Community-Onset Fungemias: Epidemiology and Genomic Characterization at a Tertiary-Care Hospital in Barcelona, Spain

<b>Background</b>: Community-onset fungemia is a clinically significant syndrome frequently linked to recent healthcare exposure and significant morbidity and mortality. Methods: We performed a 21-year, single-centre retrospective cohort of consecutive yeast bloodstream infections diagnosed at the Emergency Department (2004-2024). Clinical/epidemiological data, species identification (MALDI-TOF MS), antifungal susceptibility (CLSI M27; Sensititre YO10), and whole-genome sequencing (WGS) were analyzed. <b>Results</b>: Forty-eight episodes (51 isolates) were included; 56.3% were male, median age 74 years (IQR 63-82). Acquisition was healthcare-associated in 38/48 (79.2%). Sources were unknown (36.7%), abdominal (22.4%), urological (22.4%), catheter-related (14.3%), and 2.1% was attributed to a cardiovascular and a joint focus; 18.8% were polymicrobial. Crude mortality was 20.8% at 7 days (10/48) and 29.2% at 30 days (14/48). Species distribution: <i>Candida albicans</i> 41.2%, <i>Nakaseomyces glabratus</i> 27.5%, <i>Candida parapsilosis</i> 11.8%, <i>Candida tropicalis</i> 11.8%, <i>Pichia kudriavzevii</i> 3.9%, <i>Clavispora lusitaniae</i> 1.9%, and <i>Candida orthopsilosis</i> 1.9%. No isolate was resistant to anidulafungin, micafungin, or amphotericin B; one <i>N. glabratus</i> showed reduced susceptibility to caspofungin. Azole resistance was observed in one <i>C. albicans</i> and one <i>N. glabratus</i> isolate. WGS (44 isolates) confirmed MALDI-TOF identifications and characterized resistance markers. All 12 sequenced <i>N. glabratus</i> carried ERG2 I207V, PDR15/PDH1 E839D, and PDR1 V91I/L98S. Notable cases included one <i>N. glabratus</i> caspofungin-intermediate with FKS2 F659C, <i>N. glabratus</i> fluconazole-resistant with multiple PDR1 substitutions including a unique novel G857V, and <i>C. albicans</i> fluconazole-resistant harbouring alterations in MRR1/MRR2, CDR1, and ERG11. <b>Conclusions</b>: In this 21-year cohort, community-onset fungemia was predominantly healthcare-associated, with <i>C. albicans</i> as the predominant species, followed by <i>N. glabratus</i>. Crude mortality reached 29.2% at 30 days. Echinocandin resistance was not observed; azole resistance was uncommon. WGS provided precise speciation and actionable insight into resistance mechanisms, including a putatively novel PDR1 G857V in <i>N. glabratus</i>.