Pharmacokinetic/pharmacodynamic (PK/PD) evaluation of tulathromycin against Haemophilus parasuis in an experimental neutropenic guinea pig model

Abstract

The objective of the study was to develop an ex-vivo PK/PD model of intramuscular (IM) administration of tulathromycin and to test its efficacy against Haemophilus parasuis (H. parasuis) infection in intraperitoneal-inoculated neutropenic guinea pigs. The pharmacokinetics (PKs) of tulathromycin at doses of 1 and 10 mg/kg in H. parasuis-infected neutropenic guinea pig were studied by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). In vitro minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), mutant prevention concentration (MPC), post-antibiotic effect (PAE) and dynamic time-kill curve experiments were carried out using H. parasuis strain 13R. Tulathromycin exhibited concentration-dependent activity and PAE persisted long after administration of the antibiotic. The ratio of the 24-h area under the concentration–time curve (AUC) to MIC in serum (AUC 24h /MIC serum ) was recognized as an important PK/PD parameter that positively correlated with the in vitro antibacterial effectiveness of tulathromycin (R 2 = 0.9961 or R 2 = 1). For the 1 and 10 mg/kg treatments with tulathromycin, the values of AUC 24h /MIC for H. parasuis bacteriostatic action, bactericidal action and virtual bacterial eradication were respectively 22.73, 34.5 and 88.03 h for the 1 mg/kg treatment and respectively 24.94, 30.94 and 49.92 h for the 10 mg/kg treatment. In addition, we demonstrated that doses of 7.2–8.0 mg/kg of tulathromycin resulted in high eradication rates (99.99%). Using a previously published conversion factor of 0.296, we were able to estimate an approximate dose, 2.1–2.4 mg/kg, that should also obtain high eradication rates in the target animal, pigs. This study can help optimize tulathromycin efficacy against H. parasuis infections in swine farming.