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Cited by 54Antifungal resistance and susceptibilityCancer, Lipids, and MetabolismFungal and yeast genetics research

Synergistic antifungal activity of statin–azole associations as witnessed by Saccharomyces cerevisiae- and Candida utilis-bioassays and ergosterol quantification

Open access
Cabral, María Eugenia, Figueroa, Lucía I.C., Fariña, Julia I.·2013·Revista Iberoamericana de Micología
DOI 10.1016/j.riam.2012.09.006
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Abstract

Background Frequent opportunist fungal infections and the resistance to available antifungal drugs promoted the development of new alternatives for treatment, like antifungal drug combinations.Aims This work aimed to detect the antifungal synergism between statins and azoles by means of an agar-well diffusion bioassay with Saccharomyces cerevisiae ATCC 32051 and Candida utilis Pr(1-2) as test strains.Methods Synergistic antifungal effects were tested by simultaneously adding a sub inhibitory concentration (SIC) of statin (atorvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) plus a minimal inhibitory concentration (MIC) of azole (clotrimazole, fluconazole, itraconazole, ketoconazole or miconazole) to yeast-embedded YNB agar plates, and a positive result corresponded to a yeast growth inhibition halo higher than that produced by the MIC of the azole alone. Yeast cell ergosterol quantification by RP-HPLC was used to confirm statin-azole synergism, and ergosterol rescue bioassays were performed for evaluating statin-induced ergosterol synthesis blockage.Results Growth inhibition was significantly increased when clotrimazole, fluconazole, itraconazole, ketoconazole and miconazole were combined with atorvastatin, lovastatin, rosuvastatin and simvastatin. Highest growth inhibition increments were observed on S. cerevisiae (77.5%) and C. utilis (43.2%) with a SIC of simvastatin plus a MIC of miconazole, i.e. 4 + 2.4 μg/ml or 20 + 4.8 μg/ml, respectively. Pravastatin showed almost no significant effects (0-7.6% inhibition increase). Highest interaction ratios between antifungal agents corresponded to simvastatin-miconazole combinations and were indicative of synergism. Synergism was also confirmed by the increased reduction in cellular ergosterol levels (S. cerevisiae, 40% and C. utilis, 22%). Statin-induced ergosterol synthesis blockage was corroborated by means of ergosterol rescue bioassays, pravastatin being the most easily abolished inhibition whilst rosuvastatin being the most ergosterol-refractory.Conclusions Selected statin-azole combinations might be viable alternatives for the therapeutic management of mycosis at lower administration doses or with a higher efficiency.

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Crossref · 10.1016/j.riam.2012.09.006

Cites

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Statistics

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Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The increase in growth inhibition spanned 25.3-77.5% for S. cerevisiae and 7.0-43.2% for C. utilis.

    “The growth inhibition potentiation ranged between 25.3 and 77.5% for S. cerevisiae (Fig. 1a), and between 7.0 and 43.2% for C. utilis (Fig. 1b).”
    Quote in the paperSubstantial claim
  • Findingown data

    Rescue by ergosterol occurred at 5-25 mmol/l.

    “Ergosterol rescue could be detected at concentrations between 5 and 25 mmol/l.”
    Quote in the paperSubstantial claim
  • Findingown data

    For C. utilis, the same combination produced a 22% greater decrease in ergosterol than the two drugs given separately.

    “Likewise, in the case of C. utilis, the same drugs association led to a 22%-enhanced ergosterol level drop as compared to the summation of simvastatin and miconazole separate effects (Fig. 3b and c).”
    Quote in the paperSubstantial claim
  • Findingown data

    Despite reversion to varying extents, yeast growth could not be completely restored for some statins.

    “It should be also noted that, despite inhibition could be reverted to a higher or lesser extent, particularly for some statins, yeast growth could not be completely restored.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Pravastatin showed the weakest synergy in both yeasts, increasing inhibition by only 0-7.6% for S. cerevisiae and 0-4% for C. utilis.

    “Pravastatin exhibited the mildest synergism in both yeasts, with increment values around 0-7.6% for S. cerevisiae, and between 0 and 4% against C. utilis.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 34
  • May combine two claims. 20
  • The quote only partly states this claim. 1

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

    Findingcitation

    The statin MIC values obtained in this work are in the order of those reported by other researchers.

    “The statin MIC values obtained in the present work would be in the order of those elsewhere reported by other researchers.”
    Quote in the paperNot a substantial claim

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    Findingown data

    Statins differed in ergosterol reversion: pravastatin's inhibition was most easily reversed, while rosuvastatin's was most resistant to ergosterol rescue in both yeasts.

    “However, differences in ergosterol reversion could be observed among tested statins, pravastatin being the easiest inhibition to be abolished and rosuvastatin being the most ergosterol-refractory inhibition in both yeasts (Fig. 4).”
    Quote in the paperNot a substantial claim

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    Findingown data

    By the IR criterion, the top combinations for S. cerevisiae involved atorvastatin, rosuvastatin, or simvastatin at SIC with clotrimazole (IR 2.2-2.6), itraconazole (IR 2.3-2.6), or miconazole (IR 2.6-3); simvastatin associations usually gave the highest values.

    “According to the IR criterion, the best combinations against S. cerevisiae were those between either atorvastatin, rosuvastatin or simvastatin at SIC with MICs of clotrimazole (IR, 2.2-2.6),itraconazole (IR, 2.3-2.6) or miconazole (IR, 2.6-3).Usually, the highest values corresponded to simvastatin associations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In C. utilis, the strongest synergy appeared with miconazole-rosuvastatin (IR 1.8) and miconazole-simvastatin (IR 2.2).

    “In the case of C. utilis, the most significant synergistic effects were observed for miconazole-rosuvastatin (IR, 1.8) and miconazole-simvastatin (IR, 2.2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The most effective combination was simvastatin at SIC with miconazole at MIC, which enhanced inhibition by 77.5% in S. cerevisiae and 43.2% in C. utilis.

    “The best combination according to the in vitro activity resulted from the association between the SIC of simvastatin and the MIC of miconazole, displaying a 77.5% inhibition enhancement against S. cerevisiae, and 43.2% against C. utilis (Fig. 1a and b).”
    Quote in the paperSubstantial claim

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    Findingown data

    For atorvastatin, lovastatin, rosuvastatin, and simvastatin, the MIC was 40 g/ml for S. cerevisiae and 200 g/ml for C. utilis, i.e., 1 and 5 g per well.

    “the MICs for atorvastatin, lovastatin, rosuvastatin and simvastatin were 40 g/ml against S. cerevisiae whilst 200 g/ml in the case of C. utilis, with corresponding doses of 1 and 5 g per well, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Statins and azoles interfere with sterol biosynthesis through different mechanisms: statins inhibit HMG-CoA reductase and azoles block sterol C-14 α-demethylation.

    “By means of a different mechanism, statins by inhibiting HMG-CoA reductase, and azoles by blocking sterol C-14 ␣-demethylation, both interfere with sterol biosynthesis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    Figure 4 shows ergosterol rescue of statin-induced growth inhibition in S. cerevisiae and C. utilis.

    “Ergosterol rescue of statin-induced growth inhibition in S. cerevisiae ATCC 32051 (a) and C. utilis Pr 1-2 (b).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The inhibition haloes in the agar-well diffusion bioassay provide a valid measure of antifungal activity and of synergy between agents.

  • Classified as probably not a substantial claim.

    Findingown data

    Figure 2 shows effects of miconazole, simvastatin and their synergistic combination on cellular sterols content of S. cerevisiae and C. utilis after growth in liquid cultures, detected by TLC.

    “Effects of miconazole (MCZ), simvastatin (Sim) and their synergic combination (MCZ + Sim) on the cellular sterols content of S. cerevisiae ATCC 32051 (a) and C. utilis Pr 1-2 (b) after growth in liquid cultures, as detected by TLC.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The inhibition haloes in the agar-well diffusion bioassay provide a valid measure of antifungal activity and of synergy between agents.

  • Classified as probably not a substantial claim.

    Findingown data

    Figure 3 shows influence of miconazole, simvastatin and their synergistic combination on cellular ergosterol content of S. cerevisiae and C. utilis after growth in liquid cultures, according to RP-HPLC.

    “Influence of miconazole (MCZ), simvastatin (Sim) and their synergic combination (MCZ + Sim) on the cellular ergosterol content of S. cerevisiae ATCC 32051 (a) and C. utilis Pr 1-2 (b) after growth in liquid cultures, according to RP-HPLC.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The inhibition haloes in the agar-well diffusion bioassay provide a valid measure of antifungal activity and of synergy between agents.

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

    Premisecitation

    The incidence of systemic mycoses has increased dramatically in recent years, driven by rising AIDS prevalence and widespread use of immunosuppressive drugs.

    “The incidence of systemic mycoses has dramatically increased over last years, a fact particularly favoured by the raising prevalence of acquired immune deficiency syndrome (AIDS) and the unrestrained use of immunocompromising drugs.9”
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    Premisecitation

    S. cerevisiae, traditionally considered non-pathogenic, has been reported as an opportunistic pathogen in immunocompromised patients.

    “Numerous cases of superficial or mild systemic infections caused by Saccharomyces cerevisiae, a yeast”
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    Premisecitation

    Azole treatment for fungal infections has limitations such as poor aqueous solubility, limited bioavailability, and common adverse effects from high or prolonged dosing.

    “the administration of azoles for treating fungal infections has encountered certain limitations, such as their low water solubility, low bioavailability, and frequent side effects consequent on the requirement of high doses and/or long-term administration.21,42”
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    Study design and conductown data

    Each bioassay was performed three times, and means with standard deviations were computed.

    “Bioassays were run in triplicate and mean and standard deviation values were calculated (Microcal OriginTM version 6.0).”
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    Premisecitation

    Azoles exhibit a certain degree of toxicity that has already been demonstrated.

    “Nevertheless, in comparison, azoles exhibit a certain degree of toxicity that has been already demonstrated.5,19”
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    Premisecitation

    Lukács et al. described distinct sensitivity to statins in Mucor circinelloides, with MIC values in the order of those reported here and fluvastatin much more effective than lovastatin and simvastatin.

    “Distinct sensitivity to statins was also described by Lukács et al. in Mucor circinelloides, 22 with MIC values in the order of those herein reported and being fluvastatin much more effective than lovastatin and simvastatin.”
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  • Classified as probably not a substantial claim.

    Interpretationcitation

    The statin-driven increase in cellular permeability to exogenous sterols may additionally augment permeability, susceptibility, or both, to antifungal azoles.

    “As previously speculated, the statin-driven increase in cellular permeability to exogenous sterols may additionally augment the permeability, susceptibility or both, to antifungal azoles.21”
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  • May combine two claims.

    Interpretationreasoning

    The agar-well diffusion bioassay allowed testing five statins and five azoles in twenty-five combinations in a time-saving, simple, low-cost, reproducible way, and is a rapid, simple, low-cost and reliable approach for testing antifungal activity of statin-azole associations compared with liquid media assays.

    “According to this methodology, the effects of five statins (atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin) and five azoles (clotrimazole, fluconazole, itraconazole, ketoconazole and miconazole) in twenty-five different antifungal combinations could be tested in a time-saving, simple, low-cost and reproducible bioassay.”
    • Also stated in: § Discussion · boosted
      “In conclusion, the proposed agar-well diffusion bioassay showed to be a rapid, simple, low-cost and reliable approach to test antifungal activity of different statin-azole associations as compared to assays in liquid media.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The inhibition haloes in the agar-well diffusion bioassay provide a valid measure of antifungal activity and of synergy between agents.

  • Classified as probably not a substantial claim.

    Premisecitation

    Combining antifungal agents with other drugs to improve efficacy and/or decrease toxicity has been described as a possible approach.

    “Combination of antifungal agents with other drugs in order to improve the efficacy and/or decrease the toxicity has been described early as one of the possibilities.21,29,33”
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    Study design and conductnone given

    Controls were included in the bioassay to verify that solvents did not inhibit yeast growth.

    “Controls were included in order to verify the lack of solvent inhibitory effects on yeast growth.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The higher pravastatin concentrations found may be related to pravastatin's high hydrophilic nature, being the most polar natural statin.

    “The higher pravastatin concentrations eventually found may be related to the high hydrophilic nature of this statin, the most polar between natural statins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For fluvastatin, complete inhibition of C. albicans at physiological pH would require around 50 g/ml, while MIC values above 128 g/ml have been described for different Candida species and Cryptococcus neoformans.

    “Also for fluvastatin, a potent synthetic statin, complete inhibition of C. albicans at physiological pH would require around 50 g/ml, 32 whilst MIC values above 128 g/ml were described for different Candida species and Cryptococcus neoformans.11”
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    Study design and conductown data

    Ergosterol quantification used an RP-HPLC calibration curve with R2 = 0.994.

    “by using an ergosterol calibration curve (0-500 g/ml; R 2 = 0.994).”
    Quote in the paperNot a substantial claim

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    Interpretationcitation

    A possible explanation for divergent susceptibility among fungal genera and species may be differences in HMG-CoA reductase gene copy numbers.

    “A possible explanation may be a difference in HMG-CoA reductase gene copy numbers.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Lovastatin MIC values from 5 to 200 g/ml have been described for testing inhibitory effects and sterol level modifications on yeasts.

    “Lovastatin values ranging from 5 up to 200 g/ml have been already described for testing inhibitory effects and sterols levels modifications on yeasts.3,12,16,21”
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    Study design and conductown data

    The reversion assay included growth controls containing solvent alone or solvent with ergosterol to check that these did not suppress yeast growth.

    “growth controls with either the solvent or the solvent plus ergosterol were included to verify the lack of yeast growth inhibitory effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Interpretationcitation

    A further hypothesis for the enhancing effect is that statins reduce sterol esterification, causing accumulation of unesterified C-14 methyl sterols from azole action, and inability to accommodate them in membranes inhibits yeast growth.

    “As a further hypothesis for the enhancing effect observed, the ability of statins to reduce sterols esterification may lead to the accumulation of unsterified C-14 methyl sterols consequent on the azoles action, and the impossibility to accommodate them in cellular membranes would then inhibit yeast growth.21”
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    Premisecitation

    Repeated observations have shown that S. cerevisiae can resist some antifungal drugs.

    “the resistance of S. cerevisiae to certain antifungal agents has been also repeatedly observed.2,26,36,38”
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    Premisecitation

    An IR of 0.5-1.5 means additivity, below 0.5 means antagonism, and above 1.5 means synergism.

    “IR values between 0.5 and 1.5 correspond to additive interactions, IR < 0.5 indicates antagonism and IR > 1.5 denotes synergism.13”
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    Premisecitation

    C. utilis, a yeast used in biotechnology, has been reported as an opportunistic pathogen in fungemia.

    “Among those unconventional opportunistic pathogen Candida species, C. utilis, a yeast commonly used with biotechnological purposes such as single-cell protein production, has been reported in opportunistic fungemia.1,6,17”
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    Premisecitation

    Variables such as culture medium, pH, inoculum size or reading criteria produce a wide range of sensitivities depending on method or laboratory.

    “As also pointed out for azolic antifungals, variables such as culture medium, pH, inoculum size or reading criteria provide a wide range of sensitivities depending on the method used or the laboratory involved.9”
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    Interpretationcitation

    Controversy in statin susceptibility data may be due to differences in applied methodology and strains.

    “Controversy is frequently observed when comparing statins susceptibility data.That may be due to differences in the applied methodology and the strains involved.22”
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    Premisecitation

    Differences in effectiveness among statins have been correlated with structural divergences that may influence interaction with the catalytic site of HMG-CoA reductase.

    “Likewise, differences on the effectiveness among statins have been correlated to structural divergences, which may influence the interaction with the catalytic site of HMG-CoA reductase.13”
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    Premisecitation

    MIC definition may account for differences; some liquid-culture works defined MIC as the drug dose reducing growth by 50% by optical density, while others defined it as the minimal concentration with no visible growth.

    “For comparison purposes, the MIC definition may also account for differences.Some works, normally referring to liquid cultures, described MIC as the drug dose at which growth became reduced by 50%, as witnessed by optical density measurements.32,40 Nevertheless, there are authors that defined MIC as herein applied, i.e. the minimal concentration at which no visible growth occurred.3,21”
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    Premisecitation

    Lukács et al. demonstrated that increased hmgR gene dose by transformation decreased sensitivity to statins in M. circinelloides.

    “Lukács et al. have elegantly demonstrated a decreased sensitivity to statins in M. circinelloides when the hmgR gene dose became increased by transformation.22”
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    Premisecitation

    Macreadie et al. found MIC values higher than 40 g/ml for simvastatin and 100 g/ml for atorvastatin against Candida strains.

    “Macreadie et al. 23 found MIC values higher than 40 g/ml for simvastatin and 100 g/ml for atorvastatin against Candida strains.”
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    Premisecitation

    Research into azole-statin interactions has attracted renewed interest.

    “In this context, studies on the interaction between azoles and statins have gained renewed attention.10,11,27,32,37”
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    Interpretationown data

    The existing synergism between tested sterol biosynthetic inhibitors might be applied to reduce required azole doses for fungal treatments or to increase potency in refractory infections.

    “The existing synergism between tested sterol biosynthetic inhibitors (SBIs), which would exert an attractive multiplying effect, 12 might be applied for instance, to reduce the required doses of azoles for fungal treatments or eventually, for increasing their potency in the case of refractory infections.”
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    Premisecitation

    S. cerevisiae has been described as an attractive experimental system for studying azole toxicity mechanisms.

    “With respect to S. cerevisiae, it has been also described as an attractive experimental system for studying azole toxicity mechanisms.19”
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    Premisecitation

    Use of antifungal azoles for prophylaxis or empirical therapy was shown to promote a shift to non-albicans Candida infections in immunocompromised or cancer patients.

    “In addition, the use of antifungal azoles for prophylaxis or empirical therapy was shown to promote a shift to non-albicans Candida infections in immunocompromised or cancer patients.16”
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  • May combine two claims.

    Interpretationcitation

    Slow sterol uptake and statin-induced depletion of other mevalonate pathway endproducts may explain why sole ergosterol supplementation failed to rescue growth.

    “A slow sterol uptake as well as the deleterious statin-induced depletion of many other endproducts from the mevalonate pathway may account for the rescue fail by the sole ergosterol supplementation.40”
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    Interpretationcitation

    Co-administration of statins may be useful for increasing antifungal efficacy, decreasing toxic azole doses, and possibly obtaining desirable side effects such as tumour-abating properties.

    “The co-administration of statins may be useful not only for increasing the efficacy of the antifungal treatment or for decreasing the required doses of toxic azoles, but also for eventually obtaining desirable side effects such as tumour-abating properties.16,32,41”
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    Premisecitation

    The yeast strains tested here have already been considered low-virulent opportunistic pathogens.

    “Yeast strains herein tested have been already considered as low-virulent opportunistic pathogens.26,34”
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    Premisecitation

    Yeast isolates currently used in industrial or biotechnological processes may be potentially pathogenic.

    “From another point of view, yeasts isolates currently in use for industrial or biotechnological processes may be potentially pathogenic.20,26,34”
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    Premisecitation

    Infections caused by non-albicans Candida species are progressively increasing and are usually resistant to common antifungals, emphasizing the need for novel therapies.

    “In the case of C. utilis, infections caused by nonalbicans Candida species are progressively increasing and usually the cases are resistant to common antifungals, which emphasizes the need for novel therapies for their effective management.35”
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  • The paper relies on this without support.

    In vitro synergism between statins and azoles in S. cerevisiae and C. utilis predicts therapeutic efficacy in human mycoses.

    “Selected statin-azole combinations might be viable alternatives for the therapeutic management of mycosis at lower administration doses or with a higher efficiency.”

  • The paper relies on this without support.

    The agar-well diffusion bioassay with S. cerevisiae and C. utilis is a valid model for detecting antifungal synergism relevant to pathogenic fungi.

    “The strains S. cerevisiae ATCC 32051 (American Type Culture Collection), and Candida utilis Pr 1-2 (PROIMI-MIRCEN Culture Collection, Tucumán, Argentina), were systematically used for bioassays.”

  • The paper relies on this without support.

    The SIC of statins plus MIC of azoles is a combination that could allow lower administration doses in therapy.

    “Selected statin-azole combinations might be viable alternatives for the therapeutic management of mycosis at lower administration doses or with a higher efficiency.”

  • The paper relies on this without support.

    The strains used are representative of clinical isolates of S. cerevisiae and C. utilis.

    “The strains S. cerevisiae ATCC 32051 (American Type Culture Collection), and Candida utilis Pr 1-2 (PROIMI-MIRCEN Culture Collection, Tucumán, Argentina), were systematically used for bioassays.”

  • The paper relies on this without support.

    The inhibition haloes in the agar-well diffusion bioassay provide a valid measure of antifungal activity and of synergy between agents.

    “Agar-well diffusion bioassays demonstrated that SICs of statins significantly potentiated the activity of azoles against yeast growth, except for pravastatin.”
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  • The synergism between ATO and azole drugs might be attributed to the combined action of these drugs in reducing fungal ergosterol synthesis, which led to increasing cell membrane permeability and increasing the penetration of azoles in the fungal cell.

    “The synergism between ATO and azole drugs might be attributed to the combined action of these drugs in reducing fungal ergosterol synthesis, which led to increasing cell membrane permeability and increasing the penetration of azoles in the fungal cell (Chamilos et al. 2006; Nyilasi et al. 2010; Cabral et al. 2013; Lima et al. 2019).”

    From In vitro study on the potential fungicidal effects of atorvastatin in combination with some azole drugs against multidrug resistant Candida albicans (2021) · cites this paper as Cabral et al. 2013

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • The primary screen identified several drugs with known fluconazole chemosensitizing activities, including simvastatin, atorvastatin, lovastatin, artemisinin, amiodarone, sulfamethoxazole, doxycycline, nisoldipine, and tamoxifen.

    “In addition and as expected, the primary screen identified several drugs with known fluconazole chemosensitizing activities, such as the cholesterol-lowering agents; simvastatin, atorvastatin, and lovastatin, artemisinin, amiodarone, sulfamethoxazole, doxycycline, and the calcineurin inhibitors nisoldipine and tamoxifen19–25.”

    From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [25]

  • Pitavastatin's fluconazole chemosensitizing activity was superior to other pharmacologically related statin drugs that were reported to have fluconazole-chemosensitizing activities.

    “The pitavastatin’s fluconazole chemosensitizing activity was even more superior than the other pharmacologically-related statin drugs, which were reported to have fluconazole-chemosensitizing activities26,27.”

    From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [27]

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.

  • Reported statin MICs exceed the stated testing range

    Minor

    The methods say statins were tested only from 0.04 to 0.4 g/ml, but the results report MICs of 40 and 200 g/ml. Neither reported MIC could have been determined within the stated range.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Carrillo Muñoz, 1997, Resistencia in vitro al fluconazol e itraconazol en aislamientos clínicos de Candida spp y Cryptococcus neoformns, Rev Iberoam Micol, 14, 50

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Related

Authors
Cabral, M. E., Figueroa, L. I. C., & Fariña, J. I.
Affiliations
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
  • National University of Tucumán (AR)
Corresponding author
Fariña, Julia I.
ORCID
Venue
Revista Iberoamericana de Micología
Publisher
Elsevier BV
Published
2013-01
Volume
30
Issue
1
Pages
31-38
ISSN
1130-1406 (ISSN-L)
DOI
10.1016/j.riam.2012.09.006
OpenAlex
W2164228143
Semantic Scholar
75869b840734e085cfd59f7cd45a34b764462de7
Cited by
54
References
42
Citations by year
2025: 3 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 7 · 2014: 5 · 2013: 1
FWCI
2.87
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Revista Iberoamericana de Micología (publishedVersion)
  • PubMed (publishedVersion)
  • Conicet (submittedVersion, cc-by-nc-sa)
Funders
  • ANPCYT (PICT 38164/05)
  • CONICET (PIP 6202)
  • UNT (CIUNT D-415)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
combination antifungal therapy, statins, azoles, ergosterol, Saccharomyces cerevisiae, Candida utilis, simvastatin, miconazole, fluconazole, clotrimazole, pravastatin, rosuvastatin, lovastatin, atorvastatin, antifungal resistance, yeast growth inhibition
MeSH terms
Antifungal Agents, Candida, Drug Synergism, Ergosterol, Humans, Microbial Sensitivity Tests, Saccharomyces cerevisiae, Species Specificity, Triazoles, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Drug Resistance, Fungal, Disk Diffusion Antimicrobial Tests, In Vitro Techniques

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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