Synergistic Effects of Amiodarone and Fluconazole on Candida tropicalis Resistant to Fluconazole

Abstract

e There have recently been significant increases in the prevalence of systemic invasive fungal infections. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapies have become one of the most widely used and effective strategies to alleviate this problem. Amiodarone (AMD) is classically used for the treatment of atrial fibrillation and is the drug of choice for patients with arrhythmia. Recent studies have shown broad antifungal activity of the drug when administered in combination with fluconazole (FLC). In the present study, we induced resistance to fluconazole in six strains of Candida tropicalis and evaluated potential synergism between fluconazole and amiodarone. The evaluation of drug interaction was determined by calculating the fractional inhibitory concentration and by performing flow cytometry. We conclude that amiodarone, when administered in combination with fluconazole, exhibits activity against strains of C. tropicalis that are resistant to fluconazole, which most likely occurs via changes in the integrity of the yeast cell membrane and the generation of oxidative stress, mitochondrial dysfunction, and DNA damage that could lead to cell death by apoptosis.

A conserved mechanism for regulation of endo-lysosomal pH by histone deacetylases

“…Furthermore, many naturally occurring antifungal compounds such as terpenoid phenols, function at least in part by disrupting V-ATPase function (68). Recent studies have documented the potential benefits of repurposing FDA approved amphipathic drugs such as amiodarone, already in clinical use as calcium antagonists, that partition into acidic compartments, alkalinize endo-lysosomes and potentiates antifungal effects and reverse resistance to azole drugs (69). Here we show that an antifungal HDAC inhibitor trichostatin A (TSA) increases vacuole pH and enhances the antifungal effects of fluconazole.…”

Farmakokinetyczne interakcje międzylekowe w oddziale intensywnej terapii – obserwacje jednoośrodkowe i przegląd piśmiennictwa

“…At such doses, cases of sudden cardiac death have been reported [6]. It is worth noticing, however, that the growing number of reports emphasize the positive effect of interaction of the above drugs, which increases the activity of fluconasole against resistant fungal strains due to amiodarone-related inhibition of an antibiotic efflux pump by fungal cells [7,8].…”

Quinoline Based Monocarbonyl Curcumin Analogs as Potential Antifungal and Antioxidant Agents: Synthesis, Bioevaluation and Molecular Docking Study

“…Antioxidants play an important role in body defense system by reducing or neutralizing the free radicals that protects the cells from oxidative injury . Recently, it has been observed that reactive oxygen species participates in mechanism of action of triazole containing antifungal drugs . It is important to elucidate possible association among oxidative stress response and antifungal mechanism of action for developing new targets for novel antifungal agents by rational development of antifungal drugs.…”

“…[8] Recently, it has been observed that reactive oxygen species participates in mechanism of action of triazole containing antifungal drugs. [9] It is important to elucidate possible association among oxidative stress response and antifungal mechanism of action for developing new targets for novel antifungal agents by rational development of antifungal drugs. Hence, antifungal agents with radical scavenging properties can be a good choice in designing new fungicidal agents.…”