee Nothing to declare

3 Candida auris pathogenesis misinformation!!!

4 Candida auris fluconazole resistant Readily develops resistance to other agents Often misidentified as Candida haemulonii Identified in 2009 from Japanese patient with ear discharge Chronic otitis media confirmed in 15 patients from S. Korea Subsequent nosocomial blood stream infections reported in Korea, Japan, Malaysia Mutiple hard to control outbreaks reported from India and Pakistan Mortality rates as high as 60% S. Africa has ongoing nosocomial endemic spread in many hospitals Several thousand patients High mortality 33-72% Venezuela large multi-centre outbreaks 38% mortality, neonatal unit 28% Columbia 35% mortality Israel 40% mortality Kuwait Oman 60% mortality USA Spain ongoing > 50 candidaemia cases UK 55 infect. No attributable mortality

5 C. auris: biology and UK strains UK retrospective analyses of historical clinical and culture collection isolates 2013: first 3 isolates received by MRL from B/C from unrelated patients 2014: 1 isolate, pleural fluid 2015: 15 isolates, 9 from deep/sterile sites To date, over 220 isolates from >24 different UK centres Majority colonised, detected through enhanced surveillance. However, at least 55 infections 28 of which were candidaemia, and large outbreaks in at least 3 independent hospital centres

6 Chronology of UK outbreaks 25 UK hospitals affected Cases other W Kings JR RBH 5 0

7 Chronology of UK outbreaks Cases other W Kings JR RBH 5 0

8 220 isolates >24 UK centres 55 infections 28 candidaemia Outbreaks Brompton Kings Oxford Other isolations Transfers (23 home)

9 Candida auris: Internationally Drug-resistant to first-line agent Develops multi-drug resistance Spread readily from patient to patient

10 WGS and implications for strain-typing Number of single nucleotide polymorphism in 12.5 Mbp genome: S. African Isolates S. American Isolates < 70 SNPS < 16 SNPS 10s of thousands of SNPS Single patient Isolates < 10 SNPS Indian Isolates (from hospitals 1000s of miles apart) < 60 SNPS Lockhart et al. Simultaneous emergence of multidrug resistant Candida auris on three continents confirmed by whole genome sequencing and epidemiological analyses. Clin Infect Dis 2016;DOI:10.193/cid/ciw691.

11 C. auris: rdna sequencing Nucleotide identity over 285 bp D1-D2 portion of 28S rdna gene

12 AUXACOLOR Identification of Candida auris Pseudomycelium on cornmeal agar ++ +/- - (rudimentary)

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14 Recognised problem species: C. famata, C. haemulonii, C. lusitaniae, C. sake, Saccharomyces cerevisiae, Rhodotorula spp.

15 MALDI-TOF Matrix Assisted Laser Desorption/Ionisation Time of Flight Candida auris proteomic profiles S. African strain S. Asian strain Japanese/Korean strain Bruker Microflex MALDI-TOF and Biotyper software BDAL database

16 Candida colonies on CHROMagar Candida (MAST) Candida albicans Candida tropicalis Candida albicans + Candida glabrata Candida albicans + Candida parapsilosis Candida auris C. krusei C. tropicalis CHROMagar (Mast) 7 days C. albicans

17 Isolates of Candida auris are almost invariable fluconazole resistant so quick tests can be used to identify resistant yeast isolates Etest Disc test CLSI M44-A

18 Temperature tolerance of Candida auris Many other common commensal yeast species are inhibited at 42ºC

19 C. auris: antifungal resistance MIC distributions of C. auris isolates, no. of isolates at each MIC based on C. albicans CLSI breakpoints: Susceptible Intermediate Resistant (latest data) MIC (mg/l) >64 (single) Amphotericin B (aggr.) % Fluconazole Itraconazole Voriconazole (single) (aggr.) (single) (aggr.) (single) (aggr.) % 5% 43% Posaconazole (single) (aggr.) Caspofungin (all) % 20% Anidulafungin Flucytosine (single) (aggr.) (single) (aggr.) % 14%

20 Candida auris antifungal breakpoints UK Ref Lab data Suggested breakpoints R > 8 R > isolates MIC50 > 64 MIC90 > 64 Range 8 - > isolates MIC MIC Range 8 - > 64 R > 2 Agree R > 1 96 isolates MIC MIC Range <

21 Examples of multi-drug resistant C. auris AMB FLC ITC VRC POSA ISAV FLY TERB NYST ANID S. Asian 1 >64 16 >16 >16 8 >64 > S. Asian 1 32 < <0.03 > S. Arican 4 > < S. African 2 >

22 C. auris: environmental decontamination? Chlorhexidine plus alcohol for skin? Impregnated patches for canula sites? Hydrogen peroxide fogging for rooms once empty With thanks to Colin Brown

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25 C. albicans C. glabrata C. auris C. auris strains had significantly reduced biomass and metabolic activity as compared to C. albicans

26 Galleria mellonella model advantages Fewer ethical issues than animal models Inexpensive Available in large numbers Easy maintenance in the laboratory Easy inoculation Innate immune system mimics that of mammals at cellular and humoral level Galleria mellonella Pathogen recognition receptors Phagocytosed by hemocytes Elimination using reactive oxygen species Many microbial peptides shared with mammals Sheehan and Kavanagh Virulence 2017: 0.doi: /

27 C. auris: virulence in Galleria mellonella Wax moth larvae excellent in vivo model for studying fungal pathogenicity Look for melanisation as an early sign Virulence of Candida spp. in G. mellonella directly linked to ability to form hyphae or pseudohyphae (Borman et al. J Clin Microbiol 2013;51: ) C. glabrata C. albicans

28 Borman, Szekely and Johnson 2016 As pathogenic as Candida albicans More pathogenic than non-filamentous yeast

29 Borman, Szekely and Johnson 2016 Greater pathogenicity than most other pseudomycelial yeast

30 C. auris: UK phylogeny and clonal lineages Two morphological phenotypes in UK isolates: Single cells and Aggregate-forming Isolates of the emerging pathogen Candida auris present in the UK have several geographic origins Borman, Szekely and Johnson (2017) Previous published studies strongly support the existence of discrete clonal lineages that are specific to various countries or continents, with independent lineages in South Africa, South America/Israel, Southern Asia and the Indian subcontinent. Single cells Aggregates All same UK hospital Strain typing very difficult within each lineage hindering outbreak investigation (UK picture is likely a combination of multiple introductions followed by local transmissions) rdna gene sequences of UK C. auris isolates (asterisks)

31 Borman, Szekely and Johnson 2016 Single 10 6 cfu/ml 4 strains C. albicans, 15 larvae per strain 8 and 4 strains for non-aggregate and aggregate forming C. auris respectively, 10 larvae per strain Aggregate forming Calcofluor staining of hemolymph

32 Histological sections of kidneys stained with Grocotts stain Candida albicans Candida auris Candida haemulonii Filamentous yeast Cell aggregates No signs of infection A mode of immune evasion and persistence in tissue?

33 CDC Fact sheet

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37 Candida auris: Point prevalence study Geographically dispersed ICUs Diverse patient populations Screening of all adult admissions Axilla, groin, nose, throat, perineum and rectum + stool and urine 7 days incubation MALDI-ToF identification Target 1000 Estimated prevalence 0.0% - 1.3% 0/281

38 Summary Good evidence for multiple independent introductions of C. auris into the UK followed by widespread nosocomial transmission in high risk settings Different clonal populations (S. Africa v Southern Asia/India) have different virulence/antifungal susceptibility profiles All isolates to date from all clonal lineages are resistant to FLZ. Sporadic cases of resistance to other classes. Evidence of rapid acquisition of cross-resistance. PHE / MRL / CDC / ecdc / RBH recommendations: Increased vigilance about C. auris in clinically significant specimens in high risk patients especially when FLZ-resistant isolates are encountered Isolation/cohorting of C. auris-positive patients, with barrier nursing, enhanced infection control measures, screening of contacts, terminal deep-cleaning of rooms after transfer

39 Public Health England Mycology Reference Laboratory

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