Interactions between antifungals and everolimus against Cryptococcus neoformans

Area of Science:

• Mycology
• Infectious Diseases
• Pharmacology

Background:

• Cryptococcus causes cryptococcosis, a life-threatening infection, particularly in immunocompromised individuals.
• Limited therapeutic options necessitate novel treatment strategies for cryptococcosis.
• Cryptococcosis often presents as pneumonia or meningoencephalitis, with high mortality rates.

Purpose of the Study:

• To investigate the in vitro and in vivo synergistic interactions of everolimus (EVL) with established antifungal agents against Cryptococcus.
• To evaluate the potential of EVL in combination therapy to overcome existing treatment limitations for cryptococcosis.

Main Methods:

• Broth microdilution assays were performed according to CLSI guidelines to determine minimum inhibitory concentrations (MICs).
• Synergy was assessed using the fractional inhibitory concentration index (FICI).
• In vivo efficacy was evaluated using the Galleria mellonella infection model.

Main Results:

• Everolimus (EVL) exhibited intrinsic antifungal activity against Cryptococcus neoformans.
• Combinations of EVL with amphotericin B (AmB) and azoles (POS, FLU, ITR, VOR) showed synergistic effects against 33.3% to 88.9% of clinical isolates.
• In vivo studies confirmed improved larval survival with EVL combined with POS, FLU, and ITR.

Conclusions:

• Everolimus (EVL) demonstrates synergistic antifungal activity when combined with amphotericin B (AmB) or azoles against Cryptococcus.
• These combinations represent a promising therapeutic strategy for managing cryptococcosis.
• Further research into EVL-based combination therapies could lead to improved treatment outcomes for cryptococcosis.