On the emergence, spread and resistance of Candida auris: host, pathogen and environmental tipping points

Abstract

Over a decade ago, a multidrug-resistant nosocomial fungus Candida auris emerged worldwide and has since become a significant challenge for clinicians and microbiologists across the globe. A resilient pathogen, C. auris survives harsh disinfectants, desiccation and high-saline environments. It readily colonizes the inanimate environment, susceptible patients and causes invasive infections that exact a high toll. Prone to misidentification by conventional microbiology techniques, C. auris rapidly acquires multiple genetic determinants that confer multidrug resistance. Whole-genome sequencing has identified four distinct clades of C. auris, and possibly a fifth one, in circulation. Even as our understanding of this formidable pathogen grows, the nearly simultaneous emergence of its distinct clades in different parts of the world, followed by their rapid global spread, remains largely unexplained. We contend that certain host-pathogen-environmental factors have been evolving along adverse trajectories for the last few decades, especially in regions where C. auris originally appeared, until these factors possibly reached a tipping point to compel the evolution, emergence and spread of C. auris. Comparative genomics has helped identify several resistance mechanisms in C. auris that are analogous to those seen in other Candida species, but they fail to fully explain how high-level resistance rapidly develops in this yeast. A better understanding of these unresolved aspects is essential not only for the effective management of C. auris patients, hospital outbreaks and its global spread but also for forecasting and tackling novel resistant pathogens that might emerge in the future. In this review, we discuss the emergence, spread and resistance of C. auris, and propose future investigations to tackle this resilient pathogen.

Keywords: Candida auris; antibiotics; antifungals; emergence; resistance.

Fig. 1.

The emergence and spread of C. auris. World map showing the countries where C. auris has been isolated to date. Most countries have detected multiple cases in more than one healthcare institution, with some countries experiencing prolonged outbreaks. In contrast, some countries have so far reported only single cases with no further transmission [2]. The timeline below depicts the years in which C. auris was first isolated in different countries, showing near-simultaneous emergence and spread of C. auris across Asia, Africa and South America between 2008 and 2013.

Fig. 2.

Potential host–pathogen–environmental factors driving the emergence and spread of C. auris. (a) Environmental degradation caused by deforestation, expanded land use, industrial farming, aquaculture, human travel and climate change have probably disrupted and amplified the environmental niche of C. auris, bringing it closer to humans. An exponential increase in antimicrobial use in medicine, agriculture, animal husbandry and industry (white arrows) have also likely induced C. auris to acquire multiple resistance mechanisms. (b) Critically ill patients exposed to multiple invasive procedures and broad spectrum antimicrobials are increasing in our hospitals and are susceptible to C. auris. Within hospitals C. auris contaminates and persists on inanimate surfaces and medical equipment, causing horizontal spread and outbreaks. (c) As a pathogen, C. auris exhibits high-level resistance to antifungals and hospital disinfectants, tolerates temperatures up to 42 °C, resists desiccation, thrives in high-salt environments like human skin and sweat, forms robust biofilms, and switches into azole-resistant aggregative forms. These properties make C. auris a hardy nosocomial pathogen.

Fig. 3.

Trends in healthcare antimicrobial consumption and patient beds in countries where C. auris has been reported. This figure contrasts the trends between countries where C. auris clades I–IV have emerged independently (panels in red), versus countries where they have likely been introduced by human migration (panels in blue). Vertical black bars in country-level plots denote change-points where significant changes in trend were detected. Colour gradations indicate zero- to fourfold increase in antimicrobial consumption and patient beds. (a) Dark red gradients depict a sharp rise in antibiotic consumption beginning 2004–06 in countries where C. auris outbreak clades emerged independently during 2008–13. However, Japan, where no C. auris outbreaks have been reported to date, depicts an opposite trend. The combined trend of these countries is depicted in (b) and highlights the sharp increase in antibiotic consumption seen. (c) In contrast, the dark blue gradients in countries where C. auris was introduced by human migration over 2012–19, depict a more gradual increase in antibiotic consumption over 2004–15, which is further evident in the overall trend for these countries (d). Only sparse antifungal consumption data were available. (e, f) South Korea, where invasive C. auris infections emerged in 2011, depicts a sharp rise in antifungal consumption after 2005. (g) In contrast, countries witnessing C. auris introductions by human travel, depict a gradual increase to even significant decline (France) in antifungal consumption, which is further evident in the overall trend seen for these countries (h). (i) The number of acute and chronic care beds depict an uneven but sustained increase during 1983–2009 in countries where C. auris outbreak clades emerged independently. Venezuela however, witnessed an opposite trend. (j) The overall trend for these nations also depicts a sharp rise in the number of beds starting mid-1980s. (k) In contrast, nations where C. auris entered through human migration show a steady decline in the number of beds from mid-1980s to 2010, and the sharp decline is clearly evident in the overall trend for these countries (l). Countries with unavailable data or unconfirmed C. auris clades are not depicted. (DDD, daily defined doses.)

Fig. 4.

Antifungal resistance mechanisms in C. auris. (a) Polyene resistance is incompletely understood. Mechanisms include, non-synonymous mutations in FLO8 and utg4_968953 membrane transporter, Cdr6 and Opt1-like efflux pumps, and ERG1, ERG2, ERG6 and ERG13 upregulation. (b) C. auris resists azoles using multiple mechanisms including, mutations and copy-number variations in ERG11 and TAC1B, overexpression of Cdr1 and Mdr1 efflux pumps, and Hsp90-induced azole tolerance. (c) Echinocandin resistance involves FKS1 mutations, which reduce the affinity of β−1,3-glucan synthase for echinocandins. (d) C. auris biofilms resist all classes of antifungals by sequestering 50–90 % of the drug in the extracellular matrix, expressing large number of ATP-binding cassette (ABC) and the major facilitator superfamily (MFS) class of efflux pumps, and harbouring persister cells, which can survive high levels of environmental and chemical stress. (e) C. auris also forms aggregative forms, which exhibit high levels of azole resistance.