Direct Comparison of the Pharmacodynamics of Four Antifungal Drugs in a Mouse Model of Disseminated Candidiasis Using Microbiological Assays of Serum Drug Concentrations

Maki, Katsuyuki; Holmes, Ann R.; Watabe, Etsuko; Iguchi, Yumi; Matsumoto, Satoru; Ikeda, Fumiaki; Tawara, Shuichi; Mutoh, Seitaro

doi:10.1111/j.1348-0421.2007.tb04000.x

Cited by 8 publications

(36 citation statements)

References 22 publications

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“…FCZ. The dose of FCZ used in the present study was determined on the basis of a literature search 19 and preliminary experiments. We found that 0.5 mg/kg FCZ approximated the ED 50 of FCZ and was able to protect fungusinfected mice and prolong their survival.…”

Section: Survival Analysismentioning

confidence: 99%

“…assay is the most commonly used method to investigate infection with C. albicans. [19][20][21][22][23][24] Briefly, fungal cells were prepared and injected as described above for the mouse model of systemic candidiasis. Drug treatments were given to 10 different groups (n ¼ 5 mice in each group) for 7 consecutive days with once daily injections.…”

Section: Survival Analysismentioning

confidence: 99%

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Ascorbic acid decreases the antifungal effect of fluconazole in the treatment of candidiasis

Wang¹,

Jia

et al. 2009

Clin Exp Pharma Physio

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1. The aim of the present study was to investigate the effects of ascorbic acid (AA) on the antifungal activity of fluconazole (FCZ) in a systemic murine candidiasis model as well as in vitro. 2. The murine model was established by infusion of Candida albicans via the tail vein. Control mice received no further treatment. Other groups of mice were injected with FCZ (0.5 mg/kg, i.p.) and then treated or not with 50 or 500 mg/kg AA intragastrically (i.g.) or i.p. In all groups, FCZ was administered i.p. 2 h after fungal inoculation, whereas AA was administered 6 h after fungal inoculation. Survival rate, kidney fungal burden and renal pathological changes were evaluated. 3. The in vitro effects of AA (5, 1 and 0.2 mmol/L) on the growth of various Candida strains in the presence of FCZ (0.125-64 microg/mL) were also investigated. The in vitro effects of two anti-oxidants, namely N-acetylcysteine (NAC; 5, 1 and 0.2 mmol/L) and reduced glutathione (GSH; 5, 1 and 0.2 mmol/L), on FCZ activity were evaluated to determine the mechanism of action of AA. 4. Intragastric administration of AA (50 or 500 mg/kg) significantly decreased the antifungal effect of 0.5 mg/kg FCZ. Although i.p. administration of AA (50 or 500 mg/kg) had no significant effect on the survival of mice, it dose-dependently inhibited the activity of FCZ, with significant inhibition observed with 500 mg/kg AA. 5. In vitro, AA decreased the activity of FCZ against various Candida strains. Both NAC and GSH dose-dependently decreased the activity of FCZ. 6. The results of the present study indicate that AA inhibits the antifungal activity of FCZ, suggesting that the two should not be used together clinically for the treatment of candidiasis.

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Section: Survival Analysismentioning

confidence: 99%

Section: Survival Analysismentioning

confidence: 99%

Ascorbic acid decreases the antifungal effect of fluconazole in the treatment of candidiasis

Wang¹,

Jia

et al. 2009

Clin Exp Pharma Physio

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“…These dose-based investigations were used to indicate the optimal clinical dose regimen for improving efficacy and for prediction of the clinical outcome against susceptible and resistant pathogens (Lee et al 2000; Pai et al 2007; Clancy et al 2005). Although these MIC data contributed to progress in antifungal therapy, the values do not correspond to the in vivo effective concentrations (Maki et al 2007, 2008) and accurate pharmacodynamic parameters, such as the time to reach an effective concentration in vivo could not be determined. Furthermore, there are no criteria for determining sub-MIC values using such methods, and the sub-MIC effect cannot be discriminated from the post-antifungal effect (PAFE).…”

Section: Introductionmentioning

confidence: 99%

“…We have previously demonstrated that the use of an ex vivo (mouse serum) assay of mycelial growth (Maki et al 2006) can be applied to enable direct comparison of the serum concentrations of azoles and the polyene, amphotericin B (Maki et al 2007) and the in vivo efficacy of echinocandins (Maki et al 2008) in a mouse model of infection. The use of undiluted serum is important because the bloodstream environment determines most in vivo protein binding of drugs (Hage et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Effective concentration-based serum pharmacodynamics for antifungal azoles in a murine model of disseminated Candida albicans infection

Maki

Kaneko

2013

Eur J Drug Metab Pharmacokinet

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An assessment of the effective in vivo concentrations of antifungal drugs is important in determining their pharmacodynamics, and therefore, their optimal dosage regimen. Here we establish the effective in vivo concentration-based pharmacodynamics of three azole antifungal drugs (fluconazole, itraconazole, and ketoconazole) in a murine model of disseminated Candida albicans infection. A key feature of this study was the use of a measure of mycelial (m) growth rather than of yeast growth, and pooled mouse sera rather than synthetic media as a growth medium, for determining the minimum inhibitory concentrations (MICs) of azoles for C. albicans (denoted serum mMICs). The serum mMIC assay was then used to measure antifungal concentrations and effects as serum antifungal titers in the serum of treated mice. Both serum mMIC and sub-mMIC values reflected the effective in vivo serum concentrations. Supra-mMIC and mMIC effects exhibited equivalent efficacies and were concentration-independent, while the sub-mMIC effect was concentration-dependent. Following administration of the minimum drug dosage that inhibited an increase in mouse kidney fungal burden, the duration periods of these effects were similar for all drugs tested. The average duration of either the mMIC effect including the supra-mMIC effect, the sub-mMIC effect, or the post-antifungal effect (PAFE) were 6.9, 6.5 and 10.6 h, respectively. Our study suggests that the area under the curve for serum drug concentration versus time, between the serum mMIC and the sub-mMIC, and exposure time above the serum sub-mMIC after the mMIC effect, are major pharmacodynamic parameters. These findings have important implications for effective concentration-based pharmacodynamics of fungal infections treated with azoles.

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High-performance liquid chromatographic analysis of amphotericin B in rat plasma using α-naphthol as an internal standard

Italia

Singh

Kumar

2009

Analytica Chimica Acta

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Direct Comparison of the Pharmacodynamics of Four Antifungal Drugs in a Mouse Model of Disseminated Candidiasis Using Microbiological Assays of Serum Drug Concentrations

Cited by 8 publications

References 22 publications

Ascorbic acid decreases the antifungal effect of fluconazole in the treatment of candidiasis

Ascorbic acid decreases the antifungal effect of fluconazole in the treatment of candidiasis

Effective concentration-based serum pharmacodynamics for antifungal azoles in a murine model of disseminated Candida albicans infection

High-performance liquid chromatographic analysis of amphotericin B in rat plasma using α-naphthol as an internal standard

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