The pharmacokinetic-pharmacodynamic modeling and cut-off values of tildipirosin against Haemophilus parasuis

// Zhixin Lei 1, 2 , Qianying Liu 1, 2 , Bing Yang 1, 2 , Saeed Ahmed 1, 2 , Jiyue Cao 2, 3 and Qigai He 1 1 State Key Laboratory of Agriculture Microbiology, College of Veterinary Medicine, Huazhong Agriculture University, Wuhan, China 2 Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China 3 National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agriculture University, Wuhan, China Correspondence to: Qigai He, email: he628@mail.hzau.edu.cn Jiyue Cao, email: caojiyue2@163.com Keywords: wild-type cutoff; pharmacokinetic/pharmacodynamic cutoff; Tildipirosin; Pulmonary epithelial lining fluid; Haemophilus parasuis Received: August 21, 2017      Accepted: November 17, 2017      Published: December 07, 2017 ABSTRACT The goal of this study was to establish the epidemiological, pharmacodynamic cut-off values, optimal dose regimens for tildipirosin against Haemophilus parasuis . The minimum inhibitory concentrations (MIC) of 164 HPS isolates were determined and SH0165 whose MIC (2 μg/ml ) were selected for PD analysis. The ex vivo MIC in plasma of SH0165 was 0.25 μg/ml which was 8 times lower than that in TSB. The bacteriostatic, bactericidal and elimination activity (AUC 24h /MIC) in serum were 26.35, 52.27 and 73.29 h based on the inhibitory sigmoid E max modeling. The present study demonstrates that 97.9% of the wild-type (WT) isolates were covered when the epidemiological cut-off value (ECV) was set at 8 μg/ml. The parameters including AUC 24h , AUC, T1/2, C max , CL b and MRT in PELF were 19.56, 60.41, 2.32, 4.02, 56.6, and 2.63 times than those in plasma, respectively. Regarding the Monte Carlo simulation, the CO PD was defined as 0.5 μg/ml in vitro , and the optimal doses to achieve bacteriostatic, bactericidal and elimination effect were 1.85, 3.67 and 5.16 mg/kg for 50% target, respectively, and 2.07, 4.17 and 5.78 mg/kg for 90% target, respectively. The results of this study offer a more optimised alternative for clinical use and demonstrated that 4.17 mg/kg of tildipirosin by intramuscular injection could have an effect on bactericidal activity against HPS. These values are of great significance for the effective treatment of HPS infections, but it also be deserved to be validated in clinical practice in the future research.