Integration of pharmacokinetic-pharmacodynamic for dose optimization of doxycycline against Haemophilus parasuis in pigs.

Abstract

The aims of this study were to establish optimal doses of doxycycline (dox) against Haemophilus parasuis on the basis of pharmacokinetic-pharmacodynamic (PK-PD) integration modeling. The infected model was established by intranasal inoculation of organism in pigs and confirmed by clinical signs, blood biochemistry, and microscopic examinations. The recommended dose (20mg/kg b.w.) was administered in pigs through intramuscular routes for PK studies. The area under the concentration 0- to 24-hr curve (AUC0-24 ), elimination half-life (T½ke ), and mean residence time (MRT) of dox in healthy and H.parasuis-infected pigs were 55.51±5.72 versus 57.10±4.89μg·hr/ml, 8.28±0.91 versus 9.80±2.38hr, and 8.43±0.27 versus 8.79±0.18hr, respectively. The minimal inhibitory concentration (MIC) of dox against 40 H.parasuis isolates was conducted through broth microdilution method, the corresponding MIC50 and MIC90 were 0.25 and 1μg/ml, respectively. The Ex vivo growth inhibition data suggested that dox exhibited a concentration-dependent killing mechanism. Based on the observed AUC24hr /MIC values by modeling PK-PD data in H.parasuis-infected pigs, the doses predicted to obtain bacteriostatic, bactericidal, and elimination effects for H.parasuis over 24hr were 5.25, 8.55, and 10.37mg/kg for the 50% target attainment rate (TAR), and 7.26, 13.82, and 18.17mg/kg for 90% TAR, respectively. This study provided a more optimized alternative for clinical use and demonstrated that the dosage 20mg/kg of dox by intramuscular administration could have an effective bactericidal activity against H.parasuis.