Review Article

Antimycotic Drugs and their Mechanisms of Resistance to Candida Species

Author(s): Sweety Dahiya, Namita Sharma, Aruna Punia, Pooja Choudhary, Prity Gulia, Virinder S. Parmar and Anil K. Chhillar*

Volume 23, Issue 2, 2022

Published on: 19 July, 2021

Page: [116 - 125] Pages: 10

DOI: 10.2174/1389450122666210719124143

Price: $65


Fungal infections have shown an upsurge in recent decades, which is mainly because of the increasing number of immunocompromised patients and the occurrence of invasive candidiasis has been found to be 7-15 fold greater than that of invasive aspergillosis. The genus Candida comprises more than 150 distinct species, however, only a few of them are found to be pathogenic to humans. Mortality rates of Candida species are found to be around 45% and the reasons for this intensified mortality are inefficient diagnostic techniques and unfitting initial treatment strategies. There are only a few antifungal drug classes that are employed for the remedy of invasive fungal infections. which include azoles, polyenes, echinocandins, and pyrimidine analogs. During the last 2-3 decades, the usage of antifungal drugs has increased several folds due to which the reports of escalating antifungal drug resistance have also been recorded. The resistance is mostly to the triazole- based compounds. Due to the occurrence of antifungal drug resistance, the success rates of treatment have been reduced as well as major changes have been observed in the frequency of fungal infections. In this review, we have summarized the major molecular mechanisms for the development of antifungal drug resistance.

Keywords: Candidemia, nosocomial infection, azole-resistance, polyene-resistance, echinocandin-resistance, antimycotic drugs.

Graphical Abstract
Geddes-McAlister J, Shapiro RS. New pathogens, new tricks: Emerging, drug-resistant fungal pathogens and future prospects for antifungal therapeutics. Ann N Y Acad Sci 2019; 1435(1): 57-78.
[] [PMID: 29762860]
Denning DW. Calling upon all public health mycologists. To accompany the country burden papers from 14 countries european journal of clinical microbiology & infectious diseases. Microbiology. Germany.: Official publication of the European Society of Clinical. 2017; pp. 923-4.
Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: A persistent public health problem. Clin Microbiol Rev 2007; 20(1): 133-63.
[] [PMID: 17223626]
Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: Analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39(3): 309-17.
[] [PMID: 15306996]
Campitelli M, Zeineddine N, Samaha G, Maslak S. Combination antifungal therapy: A review of current data. J Clin Med Res 2017; 9(6): 451-6.
[] [PMID: 28496543]
Ganguly S, Mitchell AP. Mucosal biofilms of candida albicans. Curr Opin Microbiol 2011; 14(4): 380-5.
[] [PMID: 21741878]
Article R. Review on combinatorial approach for inhibiting candida albicans biofilm. OPEN ACCESS 2018; 1(5): 1-10.
Douglas LJ. Candida biofilms and their role in infection. Trends Microbiol 2003; 11(1): 30-6.
[] [PMID: 12526852]
Bongomin F, Gago S, Oladele RO, Denning DW. Global and multi-national prevalence of fungal diseases-estimate precision. J fungi (Basel, Switzerland) 2017; 3(4)
Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC. Hidden killers: Human fungal infections. Sci Transl Med 2012; 4(165): 165rv13.
[] [PMID: 23253612]
Hasan F, Xess I, Wang X, Jain N, Fries BC. Biofilm formation in clinical Candida isolates and its association with virulence. Microbes Infect 2009; 11(8-9): 753-61.
[] [PMID: 19409507]
Sudbery P, Gow N, Berman J. The distinct morphogenic states of Candida albicans. Trends Microbiol 2004; 12(7): 317-24.
[] [PMID: 15223059]
Maccallum DM. Hosting infection: Experimental models to assay Candida virulence. Int J Microbiol 2012; 2012: 363764.
[] [PMID: 22235206]
Spampinato C, Leonardi D. Candida infections, causes, targets, and resistance mechanisms: Traditional and alternative antifungal agents. BioMed Res Int 2013; 2013: 204237.
[] [PMID: 23878798]
Miceli MH, Díaz JA, Lee SA. Emerging opportunistic yeast infections. Lancet Infect Dis 2011; 11(2): 142-51.
[] [PMID: 21272794]
Healey KR, Perlin DS. Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata. J Fungi (Basel) 2018; 4(3): E105.
[PMID: 30200517]
Kett DH, Azoulay E, Echeverria PM, Vincent J-L. Candida bloodstream infections in intensive care units: Analysis of the extended prevalence of infection in intensive care unit study. Crit Care Med 2011; 39(4): 665-70.
[] [PMID: 21169817]
Sanguinetti M, Posteraro B, Lass-Flörl C. Antifungal drug resistance among Candida species: Mechanisms and clinical impact. Mycoses 2015; 58(S2)(Suppl. 2): 2-13.
[] [PMID: 26033251]
Cleveland AA, Farley MM, Harrison LH, et al. Changes in incidence and antifungal drug resistance in candidemia: Results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clin Infect Dis 2012; 55(10): 1352-61.
[] [PMID: 22893576]
Diekema DJ, Messer SA, Brueggemann AB, et al. Epidemiology of candidemia: 3-year results from the emerging infections and the epidemiology of Iowa organisms study. J Clin Microbiol 2002; 40(4): 1298-302.
[] [PMID: 11923348]
Poikonen E, Lyytikäinen O, Anttila V-J, et al. Secular trend in candidemia and the use of fluconazole in Finland, 2004-2007. BMC Infect Dis 2010; 10(1): 312.
[] [PMID: 21029444]
Odds FC, Hanson MF, Davidson AD, et al. One year prospective survey of Candida bloodstream infections in Scotland. J Med Microbiol 2007; 56(Pt 8): 1066-75.
[] [PMID: 17644714]
Sandven P, Bevanger L, Digranes A, Haukland HH, Mannsåker T, Gaustad P. Candidemia in Norway (1991 to 2003): Results from a nationwide study. J Clin Microbiol 2006; 44(6): 1977-81.
[] [PMID: 16757587]
Tortorano AM, Kibbler C, Peman J, Bernhardt H, Klingspor L, Grillot R. Candidaemia in Europe: Epidemiology and resistance. Int J Antimicrob Agents 2006; 27(5): 359-66.
[] [PMID: 16647248]
Almirante B, Rodríguez D, Park BJ, et al. Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, barcelona, Spain, from 2002 to 2003. J Clin Microbiol 2005; 43(4): 1829-35.
[] [PMID: 15815004]
Poikonen E, Lyytikäinen O, Anttila V-J, Ruutu P. Candidemia in Finland, 1995-1999. Emerg Infect Dis 2003; 9(8): 985-90.
[] [PMID: 12967498]
Spivak ES, Hanson KE. Candida auris: An Emerging Fungal Pathogen. J Clin Microbiol 2018; 56(2): e01588-17.
[] [PMID: 29167291]
Falagas ME, Roussos N, Vardakas KZ. Relative frequency of albicans and the various non-albicans Candida spp among candidemia isolates from inpatients in various parts of the world: a systematic review. Int J Infect Dis 2010; 14(11): e954-66.
[] [PMID: 20797887]
Ramage G, Martínez JP, López-Ribot JL. Candida biofilms on implanted biomaterials: A clinically significant problem. FEMS Yeast Res 2006; 6(7): 979-86.
[] [PMID: 17042747]
Perfect JR. The antifungal pipeline: A reality check. Nat Rev Drug Discov 2017; 16(9): 603-16.
[] [PMID: 28496146]
Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2002; 2(2): 73-85.
[] [PMID: 11901654]
Anderson TM, Clay MC, Cioffi AG, et al. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol 2014; 10(5): 400-6.
[] [PMID: 24681535]
Zotchev SB. Polyene macrolide antibiotics and their applications in human therapy. Curr Med Chem 2003; 10(3): 211-23.
[] [PMID: 12570708]
Méan M, Marchetti O, Calandra T. Bench-to-bedside review: Candida infections in the intensive care unit. Crit Care 2008; 12(1): 204.
[] [PMID: 18279532]
Wall G, Lopez-Ribot JL. Current antimycotics, new prospects, and future approaches to antifungal therapy. Antibiot (Basel, Switzerland) 2020; 9(8)
Padda IS, Parmar M. Flucytosine.In: StatPearls. StatPearls Publishing. 2020.
Vermes A, Guchelaar HJ, Dankert J. Flucytosine: A review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 2000; 46(2): 171-9.
[] [PMID: 10933638]
Hof H. A new, broad-spectrum azole antifungal: Posaconazole--mechanisms of action and resistance, spectrum of activity. Mycoses 2006; 49(Suppl. 1): 2-6.
[] [PMID: 16961575]
Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America. Clin Infect Dis 2016; 62(4): e1-e50. [Internet].
[] [PMID: 26679628]
Lass-Flörl C. Triazole antifungal agents in invasive fungal infections: A comparative review. Drugs 2011; 71(18): 2405-19.
[] [PMID: 22141384]
Campoy S, Adrio JL. Antifungals. Biochem Pharmacol 2017; 133: 86-96.
[] [PMID: 27884742]
Mellinghoff SC, Cornely OA, Jung N. Essentials in Candida bloodstream infection. Germany: Infection 2018; Vol. 46: pp. 897-9.
Warrilow AG, Nishimoto AT, Parker JE, et al. The evolution of azole resistance in candida albicans sterol 14-demethylase (CYP51) through incremental amino acid substitutions. Antimicrob Agents Chemother 2019; 63(5): 1-16.
[] [PMID: 30783005]
Allen D, Wilson D, Drew R, Perfect J. Azole antifungals: 35 years of invasive fungal infection management. Expert Rev Anti Infect Ther 2015; 13(6): 787-98.
[] [PMID: 25843556]
Grover ND. Echinocandins: A ray of hope in antifungal drug therapy. Indian J Pharmacol 2010; 42(1): 9-11.
[] [PMID: 20606829]
Denning DW. Echinocandin antifungal drugs. Lancet 2003; 362(9390): 1142-51.
[] [PMID: 14550704]
Bader JC, Bhavnani SM, Andes DR, Ambrose PG. We can do better: A fresh look at echinocandin dosing. J Antimicrob Chemother 2018; 73(suppl 1): i44-50.
Cappelletty D, Eiselstein-McKitrick K. The echinocandins. Pharmacotherapy 2007; 27(3): 369-88.
[] [PMID: 17316149]
Vazquez JA. Anidulafungin: A new echinocandin with a novel profile. Clin Ther 2005; 27(6): 657-73.
[] [PMID: 16117974]
Zhao Y, Perlin DS. Review of the novel echinocandin antifungal rezafungin: Animal studies and clinical data. J Fungi (Basel, Switzerland) 2020; 6(4)
Perlin DS. Resistance to echinocandin-class antifungal drugs. Drug Resist Updat 2007; 10(3): 121-30.
[] [PMID: 17569573]
Shor E, Perlin DS. Coping with stress and the emergence of multidrug resistance in fungi. PLoS Pathog 2015; 11(3): e1004668.
[] [PMID: 25790300]
Pfaller MA, Diekema DJ, Turnidge JD, Castanheira M, Jones RN. Twenty years of the sentry antifungal surveillance program: Results for Candida Species From 1997-2016. Open Forum Infect Dis 2019; 6(Suppl. 1): S79-94.
[] [PMID: 30895218]
McCarty TP, Pappas PG. Invasive Candidiasis. Infect Dis Clin North Am 2016; 30(1): 103-24.
[] [PMID: 26739610]
Revie NM, Iyer KR, Robbins N, Cowen LE. Antifungal drug resistance: evolution, mechanisms and impact. Curr Opin Microbiol 2018; 45: 70-6.
[] [PMID: 29547801]
Rodero L, Córdoba S, Cahn P, et al. In vitro susceptibility studies of Cryptococcus neoformans isolated from patients with no clinical response to amphotericin B therapy. J Antimicrob Chemother 2000; 45(2): 239-42.
[] [PMID: 10660509]
Carolus H, Pierson S, Lagrou K, Van Dijck P. Amphotericin B and Other polyenes-discovery, clinical use, mode of action and drug resistance. J fungi Basel, Switzerland 2020; 6(4)
Espinel-Ingroff A. Mechanisms of resistance to antifungal agents: Yeasts and filamentous fungi. Rev Iberoam Micol 2008; 25(2): 101-6.
[] [PMID: 18473504]
Vandeputte P, Tronchin G, Bergès T, Hennequin C, Chabasse D, Bouchara J-P. Reduced susceptibility to polyenes associated with a missense mutation in the ERG6 gene in a clinical isolate of Candida glabrata with pseudohyphal growth. Antimicrob Agents Chemother 2007; 51(3): 982-90.
[] [PMID: 17158937]
Pemán J, Cantón E, Espinel-Ingroff A. Antifungal drug resistance mechanisms. Expert Rev Anti Infect Ther 2009; 7(4): 453-60.
[] [PMID: 19400764]
Vandeputte P, Pineau L, Larcher G, et al. Molecular mechanisms of resistance to 5-fluorocytosine in laboratory mutants of Candida glabrata. Mycopathologia 2011; 171(1): 11-21.
[] [PMID: 20617462]
Chapeland-Leclerc F, Bouchoux J, Goumar A, Chastin C, Villard J, Noël T. Inactivation of the FCY2 gene encoding purine-cytosine permease promotes cross-resistance to flucytosine and fluconazole in Candida lusitaniae. Antimicrob Agents Chemother 2005; 49(8): 3101-8.
[] [PMID: 16048910]
Meis JF, Verweij PE. Current management of fungal infections. Drugs 2001; 61(Suppl. 1): 13-25.
[] [PMID: 11219547]
Hoffman HL, Ernst EJ, Klepser ME. Novel triazole antifungal agents. Expert Opin Investig Drugs 2000; 9(3): 593-605.
[] [PMID: 11060698]
Livermore DM. The need for new antibiotics. Clin Microbiol Infect 2004; 10(Suppl. 4): 1-9.
[] [PMID: 15522034]
Redding SW, Kirkpatrick WR, Saville S, et al. Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation. J Clin Microbiol 2003; 41(2): 619-22.
[] [PMID: 12574256]
Peyton LR, Gallagher S, Hashemzadeh M. Triazole antifungals: a review. Drugs Today (Barc) 2015; 51(12): 705-18.
[PMID: 26798851]
Cowen LE, Steinbach WJ. Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance. Eukaryot Cell 2008; 7(5): 747-64.
[] [PMID: 18375617]
Anderson JB. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat Rev Microbiol 2005; 3(7): 547-56.
[] [PMID: 15953931]
Cannon RD, Lamping E, Holmes AR, et al. Efflux-mediated antifungal drug resistance. Clin Microbiol Rev 2009; 22(2): 291-321.
[] [PMID: 19366916]
Coste A, Turner V, Ischer F, et al. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 2006; 172(4): 2139-56.
[] [PMID: 16452151]
Coste AT, Karababa M, Ischer F, Bille J, Sanglard D. TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2. Eukaryot Cell 2004; 3(6): 1639-52.
[] [PMID: 15590837]
Coste AT, Crittin J, Bauser C, Rohde B, Sanglard D. Functional analysis of cis- and trans-acting elements of the Candida albicans CDR2 promoter with a novel promoter reporter system. Eukaryot Cell 2009; 8(8): 1250-67.
[] [PMID: 19561319]
Yao D, Chen J, Chen W, Li Z, Hu X. Mechanisms of azole resistance in clinical isolates of Candida glabrata from two hospitals in China. Infect Drug Resist 2019; 12: 771-81.
[] [PMID: 31118695]
Torelli R, Posteraro B, Ferrari S, et al. The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol Microbiol 2008; 68(1): 186-201.
[] [PMID: 18312269]
Bennett JE, Izumikawa K, Marr KA. Mechanism of increased fluconazole resistance in Candida glabrata during Prophylaxis. Antimicrob agents chemother 2004; 48(5): 1773-7.
Cavalheiro M, Pais P, Galocha M, Teixeira MC. Host-Pathogen interactions mediated by mdr transporters in fungi: As pleiotropic as it Gets! Genes (Basel) 2018; 9(7): E332.
[] [PMID: 30004464]
Lamping E, Ranchod A, Nakamura K, et al. Abc1p is a multidrug efflux transporter that tips the balance in favor of innate azole resistance in Candida krusei. Antimicrob Agents Chemother 2009; 53(2): 354-69.
[] [PMID: 19015352]
Katiyar SK, Edlind TD. Identification and expression of multidrug resistance-related ABC transporter genes in Candida krusei. Med Mycol 2001; 39(1): 109-16.
[] [PMID: 11270397]
Vandeputte P, Ferrari S, Coste AT. Antifungal resistance and new strategies to control fungal infections. Int J Microbiol2012; 2012: 713687.
Jiang C, Dong D, Yu B, et al. Mechanisms of azole resistance in 52 clinical isolates of Candida tropicalis in China. J Antimicrob Chemother 2013; 68(4): 778-85.
[] [PMID: 23221625]
Chew KL, Cheng JWS, Jureen R, Lin RTP, Teo JWP. ERG11 mutations are associated with high-level azole resistance in clinical Candida tropicalis isolates, a Singapore study. Mycoscience 2017; 58(2): 111-5. pii/S1340354016300833 [Internet].
Spettel K, Barousch W, Makristathis A, et al. Analysis of antifungal resistance genes in Candida albicans and Candida glabrata using next generation sequencing. PLoS One 2019; 14(1): e0210397.
[] [PMID: 30629653]
Perlin DS. Mechanisms of echinocandin antifungal drug resistance. Ann N Y Acad Sci 2015; 1354(1): 1-11.
[] [PMID: 26190298]
Shields RK, Nguyen MH, Press EG, et al. The presence of an FKS mutation rather than MIC is an independent risk factor for failure of echinocandin therapy among patients with invasive candidiasis due to Candida glabrata. Antimicrob Agents Chemother 2012; 56(9): 4862-9.
[] [PMID: 22751546]
Lewis JS II, Wiederhold NP, Wickes BL, Patterson TF, Jorgensen JH. Rapid emergence of echinocandin resistance in Candida glabrata resulting in clinical and microbiologic failure. Antimicrob Agents Chemother 2013; 57(9): 4559-61.
[] [PMID: 23817368]
Kahn JN, Garcia-Effron G, Hsu M-J, Park S, Marr KA, Perlin DS. Acquired echinocandin resistance in a Candida krusei isolate due to modification of glucan synthase. Antimicrob Agents Chemother 2007; 51(5): 1876-8.
[] [PMID: 17325225]
Park S, Kelly R, Kahn JN, et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother 2005; 49(8): 3264-73.
[] [PMID: 16048935]
Balashov SV, Park S, Perlin DS. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother 2006; 50(6): 2058-63.
[] [PMID: 16723566]
Garcia-Effron G, Park S, Perlin DS. Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: Implications for interpretive breakpoints. Antimicrob Agents Chemother 2009; 53(1): 112-22.
[] [PMID: 18955538]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy