1528. In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Target Characterization of the Novel, Long Acting Echinocandin CD101 against C. albicans and C. glabrata in the Neutropenic Murine Disseminated Candidiasis Model
Session: Poster Abstract Session: Preclinical Study with New Antibiotics and Antifungals
Friday, October 6, 2017
Room: Poster Hall CD
Posters
  • CD101 ID WEEK 2017 V2.pdf (1.3 MB)
  • Background: CD101 is a novel, long acting echinocandin. The purpose of the study was to evaluate the PK/PD activity of CD101 against C. albicans (CA) and C. glabrata (CG) using the murine neutropenic disseminated candidiasis model. 

    Methods: 4 CA and 3 CG strains were used. MICs were determined by CLSI standards. Single dose plasma PK was determined in groups of three mice after IP doses of 1, 4, 16, and 64 mg/kg. For treatment studies, mice were rendered neutropenic via administration of cyclophosphamide at days -4, -1, +2 and +4. Mice were infected with 6.3 ± 0.1 CFU/ml (CA) or 6.2 ± 0.2 CFU/ml (CG) injected into the lateral tail vein.  Treatment dose range was 0.016 – 64 mg/kg, given once by IP injection 2 h after infection. Experiment duration was 7 days at which point kidneys were aseptically harvested for CFU counts. The Emax Hill equation was used to model the dose-response data to PK/PD index AUC/MIC. The static and 1-log kill doses, as well as associated total and free AUC/MIC values were determined for each isolate.

    Results: CD101 MICs were 0.008-0.06 mg/L for CA and 0.06 – 0.5 mg/L for CG. Single dose plasma PK parameter ranges include: Cmax 2.6-77 mg/L, AUC0-∞ 93-4046 mg*h/L, T1/2 28-41 h.  Dose-dependent cidal activity was observed with a maximal kill of over 2 log10 CFU/kidney. Average 24 h AUC over 7 days was used to model AUC/MIC data and fit the treatment response data well (CA R2 0.70, CG R2 0.86). The static dose (SD) and 1-log kill dose and associated total and free AUC/MIC values are shown (Table).

     

    Strain

    MIC (mg/L)

    Static Dose (mg/kg)

    Stasis

    Ave 24 h tAUC/MIC

    Stasis

    Ave 24 h fAUC/MIC

    1 log kill dose (mg/kg)

    1 log kill

    Ave 24 h tAUC/MIC

    1 log kill Ave 24 h fAUC/MIC

    CA

    K-1

    0.008

    2.52

    3426

    44.5

    5.26

    6435

    83.6

    580

    0.016

    1.20

    948

    12.3

    2.03

    1429

    18.6

    98-17

    0.06

    1.34

    274

    3.6

    2.73

    490

    6.4

    98-210

    0.016

    1.06

    868

    11.3

    2.28

    1574

    20.5

     

     

    CG

    10956

    0.5

    6.29

    120

    1.6

    17.3

    301

    3.9

    5592

    0.06

    0.03

    21.7

    0.3

    0.51

    114

    1.5

    35315

    0.25

    0.34

    17.9

    0.2

    2.39

    105

    1.4

     

    Conclusion: CD101 demonstrated in vivo potency in the neutropenic murine disseminated candidiasis model against select CA and CG strains. Similar to studies with other echinocandins, AUC/MIC fit the exposure-response data well and CG targets were numerically lower than CA. However, while CA target range was similar, CG target range was almost 10-fold lower compared with other echinocandins. 

     

    Alexander J. Lepak, M.D.1, Miao Zhao, MS2, Brian Vanscoy, BA3, Paul G. Ambrose, Pharm.D., FIDSA3 and David R. Andes, M.D., FIDSA4, (1)Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, (2)Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, (3)Institute for Clinical Pharmacodynamics, Schenectady, NY, (4)Infectious Disease, University of Wisconsin School of Medicine and Public Health, Madison, WI

    Disclosures:

    A. J. Lepak, None

    M. Zhao, None

    B. Vanscoy, Cidara: Research Contractor , Research support

    P. G. Ambrose, Cidara: Research Contractor , Research support

    D. R. Andes, Cidara: Grant Investigator , Research support

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