What You Need to Know
Serial C auris bloodstream isolates from two critically ill London patients failed anidulafungin therapy despite susceptible MICs and no FKS1/2 hot-spot mutations, and both patients died.
Resistance instead emerged through heteroresistant subpopulations, loss-of-function CRZ1 mutations enriched in fast-growing large colony variants (82.3% vs 0% in parental isolates), chitin-driven cell wall thickening, and drug-induced increases in ploidy.
For clinicians, a susceptible echinocandin MIC does not rule out refractory infection, making repeat cultures, repeat susceptibility testing, and early consideration of combination therapy the practical safeguards.
Heteroresistant Subpopulations, CRZ1 Escape Mutations, and Shifting Ploidy Under Drug Pressure
Population analysis profiling revealed subpopulations of fewer than 0.01% of cells growing at anidulafungin concentrations 256-fold above those tolerated by the susceptible majority.¹ Extended culture on 8 μg/mL anidulafungin yielded two stable colony morphotypes: slow-growing small colony variants (SCVs) and faster-growing large colony variants (LCVs). Both morphotypes persisted on drug-free replating, with mean colony sizes of 0.58 mm³ for SCVs versus 3.58 mm³ for LCVs (P < .0001).
Sequencing of 18 SCV and 17 LCV colonies again found no FKS1/2 mutations. Variation in CRZ1, encoding the calcineurin-responsive transcription factor, was significantly enriched in LCVs relative to parental isolates (14/17, 82.3%, vs 0/7; adjusted P = .032) and relative to SCVs (2/18, 11.1%; adjusted P = 5.93 × 10⁻⁵). Most of the 16 non-synonymous CRZ1 changes were nonsense or frameshift variants likely to abolish function.
By updated EUCAST criteria, LCVs reached modal anidulafungin MICs of 4 to 8 μg/mL versus 1 to 2 μg/mL for parental isolates.¹ Flow cytometry and transmission electron microscopy showed anidulafungin-induced chitin accumulation and thickening of the inner cell wall in both morphotypes. Cells also displayed heterogeneous ploidy ranging from 1n to greater than 4n, a phenotype reproduced across 10 epidemiologically divergent isolates spanning clades I through V.
The authors propose a revised stepwise model in which reversible tolerance precedes selection of genetic resistance, with polyploidy accelerating the accumulation of escape mutations. They position CRZ1 as a candidate early marker of resistance evolution warranting functional validation. Combination strategies are under evaluation in the Wellcome Trust-funded COMBAT Candida trial, comparing micafungin monotherapy with micafungin plus flucytosine for candidemia in a high-prevalence South African setting, with resistance emergence as an endpoint.¹
About Candida auris
C auris is capable of causing severe illness and spreading readily among patients in health care facilities.² Infections range from skin and wound involvement to life-threatening bloodstream infection, and symptoms track with the infection site rather than any pathognomonic presentation. The agency notes symptoms may mimic bacterial infection, including fever and chills, which complicates recognition.²
Risk concentrates among patients with serious underlying illness and invasive devices such as central venous catheters, urinary catheters, breathing tubes, and feeding tubes.² People without these risk factors, including health care personnel and visitors, generally neither carry nor become ill from the organism, and routine screening of staff or family members is unnecessary.² Colonization frequently persists on skin for prolonged periods regardless of symptoms, and colonized patients contaminate bedrails, doorknobs, and blood pressure cuffs, where the organism survives for extended intervals.²
On therapy, the CDC states most strains resist at least 1 antifungal class, with echinocandins preferred for most infections.² Some strains resist all 3 major classes, and management of those cases may involve combination regimens or investigational agents. Surveillance data show 6304 clinical cases reported in the US in 2024, with annual counts rising every year since the first domestic case in 2016 though the rate of increase has slowed since 2022.³ Separate CDC analysis found 6.9% of colonized patients progressed to a positive clinical specimen, as reported in prior Contagion coverage of colonization progression.
Clinically, the preprint reinforces a point raised in a review of the changing C auris management landscape: an MIC within the susceptible range does not guarantee therapeutic success. Repeat cultures, repeat susceptibility testing, and early consideration of combination therapy remain the practical levers while next-generation agents advance through development.
References
FKS1/2-variant independent mechanisms underlying the emergence of resistance in echinocandin-refractory Candida auris infections. bioRxiv. Preprint posted online January 17, 2026. doi:10.64898/2026.01.17.700071
Centers for Disease Control and Prevention. About C. auris. Reviewed September 28, 2026. Accessed October 16, 2026. https://www.cdc.gov/candida-auris/about/index.html
