In vitro study on synergistic antifungal effects of docetaxel combined with azoles against dematiaceous fungi and Aspergillus niger.

BACKGROUND

Dematiaceous fungal infections are frequently encountered in clinical practice with no unified treatment. Drug combination reduces drug resistance, and repurposed clinical drugs as synergists show promise in aiding azoles against phaeohyphomycosis.

OBJECTIVE

To investigate the synergistic antifungal effects of docetaxel (DTX) in combination with azoles against dematiaceous fungi and Aspergillus niger, as well as their impact on efflux pump activity.

METHODS

CLSI M38-A2 microbroth dilution method was used to detect fractional inhibitory concentration index of DTX with posaconazole (POS), itraconazole (ITC), voriconazole (VOR), and isavuconazole (ISA) against 43 fungi (including 24 strains of Exophiala dermatitidis, 7 strains of Exophiala alcalophila, 3 strains of Fonsecaea pedrosoi, 1 strain of Fonsecaea monophora, 1 strain of Exophiala verrucosa and 7 strains of Aspergillus niger). Rhodamine 6G transport efficiency and transcriptional variations of efflux pump genes were determined in strains treated with POS alone or POS combined with DTX.

RESULTS

DTX alone had no antifungal activity. 30/43 (69.8%) strains showed synergy with POS (87.5% E. dermatitidis, 100% A. niger). 7 (16.3%), 3 (7.0%) and 1 (2.3%) strains showed synergy with ITC, VOR and ISA. For strains with POS synergism, DTX treatment significantly suppressed efflux activity and modified the transcription of efflux pump genes.

CONCLUSION

The combined scheme of DTX and POS can significantly reduce the minimum inhibitory concentration of POS and show synergistic antifungal activity, especially significant against E. dermatitidis and A. niger. Its mechanism of action may be related to the reduction of efflux pump activity.