In Vitro Evidence to Support Amphotericin B and Flucytosine Combination Therapy for Talaromycosis

Area of Science:

• Mycology
• Infectious Diseases
• Pharmacology

Background:

• Talaromycosis, caused by Talaromyces marneffei, is a severe fungal infection with high mortality.
• Current treatments, including amphotericin B (AmB) and itraconazole, have limitations and significant mortality rates (15-30%).

Purpose of the Study:

• To investigate the potential synergistic antifungal activity of combining AmB and flucytosine (5FC) against T. marneffei.
• To establish a basis for potential new therapeutic strategies and optimized dosing for talaromycosis.

Main Methods:

• Evaluated in vitro antifungal activity of AmB and 5FC alone and in combination against 60 T. marneffei clinical isolates.
• Utilized colorimetric antifungal susceptibility assays and the checkerboard method to determine MIC95.
• Confirmed combination effects using fractional inhibitory concentration index and time-kill assays.

Main Results:

• AmB MIC95 ranged from 0.25-2 μg/mL (GM 0.68 μg/mL), and 5FC MIC95 ranged from 0.03-0.5 μg/mL (GM 0.28 μg/mL).
• Synergy was observed in 7% of isolates, with indifference in 93%.
• Time-kill assays confirmed synergy, demonstrating a >2-log10 reduction in colony-forming units with the combination, with no antagonism.

Conclusions:

• Demonstrated in vitro synergistic activity between AmB and 5FC against T. marneffei.
• Provides evidence to support further in vivo and clinical trials for AmB and 5FC combination therapy.
• Suggests potential for developing dosing reduction strategies for 5FC.