Assessment of in vivo efficacy of eravacycline against Enterobacteriaceae exhibiting various resistance mechanisms: a dose-ranging study and pharmacokinetic/pharmacodynamic analysis

Abstract

After the pharmacokinetic (PK) profile of eravacycline, a novel fluorocycline, was defined, understanding its pharmacodynamic (PD) profile became essential. This study aimed to assess the correlation of the PK/PD index fAUC/MIC (ratio of area under the free drug concentration–time curve to MIC) and its magnitude with eravacycline's efficacy against Enterobacteriaceae using an immunocompetent murine thigh infection model to resemble the immunocompetent environment in eravacycline's clinical trials. Eight Enterobacteriaceae isolates with various resistance mechanisms were tested. Eravacycline doses ranged from 1–10 mg/kg/day and were given either once daily (q24h) or divided into doses every 12 h (q12h) over the 24-h treatment period. Antibacterial efficacy was measured as the change in log10CFU at 24 h compared with 0 h controls. Composite data were modelled using a sigmoid Emax model. Eravacycline MICs ranged from 0.125–0.5 µg/mL. The mean fAUC/MIC magnitudes required for stasis and 1-log reduction for the eight isolates were 2.9 ± 3.1 and 5.6 ± 5.0, respectively. Whilst the humanised eravacycline regimen (2.5 mg/kg q12h) pharmacokinetically achieves an fAUC0–24 that is higher than the fAUC0–24 achieved with the 5 mg/kg q24h dose, the latter was associated with greater efficacy, raising a suggestive correlation of the peak free drug concentration to MIC (fCmax/MIC) ratio with eravacycline's efficacy. This study showed that the magnitudes associated with eravacycline's efficacy in an immunocompetent murine thigh model appear to be close to achievable targets in human. These data support further development of eravacycline for treatment of infections caused by drug-resistant Enterobacteriaceae.