Lung microdialysis and in vivo PK/PD integration of cefquinome against Actinobacillus pleuropneumoniae in a porcine experimental lung infection model.

This study aim to explore the application of microdialysis in pharmacokinetic (PK) and pharmacodynamic (PD) integration of cefquinome against Actinobacillus pleuropneumoniae in a porcine experimental lung infection model. The model was established via intratracheal inoculation where average bacterial counts (CFU) in the lungs of infected pigs reached 6.57 log10 CFU/g after 3 h. The PK profiles of unbound cefquinome in lung dialysates were determined following intramuscular injection of single doses of 0.125, 0.25, 0.5, 1, 2, and 4 mg/kg. Lung dialysate samples were collected using microdialysis at a flow rate of 1.5 µL/min until 24 h. The PD studies were conducted over 24 h based on 10 intermittent dosing regimens and total daily doses ranged from 0.25 to 4 mg/kg and dosage intervals included 12 and 24 h. The lung tissue was collected after 24 h of treatment and homogenized for bacterial counts. The relationships between PK/PD parameters derived from lung dialysates and drug efficacy were analyzed using an inhibitory sigmoid Emax model. The percentage of time the free drug concentration exceeded the minimum inhibitory concentration (%fT > MIC) was the PK/PD index best describing the antimicrobial activity (R2 = 0.96) in the porcine experimental infection model. The %fT > MIC values required to achieve net bacterial stasis, 1, 2 and 3 log10 CFU/g reductions in the lung were 22.45, 28.86, 37.62, and 56.46%, respectively. Cefquinome exhibited time-dependent characteristics against A. pleuropneumoniae in vivo. These results provide valuable insights into the application of microdialysis in PK/PD integration model studies and optima regimen of cefquinome for the treatment of porcine respiratory diseases caused by A. pleuropneumoniae.

Pharmacodynamic Parameters of Pharmacokinetic/Pharmacodynamic (PK/PD) Integration Models.

Pharmacokinetic/pharmacodynamic (PK/PD) integration models are used to investigate the antimicrobial activity characteristics of drugs targeting pathogenic bacteria through comprehensive analysis of the interactions between PK and PD parameters. PK/PD models have been widely applied in the development of new drugs, optimization of the dosage regimen, and prevention and treatment of drug-resistant bacteria. In PK/PD analysis, minimal inhibitory concentration (MIC) is the most commonly applied PD parameter. However, accurately determining MIC is challenging and this can influence the therapeutic effect. Therefore, it is necessary to optimize PD indices to generate more rational results. Researchers have attempted to optimize PD parameters using mutant prevention concentration (MPC)-based PK/PD models, multiple PD parameter-based PK/PD models, kill rate-based PK/PD models, and others. In this review, we discuss progress on PD parameters for PK/PD models to provide a valuable reference for drug development, determining the dosage regimen, and preventing drug-resistant mutations.