In vivo efficacy and PK/PD analyses of zifanocycline (KBP-7072), an aminomethylcycline antibiotic, against Acinetobacter baumannii in a neutropenic murine thigh infection model

Abstract

IntroductionZifanocycline (KBP-7072) is a novel aminomethylcycline antibiotic with a broad spectrum of antibacterial activity. This study determined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of zifanocycline in mice and the optimal PK/PD index for efficacy against Acinetobacter baumannii in a neutropenic murine thigh infection model. MethodsZifanocycline PK properties were characterized in plasma after single-dose subcutaneous injection in healthy mice at doses of 1, 4, 16, 64, and 256 mg/kg. PK/PD analyses were performed with zifanocycline against 8 clinical A. baumannii isolates in a neutropenic murine thigh infection model. ResultsPlasma total and free drug Cmax, AUC0-inf, and AUC0-24 increased with dose, where Cmax of total drug was 0.12–25.2 mg/L, AUC0-inf was 1.13–234 h*mg/L, AUC0-24 was 1.09–225 h*mg/L, and free drug Cmax was 0.03–5.68 mg/L, AUC0-inf was 0.25–52.6 h*mg/L, and AUC0-24 was 0.25–50.5 h*mg/L. MICs of zifanocycline against A. baumannii ranged from 0.06 to 0.5 mg/L, with significant activity against all 8 strains. Average daily doses of zifanocycline to achieve a static, 1-log10 kill, and 2-log10 kill effect were projected to be 6.92, 9.63, and 13.22 mg/kg, and the mean fAUC/MIC ratios were 6.91, 9.10, and 12.60, respectively. AUC/MIC was the optimal PK/PD index of zifanocycline against A. baumannii. ConclusionThe in vivo efficacy results and PK/PD analyses support the design of optimal dosing regimens in clinical studies and assist with determining clinical breakpoints for zifanocycline.