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

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.

Citing Articles

In Vitro Evaluation of Rosemary Essential Oil: GC-MS Profiling, Antibacterial Synergy, and Biofilm Inhibition.

Kabotso D, Neglo D, Gaba S, Danyo E, Dayie A, Asantewaa A Pharmaceuticals (Basel). 2025; 17(12.

PMID: 39770495 PMC: 11728608. DOI: 10.3390/ph17121653.

Evaluation of amlodipine against strains of spp. in planktonic cells, developing biofilms and mature biofilms.

Queiroz H, da Silva L, Barroso F, Sa L, de Andrade Neto J, Costa E Future Microbiol. 2024; 19(16):1365-1375.

PMID: 39235062 PMC: 11552476. DOI: 10.1080/17460913.2024.2390286.

Analysis of the anti-Candida activity of tricyclic antidepressants in association with amphotericin B and their antifungal mechanisms.

de Farias Cabral V, Rodrigues D, Sa L, Moreira L, da Silva C, de Andrade Neto J Braz J Microbiol. 2024; 55(4):3617-3628.

PMID: 39198376 PMC: 11711746. DOI: 10.1007/s42770-024-01459-y.

Antifungal activity of tannic acid against Candida spp. and its mechanism of action.

Moreira L, de Farias Cabral V, Rodrigues D, Barbosa A, Silveira M, Coutinho T Braz J Microbiol. 2024; 55(4):3679-3690.

PMID: 39179891 PMC: 11711865. DOI: 10.1007/s42770-024-01477-w.

Mangiferin potentiates the activity of antifungal agents against fluconazole-resistant spp.

Ferreira T, Leitao A, da Silva L, Sa L, de Farias Cabral V, Rodrigues D Future Microbiol. 2024; 19(13):1157-1170.

PMID: 39012219 PMC: 11529198. DOI: 10.1080/17460913.2024.2366627.

References

Wakiec R, Prasad R, Morschhauser J, Barchiesi F, Borowski E, Milewski S . Voriconazole and multidrug resistance in Candida albicans. Mycoses. 2007; 50(2):109-15. DOI: 10.1111/j.1439-0507.2006.01327.x. View

Barchiesi F, Calabrese D, Sanglard D, Di Francesco L, Caselli F, Giannini D . Experimental induction of fluconazole resistance in Candida tropicalis ATCC 750. Antimicrob Agents Chemother. 2000; 44(6):1578-84. PMC: 89916. DOI: 10.1128/AAC.44.6.1578-1584.2000. View

Pfaller M, Diekema D . Progress in antifungal susceptibility testing of Candida spp. by use of Clinical and Laboratory Standards Institute broth microdilution methods, 2010 to 2012. J Clin Microbiol. 2012; 50(9):2846-56. PMC: 3421803. DOI: 10.1128/JCM.00937-12. View

Knorre D, Krivonosova T, Markova O, Severin F . Amiodarone inhibits multiple drug resistance in yeast Saccharomyces cerevisiae. Arch Microbiol. 2009; 191(8):675-9. DOI: 10.1007/s00203-009-0493-8. View

Cavalcanti B, Bezerra D, Magalhaes H, Moraes M, Lima M, Silveira E . Kauren-19-oic acid induces DNA damage followed by apoptosis in human leukemia cells. J Appl Toxicol. 2009; 29(7):560-8. DOI: 10.1002/jat.1439. View

Perrone G, Tan S, Dawes I . Reactive oxygen species and yeast apoptosis. Biochim Biophys Acta. 2008; 1783(7):1354-68. DOI: 10.1016/j.bbamcr.2008.01.023. View

Miloshev G, Mihaylov I, Anachkova B . Application of the single cell gel electrophoresis on yeast cells. Mutat Res. 2001; 513(1-2):69-74. DOI: 10.1016/s1383-5718(01)00286-8. View

Ribeiro G, Corte-Real M, Johansson B . Characterization of DNA damage in yeast apoptosis induced by hydrogen peroxide, acetic acid, and hyperosmotic shock. Mol Biol Cell. 2006; 17(10):4584-91. PMC: 1635349. DOI: 10.1091/mbc.e06-05-0475. View

Rogers P, Vermitsky J, Edlind T, Hilliard G . Proteomic analysis of experimentally induced azole resistance in Candida glabrata. J Antimicrob Chemother. 2006; 58(2):434-8. DOI: 10.1093/jac/dkl221. View

10.

Gupta S, Ton V, Beaudry V, Rulli S, Cunningham K, Rao R . Antifungal activity of amiodarone is mediated by disruption of calcium homeostasis. J Biol Chem. 2003; 278(31):28831-9. DOI: 10.1074/jbc.M303300200. View

11.

Kobayashi D, Kondo K, Uehara N, Otokozawa S, Tsuji N, Yagihashi A . Endogenous reactive oxygen species is an important mediator of miconazole antifungal effect. Antimicrob Agents Chemother. 2002; 46(10):3113-7. PMC: 128784. DOI: 10.1128/AAC.46.10.3113-3117.2002. View

12.

Vanden Bossche H, Warnock D, DuPont B, KERRIDGE D, SEN GUPTA S, Improvisi L . Mechanisms and clinical impact of antifungal drug resistance. J Med Vet Mycol. 1994; 32 Suppl 1:189-202. DOI: 10.1080/02681219480000821. View

13.

Sellami A, Sellami H, Neji S, Makni F, Abbes S, Cheikhrouhou F . Antifungal susceptibility of bloodstream Candida isolates in Sfax hospital: Tunisia. Mycopathologia. 2010; 171(6):417-22. DOI: 10.1007/s11046-010-9388-0. View

14.

Serre L, Pereira de Jesus K, Boiteux S, Zelwer C, Castaing B . Crystal structure of the Lactococcus lactis formamidopyrimidine-DNA glycosylase bound to an abasic site analogue-containing DNA. EMBO J. 2002; 21(12):2854-65. PMC: 126059. DOI: 10.1093/emboj/cdf304. View

15.

Vandeputte P, Larcher G, Berges T, Renier G, Chabasse D, Bouchara J . Mechanisms of azole resistance in a clinical isolate of Candida tropicalis. Antimicrob Agents Chemother. 2005; 49(11):4608-15. PMC: 1280149. DOI: 10.1128/AAC.49.11.4608-4615.2005. View

16.

Graybill J, Najvar L, Holmberg J, Luther M . Fluconazole, D0870, and flucytosine treatment of disseminated Candida tropicalis infections in mice. Antimicrob Agents Chemother. 1995; 39(4):924-9. PMC: 162655. DOI: 10.1128/AAC.39.4.924. View

17.

Pfaller M, Diekema D . Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007; 20(1):133-63. PMC: 1797637. DOI: 10.1128/CMR.00029-06. View

18.

Pfaller M, Castanheira M, Diekema D, Messer S, Jones R . Wild-type MIC distributions and epidemiologic cutoff values for fluconazole, posaconazole, and voriconazole when testing Cryptococcus neoformans as determined by the CLSI broth microdilution method. Diagn Microbiol Infect Dis. 2011; 71(3):252-9. DOI: 10.1016/j.diagmicrobio.2011.07.007. View

19.

Joung Y, Kim H, Lee M, Park A . Fluconazole susceptibility testing of Candida species by flow cytometry. J Infect. 2006; 54(5):504-8. DOI: 10.1016/j.jinf.2006.09.016. View

20.

Odds F . Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother. 2003; 52(1):1. DOI: 10.1093/jac/dkg301. View