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Cited by 542Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal and yeast genetics research

Fluconazole resistance in Candida species: a current perspective

Open access
Berkow, Elizabeth, Lockhart, Shawn·2017·Infection and Drug Resistance
DOI 10.2147/idr.s118892PMC PMC5546770
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Abstract

Abstract: Candida albicans and the emerging non- albicans Candida spp. have significant clinical relevance among many patient populations. Current treatment guidelines include fluconazole as a primary therapeutic option for the treatment of these infections, but it is only fungistatic against Candida spp. and both inherent and acquired resistance to fluconazole have been reported. Such mechanisms of resistance include increased drug efflux, alteration or increase in the drug target, and development of compensatory pathways for producing the target sterol, ergosterol. While many mechanisms of resistance observed in C. albicans are also found in the non- albicans species, there are also important and unexpected differences between species. Furthermore, mechanisms of fluconazole resistance in emerging Candida spp., including the global health threat Candida auris , are largely unknown. In order to preserve the utility of one of our fundamental antifungal drugs, fluconazole, it is essential that we fully appreciate the manner by which Candida spp. manifest resistance to it. Keywords: Candida , fluconazole resistance, ERG11 , drug efflux, ergosterol

AI snapshot

Written from the paper’s full text.

TL;DR

Fluconazole remains a primary anti-Candida option but is only fungistatic, and resistance arises through increased drug efflux, altered or increased drug target, sterol biosynthesis bypass, and chromosomal changes. Resistance rates vary widely by species, with Candida auris reaching up to 93% fluconazole resistance and many mechanisms in non-albicans Candida still poorly understood.

Key findings

  • Candida spp. account for approximately 75–88% of all fungal infections in the US, with an annual attributable cost of $1.7 billion; historically 92–95% of Candida infections are caused by five species, though non-albicans species are increasingly isolated.
  • Reported fluconazole resistance rates are approximately 0.5–2% in C. albicans, 4–9% in C. tropicalis, 2–6% in C. parapsilosis, 11–13% in C. glabrata, and as high as 93% in C. auris; C. krusei can be innately resistant.
  • Resistance mechanisms include ERG11 overexpression or point mutations, ERG3 loss-of-function bypass pathways, increased efflux via ABC transporters (e.g., CDR1/CDR2, with 19 confirmed TAC1 gain-of-function mutations) and MFS transporters (e.g., MDR1, with 15 Mrr1p gain-of-function mutations), plus aneuploidy and loss of heterozygosity.
  • In C. albicans, over 140 ERG11 substitutions have been described, clustering in hot spot regions at amino acids 105–165, 266–287, and 405–488; C. auris isolates with elevated fluconazole MICs have carried Y132F, K143R, and F126T mutations.

Methods

  • Design: narrative review/current perspective; no primary experimental study design is reported.
  • Data or sample: synthesizes published literature on Candida species and fluconazole resistance mechanisms; no new patient cohort, clinical trial, or isolate collection is presented.
  • Main analysis: descriptive synthesis of resistance rates and molecular mechanisms; no statistical analysis or systematic search protocol is described.

Limitations

  • Stated in the paper: mechanisms of fluconazole resistance in emerging Candida spp., including C. auris, are largely unknown; the role of ERG11 overexpression in C. auris is unknown, efflux pumps have not been investigated in C. auris, and little information exists on chromosomal abnormalities in non-albicans Candida.
  • Stated in the paper: well-understood molecular mechanisms do not always fully account for high-level resistance; additional unknown regulators of ERG11 and efflux pumps likely exist, drug import is inadequately understood, and stress-response signal transduction pathways are not completely defined.
  • Evident from the text: as a narrative review, it lacks a described systematic search strategy, formal study-quality assessment, and quantitative synthesis, so selection bias and incomplete coverage of the literature are possible.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2147/idr.s118892

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 50 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Both inherent and acquired resistance to fluconazole have been reported in Candida spp.

    “both inherent and acquired resistance to fluconazole have been reported.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The majority of ERG11 amino acid substitutions fall into distinct hot spot regions within the protein: amino acids 105-165, 266-287, and 405-488.

    “the majority of ERG11 amino acid substitutions fall into distinct “hot spot” regions within the protein: amino acids 105–165, 266–287, and 405–488.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Marichal P Koymans L Willemsens S Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans Microbiology 1999 145 Pt 10 2701 2713 10537192

      Not checked in the free run.

  • Premisecitation

    Without prior introduction of antifungal, fluconazole resistance may be innate, as seen with C. krusei.

    “Alternatively, without prior introduction of the antifungal, fluconazole resistance may also be innate, as is seen with C. krusei.24,25”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Marichal P Gorrens J Coene MC Le Jeune L Vanden Bossche H Origin of differences in susceptibility of Candida krusei to azole antifungal agents Mycoses 1995 38 3–4 111 117 7477085

      Not checked in the free run.

    • cites [25] Pfaller MA Diekema DJ Gibbs DL Global Antifungal Surveillance Group Candida krusei, a multidrug-resistant opportunistic fungal pathogen: geographic and temporal trends from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005 J Clin Microbiol 2008 46 2 515 521 18077633 PMC2238087

      Not checked in the free run.

  • Premisecitation

    In C. auris, a collection of isolates with elevated fluconazole MIC values carried point mutations Y132F, K143R, and F126T previously shown to impact drug resistance in other Candida spp.

    “one recent study determined that a collection of C. auris isolates with elevated minimum inhibitory concentration (MIC) values to fluconazole carried point mutations which had been previously shown to impact drug resistance in other Candida spp.: Y132F, K143R, and F126T.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Lockhart SR Etienne KA Vallabhaneni S Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses Clin Infect Dis 2017 64 2 134 140 27988485 PMC5215215

      Not checked in the free run.

  • Premisecitation

    C. auris can exhibit a rate of resistance to fluconazole as high as 93%.

    “The emerging yeast C. auris can exhibit a rate of resistance to fluconazole as high as 93%.23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Lockhart SR Etienne KA Vallabhaneni S Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses Clin Infect Dis 2017 64 2 134 140 27988485 PMC5215215

      Not checked in the free run.

  • May combine two claims. 8
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    There has been a shift in the species distribution among Candida infections, with non-albicans Candida species encountered more frequently as human pathogens, and in some cases more frequently isolated than C. albicans.

    “And while this still holds true, there has been a shift in the species distribution among Candida infections. In past decades, C. albicans comprised >50% of all candidemia. However, the non-albicans Candida (NCAC) species are being encountered more frequently as human pathogens and, in some cases, NCAC species are more frequently isolated than C. albicans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Cleveland AA Harrison LH Farley MM Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US metropolitan areas, 2008–2013: results from population-based surveillance PLoS One 2015 10 3 e0120452 25822249 PMC4378850

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Mechanisms of fluconazole resistance include increased drug efflux, alteration or increase in the drug target, and development of compensatory pathways for producing ergosterol.

    “Such mechanisms of resistance include increased drug efflux, alteration or increase in the drug target, and development of compensatory pathways for producing the target sterol, ergosterol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Many mechanisms of resistance observed in C. albicans are also found in non-albicans species, but there are important and unexpected differences between species.

    “While many mechanisms of resistance observed in C. albicans are also found in the non-albicans species, there are also important and unexpected differences between species.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Mechanisms of fluconazole resistance in emerging Candida spp., including C. auris, are largely unknown.

    “mechanisms of fluconazole resistance in emerging Candida spp., including the global health threat Candida auris, are largely unknown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ERG11 does not appear to play a major role in fluconazole resistance in C. glabrata, and only two clinical isolates have been reported to display overexpression of ERG11.

    “Unlike in other species of Candida, ERG11 does not appear to play a major role in fluconazole resistance in C. glabrata, and there are only two clinical isolates reported to display overexpression of ERG11.34,35”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Redding SW Kirkpatrick WR Saville S 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 2 619 622 12574256 PMC149712

      Not checked in the free run.

    • cites [35] vanden Bossche H Marichal P Odds FC Le Jeune L Coene MC Characterization of an azole-resistant Candida glabrata isolate Antimicrob Agents Chemother 1992 36 12 2602 2610 1482129 PMC245514

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C. parapsilosis, ERG11 overexpression was UPC2-independent, as most isolates contained no UPC2 mutation.

    “when UPC2 was sequenced in such isolates, a single heterozygous mutation was identified in a single isolate – the remaining isolates contained no UPC2 mutation – indicating that the overexpression of ERG11 was UPC2-independent”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Berkow EL Manigaba K Parker JE Barker KS Kelly SL Rogers PD Multidrug transporters and alterations in sterol biosynthesis contribute to azole antifungal resistance in Candida parapsilosis Antimicrob Agents Chemother 2015 59 10 5942 5950 26169412 PMC4576097

      Not checked in the free run.

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

    Premisecitation

    Fluconazole is one of the most commonly prescribed antifungal drugs for Candida infections.

    “One of the most commonly prescribed antifungal drugs for Candida infections is fluconazole, a triazole antifungal.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Pfaller MA Diekema DJ Gibbs DL Global Antifungal Surveillance Group Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion J Clin Microbiol 2010 48 4 1366 1377 20164282 PMC2849609

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the US, C. tropicalis, C. parapsilosis, and C. glabrata have higher fluconazole resistance rates at 4-9%, 2-6%, and 11-13%, respectively.

    “C. tropicalis, C. parapsilosis, and C. glabrata, on the other hand, have higher rates at 4–9%, 2–6%, and 11–13%, respectively.21,22”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Cleveland AA Farley MM Harrison LH 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 1361 22893576 PMC4698872

      Not checked in the free run.

    • cites [22] Pfaller MA Rhomberg PR Messer SA Jones RN Castanheira M 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 proposed epidemiological cutoff values Diagn Microbiol Infect Dis 2015 82 4 303 313 25986029

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in Upc2p provide gain of function, resulting in constitutive transcriptional activity and increased production of Erg11p.

    “Mutations in Upc2p provide gain of function (GOF) for this regulator, resulting in constitutive transcriptional activity and increased production of Erg11p.27–29”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Hoot SJ Smith AR Brown RP White TC An A643V amino acid substitution in Upc2p contributes to azole resistance in well-characterized clinical isolates of Candida albicans Antimicrob Agents Chemother 2011 55 2 940 942 21078937 PMC3028767

      Not checked in the free run.

    • cites [28] Heilmann CJ Schneider S Barker KS Rogers PD Morschhäuser J An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans Antimicrob Agents Chemother 2010 54 1 353 359 19884367 PMC2798556

      Not checked in the free run.

    • cites [29] Dunkel N Liu TT Barker KS Homayouni R Morschhäuser J Rogers PD A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate Eukaryot Cell 2008 7 7 1180 1190 18487346 PMC2446669

      Not checked in the free run.

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

    Interpretationnone given

    The emergence of drug resistance is an inevitable consequence of the selective pressures imposed by antifungal drugs.

    “The emergence of drug resistance can be considered an inevitable consequence of the selective pressures imposed by antifungal drugs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Loss of heterozygosity of specific genomic regions is implicated in fluconazole resistance, most commonly associated with ERG11, TAC1, and MRR1, with point mutations arising heterozygous and evolving to homozygosity.

    “LOH of specific genomic regions is also implicated in fluconazole resistance. It is most commonly associated with genes involved in resistance mechanisms, including ERG11, TAC1, and MRR1, with point mutations arising in the heterozygous state, and evolving to homozygosity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Selmecki A Forche A Berman J Aneuploidy and isochromosome formation in drug-resistant Candida albicans Science 2006 313 5785 367 370 16857942 PMC1717021

      Not checked in the free run.

    • cites [88] Coste A Selmecki A Forche A Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates Eukaryot Cell 2007 6 10 1889 1904 17693596 PMC2043391

      Not checked in the free run.

11 of 11

  • The paper relies on this without support.

    Fluconazole is fungistatic rather than fungicidal against Candida spp.

    “Fluconazole is fungistatic rather than fungicidal, so treatment provides the opportunity for acquired resistance to develop in the presence of this antifungal.”

  • The paper relies on this without support.

    Current treatment guidelines include fluconazole as a primary therapeutic option for Candida infections.

    “Current treatment guidelines include fluconazole as a primary therapeutic option for the treatment of these infections”

  • The paper relies on this without support.

    Fluconazole uptake into the fungal cell is required for the drug to reach its target protein, Erg11p.

    “Fluconazole uptake into the fungal cell is required for the drug to reach its target protein, Erg11p.”

  • The paper relies on this without support.

    Fluconazole is a central antifungal option.

    “a central antifungal option”

  • The paper relies on this without support.

    All Candida spp. exhibit resistance to fluconazole.

    “all Candida spp. exhibit resistance to it”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Out of 140 different point mutations described for ERG11, 21 have been directly associated with fluconazole resistance.

    “Out of 140 different point mutations described for this gene, 21 have been directly associated with fluconazole resistance [73].”

    From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [73]

  • Azoles target Erg11 by directly binding to the iron atom within the heme group of the enzyme.

    “Azoles, the most common drug used to treat fungal infections, target Erg11 by directly binding to the iron atom within the heme group of the enzyme [21].”

    From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [21]

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Related

Authors
Berkow, E., & Lockhart, S.
Affiliations
Centers for Disease Control and Prevention (US)
Corresponding author
  • Berkow, Elizabeth
  • Lockhart, Shawn
ORCID
Venue
Infection and Drug Resistance
Publisher
Informa UK Limited
Published
2017-07
Volume
Volume 10
Pages
237-245
ISSN
1178-6973 (ISSN-L)
DOI
10.2147/idr.s118892
PMC
PMC5546770
OpenAlex
W2739660851
Semantic Scholar
9868ccbe44320dde1e7551a835d526d5e8110268
Cited by
542
References
111
Citations by year
2026: 39 · 2025: 75 · 2024: 66 · 2023: 76 · 2022: 78 · 2021: 63 · 2020: 73 · 2019: 47 · 2018: 22 · 2017: 3
FWCI
6.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Infection and Drug Resistance (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
Funders
Centers for Disease Control and Prevention
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
fluconazole resistance, Candida albicans, non-albicans Candida, Candida auris, ERG11, drug efflux, ergosterol biosynthesis, antifungal resistance mechanisms, fungal infection

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