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 E. coli were utilized for the studies. MICs were determined using CLSI methods and ranged from 0.125 to 0.25 mg/L. 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. Pharmacokinetic studies exhibited peak concentration (Cmax) values of 0.34 to 2.58 mg/L, area under the concentration-time curve (AUC0-) values of 2.44 to 57.6 mg*h/L, and elimination half-lives of 3.9 to 17.6 h. Dose fractionation studies, were performed using total drug doses 6.25 mg/kg to 100 mg/kg fractionated into q6-, q8-, q12-, or q24-hourly regimens. Nonlinear regression analysis demonstrated 24h 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 two-fold increasing doses (range 3.125 to 50 mg/kg) of eravacycline every 12 hours. The mean fAUC/MIC magnitude associated with net stasis and 1-log kill endpoint were 27.97 ± 8.29 and 32.60 ± 10.85, respectively.
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