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Cited by 230Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens

Open access
Ksiezopolska, Ewa, Gabaldón, Toni·2018·Genes
DOI 10.3390/genes9090461PMC PMC6162425
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Abstract

Fungal infections, such as candidiasis caused by Candida, pose a problem of growing medical concern. In developed countries, the incidence of Candida infections is increasing due to the higher survival of susceptible populations, such as immunocompromised patients or the elderly. Existing treatment options are limited to few antifungal drug families with efficacies that vary depending on the infecting species. In this context, the emergence and spread of resistant Candida isolates are being increasingly reported. Understanding how resistance can evolve within naturally susceptible species is key to developing novel, more effective treatment strategies. However, in contrast to the situation of antibiotic resistance in bacteria, few studies have focused on the evolutionary mechanisms leading to drug resistance in fungal species. In this review, we will survey and discuss current knowledge on the genetic bases of resistance to antifungal drugs in Candida opportunistic pathogens. We will do so from an evolutionary genomics perspective, focusing on the possible evolutionary paths that may lead to the emergence and selection of the resistant phenotype. Finally, we will discuss the potential of future studies enabled by current developments in sequencing technologies, in vitro evolution approaches, and the analysis of serial clinical isolates.

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Written from the paper’s full text.

TL;DR

This review surveys the genetic and evolutionary mechanisms by which Candida opportunistic pathogens acquire resistance to antifungal drugs, emphasizing genomics, serial clinical isolates, and in vitro evolution. It argues that resistance emerges through diverse, often species-specific mutational and genomic trajectories, with many mechanisms still unknown.

Key findings

  • Antifungal resistance is rising: 20–30% of candidemia cases involve species intrinsically resistant to fluconazole or echinocandins, and multidrug-resistant *C. auris* can show up to 96% fluconazole resistance versus 0.5–2% for *C. albicans*, 4–9% for *C. tropicalis*, 2–6% for *C. parapsilosis*, and 11–13% for *C. glabrata*.
  • Acquired azole resistance commonly involves *ERG11* point mutations (21 of 140 described mutations directly associated with fluconazole resistance), *ERG3* inactivation, regulator mutations (*UPC2*, *MRR1*, *TAC1*), efflux pump overexpression (*MDR1*, *CDR1/CDR2*), and genomic changes such as aneuploidy or loss of heterozygosity.
  • Echinocandin resistance is linked to hotspot mutations in *FKS1* and, in *C. glabrata*, *FKS2*; polyene resistance to ergosterol-pathway mutations (*ERG2*, *ERG3*, *ERG5*, *ERG6*, *ERG11*); and flucytosine resistance to changes in *FCY1*, *FCY2*, *FUR1*, *FPS1*, and *FPS2*.
  • Evolutionary paths include stepwise aneuploidies, copy-number variation, loss of heterozygosity, possible hypermutator phenotypes, heteroresistance, tolerance, and persistence; whole-genome sequencing of serial isolates and in vitro evolution show multiple competing trajectories rather than a single resistance route.

Methods

  • Narrative review synthesizing published literature on antifungal resistance in Candida, with no primary experimental data reported.
  • Draws on epidemiological surveillance studies, clinical isolate sequencing studies, and in vitro experimental evolution studies to discuss resistance mechanisms and evolutionary trajectories.
  • Organizes evidence by antifungal drug class and by evolutionary genomics approaches; no systematic search strategy or meta-analysis is described.

Limitations

  • Stated: few studies have focused on evolutionary mechanisms of drug resistance in fungi compared with bacteria; mutation rates and frequencies in pathogenic Candida are largely unknown; unknown resistance mechanisms remain; the impact of aneuploidy outside *C. albicans* is unclear; heteroresistance is poorly understood; and in vitro evolution studies are scarce and limited to few species and drugs.
  • Evident: as a narrative review, it provides no new primary data, no systematic search criteria, and no quantitative synthesis, so conclusions depend on the selected cited literature.

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Integrity signals

Registry

Crossref · 10.3390/genes9090461

Cites

Statistics

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Claims the paper makes

0 of 196 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Currently, there are only four major classes of antifungals in clinical use: azoles, polyenes, echinocandins, and pyrimidine analogs.

    “Currently, there are only four major classes of antifungals in clinical use: azoles, polyenes, echinocandins, and pyrimidine analogs [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Odds, 2003, Antifungal agents: Mechanisms of action, Trends Microbiol. source

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  • Interpretationreasoning

    The fungistatic character of fluconazole and its extended use is inevitably leading to increasing selection in favor of resistant yeast isolates.

    “Unfortunately, the fungistatic character of fluconazole and its extended, perhaps excessive, use is inevitably leading to an increasing selection in favor of resistant yeast isolates.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The emergence of resistant Candida strains, including those resistant to multiple drugs, has been increasingly reported in recent years.

    “The emergence of resistant strains, including those becoming resistant to multiple drugs, has been increasingly reported in recent years [14,15,16].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Pfaller, M.A., Andes, D.R., Diekema, D.J., Horn, D.L., Reboli, A.C., Rotstein, C., Franks, B., and Azie, N.E. (2014). Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2496 patients: Data from the Prospective Antifungal Therapy (PATH) registry 2004–2008. PLoS ONE, 9. source

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    • cites [15] Pfaller, 2013, Echinocandin and triazole antifungal susceptibility profiles for clinical opportunistic yeast and mold isolates collected from 2010 to 2011: Application of new CLSI clinical breakpoints and epidemiological cutoff values for characterization of geographic, J. Clin. Microbiol. source

      Not checked in the free run.

    • cites [16] Lockhart, 2017, Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses, Clin. Infect. Dis. source

      Not checked in the free run.

  • Premisenone given

    5-fluorodeoxyuridine interferes with DNA, RNA, and protein synthesis.

    “Subsequently, 5-fluorodeoxyuridine interferes with DNA, RNA, and protein synthesis.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Resistant phenotypes can develop over the course of an infection and in response to treatment.

    “In addition, it has been demonstrated that such resistant phenotypes can develop over the course of an infection, and in response to treatment, which adds yet another threat to patients [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Pfaller, 2012, Antifungal drug resistance: Mechanisms, epidemiology, and consequences for treatment, Am. J. Med. source

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  • Classified as probably not a substantial claim. 41
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    Premisecitation

    The overall death toll from fungal infections has been estimated to be around 1,350,000 deaths per year.

    “Globally, fungi can affect millions of people every year, and the overall death toll has been estimated to be around 1,350,000 deaths per year [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Brown, 2012, Hidden killers: Human fungal infections, Sci. Transl. Med. source

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    Premisecitation

    Around 300 of an estimated 1.5 million fungal species have been reported to present virulence towards humans.

    “From the estimated 1.5 million fungal species, around 300 have been reported to present virulence towards humans, even if sporadically [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] (2017). Stop neglecting fungi. Nat. Microbiol., 2, 17120.

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The four most common Candida species can account for more than 80% of candidemia cases, and over 30 Candida species have been identified as candidemia agents.

    “although the four most common Candida (C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis) can account for more than 80% of the cases, there is a long list with over 30 Candida that have been identified as candidemia agents [9]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] 2016, Evolutionary genomics of yeast pathogens in the Saccharomycotina, FEMS Yeast Res. source

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    Premisecitation

    Flucytosine is the only pyrimidine analog with antimycotic properties currently in use for human treatment, and it can convert into 5-fluorouracyl and further into 5-fluorodeoxyuridine inside the fungal cell.

    “The only pyrimidine analog with antimycotic properties currently in use for human treatment is flucytosine, which has the potential to convert into 5-fluorouracyl and further to 5-fluorodeoxyuridine inside the fungal cell [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Chandra, 2009, Flucytosine: Site of Action, Mechanism of Resistance and Use in Combination Therapy, Antimicrobial Drug Resistance source

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    Premisecitation

    Candida is responsible for the most common invasive fungal disease in developed countries, candidiasis.

    “Species belonging to the genera Candida, Aspergillus, and Cryptococcus are the most prevalent cause of invasive infections, with Candida being responsible for the most common invasive fungal disease in developed countries—candidiasis [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Bassetti, 2016, The current treatment landscape: Candidiasis, J. Antimicrob. Chemother. source

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    Premisecitation

    Polyenes bind to and remove ergosterol from the fungal cell membrane, causing loss of membrane permeability, membrane leakage, and cell death.

    “Their antimycotic action is mediated by direct binding to and removal of ergosterol present in the fungal cell membrane. This results in the loss of membrane permeability, subsequent membrane leakage, and eventually cell death [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Kathiravan, 2012, The biology and chemistry of antifungal agents: A review, Bioorg. Med. Chem. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Azoles target the cytochrome P450 enzyme lanosterol 14α-demethylase, which converts lanosterol to ergosterol and is encoded by ERG11 in yeast.

    “These drugs act by targeting the cytochrome P450 enzyme-lanosterol 14α-demethylase, that converts lanosterol to ergosterol. In yeast, this enzyme is encoded by the ERG11 gene.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Ergosterol is the main membrane sterol in most fungal species and has an important role in controlling membrane fluidity.

    “Similar to cholesterol in animals, ergosterol is the main membrane sterol in most fungal species, holding an important role in controlling membrane fluidity [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Weete, J.D., Abril, M., and Blackwell, M. (2010). Phylogenetic distribution of fungal sterols. PLoS ONE, 5. source

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    Premisereasoning

    Amphotericin B continues to be broadly used despite its high toxicity, which results from structural similarities between ergosterol and human cholesterol.

    “Nowadays, amphotericin B continues to be broadly used despite its high toxicity, which results from structural similarities between ergosterol and human cholesterol.”
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    Premisenone given

    Existing antimycotic drugs target processes that are highly divergent between fungi and the human host, such as the ergosterol synthesis pathway.

    “Existing antimycotic drugs target processes that are highly divergent between fungi and the human host, such as the ergosterol synthesis pathway.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The evolutionary relatedness of fungi and humans makes finding specific antifungal targets difficult and increases the likelihood of undesired secondary effects.

    “This evolutionary relatedness makes the finding of specific targets difficult and increases the likelihood of undesired secondary effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Candidemia affects more than 250,000 persons worldwide every year and leads to more than 50,000 deaths.

    “candidemia (Candida bloodstream infection) affects more than 250,000 persons worldwide every year, leading to more than 50,000 deaths [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Kullberg, 2015, Invasive Candidiasis, N. Engl. J. Med. source

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    Premisecitation

    In the 1950s, the polyene amphotericin B deoxycholate was the first approved successful antifungal drug.

    “In the 1950s, the polyene amphotericin B deoxycholate was the first approved successful antifungal drug [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Perfect, 2017, The antifungal pipeline: A reality check, Nat. Rev. Drug Discov. source

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    Premisecitation

    High concentrations of amphotericin B may be harmful and cause damage to human tissues, such as the kidneys.

    “Due to this toxicity, the use of amphotericin B in high concentrations may be harmful and cause damage to human tissues, such as the kidneys [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Groll, 1998, Clinical pharmacology of systemic antifungal agents: A comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development, Adv. Pharmacol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Candidemia brings a substantial economic burden, involving on average three to 13 days of hospitalization in the US, with total associated costs ranging from $6000 to $29,000.

    “In addition, candidemia brings a substantial economic burden, involving, on average, three to 13 days of hospitalization in the US, with total associated costs ranging from $6000 to $29,000 [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Morgan, 2005, Excess mortality, hospital stay, and cost due to candidemia: A case-control study using data from population-based candidemia surveillance, Infect. Control Hosp. Epidemiol. source

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    Premisecitation

    Echinocandins are currently the preferred agents for most episodes of candidemia and invasive candidiasis, except those affecting the central nervous system, the eye, and the urinary tract.

    “Due to their safety profile, better outcomes, and the emergence of azole-resistant species, echinocandins are currently the preferred agents for most episodes of candidemia and invasive candidiasis, with the exception of those affecting the central nervous system, the eye, and the urinary tract [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Pappas, 2015, Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America, Clin. Infect. Dis. source

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    Premisecitation

    The incidence rate of candidiasis has been estimated at two to 14 cases per 100,000 inhabitants.

    “Population-based studies have estimated the incidence rate of candidiasis to be two to 14 cases per 100,000 inhabitants”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Kullberg, 2015, Invasive Candidiasis, N. Engl. J. Med. source

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    Premisecitation

    Standard diagnostic approaches require blood cultures, which are slow and can have low sensitivity, with some studies reporting sensitivities as low as 17% or 45%.

    “standard diagnostic approaches require blood cultures, which are slow and can have a low sensitivity. For instance, some studies reported sensitivities as low as 17% [7] or 45% [8].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Nguyen, 2012, Performance of Candida real-time polymerase chain reaction, β-d-glucan assay, and blood cultures in the diagnosis of invasive candidiasis, Clin. Infect. Dis. source

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    • cites [8] Meije, 2014, Clinical validation of a multiplex real-time PCR assay for detection of invasive candidiasis in intensive care unit patients, J. Antimicrob. Chemother. source

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The intensive use of azoles has promoted a shift in the epidemiology of candidiasis in which the incidence of C. albicans has decreased in favor of species naturally less susceptible to azoles, such as C. glabrata.

    “Over the last years, the intensive use of some antifungal drugs, such as azoles, has promoted a shift in the epidemiology of candidiasis, in which the incidence of C. albicans has decreased in favor of other species that are naturally less susceptible to this drug, such as C. glabrata.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Azoles deplete the Candida cell membrane of ergosterol and cause accumulation of toxic 14α-methylated sterols, decreasing membrane fluidity and in most cases inhibiting cell growth.

    “As a result of the action of azoles, the Candida cell membrane is depleted of ergosterol and accumulates other toxic 14α-methylated sterols. Subsequently, this causes the decrease in membrane fluidity and, in most of the cases, inhibits cell growth [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Sheehan, 1999, Current and emerging azole antifungal agents, Clin. Microbiol. Rev. source

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  • Classified as probably not a substantial claim.

    Premisenone given

    Recent developments in sequencing technologies are enabling the cataloging and tracing of the origins of mutations conferring resistance to antifungal drugs in different species.

    “Fortunately, recent developments in sequencing technologies are enabling us to catalog and trace the origins of mutations conferring resistance to antifungal drugs in different species.”
    Quote in the paperSubstantial claim

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    Premisereasoning

    The development of new antifungal drugs is challenging because fungi are eukaryotic organisms that share many basic cellular processes with humans.

    “The development of new antifungal drugs is challenging, as fungi are eukaryotic organisms that share many basic cellular processes with us.”
    Quote in the paperNot a substantial claim

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    Premisereasoning

    Mutations can affect drug resistance by directly interfering with drug binding to its target or by inducing gene expression changes that reduce drug susceptibility.

    “These mutations can affect drug resistance in different ways, ranging from directly interfering with the binding of the drug to its target to inducing gene expression changes that promote physiological states that reduce drug susceptibility.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    A large study of more than 1800 clinical fungal isolates from 31 countries found that 82% of fungal infections in 2013 were caused by Candida.

    “A large study of more than 1800 clinical fungal isolates from 31 countries found that 82% of the fungal infections in 2013 were caused by Candida [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Castanheira, 2016, Antifungal susceptibility patterns of a global collection of fungal isolates: Results of the SENTRY Antifungal Surveillance Program (2013), Diagn. Microbiol. Infect. Dis. source

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  • May combine two claims.

    Premisecitation

    Echinocandins inhibit the biosynthesis of 1,3-ß-glucan by targeting two subunits of the 1,3-ß-glucan synthase encoded by FKS1 and FKS2 in Candida, eventually causing cell lysis.

    “Echinocandins inhibit the biosynthesis of an essential component of the fungal cell wall, the 1,3-ß-glucan. In Candida, they target two subunits of the 1,3-ß-glucan synthase, encoded by the FKS1 and FKS2 genes [22], and eventually cause cell lysis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Sucher, 2009, Echinocandins: The newest class of antifungals, Ann. Pharmacother. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Fluconazole is the azole drug most widely used for the treatment of Candida infections, and its utility is attributed to high bioavailability, high water solubility, and low affinity to plasma proteins.

    “Fluconazole is the azole drug most widely used for the treatment of Candida infections. Its utility is attributed to its high bioavailability, high water solubility, and low affinity to plasma proteins [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Andriole, 2000, Current and future antifungal therapy: New targets for antifungal therapy, Int. J. Antimicrob. Agents source

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    Premisecitation

    Other studies on C. glabrata report that 14% of fluconazole-resistant strains exhibit resistance to at least one echinocandin, with 3.5% MDR at Duke University hospital, 7% MDR at MD Anderson Cancer Center, and azole resistance in 36% of echinocandin-resistant strains in a five-year USA surveillance study.

    “Other studies on C. glabrata report that 14% of fluconazole-resistant strains exhibit resistance to at least one echinocandin and a total of 3.5% of MDR cases were noted in Duke University hospital [48], 7% of MDR at MD Anderson Cancer Center [45], and a resistance to azoles in 36% echinocandin-resistant strains was indicated in a five-year surveillance study in the USA [49].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] Alexander, 2013, Increasing echinocandin resistance in Candida glabrata: Clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations, Clin. Infect. Dis. source

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    • cites [45] Farmakiotis, 2014, Drug-Resistant Candida glabrata infection in cancer patients, Emerg. Infect. Dis. source

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    • cites [49] Pham, 2014, Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance, Antimicrob. Agents Chemother. source

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    Premisecitation

    C. auris is an intrinsic multidrug-resistant Candida that was recently reported as an emerging cause of healthcare-associated infections worldwide in at least a dozen countries on four continents during 2009-2015.

    “Importantly, an intrinsic multidrug resistant Candida auris has been recently reported as an emerging cause of healthcare-associated infections worldwide in at least a dozen countries on four continents during 2009–2015 [38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Vallabhaneni, 2017, Investigation of the first Seven reported cases of Candida auris, a globally emerging invasive, multidrug-resistant fungus-United States, May 2013–August 2016, Am. J. Transplant. source

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  • May combine two claims.

    Premisenone given

    The transformation of flucytosine into 5-fluorouracyl is catalyzed by the fungal enzyme cytosine deaminase, encoded by FCY1, which is not present in humans.

    “The transformation of flucytosine into 5-fluorouracyl is catalyzed by the action of the fungal enzyme cytosine deaminase (encoded by the yeast gene FCY1), which is not present in humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Various Candida species present distinct susceptibility profiles towards antifungal drugs and different trajectories to acquire resistance when exposed to antifungals.

    “Accordingly, various Candida present distinct susceptibility profiles towards antifungal drugs and different trajectories to acquire resistance when exposed to antifungals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Different Candida species may use different mechanisms for evasion of the host immune system and exhibit different virulence-related phenotypes.

    “As a consequence, different Candida may use different mechanisms for evasion of the host immune system and exhibit different virulence-related phenotypes [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Silva, 2012, Candida glabrata, Candida parapsilosis and Candida tropicalis: Biology, epidemiology, pathogenicity and antifungal resistance, FEMS Microbiol. Rev. source

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  • May combine two claims.

    Premisecitation

    Up to 96% of C. auris may exhibit resistance to fluconazole, compared with 0.5-2% for C. albicans, 4-9% for C. tropicalis, 2-6% for C. parapsilosis, and 11-13% for C. glabrata.

    “Indeed, up to 96% of C. auris may exhibit resistance to fluconazole, an exceptionally high value compared to 0.5–2% for C. albicans, 4–9% for C. tropicalis, 2–6% for C. parapsilosis, and 11–13% for C. glabrata [16,40,41].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Lockhart, 2017, Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses, Clin. Infect. Dis. source

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    • cites [40] Cleveland, 2012, Changes in incidence and antifungal drug resistance in candidemia: Results from population-based laboratory surveillance in Atlanta and Baltimore, 2008–2011, Clin. Infect. Dis. source

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    • cites [41] Pfaller, 2015, Isavuconazole, micafungin, and 8 comparator antifungal agents’ susceptibility profiles for common and uncommon opportunistic fungi collected in 2013: Temporal analysis of antifungal drug resistance using CLSI species-specific clinical breakpoints and prop, Diagn. Microbiol. Infect. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Epidemiology is shifting towards non-albicans Candida, with specific relative incidences being time- and space-dependent.

    “Although infections with C. albicans are still the most common, epidemiology is shifting towards non-albicans Candida, wherein the specific relative incidences are being time- and space-dependent [30]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] 2014, Epidemiology of candidaemia and invasive candidiasis. A changing face, Rev. Iberoam. Micol. source

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  • May combine two claims.

    Premisecitation

    C. glabrata and C. krusei have a naturally low susceptibility to azoles, while C. parapsilosis strains tend to have a lower susceptibility to echinocandins.

    “For instance, C. glabrata and C. krusei have a naturally low susceptibility to azoles, while C. parapsilosis strains tend to have a lower susceptibility to echinocandins [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Sanguinetti, 2015, Antifungal drug resistance among Candida species: Mechanisms and clinical impact, Mycoses source

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  • May combine two claims.

    Premisecitation

    For naturally susceptible species, both the relative amount of resistant strains and the overall MIC levels in clinical isolates often increase after continuous use of a given antifungal drug.

    “Often, for naturally susceptible species, both the relative amount of resistant strains and the overall MIC levels in clinical isolates increase after the continuous use of a given antifungal drug [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Lortholary, 2011, Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: A prospective multicenter study involving 2441 patients, Antimicrob. Agents Chemother. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis, generally in this order, account for up to 80% of candidiasis cases.

    “Out of the 30 different species of Candida able to infect humans, C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis, generally in this order, account for up to 80% of candidiasis cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The acquisition of resistance towards one drug in species that are intrinsically resistant to another is not uncommon and leads to multidrug resistance.

    “Furthermore, the acquisition of resistance towards one drug in species that are intrinsically resistant to another one is not uncommon and leads to dangerous multidrug resistance (MDR).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Infections caused by C. auris can have high mortality rates ranging from 30-60%.

    “Infections caused by this species can have high mortality rates ranging from 30–60% [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Chowdhary, 2016, Multidrug-resistant Candida auris: ‘New kid on the block’ in hospital-associated infections?, J. Hosp. Infect. source

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    Premisecitation

    The increased use of antifungals during the last 15 years correlates with an alarming development of multidrug resistance, especially in C. glabrata.

    “The increased use of antifungals during the last 15 years correlates with an alarming development of MDR, especially in C. glabrata [45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Farmakiotis, 2014, Drug-Resistant Candida glabrata infection in cancer patients, Emerg. Infect. Dis. source

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    Premisecitation

    ERG3 mutations result in reduction of ergosterol and accumulation of other sterols, often leading to cross-resistance to polyenes.

    “Furthermore, ERG3 mutations result in the reduction of ergosterol and accumulation of other sterols, often leading to cross-resistance to polyenes [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Cowen, 2014, Mechanisms of Antifungal Drug Resistance, Cold Spring Harb. Perspect. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Factors that promote the acquisition of resistance and treatment failure include the use of sub-therapeutic concentrations, drug sequestration in the biofilm matrix, and poor control of infections.

    “Besides the overall use and exposure to antifungals (often used in prophylactic measures), other factors that promote the acquisition of resistance and a treatment failure include the use of sub-therapeutic concentrations, drug sequestration in the biofilm matrix, and poor control of infections [67,68].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] White, 1998, Clinical, cellular, and molecular factors that contribute to antifungal drug resistance, Clin. Microbiol. Rev. source

      Not checked in the free run.

    • cites [68] Morio, 2017, Molecular basis of antifungal drug resistance in yeasts, Int. J. Antimicrob. Agents source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multidrug resistance is not restricted to C. glabrata or C. auris; other examples include C. kefyr, C. lusitaniae, and C. albicans.

    “However, MDR is not restricted to C. glabrata or C. auris. Other examples include C. kefyr [57], C. lusitaniae [58], and C. albicans [59,60,61].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [57] Fekkar, 2013, Rapid emergence of echinocandin resistance during Candida kefyr fungemia treatment with caspofungin, Antimicrob. Agents Chemother. source

      Not checked in the free run.

    • cites [58] Asner, 2015, Acquired multidrug antifungal resistance in Candida lusitaniae during therapy, Antimicrob. Agents Chemother. source

      Not checked in the free run.

    • cites [59] Morio, 2012, Amino acid substitutions in the Candida albicans sterol δ5,6-desaturase (Erg3p) confer azole resistance: Characterization of two novel mutants with impaired virulence, J. Antimicrob. Chemother. source

      Not checked in the free run.

    • cites [60] Martel, 2010, A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14α-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B, Antimicrob. Agents Chemother. source

      Not checked in the free run.

    • cites [61] Jensen, 2015, Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations, J. Antimicrob. Chemother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acquired resistance to azoles appears to be a result of mutations selected by the pressure exerted by the drug, and the adaptation is said to appear gradually during continuous contact with the antifungal.

    “Acquired resistance to this group of antimycotics seems to be a result of mutations selected by the pressure exerted by the drug [13]. The adaptation is said to appear gradually during continuous contact with the antifungal [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Rodrigues, C., Rodrigues, M., Silva, S., and Henriques, M. (2017). Candida glabrata biofilms: How far have we come?. J. Fungi, 3. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resistance to azoles in C. parapsilosis has been attributed to mutations in MRR1 and ERG11 (Y132F alone or with R398I), and overexpression of CDR1, MDR1, and ERG11.

    “Resistance to azoles in C. parapsilosis has been attributed to mutations in the transcription factor gene MRR1 [84] and ERG11 (Y132F, either alone or in combination with an R398I) [85,86,87], and overexpression of CDR1, MDR1, and ERG11 [85,86,88].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [84] Zhang, L., Xiao, M., Watts, M.R., Wang, H., Fan, X., Kong, F., and Xu, Y.C. (2015). Development of fluconazole resistance in a series of Candida parapsilosis isolates from a persistent candidemia patient with prolonged antifungal therapy. BMC Infect. Dis., 15. source

      Not checked in the free run.

    • cites [85] Souza, 2015, Candida parapsilosis resistance to fluconazole: Molecular mechanisms and in vivo impact in infected Galleria mellonella larvae, Antimicrob. Agents Chemother. source

      Not checked in the free run.

    • cites [86] Berkow, 2015, Multidrug transporters and alterations in sterol biosynthesis contribute to azole antifungal resistance in Candida parapsilosis, Antimicrob. Agents Chemother. source

      Not checked in the free run.

    • cites [87] Grossman, 2015, Molecular mechanisms of fluconazole resistance in Candida parapsilosis isolates from a U.S. surveillance system, Antimicrob. Agents Chemother. source

      Not checked in the free run.

    • cites [88] Silva, 2011, Transcriptional profiling of azole-resistant Candida parapsilosis strains, Antimicrob. Agents Chemother. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Multidrug resistance in species with no intrinsic tolerance to drugs is rare, probably because it requires multiple steps, each associated with a fitness cost.

    “MDR in species with no intrinsic tolerance to drugs is rare, probably because it requires multiple steps, each associated with a fitness cost.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Azoles and echinocandins are the two most used antifungal drugs in hospitals, and the emergence of combined resistance to both severely hampers the ability to treat fungal infections.

    “Azoles and echinocandins are the two most used antifungal drugs in hospitals, and the emergence of combined resistance to both of them severely hampers our ability to treat fungal infections.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The fraction of C. glabrata infecting strains resistant to caspofungin in the United States is 10%, while in Europe it is much lower, with 0% reported in Italy and Spain, 2.1% in Lombardy, Italy, and 2% in Turkey.

    “Other studies have shown that while the fraction of C. glabrata infecting strains resistant to caspofungin in the United States is significant (10%) [45], in Europe, it is much lower, with 0% reported in studies performed in Italy and Spain [54]; 2.1% in Lombardy, Italy [55]; and 2% in Turkey [56].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Farmakiotis, 2014, Drug-Resistant Candida glabrata infection in cancer patients, Emerg. Infect. Dis. source

      Not checked in the free run.

    • cites [54] Bassetti, 2013, Epidemiology, species distribution, antifungal susceptibility, and outcome of Candidemia across five sites in Italy and Spain, J. Clin. Microbiol. source

      Not checked in the free run.

    • cites [55] Tortorano, 2013, A 1-year prospective survey of candidemia in Italy and changing epidemiology over one decade, Infection source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C. glabrata, echinocandin resistance has increased from 2-3% to more than 13% in a 10-year period and can be present in up to one-third of isolates in the US.

    “In C. glabrata, this phenomenon has increased from 2–3% to more than 13% in a 10-year period [48] and can be present in up to one-third of isolates in the US [49].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Alexander, 2013, Increasing echinocandin resistance in Candida glabrata: Clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations, Clin. Infect. Dis. source

      Not checked in the free run.

    • cites [49] Pham, 2014, Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance, Antimicrob. Agents Chemother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Candida can evade the activity of echinocandins by mutations in hotspot regions in the FKS1 gene and, in C. glabrata, also in FKS2.

    “Candida can evade the activity of echinocandins by mutations in particular regions (called hotspots) in the FKS1 gene and in the case of C. glabrata, as well in FKS2 (Table 4) [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Arendrup, 2014, Echinocandin resistance: An emerging clinical problem?, Curr. Opin. Infect. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alternative mechanisms for azole resistance in C. glabrata involve petite mutants lacking mitochondrial DNA and mitochondrial dysfunction, which show upregulation of ABC transporter genes, improved fitness, and increased resistance towards azoles.

    “Alternative mechanisms for azole resistance in C. glabratas involve ‘petite mutants’, which are characterized by a lack of mitochondrial DNA and mitochondrial dysfunction, and which also show upregulation of ABC transporter genes, improved fitness, and increased resistance towards azoles [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Ferrari, 2011, Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice, Antimicrob. Agents Chemother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acquisition of resistance towards echinocandins is not as common as towards azoles, yet it is far from rare and is significantly linked with prior exposure to the drugs.

    “Acquisition of resistance towards echinocandins is not as common as towards azoles, yet it is far from rare and is significantly linked with prior exposure to the drugs [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Vallabhaneni, S., Cleveland, A.A., Farley, M.M., Harrison, L.H., Schaffner, W., Beldavs, Z.G., Derado, G., Pham, C.D., Lockhart, S.R., and Smith, R.M. (2015). Epidemiology and risk factors for echinocandin nonsusceptible Candida glabrata bloodstream infections: Data from a large multisite population-based candidemia surveillance program, 2008–2014. Open Forum Infect. Dis., 2. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alterations in PDR1 have been described as the main mechanism for enhancement of azole resistance in C. glabrata, with efflux pumps often induced during azole therapy.

    “Alterations in this transcription factor have been described as the main mechanism for the enhancement of azole resistance in C. glabrata, with efflux pumps often induced during azole therapy [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Tumbarello, 2008, Fungaemia caused by Candida glabrata with reduced susceptibility to fluconazole due to altered gene expression: Risk factors, antifungal treatment and outcome, J. Antimicrob. Chemother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro induced resistance in C. tropicalis unveiled increased expression of CDR1 and MDR1, but there is no conclusive proof that these mechanisms act in clinical isolates.

    “In addition, in vitro induced resistance unveiled the presence of increased expression of multidrug transporter genes of two different families, the ABC transporters and the major facilitators, CDR1 and MDR1, respectively. Yet, there is no conclusive proof that these mechanisms are acting in clinical isolates [91].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Barchiesi, 2000, Experimental induction of fluconazole resistance in Candida tropicalis ATCC 750, Antimicrob. Agents Chemother. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    For C. auris, little is known on the precise contribution of ERG11 mutations to fluconazole resistance.

    “For C. auris, little is known on the precise contribution of ERG11 mutations to fluconazole resistance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    So far, there is no information on altered expression of efflux pumps being connected with resistance in C. auris.

    “So far, there is no information on the altered expression of efflux pumps being connected with resistance in this microorganism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Calcium signaling is essential for survival of azole treatment, and its absence has the potential to change fluconazole from fungistatic to fungicidal.

    “Another study included calcium signaling as essential for the survival of azole treatment and its absence has the potential to change the character of fluconazole from fungistatic to fungicidal [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Miyazaki, 2010, Roles of calcineurin and Crz1 in antifungal susceptibility and virulence of Candida glabrata, Antimicrob. Agents Chemother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Changes in FCY2 interfere with drug uptake, alterations in FCY1 and FUR1 inactivate enzymes involved in the pyrimidine pathway, and absence of FPS1 and FPS2 reduces accumulation of the drug in the cell.

    “Changes in FCY2 interfere with the drug uptake and alterations in FCY1 and FUR1 inactivate enzymes involved in the pyrimidine pathway, while the absence of FPS1 and FPS2 reduced the accumulation of the drug in the cell.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Resistance to amphotericin B in Candida is still rare, and when it occurs it is generally connected with a decrease in the levels of ergosterol in the cell membrane.

    “Resistance to amphotericin B in Candida is still rare. When it occurs, it is generally connected with a decrease in the levels of ergosterol in the cell membrane.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Susceptibility testing to monitor the resistance profile of infecting strains is problematic, expensive, and time-consuming because it requires isolation and culturing of strains before the test can be performed.

    “However, this is problematic, expensive, and time-consuming, as it requires isolation and culturing of strains before the test can be performed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In C. glabrata, expression of the FKS2 gene is calcineurin-dependent, and the resistance phenotype can be reversed upon application of calcineurin inhibitors such as FK506.

    “Additionally, in C. glabrata, the expression of the FKS2 gene has been shown to be calcineurin-dependent, and the resistance phenotype can be reversed upon the application of calcineurin inhibitors such as FK506 [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Katiyar, 2012, Fks1 and Fks2 are functionally redundant but differentially regulated in Candida glabrata: Implications for echinocandin resistance, Antimicrob. Agents Chemother. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypermutator phenotypes resulting from mutations in DNA repair genes have been proposed to precede the appearance of resistance in bacteria.

    “Furthermore, the appearance of ‘hypermutator phenotypes’ resulting from mutations in DNA repair genes has been proposed to precede the appearance of resistance in bacteria [133].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Woodford, 2007, The emergence of antibiotic resistance by mutation, Clin. Microbiol. Infect. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Aneuploidies are acknowledged to play a role in mediating drug resistance in C. albicans, but the impact of this phenomenon in other species is not clear.

    “Thus, aneuploidies are acknowledged to play a role in mediating drug resistance in C. albicans, but the impact of this phenomenon in other species is not clear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    EUCAST or CLSI methods are not recommended for testing susceptibility towards caspofungin due to a lack of reproducibility across laboratories or drug batches and paradoxical growth of Candida at concentrations above MIC.

    “For example, these methods are not recommended for testing the susceptibility towards caspofungin (an echinocandin), given a lack of reproducibility across laboratories or even drug batches [120] and the paradoxical growth of Candida at concentrations above MIC [121].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] Arendrup, 2013, Interlaboratory variability of caspofungin MICs for Candida spp. using CLSI and EUCAST methods: Should the clinical laboratory be testing this agent?, Antimicrob. Agents Chemother. source

      Not checked in the free run.

    • cites [121] Chamilos, 2007, Paradoxical effect of echinocandins across Candida species in vitro: Evidence for echinocandin-specific and Candida species-related differences, Antimicrob. Agents Chemother. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Various evolutionary outcomes might be driven by different selection strategies that influence the way in which the relative frequencies of drug-resistant genotypes increase within a population.

    “Finally, various evolutionary outcomes might be driven by different selection strategies that influence the way in which the relative frequencies of drug-resistant genotypes increase within a population.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Factors such as the size of the population or the possibility of exchanging genetic material through mating and recombination can influence the pace at which an infecting population can adapt to the drug.

    “Moreover, such mutations appear in the context of evolving populations, and factors such as the size of the population or the possibility of exchanging genetic material through mating and recombination, can influence the pace at which an infecting population can adapt to the drug.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Azole-induced aneuploidies were lost during cultivation in a stress-free environment and were considered providers of raw genetic material in the process towards the acquisition of resistance.

    “Yet, azole-induced aneuploidies were lost during cultivation in a stress-free environment and were thus considered providers of raw genetic material in the process towards the acquisition of resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Selmecki, A.M., Dulmage, K., Cowen, L.E., Anderson, J.B., and Berman, J. (2009). Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance. PLoS Genet., 5. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genome rearrangements have also been suggested to play a role in the adaptation of C. glabrata to stressful conditions.

    “Genome rearrangements have also been suggested to play a role in the adaptation of C. glabrata to stressful conditions [128].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Healey, K.R., Ortigosa, C.J., Shor, E., and Perlin, D.S. (2016). Genetic drivers of multidrug resistance in Candida glabrata. Front. Microbiol., 7. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    How a drug actually affects the pathogen may constrain the ways in which the yeast can adapt to it.

    “In addition, how a drug actually affects the pathogen may constrain the ways in which the yeast can adapt to it.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypermutator phenotypes resulting from mutations in the DNA mismatch repair gene MSH2 have been suggested to enable fast adaptation to drugs in Cryptococcus neoformans and C. glabrata.

    “Similarly, hypermutator phenotypes resulting from mutations in the DNA mismatch repair gene MSH2, have been suggested to enable fast adaptation to drugs in Cryptococcus neoformans and C. glabrata [134,135].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [134] Boyce, K.J., Wang, Y., Verma, S., Shakya, V.P.S., Xue, C., and Idnurm, A. (2017). Mismatch repair of DNA replication errors contributes to microevolution in the pathogenic fungus Cryptococcus neoformans. MBio, 8. source

      Not checked in the free run.

    • cites [135] Healey, K.R., Zhao, Y., Perez, W.B., Lockhart, S.R., Sobel, J.D., Farmakiotis, D., Kontoyiannis, D.P., Sanglard, D., Taj-Aldeen, S.J., and Alexander, B.D. (2016). Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat. Commun., 7. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other investigations led to similar claims based on differences among karyotypes of serial clinical isolates of C. glabrata exhibiting increased resistance to antifungals.

    “Other investigations led to similar claims based on differences among karyotypes of serial clinical isolates of the species exhibiting an increased resistance to antifungals [130].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Ahmad, 2014, Genome structure and dynamics of the yeast pathogen Candida glabrata, FEMS Yeast Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Fungistatic drugs that stop growth but do not kill the pathogen open a window of opportunity for mutations to appear.

    “For instance, fungistatic drugs that stop the growth but do not kill the pathogen open a window of opportunity for mutations to appear.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    In experimental evolution, samples can be stored at intermediate time points and the experiment can be re-started with alternative conditions from any point, allowing researchers to 'retape' evolution.

    “Moreover, samples can be stored at intermediate time points and the experiment can be re-started with alternative conditions from any point, thus allowing researchers to ‘retape’ evolution.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In in vivo studies, results are not easily replicable, population size parameters are not controlled, and usually only the mutational composition of the final isolate is assessed.

    “In in vivo studies, the results are not easily replicable, the population size parameters are not controlled, and usually only the mutational composition of the final isolate is assessed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both batch serial transfer and continuous culture methods have been successfully used to study the emergence of drug resistance in Candida yeasts.

    “Both methods have been successfully used to study the emergence of drug resistance in Candida yeasts [150,151].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Cowen, 2000, Evolution of drug resistance in experimental populations of Candida albicans, J. Bacteriol. source

      Not checked in the free run.

    • cites [151] Huang, 2011, Evolutionary dynamics of Candida albicans during in vitro evolution, Eukaryot. Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Persistence occurs when microorganisms are not only able to withstand the antifungal therapy, but can also cause a relapse, even after a successful one.

    “Finally, persistence occurs when microorganisms are not only able to withstand the antifungal therapy, but can also cause a relapse, even after a successful one [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Rosenberg, A., Ene, I.V., Bibi, M., Zakin, S., Segal, E.S., Ziv, N., Dahan, A.M., Colombo, A.L., Bennett, R.J., and Berman, J. (2018). Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia. Nat. Commun., 9. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Although aneuploidies were present and may be important adaptive intermediates, they did not seem to correlate with the resistant phenotype.

    “On the other hand, although aneuploidies were present and may be important adaptive intermediates (see above), they did not seem to correlate with the resistant phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Heteroresistance might cause false outcomes in susceptibility tests, which may result in the misidentification of potentially resistant isolates as susceptible and even in fatal treatment failure.

    “To complicate things further, heteroresistance might cause false outcomes in susceptibility tests, which may result in the misidentification of potentially resistant isolates as susceptible and even in fatal treatment failure [137].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Ben-Ami, R., Zimmerman, O., Finn, T., Amit, S., Novikov, A., Wertheimer, N., Lurie-Weinberger, M., and Berman, J. (2016). Heteroresistance to fluconazole is a continuously distributed phenotype among Candida glabrata clinical strains associated with in vivo persistence. MBio, 7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two C. glabrata clinical isolates obtained from the same patient separated by 50 days of azole treatment had 17 non-synonymous SNPs, including one gain of function substitution in the PDR1 gene (L280F) and small-sized indels mainly affecting adhesin-like genes.

    “The identified genetic differences comprised 17 non-synonymous SNPs, including one gain of function substitution in the PDR1 gene (L280F) and small-sized indels mainly affecting adhesin-like genes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Beaudoing, 2017, Comparative Genomics of Two Sequential Candida glabrata Clinical Isolates, G3 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The functions of the orthologs in S. cerevisiae of these eight genes suggested that they were not directly related to the resistance phenotype, but rather might be connected to the adaptation of C. glabrata to the host or compensate for the effect of FKS2 mutations.

    “Yet, the functions of the orthologs in S. cerevisae of these eight genes suggested that they were not directly related to the resistance phenotype, but rather that they might be connected to the adaptation of C. glabrata to the host or, alternatively, they might compensate for the effect of FKS2 mutations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tolerance is reversible and results from epigenetic mechanisms, while resistance is an inheritable property determined by genes and their mutations.

    “Furthermore, tolerance is reversible and results from epigenetic mechanisms, while resistance is an inheritable property determined by genes and their mutations [139].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Delarze, 2015, Defining the frontiers between antifungal resistance, tolerance and the concept of persistence, Drug Resist. Updat. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    The important advantages of a serial dilution system over continuous culture are lower costs, the use of generally available laboratory equipment, and the feasibility of conducting experiments involving a high number of replicates in parallel.

    “The important advantages of a serial dilution system over the continuous culture are related to lower costs, the use of generally available laboratory equipment, and, most importantly, the feasibility of conducting experiments involving a high number of replicates in parallel, enabling a comprehensive analysis of a variety of changes, mechanisms, and evolutionary trajectories of adaptation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some MSH2 mutations were found to be ancient polymorphisms within different C. glabrata clades, and to be equally widespread among non-resistant isolates.

    “For instance, some of these mutations were found to be ancient polymorphisms within different C. glabrata clades, and to be equally widespread among non-resistant isolates [63].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Ksiezopolska, 2018, Patterns of genomic variation in the opportunistic pathogen Candida glabrata suggest the existence of mating and a secondary association with humans, Curr. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro evolution experiments coupled with whole genome sequencing have been extensively used to understand the emergence of antibiotic resistance in bacteria, but their use in the field of antifungal drug resistance is still in its infancy.

    “In vitro evolution experiments coupled with whole genome sequencing have been extensively used to understand the emergence of antibiotic resistance in bacteria [149], but their use in the field of antifungal drug resistance is still in its infancy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Bryant, 2012, Developing insights into the mechanisms of evolution of bacterial pathogens from whole-genome sequences, Future Microbiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Next-generation sequencing and comparative genomics allow recording the footprints of genetic evolution and tracking the genomic changes that follow the emergence of a phenotype of interest.

    “Next-generation sequencing and comparative genomics not only allow us to record the footprints of genetic evolution of new species, but also help us in tracking the genomic changes that follow the emergence of a phenotype of interest.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cowen et al. serially propagated six experimental populations of C. albicans derived from a single colony for 330 generations in medium supplemented with fluconazole at a concentration doubling their MIC.

    “For example, Cowen et al. [150] serially propagated six experimental populations of C. albicans derived from a single colony for 330 generations in medium supplemented with fluconazole at a concentration doubling their MIC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Cowen, 2000, Evolution of drug resistance in experimental populations of Candida albicans, J. Bacteriol. source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Changes in the FKS2 gene were associated with the highest increase in echinocandin resistance and a considerable cost in fitness.

    “Additionally, changes in the FKS2 gene were associated with the highest increase in echinocandin resistance and a considerable cost in fitness.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Drug tolerance is an evolvable phenotype, which is distinct from and does not correlate with antifungal drug resistance.

    “It has been also suggested that drug tolerance is an evolvable phenotype, which is distinct from and does not correlate with antifungal drug resistance [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Rosenberg, A., Ene, I.V., Bibi, M., Zakin, S., Segal, E.S., Ziv, N., Dahan, A.M., Colombo, A.L., Bennett, R.J., and Berman, J. (2018). Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia. Nat. Commun., 9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. albicans, naturally susceptible to all drugs, used to account for 85% of the cases before the advent of antimycotics.

    “This is a significant change as C. albicans, naturally susceptible to all drugs, used to account for 85% of the cases before the advent of antimycotics [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Arendrup, 2014, Update on antifungal resistance in Aspergillus and Candida, Clin. Microbiol. Infect. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    Emerging and dangerous species, like multidrug-resistant C. auris, pose a constant threat and we are likely to witness the rise of new such multidrug-resistant pathogenic yeasts in the near future.

    “Emerging and dangerous species, like multidrug-resistant C. auris, pose a constant threat and we are likely to witness the rise of new such multidrug-resistant pathogenic yeasts in the near future.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Resistance can be based on diverse mechanisms, which can vary from species to species.

    “Resistance can be based on diverse mechanisms, which can vary from species to species.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Technical developments such as next-generation sequencing are allowing interrogation of mutational processes at unprecedented levels of scale and resolution.

    “Fortunately, technical developments such as next-generation sequencing are allowing us to interrogate mutational processes at unprecedented levels of scale and resolution.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    C. glabrata is a good illustrating example of how a well-understood mechanism in one species does not necessarily apply to other species.

    “C. glabrata is a good illustrating example of how a well-understood mechanism in one species does not necessarily apply to other species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Such in vitro evolution studies are scarce and limited to a few species and drugs, which suggests that many alternative adaptation pathways remain unknown.

    “Yet, such studies are scarce and limited to a few species and drugs, which suggests that many alternative adaptation pathways remain unknown.”
    Quote in the paperSubstantial claim
93 of 93

  • The paper relies on this without support.

    Few studies have focused on the evolutionary mechanisms leading to drug resistance in fungal species, at least compared with antibiotic resistance in bacterial pathogens.

    “However, in contrast to the situation of antibiotic resistance in bacteria, few studies have focused on the evolutionary mechanisms leading to drug resistance in fungal species.”
    “Despite the clinical and economic relevance of drug resistance in the context of yeast infections, this subject remains poorly studied, at least in comparison with the similar issue of antibiotic resistance in bacterial pathogens.”

  • The paper relies on this without support.

    We are far from having a broad understanding of how resistance towards antifungal drugs emerges in the context of infection or commensalism in yeast pathogens.

    “Still, we are far from having a broad understanding of how resistance towards antifungal drugs emerges in the context of infection or commensalism in yeast pathogens.”

  • The paper relies on this without support.

    Mutations can have synergistic or antagonistic effects with respect to the resistant phenotype.

    “Finally, mutations can also have synergistic or antagonistic effects with respect to the resistant phenotype.”
3 of 3

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References 153 · Cited by 230

Authors
Ksiezopolska, E., & Gabaldón, T.
Affiliations
  • Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain
  • Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author
Gabaldón, Toni
ORCID
Gabaldón, Toni
Venue
Genes
Publisher
MDPI AG
Published
2018-09-19
Volume
9
Issue
9
Pages
461
ISSN
2073-4425 (ISSN-L)
DOI
10.3390/genes9090461
PMC
PMC6162425
OpenAlex
W2891298374
Semantic Scholar
b7e05c2454a717bfce0f2ca11b057c828ba6b837
Cited by
230
References
153
Citations by year
2026: 8 · 2025: 24 · 2024: 37 · 2023: 38 · 2022: 36 · 2021: 45 · 2020: 33 · 2019: 7 · 2018: 2
FWCI
3.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Genes (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
Funders
  • Ministerio de Economía y Competitividad (BFU2015-67107)
  • H2020 Marie Skłodowska-Curie Actions (H2020-MSCA-ITN-2014-642095)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords
Candida, antifungal resistance, candidiasis, opportunistic fungal infection, resistance evolution, evolutionary genomics, genetic basis of resistance, in vitro evolution, immunocompromised patients

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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