Background and Purpose: Cryptococcal meningitis (CM) remains a serious opportunistic infection, particularly among individuals living with HIV/AIDS. Fluconazole (FLC), favored for its accessibility and cost-effectiveness, faces growing resistance globally, especially in low-resource settings like India where antifungal susceptibility data are scarce. The study aimed to assess the prevalence of reduced fluconazole susceptibility among Cryptococcus neoformans clinical isolates in North India and to evaluate its clinical implications in the management of CM.

Materials and Methods: We analyzed 21 cases of Cryptococcal Meningitis diagnosed between 2022 and 2024. Clinical features, demographic data, laboratory parameters, and antifungal susceptibility profiles were assessed, with subgroup comparisons between HIV-positive and HIV-negative patients. Antifungal susceptibility testing for amphotericin B, fluconazole, itraconazole, and voriconazole was performed using broth microdilution as per CLSI guidelines (M27-A3 document).

Results: A total of 21 patients with CM were included; 12 (57.1%) were HIV-positive and 9 (42.9%) HIV-negative. Cases showed seasonal clustering with peaks during May–August, highest in July 2024. Antifungal susceptibility testing was performed for 17 clinical isolates. Fluconazole MICs ranged from 1–16 µg/mL with MIC50/MIC90 of 8/8 µg/mL (geometric mean 6.4 µg/mL). Amphotericin B MICs ranged from 0.25–2 µg/mL (MIC50: 1 µg/mL; MIC90: 2 µg/mL; geometric mean: 1.18 µg/mL). Itraconazole and voriconazole showed low MICs (itraconazole 0.0625–0.125 µg/mL; voriconazole 0.03–0.25 µg/mL). Univariate analysis revealed no significant association between elevated FLC MIC (≥8 µg/mL) and age, gender, HIV status, or mortality.

Conclusions: The findings underscore rising fluconazole MICs in C. neoformans isolates in North India, necessitating enhanced antifungal surveillance and stewardship to optimize CM treatment outcomes.