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 (C max ) values of 0.34 to 2.58 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC 0 -∞ ) 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 (R 2 ϭ 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 Ϯ 8.29 and 32.60 Ϯ 10.85, respectively. KEYWORDS eravacycline, pharmacodynamics, Escherichia coli D iseases due to antibiotic-resistant bacteria are emerging at an alarming rate worldwide, warranting the development of new antimicrobial agents. Eravacycline is a novel synthetic fluorocycline that belongs to the tetracycline class of antibacterial agents and is currently in development for the treatment of complicated intraabdominal infection (cIAI) (1) and complicated urinary tract infection (cUTI) (2). Oral and intravenous formulations have been developed. As with other tetracyclines, eravacycline inhibits bacterial protein synthesis through binding to the 30S ribosomal subunit and demonstrates potent and broad-spectrum antimicrobial activity. Importantly, the drug maintains activity against many drug-resistant bacteria, including bacteria exhibiting tetracycline-specific efflux and ribosomal protection (2).Escherichia coli organisms are the predominant pathogens in intra-abdominal infections (3) and urinary tract infections, accounting for 47 to 94% of isolates (4). Given this,