In vitro Combinatorial Effects of 18β-Glycyrrhetinic Acid with Azole Antifungals.

OBJECTIVE

To explore the combined effects of multiple drugs and provide more therapeutic options for invasive fungal infections, this study evaluated the in vitro susceptibility of Aspergillus spp. Candida spp. Cryptococcus neoformans, and Exophiala dermatitidis to 18β-glycyrrhetinic acid(GA) in combination with itraconazole(ITC), voriconazole(VRC), posaconazole(POS), and fluconazole(FLU).

METHODS

The antifungal activity of GA combined with ITC, VRC, POS, and FLU against 107 clinical isolates was evaluated using the CLSI broth microdilution method (M27-A3 and M38-A2), including 56 strains of Aspergillus spp. 16 strains of E. dermatitidis, 26 strains of Candida spp. and 9 strains of C. neoformans. Minimum inhibitory concentrations(MICs) and fractional inhibitory concentration indices(FICIs) were determined to evaluate the synergistic effects.

RESULTS

GA alone exhibited no antifungal activity. However, its combination with azoles showed complex biphasic effects. The synergistic rates of GA-POS against Aspergillus spp. E. dermatitidis, Candida spp. and C. neoformans were 87.50%(49/56), 43.75%(7/16), 30.77%(8/26), and 55.56%(5/9), respectively, with no antagonism observed, indicating broad-spectrum synergistic potential. In contrast, the synergistic rates of GA-ITC against the above pathogens were only 5.36%(3/56), 6.25%(1/16), 26.92%(7/26), and 22.22%(2/9), respectively. GA-FLU exerted synergistic effects only against C. neoformans(11.11%, 1/9). The overall synergistic rate ranked POS(64.49%, 69/107) > ITC(12.15%, 13/107) > FLU(4.00%, 1/25). Additionally, partial antagonistic effects were observed in Candida spp. and C. neoformans. For Candida spp. the antagonistic rates of GA-VRC and GA-FLU were 23.08%(6/26) and 25.00%(4/16), respectively. For C. neoformans, the antagonistic rate of GA-FLU was 22.22%(2/9).

CONCLUSION

In vitro experiments demonstrate that synergistic or antagonistic effects can be observed when GA is combined with azoles. These findings deepen our understanding of the combinatorial efficacy of GA and azoles and provide new perspectives for targeted antifungal combination therapy.