title: In vivo activity of cefquinome against Escherichia coli in the thighs of neutropenic mice.
abstract: Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against enteric Gram-negative bacilli such as Escherichia coli. We utilized a neutropenic mouse model of colibacillosis to examine the pharmacodynamic (PD) characteristics of cefquinome, as measured by organism number in homogenized thigh cultures after 24 h of therapy. Serum drug levels following 4-fold-escalating single doses of cefquinome were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic (PK) properties of cefquinome were linear over a dose range of 10 to 640 mg/kg of body weight. Serum half-lives ranged from 0.29 to 0.32 h. Dose fractionation studies over a 24-h dose range of 2.5 to 320 mg/kg were conducted every 3, 6, 12, or 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. The free percentage of the dosing interval that the serum levels exceed the MIC (fT>MIC) was the PK-PD index that best correlated with efficacy (R(2) = 73% for E. coli, compared with 13% for the maximum concentration of the free drug in serum [fCmax]/MIC and 45% for the free-drug area under the concentration-time curve from 0 to 24 h [fAUC0-24]/MIC). Subsequently, we employed a similar dosing strategy by using 4-fold-increasing total cefquinome doses administered every 4 h to treat animals infected with four additional E. coli isolates. A sigmoid maximum-effect (Emax) model was used to estimate the magnitudes of the %fT>MIC associated with net bacterial stasis, a 1-log10 CFU reduction from baseline, and a 2-log10 CFU reduction from baseline; the corresponding values were 28.01% ± 2.27%, 37.23% ± 4.05%, and 51.69% ± 9.72%. The potent bactericidal activity makes cefquinome an attractive option for the treatment of infections caused by E. coli.
authors: National Reference Laboratory of Veterinary Drug Residues (SCAU), College of Veterinary Medicine, South China Agricultural University, Guangzhou, China Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation of Ministry of Agriculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.
authors: Qi
authors: Q
authors: Shan
authors: National Reference Laboratory of Veterinary Drug Residues (SCAU), College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors: Chaoping
authors: C
authors: Liang
authors: National Reference Laboratory of Veterinary Drug Residues (SCAU), College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors: Jing
authors: J
authors: Wang
authors: First Affiliated Hospital, Jinan University, Guangzhou, China.
authors: Jufeng
authors: J
authors: Li
authors: National Reference Laboratory of Veterinary Drug Residues (SCAU), College of Veterinary Medicine, South China Agricultural University, Guangzhou, China zlzeng@scau.edu.cn.
authors: Zhenling
authors: Z
authors: Zeng
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002511:Cephalosporins / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D004926:Escherichia coli / Q000187:drug effects* / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy* / Q000382:microbiology*; D053719:Tandem Mass Spectrometry; D013848:Thigh / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C068212:cefquinome