title: In VivoPharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model.
abstract: Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against sevenKlebsiella pneumoniaeisolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally withK. pneumoniaeand treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. TheEmaxHill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log10or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentration-time curve over 24 h (AUC0-24)/MIC ratio was the PD index most closely linked to efficacy (R2= 0.96). The mean free-drug AUC0-24/MIC ratios required to achieve net bacterial stasis, a 1-log10kill, and a 2-log10kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involvingK. pneumoniae.
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Zhou
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
authors.forename: Meng-Ting
authors.initials: MT
authors.lastname: Tao
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huo
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Liao
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China lyh@scau.edu.cn.|Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
authors.forename: Ya-Hong
authors.initials: YH
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000302:isolation & purification; D008168:Lung / Q000382:microbiology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy / Q000382:microbiology; D015242:Ofloxacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; C522674:antofloxacin; D015242:Ofloxacin
keywords: Klebsiella pneumoniae; PK/PD; antofloxacin; murine lung infection