Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris

Abstract

Candida auris was first described in 2009, and it has since caused nosocomial outbreaks, invasive infections, and fungaemia across at least 19 countries on five continents. An outbreak of C. auris occurred in a specialized cardiothoracic London hospital between April 2015 and November 2016, which to date has been the largest outbreak in the UK, involving a total of 72 patients. To understand the genetic epidemiology of C. auris infection both within this hospital and within a global context, we sequenced the outbreak isolate genomes using Oxford Nanopore Technologies and Illumina platforms to detect antifungal resistance alleles and reannotate the C. auris genome. Phylogenomic analysis placed the UK outbreak in the India/Pakistan clade, demonstrating an Asian origin; the outbreak showed similar genetic diversity to that of the entire clade, and limited local spatiotemporal clustering was observed. One isolate displayed resistance to both echinocandins and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FKS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1. These mutations add to a growing body of research on multiple antifungal drug targets in this organism. Multiple differential episodic selection of antifungal resistant genotypes has occurred within a genetically heterogenous population across this outbreak, creating a resilient pathogen and making it difficult to define local-scale patterns of transmission and implement outbreak control measures.

Fig. 1. Phylogenetic analysis of C. auris isolates with bootstrap support (500 replicates) performed on WGS SNP data to generate maximum-likelihood phylogenies.

Branches were supported 75% or higher unless otherwise stated. Branch lengths represent the average expected rate of substitutions per site. a Outbreak isolates from the UK (shown in blue) were combined with isolates from around the globe, including India (orange), Pakistan (red), Venezuela (pink), Japan (turquoise), and South Africa (green), to infer a possible geographical origin. Isolates with known mutations in the ERG11 gene associated with resistance to fluconazole in C. albicans are shaded: Y132F in red, K143R in yellow, and F126L in blue. b Given the likely Indian/Pakistani origin of the outbreak isolates, phylogenetic analysis was repeated (as stated above), excluding isolates from South Africa, Venezuela, and Japan, to illustrate the UK outbreak. Isolates separating either into Cluster A (green), B (purple), or C (pink) are depicted to reflect likely introductions into the hospital

Fig. 2. Root-to-tip regression analysis of all 27 C. auris outbreak isolates.

Genetic distance is plotted against sampling time for the phylogeny of the C. auris outbreak. Each data point represents a tip on the phylogeny. The R² for the regression and the slope, reflecting the evolutionary rate (in substitutions per site per day) is also shown