Difference in the PK of ceftiofur in the presence and absence of nimesulide and implications for dose determination through PK/PD integration

Abstract

The study was planned to determine the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ceftiofur crystalline free acid (CCFA) and nimesulide (NS). The CCFA was administered to six adult non-lactating goats alone and in combination with NS in a two period cross-over study so that each goat receives each treatment. CCFA (6.6 mg/kg) and NS (2 mg/kg) were injected SC and IM, respectively. Blood samples were collected from jugular vein before and at 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 30, 36, 48, 72, 96, 120, 144, 168, 192, 240, 288 and 336 h post CCFA + NS administration. The MIC, MBC, MPC and ex-vivo antibacterial activity of ceftiofur against P. multocida were determined in presence of NS. PK-PD data were integrated and modelled to determine AUC24h/MIC values for three levels of effect on the bacteria to predict ceftiofur doses. The MIC, MBC, MPC and exvivo growth inhibition curves indicated time-dependent bactericidal activity of ceftiofur against P. multocida. The mean peak concentration (Cmax), absorption (K01HL) and terminal half-lives (K10HL) of ceftiofur were 2.89 μg/mL, 2.31 h and 54.8 h, respectively. The predicted AUC0-24h/MIC ratios required to produce bacteriostatic, bactericidal and eradication activity for P. multocida were higher (15.4, 70.1, 114.9 h) with CCFA alone compared to CCFA + NS treatment (12.8 h, 57.6 h, 92.1 h). The study supports using CCFA at 6.6 mg/kg in combination with NS to treat respiratory infectious diseases in goats caused by P. multocida since it may decrease the selection for resistant mutants.