Worsening Spread of Candida auris in the United States, 2019 to 2021
Meghan LymanKaitlin ForsbergD. Joseph SextonNancy A. ChowShawn R. LockhartBrendan R. JacksonTom Chiller
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Background: Candida auris is an emerging fungal threat that has been spreading in the United States since it was first reported in 2016. Objective: To describe recent changes in the U.S. epidemiology of C auris occurring from 2019 to 2021. Design: Description of national surveillance data. Setting: United States. Patients: Persons with any specimen that was positive for C auris. Measurements: Case counts reported to the Centers for Disease Control and Prevention by health departments, volume of colonization screening, and antifungal susceptibility results were aggregated and compared over time and by geographic region. Results: A total of 3270 clinical cases and 7413 screening cases of C auris were reported in the United States through 31 December 2021. The percentage increase in clinical cases grew each year, from a 44% increase in 2019 to a 95% increase in 2021. Colonization screening volume and screening cases increased in 2021 by more than 80% and more than 200%, respectively. From 2019 to 2021, 17 states identified their first C auris case. The number of C auris cases that were resistant to echinocandins in 2021 was about 3 times that in each of the previous 2 years. Limitation: Identification of screening cases depends on screening that is done on the basis of need and available resources. Screening is not conducted uniformly across the United States, so the true burden of C auris cases may be underestimated. Conclusion: C auris cases and transmission have risen in recent years, with a dramatic increase in 2021. The rise in echinocandin-resistant cases and evidence of transmission is particularly concerning because echinocandins are first-line therapy for invasive Candida infections, including C auris. These findings highlight the need for improved detection and infection control practices to prevent spread of C auris. Primary Funding Source: None.Keywords:
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Candida auris is responsible for hospital outbreaks worldwide. Some C. auris isolates may show concomitant resistance to azoles, echinocandins, and polyenes, thereby possibly leaving clinicians with few therapeutic options.Antifungal agents both in early and in late phases of clinical development showing anti-C. auris activity.The research on antifungal agents active against C. auris has made important steps forward in recent years: (i) the development of drugs with novel mechanisms of action, such as ibrexafungerp and fosmanogepix, could provide a valid option against C. auris strains resistant to one or more older antifungals, including pan-resistant strains; (ii) rezafungin could allow once weekly administration of an active drug in the case of echinocandin-susceptible isolates, providing an effective outpatient treatment, while at the same time relieving selective pressure on novel classes; (iii) the development of oral formulations could allow step-down therapy and/or early discharge, or even to avoid hospitalization in mild or noninvasive diseases; (iv) according to available data, these novel agents show a good safety profile and a low potential for drug-drug interactions.
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Fungal infections are on the rise, and emergence of drug-resistant Candida strains refractory to treatment is particularly alarming. Resistance to azole class antifungals, which have been extensively used worldwide for several decades, is so high in several prevalent fungal pathogens, that another drug class, the echinocandins, is now recommended as a first line antifungal treatment. However, resistance to echinocandins is also prominent, particularly in certain species, such as Candida glabrata . The echinocandins target 1,3-β-glucan synthase (GS), the enzyme responsible for producing 1,3-β-glucans, a major component of the fungal cell wall. Although echinocandins are considered fungicidal, C. glabrata exhibits echinocandin tolerance both in vitro and in vivo , where a subset of the cells survives and facilitates the emergence of echinocandin-resistant mutants, which are responsible for clinical failure. Despite this critical role of echinocandin tolerance, its mechanisms are still not well understood. Additionally, most studies of tolerance are conducted in vitro and are thus not able to recapitulate the fungal-host interaction. In this study, we focused on the role of cell wall integrity factors in echinocandin tolerance in C. glabrata. We identified three genes involved in the maintenance of cell wall integrity – YPS1 , YPK2 , and SLT2 – that promote echinocandin tolerance both in vitro and in a mouse model of gastrointestinal (GI) colonization. In particular, we show that mice colonized with strains carrying deletions of these genes were more effectively sterilized by daily caspofungin treatment relative to mice colonized with the wild-type parental strain. Furthermore, consistent with a role of tolerant cells serving as a reservoir for generating resistant mutations, a reduction in tolerance was associated with a reduction in the emergence of resistant strains. Finally, reduced susceptibility in these strains was due both to the well described FKS -dependent mechanisms and as yet unknown, FKS -independent mechanisms. Together, these results shed light on the importance of cell wall integrity maintenance in echinocandin tolerance and emergence of resistance and lay the foundation for future studies of the factors described herein.
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ABSTRACT Candida kefyr is an increasingly reported pathogen in patients with hematologic malignancies. We studied a series of bloodstream isolates that exhibited reduced echinocandin susceptibilities (RES). Clinical and surveillance isolates were tested for susceptibilities to all three echinocandins, and those isolates displaying RES to one or more echinocandins were selected for molecular and biochemical studies. The isolates were analyzed for genetic similarities, and a subset was analyzed for mutations in the echinocandin target gene FKS1 and glucan synthase echinocandin sensitivities using biochemical methods. The molecular typing did not indicate strong genetic relatedness among the isolates except for a series of strains recovered from a single patient. Two unrelated isolates with RES had previously uncharacterized FKS1 mutations: R647G and deletion of amino acid 641 (F641Δ). Biochemical analysis of the semipurified R647G glucan synthase generated differential echinocandin sensitivity (resistance to micafungin only), while the deletion of F641 resulted in a glucan synthase highly insensitive to all three echinocandins. The consecutive isolates from a single patient with RES all harbored the common S645P mutation, which conferred resistance to all three echinocandins. The MIC values paralleled the glucan synthase inhibition kinetic data, although the S645P isolates displayed relatively higher susceptibility to caspofungin (2 μg/ml) than the other two echinocandins (>8 μg/ml). These findings highlight novel and common FKS1 mutations in C. kefyr isolates. The observation of differential susceptibilities to echinocandins may provide important mechanistic insights for echinocandin antifungals.
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Echinocandins are antifungal agents that specifically inhibit the biosynthesis of 1,3-β-D-glucan, a major structural component of fungal cell walls. Echinocandins are recommended as first-line or alternative/salvage therapy for candidiasis and aspergillosis in antifungal guidelines of various countries. Resistance to echinocandins has been reported in recent years. The mechanism of echinocandin resistance involves amino acid substitutions in hot spot regions of the FKS gene product, the catalytic subunit of 1,3-β-D-glucan synthase. This resistance mechanism contributes to not only acquired resistance in Candida spp., but also inherent resistance in some pathogenic fungi. An understanding of the echinocandin resistance mechanism is important to develop both effective diagnosis and treatment options for echinocandin-resistant fungal diseases.
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Candida auris is an emerging multiresistant nosocomial pathogen responsible for outbreaks around the world. It is associated with therapeutic failure and high mortality rates. Echinocandins are the empiric treatment choice for C. auris infections. However, clinical reports show that some patients respond poorly to this therapy. The aim of this study was to determine the in vitro activity of Caspofungin and Anidulafungin against C. auris by time–kill curves method. Twenty C. auris strains were studied. They were isolated from patients with proven invasive fungal infection. Susceptibility testing was performed following the Clinical and Laboratory Standards Institute (CLSI) M27-A3 and S4 documents. Time-killing experiments were conducted for 10 of the 20 isolates (in duplicate on 2 separate days) using RPMI-1640 buffered with MOPS. Caspofungin and anidulafungin tested concentrations were 0.12, 0.25, 0.50, 1.00 and 8.00 µg/mL. The inoculum was adjusted to 1 × 105 CFU/mL using a Neubauer chamber. A 0.05 mL aliquot of each dilution was taken at different time points (0, 2, 4, 6, 8, 10, 24 and 48 hours). These aliquots were serially diluted in sterile water, spread onto Sabouraud plates and incubated at 35°C to determine the numbers of CFU per milliliter. The killing kinetics and the fungicidal activity were analyzed by fitting the mean data at each time point to an exponential equation: Nt = N0 × e−kt (Nt viable yeasts at time t; N0 starting inoculum; K killing rate; t incubation time). Anidulafungin and caspofungin MICs geometric means were 1.68 µg/mL (range: 0.5–8.0 µg/mL) and 2.55 µg/mL (range 0.25–8.0 μg/mL), respectively. None of the drugs were able to reach fungicidal activity (no 99.9% inhibition). The mean time to reach 50% growth reduction were 1.74 ± 0.45 hours and 5.30 ± 2.81 hours for the MIC values of each strain for anidulafungin and caspofungin, respectively The tested echinocandins showed no in vitro fungicidal activity against C. auris at concentrations reached in serum despite strain’s MICs. Caspofungin exhibited a significant lowest killing rate. All authors: No reported disclosures.
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Candida auris has been reported in the past few years as an invasive fungal pathogen of high interest. Its recent emergence in healthcare-associated infections triggered the efforts of researchers worldwide, seeking additional alternatives to the use of traditional antifungals such as azoles. Lipopeptides, specially the echinocandins, have been reported as an effective approach to control pathogenic fungi. However, despite its efficiency against C. auris, some isolates presented echinocandin resistance. Thus, therapies focused on echinocandins' synergism with other antifungal drugs were widely explored, representing a novel possibility for the treatment of C. auris infections.
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