ESCMID 2024: C.aurisa Growing Threat
Candida auris is a multidrug-resistant fungal pathogen identified as a global threat due to its resistance to antifungal drugs, limited treatment options, high pathogenicity, and environmental persistence. It is listed by the CDC and WHO as a critical pathogen and is known for nosocomial transmission, contributing to rapid spread in healthcare settings. It was first isolated from the external ear channel of a Japanese patient in 2009. C.auris is part of the Candida haemulonii clade within the Metschnikowiaceae family. Initially deemed non-threatening, it caused its first nosocomial fungemia cases in South Korea in 2011, with subsequent outbreaks in India, South Africa, and Venezuela by 2014-15. Recent genomic studies suggest that C. auris could be reclassified into a new genus, Candidozyma, but the clinical implications are uncertain. As of 2019, its spread has accelerated, with over 50 countries reporting its emergence, underscoring its significant impact and continued risk in healthcare environments.
Unlike other Candida species, C. auris primarily colonizes the skin rather than the gastrointestinal (GI) tract or mucosal surfaces, leading to persistent skin colonization. This characteristic promotes its transmission in hospital settings, as contaminated skin particles can spread between patients. The risk factors for C. auris infections align with those for other Candida species and multidrug-resistant pathogens, often involving indwelling medical devices, which can lead to a breach in the skin, ultimately resulting in candidiasis or invasive bloodstream infections. Clinical presentations of C.auris resemble those of other Candida species, with bloodstream infections frequently seen in intensive care units (ICUs). The fungus can also cause urinary tract infections (UTIs), wound infections, and disseminated infections. Studies show that C.auris forms biofilms in human sweat conditions, which contribute to sustained colonization in areas like the groin, axilla, and nails and even deep within hair follicles, where it can evade detection. A recent study identified an adhesin, ScF1, as crucial for skin colonization and virulence, facilitating the fungus's ability to colonize abiotic surfaces and contribute to its pathogenicity. Additionally, a decrease in certain immune pathways, like the IL-17 pathway, can lead to prolonged C.auris colonization and complicate efforts to control and treat infections.
C.auris is a challenging fungal pathogen, often misidentified with traditional diagnostic methods like VITEK MS and MicroScan. More accurate methods involve research-use-only libraries, certain FDA-approved databases, and sequencing. Tools like the Eplex and BioFire FilmArray are FDA-approved for direct detection in blood cultures. A significant development in identification is the Candida Plus System, a chromogenic medium where C.auris forms white colonies with a distinct blue halo. Genomic studies reveal four main clades—South Asian, East Asian, South African, and South American—each with distinct resistance patterns. Almost 80% of isolates are resistant to fluconazole, only 20% to amphotericin B and 5-7% to echinocandins. The East Asian clade has a greater susceptibility to fluconazole. Clade-specific resistance is due to unique mutations leading to azole resistance. Newer clades identified from Bangladesh highlight the need for ongoing genomic analysis, though the four primary clades continue to dominate transmissions and global spread.
Initial reports of pan-resistant strains of C.auris surfaced in 2019 without evident transmission. However, recent data revealed transmission of these strains in both Colombia and Texas. During the COVID-19 pandemic, C.auris transmission increased within intensive care units (ICUs), particularly among COVID-19 patients worldwide. The CDC's focus on Florida outbreaks, along with data from Valencia, Spain, indicated that C.auris cases in ICUs and large hospitals doubled between 2020 and 2021, with a higher occurrence among ventilated patients. In the US, C.auris cases rose by 44% in 2019 and 95% by 2021, with a tripled resistance rate in two years. While transmission was initially linked to imported cases, local spread now occurs, especially in long-term acute care and skilled nursing facilities using ventilators. The potential for C.auris to persist outside hospital settings remains unclear, raising concerns about environmental spread, unlike other species in the Metschnikowia clade.
The hypothesis proposed by Arturo Casadevall and Dimitrios Kontoyiannis suggested that C.auris has adapted to higher temperatures and saline conditions due to global warming. They speculated that this adaptation could have originated from wetlands and might have involved birds as intermediate hosts, leading to human transmission. In order to test this hypothesis, a study was conducted in the Andaman Islands of the Indian subcontinent, where C.auris was isolated from salt marshes and sandy beaches. In addition, other fungi with lower temperature adaptation were also identified in these wetlands. Moreover, C.auris was isolated from coastal habitats in Colombia, indicating its presence in various environments. The study also highlighted the potential of using wastewater surveillance to detect C.auris outbreaks through effluent and seawater samples using qPCR, suggesting that this method could predict outbreaks even when not formally reported in the locality. Outside hospital settings, C.auris was found on apple surfaces in India, suggesting that storage fungicides used to extend apple shelf life could aid in the fungus's persistence. Genomic analysis showed that these strains were similar to Clade 1, found in India and other countries, with links to patients who travelled to India. Additionally, C.auris was isolated from companion animals like dogs in both India and the US, indicating possible environmental transmission.
In terms of drug resistance, C.auris shows resistance to antifungal drugs through various mechanisms. Azole resistance is often associated with mutations in azole-target genes and TAC1B zinc cluster mutations, with overexpression of drug transporters further contributing to resistance. Echinocandin resistance, currently low globally (around 5%), is linked to mutations in the Fks gene, especially in a hotspot region. Clinical strains with these mutations tend to have enhanced adhesion but are more easily phagocytized. The resistance to amphotericin B, affecting about 20% of isolates, is primarily found in Clade 1, but the underlying mechanisms are not fully understood. Clinical observations suggest that Echinocandin resistance may emerge in patients with C.auris colonization in the gastrointestinal tract who receive Echinocandins, as seen in a murine model where mutation rates increased under these conditions.
From a treatment perspective, the CDC recommends treating patients with C.auris bloodstream infections with Echinocandins due to their lower resistance rates, while colonized patients generally do not require treatment. However, susceptibility tests are vital to identify the appropriate treatment, as resistance can emerge during therapy, potentially leading to multidrug or pan-drug resistance. Amphotericin B is advised for central nervous system infections and in areas where Echinocandins are less accessible, such as India. While multidrug resistance remains relatively low, resistance is mainly seen in bloodstream infections, posing a risk for patient outcomes. New treatments like Rezafungin, a long-acting Echinocandin, and Ibrexafungerp, a recently approved oral triterpenoid, demonstrate strong activity against C.auris. The ReSTORE trial has shown Rezafungin's efficacy, with additional trials underway. Fosmanogepix, a novel drug targeting the cell wall and protein synthesis, presents a different mechanism against resistant isolates. These emerging therapies offer potential solutions to combat drug-resistant C.auris infections.
The most critical issue is transmission of C.auris, as once a patient is colonized, there is a 25% chance that a critically ill patient may develop bloodstream infections. To mitigate this risk, effective prevention strategies are essential, with admission screening being a key tool to identify and control new infections. However, screening might not always be feasible, especially in hospitals with limited resources or in crowded settings. The epidemiology of C.auris shows that it is more prevalent in hospitals with compromised infection control practices. Transmission-based precautions and cohorting are recommended to manage transmission, ideally isolating colonized patients in single rooms. Regular point prevalence surveys can help monitor transmission. If a patient is identified as colonized with C.auris, single-use equipment should be used whenever possible. It is also crucial to use effective disinfectants, as common quaternary ammonium compounds are not effective against C.auris. The CDC recommends using EPA-registered hospital-grade disinfectants that are effective against grade disinfectant effective against Clostridioides difficile spores.
In conclusion, C. auris primarily contaminates hospital environments and spreads from patient to patient. Effective control measures can reduce the transmission of drug-resistant isolates. The resistance mechanisms in C. auris are clade-specific, and ongoing research is needed to better understand them.
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2024, 27th April–30th April 2024, Barcelona, Spain
