Distinct virulence and azole resistance profiles of <i>Candida albicans</i> clinical isolates from patients with acute and recurrent vulvovaginal candidiasis

Candida albicans is the primary etiological agent of acute vulvovaginal candidiasis (AVVC) and its recurrent form (RVVC), conditions that differ in clinical presentation, inflammatory context, and response to antifungal therapy. Although virulence factors and antifungal resistance have been individually linked to disease severity, their integrated contribution to distinct clinical outcomes remains poorly defined. Here, we performed a comprehensive phenotypic characterization of 58 clinical C. albicans isolates recovered from women with AVVC (n = 25) or RVVC (n = 33), and C. albicans SC5314 was included for comparison. We assessed fungal dimorphism, cell surface hydrophobicity, biofilm-forming capacity (BFC), and the production of secreted aspartyl proteinases (SAP) and lipases (LIP). Antifungal susceptibility to azoles and other clinically relevant agents was determined using an automated system. Multivariate unsupervised analyses were applied to identify integrated virulence phenotypes. All clinical isolates exhibited efficient filamentation. AVVC isolates displayed enhanced adherence, biofilm metabolic activity, and LIP production, whereas RVVC isolates exhibited increased SAP activity and reduced BFC. Unsupervised clustering and UMAP analysis identified four virulence clusters, including profiles specifically associated with AVVC or RVVC, as well as mixed phenotypes. Notably, a high prevalence of azole resistance was observed in both groups, with resistance patterns aligning with specific virulence clusters. Collectively, these findings indicate that AVVC and RVVC are associated with distinct, niche-adapted C. albicans virulence programs that integrate enzymatic activity, biofilm traits, and antifungal resistance. This structured phenotypic heterogeneity provides a framework to reinterpret vulvovaginal candidiasis as a multifactorial and adaptive process with important implications for disease persistence and therapeutic failure.