Differential Effects of Low-Intensity Pulsed Ultrasound and Antifungals on Candida albicans and Candida glabrata: Implications for Drug Efficacy.

Invasive fungal infections pose significant clinical challenges, owing to limited antifungal efficacy and poor tissue drug penetration. This study investigated whether low-intensity pulsed ultrasound (LIPUS) could enhance the antifungal activity of sub-minimal inhibitory concentrations (sub-MICs) of amphotericin B (AmB) and micafungin (MFG) against two strains from two phylogenetically distinct Candida species: Candida albicans and Candida glabrata. Growth inhibition was assessed following LIPUS (15 min, 50% duty cycle, 1 W/cm2) alone or in combination with sub-MIC antifungals. Time-kill assays and adenylate kinase (AK) release evaluated the cell viability and membrane integrity, respectively. LIPUS transiently but markedly delayed C. albicans growth and enhanced the antifungal effects of both AmB and MFG at sub-MIC levels. The combination of LIPUS and ¼ MIC AmB reduced CFU counts by over 3 log at 12 h and induced higher AK release compared to controls, indicating membrane leakage. In contrast, Candida glabrata showed minimal susceptibility to LIPUS, with low AK release and mitigation of the fungistatic effects of sub-MIC MFG. Our study demonstrates that LIPUS can potentiate sub-MIC antifungals against C. albicans but may have the opposite effect in C. glabrata. This strain-specific variation in response to LIPUS underscores the need for further investigation before LIPUS can be considered as a treatment-enhancement strategy.