Minocycline and Fluconazole Have a Synergistic Effect Against Cryptococcus neoformans Both in vitro and in vivo

Abstract

In recent decades, the incidence of Cryptococcus neoformans infection, which causes cryptococcosis, has consistently increased. Fluconazole (FLU) is frequently used in the treatment of this disease, mainly in the immunocompromised population, and longterm therapy usually produces drug resistance. Research on antifungal sensitizers has gained attention as a possible means of overcoming this drug resistance. Minocycline (MINO) has an inhibitory effect in vitro on FLU-resistant Candida albicans, and the combination of MINO and FLU has a synergistic effect on FLU-resistant C. albicans. A synergistic effect of MINO/FLU has been reported against C. neoformans, but this effect has not been evaluated on FLU-resistant isolates. This study aimed to investigate the interaction of MINO and FLU against FLU-resistant C. neoformans both in vitro and in vivo. We found that the combination of MINO and FLU had a synergistic effect on FLUresistant C. neoformans in vitro. For all FLU-resistant strains, the minimum inhibitory concentration (MIC) of FLU decreased significantly when used in combination with MINO, dropping from >128 µg/ml down to 4-8 µg/ml. Additionally, MINO and FLU had a synergistic effect on both susceptible and resistant C. neoformans biofilms, in which the MIC of FLU decreased from >256 µg/ml down to 4-16 µg/ml. Compared with FLU alone, the combination of MINO with FLU prolonged the survival rate of Galleria mellonella larvae infected with FLU-resistant C. neoformans, and also significantly decreased the fungal burden of infected larvae and reduced the tissue damage and destruction caused by FLU-resistant C. neoformans. These findings will contribute to the discovery of antifungal agents and may yield a new approach for the treatment of cryptococcosis caused by FLU-resistant C. neoformans.

In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates

“…Moreover, we confirmed that the efficacy of VRZ treatment was associated with fewer and less severe tissue lesions in treated animals compared to untreated controls. These results confirm and extend previous studies that used histopathology in models of invasive fungal infections in G. mellonella [25,26]. One limitation of our study is that only one larva was tested for each condition (strain, dose of VRZ and time-point after treatment).…”

Antifungal Activity of Minocycline and Azoles Against Fluconazole-Resistant Candida Species

“…MIN has also been shown to synergize with azoles in the treatment of other fungal species. Kong et al (2020) determined that MIN was able to synergize with FLU in vivo and in vitro when treating Cryptococcus neoformans , while Gao et al (2020) reported synergy between MIN and azoles when treating clinically important Aspergillus , Fusarium , and Exophiala dermatitidis isolates. Herein, we explored the synergistic activity of MIN in combination with azoles when treating FLU-resistant C. albicans , C. parapsilosis , C. tropicalis , C. glabrata , and C. auris .…”

Phytochemical Analysis and Antifungal Potentiating Activity of Extracts from Loquat (Eriobotrya japonica) against Cryptococcus neoformans Clinical Isolates

“…After MICs were determined, the two most active extracts were selected to evaluate their effect in association with nystatin and clotrimazole. The checkerboard method used was the broth microdilution assay, miniaturized in a 96-well plate as described by Kong et al (2020) with slight modifications [ 21 ]. Briefly, 50 µ L of culture media were introduced in each well of the two microplates.…”