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Experimental Therapeutics

In Vivo Pharmacodynamic Target Assessment of Eravacycline against Escherichia coli in a Murine Thigh Infection Model

Miao Zhao, Alexander J. Lepak, Karen Marchillo, Jamie VanHecker, David R. Andes
Miao Zhao
aDepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
cWilliam S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA
dInstitute of Antibiotics, Hua-shan Hospital, Fudan University, and Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China
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Alexander J. Lepak
aDepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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Karen Marchillo
aDepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
cWilliam S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA
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Jamie VanHecker
aDepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
cWilliam S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA
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David R. Andes
aDepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
bDepartment of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA
cWilliam S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA
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DOI: 10.1128/AAC.00250-17
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ABSTRACT

Eravacycline is a novel fluorocycline antibiotic with potent activity against a broad range of pathogens, including strains with tetracycline and other drug resistance phenotypes. The goal of the studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy in the murine thigh infection model. Six Escherichia coli isolates were utilized for the studies. MICs were determined using CLSI methods and ranged from 0.125 to 0.25 mg/liter. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after administration of 2.5, 5, 10, 20, 40, and 80 mg/kg of body weight. Pharmacokinetic studies exhibited maximum plasma concentration (Cmax) values of 0.34 to 2.58 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC0–∞) values of 2.44 to 57.6 mg · h/liter, and elimination half-lives of 3.9 to 17.6 h. Dose fractionation studies were performed using total drug doses of 6.25 mg/kg to 100 mg/kg fractionated into 6-, 8-, 12-, or 24-h regimens. Nonlinear regression analysis demonstrated that the 24-h free drug AUC/MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy (R2 = 0.80). In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of eravacycline varied among pathogens. Mice were treated with 2-fold increasing doses (range, 3.125 to 50 mg/kg) of eravacycline every 12 h. The mean fAUC/MIC magnitudes associated with the net stasis and the 1-log-kill endpoints were 27.97 ± 8.29 and 32.60 ± 10.85, respectively.

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In Vivo Pharmacodynamic Target Assessment of Eravacycline against Escherichia coli in a Murine Thigh Infection Model
Miao Zhao, Alexander J. Lepak, Karen Marchillo, Jamie VanHecker, David R. Andes
Antimicrobial Agents and Chemotherapy Jun 2017, 61 (7) e00250-17; DOI: 10.1128/AAC.00250-17

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In Vivo Pharmacodynamic Target Assessment of Eravacycline against Escherichia coli in a Murine Thigh Infection Model
Miao Zhao, Alexander J. Lepak, Karen Marchillo, Jamie VanHecker, David R. Andes
Antimicrobial Agents and Chemotherapy Jun 2017, 61 (7) e00250-17; DOI: 10.1128/AAC.00250-17
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KEYWORDS

Anti-Bacterial Agents
tetracyclines
Thigh
eravacycline
pharmacodynamics
Escherichia coli

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