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Experimental Therapeutics

Optimizing Echinocandin Dosing and Susceptibility Breakpoint Determination via In Vivo Pharmacodynamic Evaluation against Candida glabrata with and without fks Mutations

Alexander Lepak, Mariana Castanheira, Daniel Diekema, Michael Pfaller, David Andes
Alexander Lepak
aUniversity of Wisconsin, Madison, Wisconsin, USA
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Mariana Castanheira
cJMI Laboratories, North Liberty, Iowa, USA
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Daniel Diekema
bUniversity of Iowa, Iowa City, Iowa, USA
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Michael Pfaller
bUniversity of Iowa, Iowa City, Iowa, USA
cJMI Laboratories, North Liberty, Iowa, USA
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David Andes
aUniversity of Wisconsin, Madison, Wisconsin, USA
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DOI: 10.1128/AAC.01102-12
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  • Fig 1
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    Fig 1

    Dose-response relationships for anidulafungin against multiple C. glabrata isolates, including the wild type and fks mutants. Each point represents the mean burden of infection in the kidneys of three neutropenic mice. The dashed line represents the burden of organisms at the start of therapy. Points above the line represent organism growth, whereas points below the line represent organism death (i.e., fungicidal activity).

  • Fig 2
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    Fig 2

    Dose-response relationships for caspofungin against multiple C. glabrata isolates, including the wild type and fks mutants. Each point represents the mean burden of infection in the kidneys of three neutropenic mice. The dashed line represents the burden of organisms at the start of therapy. Points above the line represent organism growth, whereas points below the line represent organism death (i.e., fungicidal activity).

  • Fig 3
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    Fig 3

    Dose-response relationships for micafungin against multiple C. glabrata isolates, including the wild type and fks mutants. Each point represents the mean burden of infection in the kidneys of three neutropenic mice. The dashed line represents burden of organisms at the start of therapy. Points above the line represent organism growth, whereas points below the line represent organism death (i.e., fungicidal activity).

  • Fig 4
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    Fig 4

    Relationship between the free drug 24-h AUC/MIC (AUCf/MIC) and efficacy of anidulafungin (A), caspofungin (B), and micafungin (C) against the wild type and fks mutant C. glabrata isolates. Each symbol represents the mean from three mice. The dashed line represents the burden of organisms at the start of therapy. The sigmoid line is the dose-effect best-fit line and is based on the Hill equation. The PD parameters for Emax, ED50, and the slope of the dose-response line (N) are listed for each drug. R2 is the coefficient of determination.

Tables

  • Figures
  • Table 1

    In vitro activities of echinocandins against C. glabrata study isolates

    C. glabrata strain and isolate no.MIC (mg/liter)fks hot spot mutationIn vivo fitnessa
    AnidulafunginCaspofunginMicafungin
    Wild-type isolates
        CG 55920.060.030.022.84
        CG 5130.060.030.022.58
        CG 336090.030.030.022.37
        CG 323900.060.030.011.29
        CG 353150.250.130.061.88
        CG 53760.030.030.012.22
        CG 343410.130.250.061.81
        CG 5700.030.13NAb2.45
    Mutant fks-1 or fks-2 isolates
        CG 47470.0610.25Fks2_HS1_L646R1.97
        CG 4720484Fks2_HS1_S645P2.46
        CG 10956120.25Fks2_HS1_F659V1.01
        CG 7294168Fks2_HS1_S663P2.24
        CG 14378242Fks1_HS1_S629P3.17
        CG 211110.25Fks2_HS1_S663P3.11
        CG 760110.25Fks2_HS1_S663F3.22
        CG 20920.510.13Fks1_HS1_L630I2.90
        CG 47420.2510.5Fks2_HS1_L632R1.92
        CG 3361610.250.252.33
        CG 3766120.250.252.00
    • ↵a Growth in control animals over 96 h (log10 CFU/kidney).

    • ↵b NA, not available.

  • Table 2

    In vivo activities of anidulafungin, caspofungin, and micafungin against wild-type C. glabrata isolates in a neutropenic murine disseminated candidiasis model

    Antifungal agent and C. glabrata isolate no.MIC (μg/ml)Static dose (mg/kg/24 h)1-log kill (mg/kg/24 h)AUCf/MIC based on:
    Static dose1-log kill
    Anidulafungin
        CG 5700.031.973.7212.623.8
        CG 55920.063.5711.811.437.5
        CG 5130.062.454.137.8313.2
        CG 336090.032.004.2112.626.9
        CG 329300.061.583.315.0010.6
        CG 353150.256.40NAb4.92NA
        CG 53760.036.807.5040.447.7
        CG 343410.126.90NA11.0NA
    Meana0.083.965.7813.226.6
    Median0.063.014.1711.225.4
    SD0.072.353.3111.414.2
    Caspofungin
        CG 5700.120.170.211.391.72
        CG 55920.030.120.163.945.25
        CG 5130.030.080.142.624.59
        CG 336090.030.060.101.973.28
        CG 329300.030.000.020.100.49
        CG 353150.120.071.030.578.45
        CG 53760.030.170.325.5810.5
        CG 343410.250.030.860.123.38
    Meana0.080.090.352.044.71
    Median0.030.080.191.683.99
    SD0.080.060.381.953.35
    Micafungin
        CG 55920.021.805.468.4025.0
        CG 5130.021.34NA6.20NA
        CG 336090.020.411.401.906.5
        CG 329300.010.291.522.6614.2
        CG 353150.062.403.772.804.33
        CG 53760.012.674.0023.034.5
        CG 343410.062.184.262.514.9
    Meana0.031.583.406.7814.9
    Median0.021.803.892.8010.3
    SD0.020.951.617.5412.4
    • ↵a Statistically significant comparisons included the anidulafungin versus caspofungin static dose free drug AUC/MIC and the 1-log kill free drug AUC/MIC P = 0.003 and 0.004, respectively).

    • ↵b NA, pharmacodynamic endpoint was not achieved.

  • Table 3

    In vivo activities of anidulafungin, caspofungin, and micafungin against fks mutant C. glabrata isolates in a neutropenic murine disseminated candidiasis model

    Antifungal agent and C. glabrata isolate no.MIC (μg/ml)Static dose (mg/kg/24 h)1-log kill (mg/kg/24 h)AUCf/MIC based on:
    Static dose1-log kill
    Anidulafungin
        CG 47470.061.31NAa4.19NA
        CG 47204NANANANA
        CG 1095615.69NA1.09NA
        CG 7294NANANANA
        CG 143782NANANANA
        CG 211118.8NA3.59NA
        CG 760134.9NA7.77NA
        CG 20920.503.3811.21.304.29
        CG 47420.253.4517.62.6513.5
        CG 336161NANANANA
        CG 376612NANANANA
    Meanb1.5311.314.43.438.87
    Median1.004.5714.43.128.87
    SD1.3613.24.532.456.49
    Caspofungin
        CG 474710.250.430.250.42
        CG 4720814.9NA1.06NA
        CG 1095622.3820.31.175.20
        CG 72916NANANANA
        CG 143784NANANANA
        CG 21114.2624.84.1911.1
        CG 76017.4752.45.8115.6
        CG 209210.360.810.360.79
        CG 474210.322.400.312.36
        CG 336160.252.086.648.1922.1
    Meanb3.534.0115.42.678.21
    Median1.002.236.641.125.20
    SD4.955.0619.03.038.30
    Micafungin
        CG 47470.251.121.770.310.49
        CG 47204NANANANA
        CG 109560.250.222.630.060.73
        CG 7298NANANANA
        CG 143782NANANANA
        CG 2110.254.83NA1.33NA
        CG 7600.254.24NA1.17NA
        CG 20920.130.942.650.521.47
        CG 47420.501.3010.280.181.36
        CG 336160.253.887.891.12.2
        CG 376610.259.2520.602.55.2
    Meanb1.473.227.640.901.91
    Median0.252.595.270.811.41
    SD2.472.997.200.811.72
    • ↵a NA, not achieved.

    • ↵b There was not a statistical difference between the median static dose or 1-log kill free drug AUC/MIC target endpoint for any of the three drugs.

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Optimizing Echinocandin Dosing and Susceptibility Breakpoint Determination via In Vivo Pharmacodynamic Evaluation against Candida glabrata with and without fks Mutations
Alexander Lepak, Mariana Castanheira, Daniel Diekema, Michael Pfaller, David Andes
Antimicrobial Agents and Chemotherapy Oct 2012, 56 (11) 5875-5882; DOI: 10.1128/AAC.01102-12

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Optimizing Echinocandin Dosing and Susceptibility Breakpoint Determination via In Vivo Pharmacodynamic Evaluation against Candida glabrata with and without fks Mutations
Alexander Lepak, Mariana Castanheira, Daniel Diekema, Michael Pfaller, David Andes
Antimicrobial Agents and Chemotherapy Oct 2012, 56 (11) 5875-5882; DOI: 10.1128/AAC.01102-12
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