Abstract / Summary
Yixin Zeng,1,2,* Jing Hu,3,* Lu Ge,1,2,* Junhao Yu,1,2 Menghua Tang,1,2 Jufang Tan,4 Heng Zhang,2,5 Yi Sun2,51Department of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, People’s Republic of China; 2Hubei Provincial Clinical Medical Research Center for Diagnosis and Treatment of Pathogenic Fungal Infections, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei Province, 434100, People’s Republic of China; 3Department of Medicine, Xiangyang Polytechnic University, Xiangyang, Hubei Province, 441050, People’s Republic of China; 4Department of Pediatrics, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei Province, 434100, People’s Republic of China; 5Department of Dermatology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei Province, 434100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Sun, Email jzzxyysy@163.comObjective: 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.Keywords: synergism, antagonism, azole sensitizer, clinical isolates, biphasic effects