Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae

Nemonoxacin, a novel nonfluorinated quinolone for the treatment of community-acquired pneumonia. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets and PK/PD breakpoints of nemonoxacin against Streptococcus pneumoniae using a neutropenic murine lung infection model. Single-dose PK analysis after subcutaneous administration of nemonoxacin at doses from 2.5 to 80 mg/kg showed maximum plasma concentration (C(max)) 0.56–7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC(0-24)) 0.67–26.10 mg·h/L, and elimination half-life (T(1/2)) 0.8–1.4 h. The epithelial lining fluid (ELF) penetration ratio of total drug was 1.40. Dose fractionation (1.25–80 mg/kg/day, every 24, 12, 8, and 6 h) and dose escalation studies (1.25–160 mg/kg, every 24 h) were conducted. The sigmoid E(max) Hill equation was used to describe the dose-response data. The free-drug plasma fAUC(0-24)/MIC ratio was considered the PK/PD index most closely associated with efficacy (R(2) 0.9268). Median fAUC(0-24)/MIC associated with static, 1-log(10) and 2-log(10) CFU reduction from baseline were 8.6, 23.2 and 44.4, respectively. Monte Carlo simulation showed 500 mg qd and 750 mg qd oral doses of nemonoxacin were able to achieve 90% probability of target attainment (PTA) against bacteria with MIC of 0.5 mg/L and 1 mg/L. We recommended susceptibility (S) ≤ 0.5 mg/L, intermediate (I) = 1 mg/L and resistant (R) ≥ 2 mg/L as the PK/PD breakpoints for nemonoxacin against S. pneumoniae.