scholarly journals Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance

1998 ◽  
Vol 11 (2) ◽  
pp. 382-402 ◽  
Author(s):  
Theodore C. White ◽  
Kieren A. Marr ◽  
Raleigh A. Bowden
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Cellular Level ◽  
Antifungal Drug ◽  
Clinical Factors ◽  
Antifungal Drug Resistance ◽  
Aids Epidemic ◽  
Immunosuppressed Patients ◽  
Target Enzyme

SUMMARY In the past decade, the frequency of diagnosed fungal infections has risen sharply due to several factors, including the increase in the number of immunosuppressed patients resulting from the AIDS epidemic and treatments during and after organ and bone marrow transplants. Linked with the increase in fungal infections is a recent increase in the frequency with which these infections are recalcitrant to standard antifungal therapy. This review summarizes the factors that contribute to antifungal drug resistance on three levels: (i) clinical factors that result in the inability to successfully treat refractory disease; (ii) cellular factors associated with a resistant fungal strain; and (iii) molecular factors that are ultimately responsible for the resistance phenotype in the cell. Many of the clinical factors that contribute to resistance are associated with the immune status of the patient, with the pharmacology of the drugs, or with the degree or type of fungal infection present. At a cellular level, antifungal drug resistance can be the result of replacement of a susceptible strain with a more resistant strain or species or the alteration of an endogenous strain (by mutation or gene expression) to a resistant phenotype. The molecular mechanisms of resistance that have been identified to date in Candida albicans include overexpression of two types of efflux pumps, overexpression or mutation of the target enzyme, and alteration of other enzymes in the same biosynthetic pathway as the target enzyme. Since the study of antifungal drug resistance is relatively new, other factors that may also contribute to resistance are discussed.

Antimycotic drugs and their mechanisms of resistance to Candida species

2021 ◽  
Vol 22 ◽  
Author(s):  
Sweety Dahiya ◽  
Namita Sharma ◽  
Aruna Punia ◽  
Pooja Choudhary ◽  
Prity Gulia ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Species ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Treatment Strategies ◽  
Distinct Species ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Success Rates ◽  
Antifungal Drug Resistance

: Fungal infections have shown an upsurge in recent decades, mainly because of the increasing number of immunocompromised patients, and the occurrence of invasive candidiasis is found to be 7-15 folds greater than that of invasive aspergillosis. The genus Candida comprises of 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, including 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 antifungal drug resistance, the success rates of treatment have been reduced and 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.

scholarly journals Molecular Mechanisms of Antifungal Drug Resistance in Candida Species

2018 ◽  
Author(s):  
Lakshmi Krishnasamy ◽  
Sharanya Krishnakumar ◽  
Govindasamy Kumaramanickavel ◽  
Chitralekha Saikumar
Keyword(s):  
Drug Resistance ◽  
Candida Species ◽  
Molecular Mechanisms ◽  
Antifungal Drug ◽  
Antifungal Drug Resistance

scholarly journals Changing scenario of superficial fungal infection: Emerging resistance, recurrence and remedy in Bangladesh

2020 ◽  
Vol 8 (2) ◽  
pp. 108-111
Author(s):  
Mohammad Kamrul Ahsan ◽  
Mir Nazrul Islam
Keyword(s):  
Drug Resistance ◽  
Fungal Infection ◽  
Antifungal Therapy ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Genetic Alterations ◽  
Antifungal Drug ◽  
Fungal Resistance ◽  
Related Factors ◽  
Clinical Resistance

Superficial fungal infections (dermatophytes) affecting skin, nail and hair are the most common infective dermatosis seen in dermatology outpatient clinics. There is a rising prevalence of dermatophytosis, especially in tropical countries like Bangladesh, with a concomitant increase in the number of difficult to treat cases. The reason for this phenomenon is not yet clear, but may be related to inadequate treatment regimen or discontinuation of medication, difficulties in eliminating predisposing factors and sources of re-infection. The pathogenesis and severity of fungal infection depend on various immunological and nonimmunological factors. The rampant use of antifungal therapy in immunocompromised individuals marked the onset of antifungal drug resistance. Fungal resistance can be microbiological or clinical. Genetic alterations in the fungi cause microbiological resistance. Clinical resistance is due to host or drug related factors. All these factors may cause fungal resistance individually or in tandem. Appropriate drug dosing along with antifungal drug susceptibility testing, especially for the dermatophytes isolated from chronic, recurrent cases or those with atypical presentation should be encouraged. Other ways to avoid resistance is the use of combination antifungal therapy. Combination therapy offers advantages in increased synergistic action with enhanced spectrum activity. Finally, newer insights into molecular mechanisms of drug resistance will help in the development of appropriate antifungal therapy. Till then experience based treatment of dermatophytosis is more effective than the standard guideline. Bangladesh Crit Care J September 2020; 8(2): 108-111

scholarly journals Fungal biofilm architecture produces hypoxic microenvironments that drive antifungal resistance

2020 ◽  
Vol 117 (36) ◽  
pp. 22473-22483 ◽  
Author(s):  
Caitlin H. Kowalski ◽  
Kaesi A. Morelli ◽  
Daniel Schultz ◽  
Carey D. Nadell ◽  
Robert A. Cramer
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Drug Resistant ◽  
Antifungal Drug Resistance ◽  
Oxygen Gradients ◽  
Biofilm Architecture

Human fungal infections may fail to respond to contemporary antifungal therapies in vivo despite in vitro fungal isolate drug susceptibility. Such a discrepancy between in vitro antimicrobial susceptibility and in vivo treatment outcomes is partially explained by microbes adopting a drug-resistant biofilm mode of growth during infection. The filamentous fungal pathogenAspergillus fumigatusforms biofilms in vivo, and during biofilm growth it has reduced susceptibility to all three classes of contemporary antifungal drugs. Specific features of filamentous fungal biofilms that drive antifungal drug resistance remain largely unknown. In this study, we applied a fluorescence microscopy approach coupled with transcriptional bioreporters to define spatial and temporal oxygen gradients and single-cell metabolic activity withinA. fumigatusbiofilms. Oxygen gradients inevitably arise duringA. fumigatusbiofilm maturation and are both critical for, and the result of,A. fumigatuslate-stage biofilm architecture. We observe that these self-induced hypoxic microenvironments not only contribute to filamentous fungal biofilm maturation but also drive resistance to antifungal treatment. Decreasing oxygen levels toward the base ofA. fumigatusbiofilms increases antifungal drug resistance. Our results define a previously unknown mechanistic link between filamentous fungal biofilm physiology and contemporary antifungal drug resistance. Moreover, we demonstrate that drug resistance mediated by dynamic oxygen gradients, found in many bacterial biofilms, also extends to the fungal kingdom. The conservation of hypoxic drug-resistant niches in bacterial and fungal biofilms is thus a promising target for improving antimicrobial therapy efficacy.

scholarly journals Efflux-Mediated Antifungal Drug Resistance

2009 ◽  
Vol 22 (2) ◽  
pp. 291-321 ◽  
Author(s):  
Richard D. Cannon ◽  
Erwin Lamping ◽  
Ann R. Holmes ◽  
Kyoko Niimi ◽  
Philippe V. Baret ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Efflux Pump ◽  
Fungal Infections ◽  
Efflux Pumps ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Model Systems ◽  
Attributable Mortality ◽  
Azole Resistance ◽  
Antifungal Drug Resistance

SUMMARY Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps.

scholarly journals Molecular Mechanisms of Resistance to Antifungals in Candida albicans

2021 ◽  
Author(s):  
Estela Ruiz-Baca ◽  
Rosa Isela Arredondo-Sánchez ◽  
Karina Corral-Pérez ◽  
Angélica López-Rodríguez ◽  
Iván Meneses-Morales ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Antifungal Agents ◽  
Point Mutations ◽  
Antifungal Resistance ◽  
Antifungal Drug ◽  
Antifungal Drug Resistance ◽  
Etiological Agents ◽  
Nosocomial Disease

Invasive Candidiasis (IC) presents a global mortality rate greater than 40%, occupying the fourth place worldwide as the most frequent opportunistic nosocomial disease. Although the genus Candida consists of around 200 species, only 20 are reported as etiological agents of IC, being Candida albicans the most frequent causal agent. Even when there is a broad range of antifungals drugs for Candida infections, azoles, polyenes, and echinocandins are considered among the most effective treatment. However, there is some incidence for antifungal resistance among some Candida strains, limiting treatment options. Several molecular mechanisms with antifungal agents have been reported for C. albicans where insertions, deletions, and point mutations in genes codifying target proteins are frequently related to the antifungal drug resistance. Furthermore, gene overexpression is also frequently associated to antifungal resistance as well as an increase in the activity of proteins that reduce oxidative damage. This chapter summarizes the main molecular mechanisms to C. albicans antifungal drug resistance, besides offering an overview of new antifungal agents and new antifungal targets to combat fungal infections.

scholarly journals Insights into the global emergence of antifungal drug resistance

2019 ◽  
Vol 40 (2) ◽  
pp. 87
Author(s):  
Kylie Boyce ◽  
Orla Morrissey ◽  
Alexander Idnurm ◽  
Ian Macreadie
Keyword(s):  
Drug Resistance ◽  
Intensive Care ◽  
Fungal Infections ◽  
Invasive Fungal Disease ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Global Burden ◽  
Median Cost ◽  
Antifungal Drug Resistance ◽  
Drug Classes

The global prevalence of fungal diseases has escalated in the last several decades. Currently, it is estimated that fungi infect 1.7 billion people annually and result in 1.5 million deaths every year1. Deaths due to fungal infections are increasing, with mortality often exceeding 50%, further increasing to 100% if treatment is delayed1. Despite these staggering figures, the contribution of fungal infections to the global burden of disease remains under-recognised. In Australia, over a 5-year period fungal infections cost Australia an estimated $583 million2. The median cost for one invasive fungal disease (IFD) is AU$30957, increasing to AU$80291 if the patient is admitted to an intensive care unit3. Treatment of fungal infections poses significant challenges due to the small number of safe and effective antifungal drugs available and emerging antifungal drug resistance. Resistance to every class of antifungal drugs has been described and for some drug classes is extremely common4,5.

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