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Cited by 411Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal and yeast genetics research

Candida Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

Open access
Spampinato, Claudia, Leonardi, Darío·2013·BioMed Research International
DOI 10.1155/2013/204237PMC PMC3708393
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Abstract

The genus Candida includes about 200 different species, but only a few species are human opportunistic pathogens and cause infections when the host becomes debilitated or immunocompromised.Candida infections can be superficial or invasive. Superficial infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs. However, invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies. Here, we briefly review our current knowledge of pathogenic species of the genus Candida and yeast infection causes and then focus on current antifungal drugs and resistance mechanisms. An overview of new therapeutic alternatives for the treatment of Candida infections is also provided.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes Candida infections, current antifungal drug classes and resistance mechanisms, and emerging alternative agents. It highlights rising resistance and three investigational compounds—E1210, albaconazole, and isavuconazole—as promising for invasive candidiasis.

Key findings

  • The genus Candida includes about 200 species; five species (C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei) cause more than 90% of invasive infections. Candida species are reported by the NNISS as the fourth most common nosocomial bloodstream pathogen, with mortality rates estimated as high as 45%.
  • Current antifungals act mainly by inhibiting lanosterol 14-α-demethylase (azoles), (1,3)-β-D-glucan synthase (echinocandins), binding ergosterol (polyenes), inhibiting DNA/RNA synthesis (flucytosine), inhibiting squalene-epoxidase (allylamines/thiocarbamates), or disrupting microtubules (griseofulvin). Resistance mechanisms include reduced drug accumulation via efflux pumps, decreased target affinity/processivity, and counteraction of drug effect.
  • Echinocandin resistance in C. glabrata increased from 4.9% to 12.3% between 2001 and 2010; primary resistance to flucytosine remains low (<2%). Azole-resistant C. albicans is frequent in HIV-infected patients with oropharyngeal candidiasis.
  • Three agents with actual promise are E1210 (Phase II), albaconazole (Phase II), and isavuconazole (Phase III). Albaconazole oral bioavailability was calculated as 80% in rats and 100% in dogs, and a single dose ≥40 mg was more effective than 150 mg fluconazole for acute vulvovaginal candidiasis.

Methods

  • Narrative review; no primary experiments are reported. It synthesizes literature on pathogenic Candida species, antifungal drug classes, resistance mechanisms, and alternative antifungal agents.
  • No systematic search strategy, inclusion/exclusion criteria, or quantitative synthesis is stated. The main analysis is descriptive, with referenced tables for pharmacokinetic parameters, resistance mechanisms, and alternative compounds.

Limitations

  • Stated: pharmacokinetic parameters are not always directly comparable because data derive from multiple sources and trials.
  • Evident: as a narrative review, it lacks a systematic search strategy, quality assessment, and meta-analysis; many alternative agents are described as active in vitro but not used in clinical treatments.
  • Evident: several referenced tables (Tables 1–4) are not included in the provided text, limiting verification of specific pharmacokinetic values.

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

Integrity signals

Registry

Crossref · 10.1155/2013/204237

Cites

150 of 150 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 110 cited sources checked · 0 supported · 0 flagged

  • Premisereasoning

    Since fluconazole and caspofungin are primarily excreted into the urine as active forms, they are agents of choice for the treatment of urinary tract fungal infections.

    “Since fluconazole and caspofungin are primarily excreted into the urine as active forms (Table 1), they are agents of choice for the treatment of urinary tract fungal infections.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Advances in medical management such as antineoplasic chemotherapy, organ transplantation, hemodialysis, parenteral nutrition, and central venous catheters contribute to fungal invasion and colonization.

    “Advances in medical management as antineoplasic chemotherapy, organ transplantation, hemodialysis, parenteral nutrition, and central venous catheters also contribute to fungal invasion and colonization [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Mikulska M del Bono V Ratto S Viscoli C Occurrence, presentation and treatment of candidemia Expert Review of Clinical Immunology 2012 8 755 765 23167687 source

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  • Premisecitation

    Only few classes of antifungal agents are currently available to treat mucosal or systemic infections with Candida spp.

    “Although the antifungal drugs used in clinical treatments appear to be diverse and numerous, only few classes of antifungal agents are currently available to treat mucosal or systemic infections with Candida spp. (Figure 1) [18–20].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Mathew BP Nath M Recent approaches to antifungal therapy for invasive mycoses ChemMedChem 2009 4 3 310 323 2-s2.0-62749128097 19170067 source

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    • cites [19] Kathiravan MK Salake AB Chothe AS The biology and chemistry of antifungal agents: a review Bioorganic & Medicinal Chemistry 2012 20 5678 5698 22902032 source

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    • cites [20] Denning DW Hope WW Therapy for fungal diseases: opportunities and priorities Trends in Microbiology 2010 18 5 195 204 2-s2.0-77952547165 20207544 source

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  • Premisereasoning

    Most antifungal agents targeted to ergosterol binding or biosynthesis do not cross-react with host cells because ergosterol and cholesterol have sufficient structural differences.

    “Since ergosterol and cholesterol have sufficient structural differences, most antifungal agents targeted to ergosterol binding or biosynthesis does not cross-react with host cells.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Fluconazole resistance has been described in a high percentage of patients after extensive use.

    “Afterwards, fluconazole resistance has been described in a high percentage of patients [87].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] 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 Journal of Clinical Microbiology 2003 41 2 619 622 2-s2.0-12244280807 12574256 PMC149712 source

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  • Classified as probably not a substantial claim. 18
  • May combine two claims. 34
  • The quote only partly states this claim. 1

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

    Premisecitation

    The National Nosocomial Infections Surveillance System (NNISS) reports Candida species as the fourth most common nosocomial bloodstream pathogen.

    “In fact, the National Nosocomial Infections Surveillance System (NNISS) reports Candida species as the fourth most common nosocomial bloodstream pathogen [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Wisplinghoff H Bischoff T Tallent SM Seifert H Wenzel RP Edmond MB Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study Clinical Infectious Diseases 2004 39 309 317 15306996 source

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  • May combine two claims.

    Premisenone given

    Ergosterol is the largest sterol component of the fungal cell membrane and is analogous to cholesterol in animal cells.

    “Ergosterol, analogous to cholesterol in animal cells, is the largest sterol component of the fungal cell membrane.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Risk factors for invasive candidiasis include surgery (especially abdominal surgery), burns, long-term stay in an intensive care unit, and previous administration of broad-spectrum antibiotics and immunosuppressive agents.

    “Risk factors for invasive candidiasis include surgery (especially abdominal surgery), burns, long-term stay in an intensive care unit, and previous administration of broad-spectrum antibiotics and immunosuppressive agents [7–10].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [7] Kontoyiannis DP Mantadakis E Samonis G Systemic mycoses in the immunocompromised host: an update in antifungal therapy Journal of Hospital Infection 2003 53 4 243 258 2-s2.0-0038159878 12660121

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    • cites [8] Zaoutis TE Argon J Chu J Berlin JA Walsh TJ Feudtner C The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis Clinical Infectious Diseases 2005 41 9 1232 1239 2-s2.0-27444432361 16206095 source

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    • cites [9] Sydnor ERM Perl TM Hospital epidemiology and infection control in acute-care settings Clinical Microbiology Reviews 2011 24 1 141 173 2-s2.0-78751507447 21233510 PMC3021207

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    • cites [10] Pfaller MA Diekema DJ Rare and emerging opportunistic fungal pathogens: concern for resistance beyond Candida albicans and Aspergillus fumigatus Journal of Clinical Microbiology 2004 42 10 4419 4431 2-s2.0-5444272819 15472288 PMC522363

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

    Premisenone given

    Candida infections can be superficial or invasive.

    “Candida infections can be superficial or invasive.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Flucytosine inhibits thymidylate synthase and DNA synthesis, and its metabolite can be incorporated into RNA, affecting RNA and protein synthesis.

    “This fluorinated nucleotide inhibits thymidylate synthase and thus interferes with DNA synthesis (Figure 1, [31]). The 5-fluorodeoxyuridine monophosphate can be further phosphorylated and incorporated to RNA, thus affecting RNA and protein synthesis (Figure 1, [32]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Vermes A Guchelaar H-J Dankert J Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions Journal of Antimicrobial Chemotherapy 2000 46 2 171 179 2-s2.0-0033869563 10933638 source

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    • cites [32] Onishi J Meinz M Thompson J Discovery of novel antifungal (1,3)-β-D-glucan synthase inhibitors Antimicrobial Agents and Chemotherapy 2000 44 2 368 377 2-s2.0-0033966183 10639364 PMC89685

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

    Premisecitation

    Mortality rates for Candida infections are estimated to be as high as 45%, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies.

    “Mortality rates are estimated to be as high as 45% [16], probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies [17].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Cheng M-F Yang Y-L Yao T-J Risk factors for fatal candidemia caused by Candida albicans and non-albicans Candida species BMC Infectious Diseases 2005 5, article 22 2-s2.0-25444434148 PMC1090575 15813977

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    • cites [17] Morrell M Fraser VJ Kollef MH Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality Antimicrobial Agents and Chemotherapy 2005 49 9 3640 3645 2-s2.0-24144483474 16127033 PMC1195428 source

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

    Premisenone given

    The genus Candida includes about 200 different species, but only a few species are human opportunistic pathogens that cause infections when the host becomes debilitated or immunocompromised.

    “The genus Candida includes about 200 different species, but only a few species are human opportunistic pathogens and cause infections when the host becomes debilitated or immunocompromised.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    C. albicans usually resides as a commensal in the gastrointestinal and genitourinary tracts and in the oral and conjunctival flora, but causes infection when the host becomes debilitated or immunocompromised.

    “It usually resides as a commensal in the gastrointestinal and genitourinary tracts and in the oral and conjunctival flora [1–5]. However, it causes infection when the host becomes debilitated or immunocompromised.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [1] Jackson BE Wilhelmus KR Mitchell BM Genetically regulated filamentation contributes to Candida albicans virulence during corneal infection Microbial Pathogenesis 2007 42 2-3 88 93 2-s2.0-33847146682 17241762 PMC1892154

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    • cites [2] Wu TG Mitchell BM Carothers TS Molecular analysis of the pediatric ocular surface for fungi Current Eye Research 2003 26 1 33 36 2-s2.0-0042266466 12789534

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    • cites [3] Achkar JM Fries BC Candida infections of the genitourinary tract Clinical Microbiology Reviews 2010 23 2 253 273 2-s2.0-77950675511 20375352 PMC2863365 source

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    • cites [4] Rosenbach A Dignard D Pierce JV Whiteway M Kumamoto CA Adaptations of Candida albicans for growth in the mammalian intestinal tract Eukaryotic Cell 2010 9 7 1075 1086 2-s2.0-77956799388 20435697 PMC2901676

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    • cites [5] Naglik JR Moyes DL Wächtler B Hube B Candida albicans interactions with epithelial cells and mucosal immunity Microbes and Infection 2011 13 12-13 963 976 2-s2.0-80053385024 21801848 PMC3185145 source

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

    Premisecitation

    All five mentioned Candida species cause more than 90% of invasive infections, although the relative prevalence of the species depends on geographical location, patient population, and clinical settings.

    “All five mentioned species cause more than 90% of invasive infections, although the relative prevalence of the species depends on the geographical location, patient population, and clinical settings [12–14].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] MacCallum DM Hosting infection: experimental models to assay Candida virulence International Journal of Microbiology 2012 2012 12 pages 2-s2.0-84855598556 363764 PMC3253448 22235206

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    • cites [13] Pfaller MA Diekema DJ Epidemiology of invasive candidiasis: a persistent public health problem Clinical Microbiology Reviews 2007 20 1 133 163 2-s2.0-33846466508 17223626 PMC1797637 source

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    • cites [14] Miceli MH Díaz JA Lee SA Emerging opportunistic yeast infections The Lancet Infectious Diseases 2011 11 2 142 151 2-s2.0-78751683832 21272794

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

    Premisenone given

    Superficial Candida infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs.

    “Superficial infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Polyenes such as nystatin and amphotericin B bind ergosterol and disrupt the fungal cell membrane, producing aqueous pores that alter permeability and lead to leakage of cytosolic components and fungal death.

    “Polyenes such as nystatin and amphotericin B (both isolated from Streptomyces spp.) bind ergosterol and disrupt the major lipidic component of the fungal cell membrane resulting in the production of aqueous pores (Figure 1). Consequently, the cellular permeability is altered and leads to the leakage of cytosolic components and, therefore, fungal death [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Sanglard D Odds FC Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences The Lancet Infectious Diseases 2002 2 2 73 85 2-s2.0-0036488166 11901654 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Premisenone given

    Invasive Candida infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies.

    “However, invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Antifungal resistance is based on different mechanisms: reduced drug intracellular accumulation, decreased target affinity/processivity for the drug, and counteraction of the drug effect.

    “Antifungal resistance is based on different mechanisms, namely, (i) reduced drug intracellular accumulation, (ii) decreased target affinity/processivity for the drug, and (iii) counteraction of the drug effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Plants contain diverse components that are important sources of biologically active molecules, and essential oils have strong antifungal activity.

    “Among the natural products, plants contain diverse components that are important sources of biologically active molecules [50, 133, 134]. In fact, the activity of plant crude extracts against different microorganisms has been reported, that is, strong antifungal activity of some major components of essential oils [135, 136].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [50] Sortino M Derita M Svetaz L Filho VC 6. The role of natural products in discovery of new anti-infective agents with emphasis on antifungal compounds Plant Bioactives and Drug Discovery: Principles, Practice, and Perspectives 2012 205 239

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    • cites [133] Duarte MCT Figueira GM Sartoratto A Rehder VLG Delarmelina C Anti-Candida activity of Brazilian medicinal plants Journal of Ethnopharmacology 2005 97 2 305 311 2-s2.0-13544272742 15707770

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    • cites [134] Butler MS The role of natural product chemistry in drug discovery Journal of Natural Products 2004 67 12 2141 2153 2-s2.0-11344292132 15620274 source

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    • cites [135] Mondello F de Bernardis F Girolamo A Cassone A Salvatore G In vivo activity of terpinen-4-ol, the main bioactive component of Melaleuca alternifolia Cheel (tea tree) oil against azole-susceptible and -resistant human pathogenic Candida species BMC Infectious Diseases 2006 6, article 158 2-s2.0-33751341585 PMC1637110 17083732

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    • cites [136] Manohar V Ingram C Gray J Antifungal activities of origanum oil against Candida albicans Molecular and Cellular Biochemistry 2001 228 1-2 111 117 2-s2.0-0035707457 11855736

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

    Premisecitation

    Higher than usual doses of amphotericin B have been recommended by the Infectious Diseases Society of America for treating candidemia caused by C. glabrata and C. krusei.

    “In this regard, higher than usual doses of amphotericin B have been recommended by the Infectious Diseases Society of America for treating candidemia caused by C. glabrata and C. krusei [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Rex JH Walsh TJ Sobel JD Practice guidelines for the treatment of candidiasis Clinical Infectious Diseases 2000 30 4 662 678 2-s2.0-0033796346 10770728 source

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  • May combine two claims.

    Interpretationcitation

    Terpenoids may be useful in the near future not only as an antifungal chemotherapeutic agent but also to synergize effects of conventional drugs like fluconazole.

    “Thus, terpenoids may be useful in the near future not only as an antifungal chemotherapeutic agent but also to synergize effects of conventional drugs like fluconazole [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Zore GB Thakre AD Jadhav S Karuppayil SM Terpenoids inhibit Candida albicans growth by affecting membrane integrity and arrest of cell cycle Phytomedicine 2011 18 13 1181 1190 2-s2.0-80053917396 21596542

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

    Premisenone given

    Primary resistance to flucytosine remains low (<2%).

    “Primary resistance to flucytosine remains low (<2%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Alteration of late steps of ergosterol biosynthesis through ERG3 inactivation leads to total inactivation of C5 sterol desaturase, so toxic 14α-methylated sterols are no longer accumulated and yeast produce membranes devoid of ergosterol but containing other sterols.

    “Alteration of the late steps of the biosynthesis of ergosterol through ERG3 inactivation leads to the total inactivation of the C5 sterol desaturase [110]. Thus, toxic 14α-methylated sterols are no longer accumulated, and yeast strains produce cell membranes devoid of ergosterol but containing other sterols [110].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Miyazaki Y Geber A Miyazaki H Cloning, sequencing, expression and allelic sequence diversity of ERG3 (C-5 sterol desaturase gene) in Candida albicans Gene 1999 236 1 43 51 2-s2.0-0032783722 10433965

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    Premisecitation

    Mutations in FKS1 did not alter substrate binding but lowered Vmax values.

    “Mutations in FKS1 did not alter substrate binding but lowered V max⁡ values [122].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Garcia-Effron G Park S Perlin DS Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints Antimicrobial Agents and Chemotherapy 2009 53 1 112 122 2-s2.0-59749090444 18955538 PMC2612148 source

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  • May combine two claims.

    Premisecitation

    Upregulation of ERG11 leads to an intracellular increase of the target protein, and ERG11 overexpression occurs by transcription factor regulation and gene duplication.

    “The first system involves an upregulation of the ERG11 gene leading to an intracellular increase of the target protein. ERG11 overexpression occurs by transcription factor regulation and gene duplication (reviewed in [95]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Noël T The cellular and molecular defense mechanisms of the Candida yeasts against azole antifungal drugs Journal de Mycologie Médicale 2012 22 173 178 23518020

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  • May combine two claims.

    Premisenone given

    Polyene resistance tends to be species dependent; C. glabrata and C. krusei are usually considered susceptible to amphotericin B, although they show higher MICs to polyenes than C. albicans.

    “Resistance tends to be species dependent. C. glabrata and C. krusei are usually considered to be susceptible to amphotericin B, although they show higher MICs to polyenes than C. albicans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Terpenes have antibiofilm activity, and carvacrol, geraniol, and thymol are exceptionally efficient in the treatment of candidiasis associated with medical devices.

    “In this regard, the antibiofilm activity of terpenes and the exceptional efficiency of carvacrol, geraniol, and thymol, in the treatment of candidiasis associated with medical devices, have been demonstrated [137].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Dalleau S Cateau E Bergès T Berjeaud J-M Imbert C In vitro activity of terpenes against Candida biofilms International Journal of Antimicrobial Agents 2008 31 6 572 576 2-s2.0-43549118135 18440786

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

    Premisenone given

    Echinocandin drugs are recommended as the first line for invasive candidiasis.

    “Echinocandin drugs are recommended as the first line for invasive candidiasis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Upregulation of CDR1/CDR2 and MDR1 arises from mutations in TAC1 and MRR1 transcription factors, respectively.

    “Upregulation of CDR1/CDR2 and MDR1 arises from mutations in TAC1 and MRR1 transcription factors, respectively [97, 98].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [97] Coste AT Karababa M Ischer F Bille J Sanglard D TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2 Eukaryotic Cell 2004 3 6 1639 1652 2-s2.0-11144270183 15590837 PMC539021 source

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    • cites [98] Coste A Turner V Ischer F A mutation in TAC1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans Genetics 2006 172 4 2139 2156 2-s2.0-33646171879 16452151 PMC1456413 source

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  • May combine two claims.

    Premisecitation

    The target of azole antifungals is lanosterol 14-α-demethylase encoded by ERG11, and several point mutations in ERG11 are associated with azole MIC increases.

    “The target of azole antifungals is the lanosterol 14-α-demethylase encoded by the ERG11 gene. Several point mutations have been characterized and associated to azole minimum inhibitory concentration (MIC) increases (reviewed in [95]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Noël T The cellular and molecular defense mechanisms of the Candida yeasts against azole antifungal drugs Journal de Mycologie Médicale 2012 22 173 178 23518020

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

    Interpretationnone given

    The rapid development of antifungal resistance, the toxicity and variability in available formulations of some agents, and the increase in frequency of non-albicans Candida spp. infections support the need for more effective and less toxic treatment strategies.

    “The rapid development of antifungal resistance, the toxicity and the variability in available formulations of some agents, and the increase in the frequency of non-albicans Candida spp. infections support the need for more effective and less toxic treatment strategies.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    E1210 is currently in Phase II.

    “Currently, E1210 is in Phase II.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In neutropenic mice with disseminated C. tropicalis or C. krusei infections, isavuconazole treatment significantly reduced kidney burden in C. tropicalis and both kidney and brain burden in C. krusei.

    “Studies carried out with neutropenic mice of disseminated C. tropicalis or C. krusei infections showed that the treatment significantly reduced kidney burden in mice infected with C. tropicalis and both kidney and brain burden in mice infected with C. krusei [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Majithiya J Sharp A Parmar A Denning DW Warn PA Efficacy of isavuconazole, voriconazole and fluconazole in temporarily neutropenic murine models of disseminated Candida tropicalis and Candida krusei Journal of Antimicrobial Chemotherapy 2009 63 1 161 166 2-s2.0-57649180452 19008255 PMC2721698

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  • May combine two claims.

    Premisecitation

    Oral bioavailability of albaconazole was calculated to be 80% in rats and 100% in dogs.

    “Oral bioavailability was calculated to be 80% in rats and 100% in dogs [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Pasqualotto AC Denning DW New and emerging treatments for fungal infections The Journal of Antimicrobial Chemotherapy 2008 61 i19 i30 2-s2.0-41949128129 18063600

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  • May combine two claims.

    Premisecitation

    N,N-dimethylbiguanide complexes displayed low cytotoxicity and could be considered as potential broad-spectrum agents.

    “The first group includes chemicals based on N,N-dimethylbiguanide complexes [52]. These compounds displayed low cytotoxicity and could be considered as potential broad-spectrum agents [53].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Olar R Badea M Marinescu D Prospects for new antimicrobials based on N,N-dimethylbiguanide complexes as effective agents on both planktonic and adhered microbial strains European Journal of Medicinal Chemistry 2010 45 7 2868 2875 2-s2.0-77954348554 20363535

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    • cites [53] Olar R Badea M Marinescu D N, N-dimethylbiguanide complexes displaying low cytotoxicity as potential large spectrum antimicrobial agents European Journal of Medicinal Chemistry 2010 45 7 3027 3034 2-s2.0-77954349758 20403647

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  • May combine two claims.

    Premisecitation

    Both oral and intravenous formulations of isavuconazole showed favorable pharmacokinetic and pharmacodynamic profiles.

    “Both oral and intravenous formulations showed favorable pharmacokinetic (Table 4) and pharmacodynamic profiles [82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Girmenia C New generation azole antifungals in clinical investigation Expert Opinion on Investigational Drugs 2009 18 9 1279 1295 2-s2.0-68849117064 19678798

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  • May combine two claims.

    Premisecitation

    Albaconazole is a new oral triazole with broad-spectrum antifungal activity, unique pharmacokinetics, and excellent tolerability.

    “Albaconazole is a new oral triazole with broad-spectrum antifungal activity, unique pharmacokinetics, and excellent tolerability [146].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Bartroli J Merlos M Overview of albaconazole European Infectious Disease 2011 5 2 88 91 2-s2.0-84857583704

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  • May combine two claims.

    Premisenone given

    Isavuconazole is the active metabolite of the water-soluble prodrug isavuconazonium, a novel second-generation water-soluble triazole with broad-spectrum antifungal activity, also against azole-resistant strains.

    “Finally, isavuconazole (the active metabolite of the water-soluble prodrug isavuconazonium) is a novel second-generation water-soluble triazole with broad-spectrum antifungal activity, also against azole-resistant strains.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Antifungal resistance based on different mechanisms continues to grow and evolve and exacerbates the need for new treatments against Candida infections.

    “Additionally antifungal resistance based on different mechanisms continues to grow and evolve and exacerbate the need of new treatments against Candida infections.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Three agents with actual promise for the treatment of Candida infections are E1210, albaconazole, and isavuconazole.

    “The mentioned agents have been tried in vitro against Candida; however, many of them are not used in clinical treatments; in this regard, there are three agents with actual promise: E1210, albaconazole, and isavuconazole (Figure 2).”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    New formulations of antifungals, combination therapies, and development of new bioactive compounds might be useful for a better therapeutic outcome.

    “In this regard, new formulations of antifungals, combination therapies and development of new bioactive compounds might be useful for a better therapeutic outcome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    E1210 is a broad-spectrum antifungal agent with a novel mechanism of action based on inhibition of fungal glycosylphosphatidylinositol biosynthesis.

    “E1210 is a broad-spectrum antifungal agent with a novel mechanism of action based on the inhibition of fungal glycosylphosphatidylinositol biosynthesis [144, 145].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [144] Watanabe N-A Miyazaki M Horii T Sagane K Tsukahara K Hata K E1210, a new broad-spectrum antifungal, suppresses Candida albicans hyphal growth through inhibition of glycosylphosphatidylinositol biosynthesis Antimicrobial Agents and Chemotherapy 2012 56 2 960 971 2-s2.0-84856073587 22143530 PMC3264227 source

      Not checked in the free run.

    • cites [145] Miyazaki M Horii T Hata K In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds Antimicrobial Agents and Chemotherapy 2011 55 10 4652 4658 2-s2.0-80052854203 21825291 PMC3186989 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Albaconazole was highly effective in vitro against pathogenic yeasts and in animal models of systemic candidiasis.

    “It has been demonstrated that this compound was highly effective in vitro against pathogenic yeasts and also in animal models of systemic candidiasis [146].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Bartroli J Merlos M Overview of albaconazole European Infectious Disease 2011 5 2 88 91 2-s2.0-84857583704

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Enfumafungin is a new triterpene glycoside that inhibits (1,3)-β-D-glucan synthase and has comparable activity to caspofungin acetate against Candida pathogenic fungal strains.

    “A natural antifungal with comparable activity to that of caspofungin acetate against Candida pathogenic fungal strains was isolated [51]. The compound, named enfumafungin, is a new triterpene glycoside that inhibits the (1,3)-β-D-glucan synthase.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Peláez F Cabello A Platas G The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms Systematic and Applied Microbiology 2000 23 3 333 343 2-s2.0-0033678540 11108011

      Not checked in the free run.

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

    Premisenone given

    Although antifungal drugs used in clinical treatments appear diverse and numerous, only few classes of antifungal agents are currently available in oral and intravenous forms.

    “Although the antifungal drugs used in clinical treatments appear to be diverse and numerous, only few classes of antifungal agents are currently available in oral and intravenous forms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Oral E1210 significantly reduced the number of viable Candida in the oral cavity compared to control and prolonged survival of mice infected with Candida spp.; therapeutic responses were dose dependent.

    “Results indicate that E1210 significantly reduced the number of viable Candida in the oral cavity in comparison to that of the control treatment and prolonged survival of mice infected with Candida spp. Therapeutic responses were dose dependent [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Hata K Horii T Miyazaki M Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis Antimicrobial Agents and Chemotherapy 2011 55 10 4543 4551 2-s2.0-80052856780 21788462 PMC3187015 source

      Not checked in the free run.

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

    Premisenone given

    Echinocandin derivatives are poorly absorbed when administered orally and therefore are used only for IV administration.

    “Unfortunately, echinocandins derivatives are poorly absorbed when administered orally and, therefore, are used only for IV administration.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Albaconazole is currently in Phase II.

    “Currently, albaconazole is in Phase II.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    There are three compounds in Phase II or III studies with actual promise for the treatment of invasive candidiasis.

    “Particularly, there are three compounds in Phase II or III studies with actual promise for the treatment of invasive candidiasis.”
    Quote in the paperNot a substantial claim
44 of 44

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?

  • C. lusitaniae, C. guilliermondii, C. glabrata, and C. krusei have a generally lower susceptibility to polyenes.

    “Finally, C. lusitaniae, C. guilliermondii, C. glabrata, and C. krusei have a generally lower susceptibility to polyenes [36,37].”

    From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [36]

  • Decreased susceptibility towards flucytosine has been associated with point mutations in FCY1, FCY2, and FUR1 genes and the deletion of FPS1 and FPS2 genes.

    “Decreased susceptibility towards flucytosine has been associated with point mutations in FCY1, FCY2, and FUR1 genes and the deletion of FPS1 and FPS2 genes [36,114,115,116,117].”

    From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [36]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Soykan et al. study dated 2011 in text but 2007 in reference

    Minor

    The text dates the cited Soykan et al. study to 2011, while reference 73 lists its publication year as 2007.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 9

  1. 2003, Antifungal drugs, 700
  2. 2004, Current Medicinal Chemistry, 11, 1645
  3. 2007, Arkivoc, 2007, 116
  4. 2007, Journal of Biomedical Materials Research B, 83, 609
  5. 2001, Drugs, 61, 13
  6. 2004, Clinical Microbiology and Infection, 10, 1
  7. 2002, Journal of Antimicrobial Chemotherapy, 49, 7
  8. 2011, European Infectious Disease, 5, 88
  9. 2006, Current Opinion in Investigational Drugs, 7, 766

Cited by

Sorted by citations

Related

Authors
Spampinato, C., & Leonardi, D.
Affiliations
Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
Corresponding author
Leonardi, Darío
ORCID
Venue
BioMed Research International
Publisher
Wiley
Published
2013
Volume
2013
Pages
1-13
ISSN
  • 1110-7243 (ISSN-L)
  • 2314-6133
  • 2314-6141
DOI
10.1155/2013/204237
PMC
PMC3708393
OpenAlex
W1994957997
Semantic Scholar
e1fa63d07f16ff5fd20d0ede8f7457e6fc44297f
Cited by
411
References
150
Citations by year
2026: 12 · 2025: 31 · 2024: 37 · 2023: 37 · 2022: 50 · 2021: 58 · 2020: 47 · 2019: 32 · 2018: 29 · 2017: 22 · 2016: 20 · 2015: 14 · 2014: 20 · 2013: 2
FWCI
2.41
Type
journal article
Language
en
Open access
Licence
Locations
  • BioMed Research International (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repositorio Hipermedial UNR (Universidad Nacional de Rosario) (publishedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
  • Americanae (AECID Library) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Agencia Nacional de Promoción Científica y Tecnológica
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
candidiasis, invasive candidiasis, superficial candidiasis, antifungal agents, antifungal resistance mechanisms, opportunistic fungal pathogens, immunocompromised patients, alternative antifungal therapy, Candida species
MeSH terms
Antifungal Agents, Candida, Candidiasis, Humans, Drug Resistance, Fungal

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.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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