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Pharmacology

Daptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis/oralis in an Ex Vivo Simulated Endocarditis Vegetation Model

Razieh Kebriaei, Seth A. Rice, Kyle C. Stamper, Ravin Seepersaud, Cristina Garcia-de-la-Maria, Nagendra N. Mishra, Jose M. Miro, Cesar A. Arias, Truc T. Tran, Paul M. Sullam, Arnold S. Bayer, Michael J. Rybak
Razieh Kebriaei
aAnti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
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Seth A. Rice
aAnti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
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Kyle C. Stamper
aAnti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
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Ravin Seepersaud
eUniversity of California, San Francisco, San Francisco, California, USA
jSan Francisco VA Medical Center, San Francisco, California, USA
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Cristina Garcia-de-la-Maria
bInfectious Diseases Service, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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Nagendra N. Mishra
cLA Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
iThe Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Jose M. Miro
bInfectious Diseases Service, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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Cesar A. Arias
dCenter for Antimicrobial Resistance and Microbial Genomic, Division of Infectious Diseases, UTHealth McGovern Medical School, Houston, Texas, USA
gCenter for Infectious Diseases, UTHealth School of Public Health, Houston, Texas, USA
hMolecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia
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Truc T. Tran
dCenter for Antimicrobial Resistance and Microbial Genomic, Division of Infectious Diseases, UTHealth McGovern Medical School, Houston, Texas, USA
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Paul M. Sullam
eUniversity of California, San Francisco, San Francisco, California, USA
jSan Francisco VA Medical Center, San Francisco, California, USA
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Arnold S. Bayer
cLA Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
iThe Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Michael J. Rybak
aAnti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
fSchool of Medicine, Wayne State University, Detroit, Michigan, USA
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DOI: 10.1128/AAC.00386-19
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  • FIG 1
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    FIG 1

    Comparison of daptomycin activity with and without CRO in various models in S. mitis/oralis 351. There was an 18-h delay in reaching the detection limit for DAP 6 mg/kg-CRO 0.5 g (single dose) in comparison to that for DAP 6 mg/kg-CRO 2 g.

  • FIG 2
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    FIG 2

    Comparison of daptomycin activity with and without CRO in various models in S. mitis/oralis SF100. DAP 6 mg/kg-CRO 0.5 g (single dose) and DAP 6 mg/kg-CRO 2 g reached the detection limit at the same time, but slight regrowth was observed in DAP 6 mg/kg-CRO 0.5 g (single dose) after 48 h.

  • FIG 3
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    FIG 3

    Phospholipid spots shown in 2D-TLC plates were developed with CuSO4 (100 mg/ml) spray containing 8% phosphoric acid and heated at 180°C. PG, phosphatidylglycerol; CL, cardiolipin; PA, phosphatidic acid; UI, unidentified; phospholipid, glycolipid contaminant seen in all S. mitis/oralis strains (previously detailed [29]).

Tables

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  • TABLE 1

    MIC values for DAP, CRO, and DAP in the presence of CRO

    StrainMIC (μg/ml)
    DAPCRODAP-CRO
    3510.580.25
    SF1000.50.1250.25
    Strain pairsa
        351/D12T96 A10.5/>256
        SF100/D12T96 B20.5/>256
    • ↵a First strain in each pair is the DAP-S parental strain, and the second is the DAP-R strain.

  • TABLE 2

    PK data for different doses in SEV model

    DoseCmax (mg/liter)AUC0–24 (mg · h/liter)t1/2 (h)
    DAP 6 mg/kg93.27 ± 0.511,029.19 ± 43.737.89 ± 0.19 h
    DAP 8 mg/kg124.82 ± 0.721,404.865 ± 7.827.93 ± 0.03
    DAP 10 mg/kg143.98 ± 0.351,759.41 ± 59.908.21 ± 0.11
    DAP 12 mg/kg186 ± 3.322,251.99 ± 80.317.98 ± 0.08
    CRO 2 g/kg278.9 ± 8.413,346.35 ± 108.527.88 ± 0.01
    CRO 0.5 g/kg66.75 ± 2.41756.27 ± 7.457.86 ± 0.08
  • TABLE 3

    Relative surface charge and CM fluidity of study strains

    Strain pairsaSurface charge (%)bCM fluidity (PI value)
    351/D12T96 A159 ± 9/30 ± 4c0.31 ± 0.02/0.29 ± 0.03c
    SF100/D12T96 B224 ± 4/25 ± 50.29 ± 0.00/0.30 ± 0.01
    • ↵a First strain in each pair is the DAP-S parental strain, and the second one is the DAP-R strain.

    • ↵b Percentage of bacterial-bound Cyt C calculated from the proportion of unbound Cyt C remaining in the supernatant.

    • ↵c P value of <0.05 in 351 DAP-R (D12T96 A1) versus 351 DAP-S S. mitis/oralis parental strain.

  • TABLE 4

    CM phospholipid composition of study strains

    Strain pairsa% of total PLs (mean ± SD)b
    PGCLPA
    351/D12T96 A111 ± 15/0 ± 0c85 ± 16/0 ± 0c4 ± 2/100 ± 0c
    SF100/D12T96 B210 ± 6/20 ± 847 ± 5/69 ± 315 ± 7/6 ± 4
    • ↵a First strain in each pair is the DAP-S parental strain, and the second one is the DAP-R strain.

    • ↵b PG, phosphatidylglycerol; CL, cardiolipin; PA, phosphatidic acid.

    • ↵c P value of <0.001 351 DAP-R (D12T96 A1) strain versus 351 DAP-S S. mitis/oralis parental strain.

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Daptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis/oralis in an Ex Vivo Simulated Endocarditis Vegetation Model
Razieh Kebriaei, Seth A. Rice, Kyle C. Stamper, Ravin Seepersaud, Cristina Garcia-de-la-Maria, Nagendra N. Mishra, Jose M. Miro, Cesar A. Arias, Truc T. Tran, Paul M. Sullam, Arnold S. Bayer, Michael J. Rybak
Antimicrobial Agents and Chemotherapy May 2019, 63 (6) e00386-19; DOI: 10.1128/AAC.00386-19

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Daptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis/oralis in an Ex Vivo Simulated Endocarditis Vegetation Model
Razieh Kebriaei, Seth A. Rice, Kyle C. Stamper, Ravin Seepersaud, Cristina Garcia-de-la-Maria, Nagendra N. Mishra, Jose M. Miro, Cesar A. Arias, Truc T. Tran, Paul M. Sullam, Arnold S. Bayer, Michael J. Rybak
Antimicrobial Agents and Chemotherapy May 2019, 63 (6) e00386-19; DOI: 10.1128/AAC.00386-19
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KEYWORDS

ceftriaxone
daptomycin
SEVs

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