Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida

Abstract

Pasteurella multocida (PM) can invade the upper respiratory tract of the body and cause death and high morbidity. Tildipirosin, a new 16-membered-ring macrolide antimicrobial, has been recommended for the treatment of respiratory diseases. The objective of this research was to improve the dose regimes of tildipirosin to PM for reducing the macrolides resistance development with the pharmacokinetic/pharmacodynamic (PK/PD) modeling approach and to establish an alternate cutoff for tildipirosin against PM. A single dose (4 mg/kg body weight) of tildipirosin was administered via intramuscular (i.m.) and intravenous (i.v.) injection to the pigs. The minimum inhibitory concentration (MIC) values of clinical isolates (112) were measured in the range of 0.0625–32 μg/ml, and the MIC50 and MIC90 values were 0.5 and 2 μg/ml, respectively. The MIC of the selected PM04 was 2 and 0.5 μg/ml in the tryptic soy broth (TSB) and serum, respectively. The main pharmacokinetic (PK) parameters including the area under the curve at 24 h (AUC24 h), AUC, terminal half-life (T1/2), the time to peak concentration (Tmax), peak concentration (Cmax), relative total systemic clearance (CLb), and the last mean residence time (MRTlast) were calculated to be 7.10, 7.94 μg∗h/ml, 24.02, NA h, NA μg/ml, 0.46 L/h∗kg, 8.06 h and 3.94, 6.79 μg∗h/ml, 44.04, 0.25 h, 0.98 μg/ml, 0.43 L/h∗kg, 22.85 h after i.v. and i.m. induction, respectively. Moreover, the bioavailability of i.m. route was 85.5%, and the unbinding of tildipirosin to serum protein was 78%. The parameters AUC24 h/MIC in serum for bacteriostatic, bactericidal, and elimination activities were calculated as 18.91, 29.13, and 34.03 h based on the inhibitory sigmoid Emax modeling. According to the Monte Carlo simulation, the optimum doses for bacteriostatic, bactericidal, and elimination activities were 6.10, 9.41, and 10.96 mg/kg for 50% target and 7.86, 12.17, and 14.57 mg/kg for 90% target, respectively. The epidemiological cutoff value (ECV) was calculated to be 4 μg/ml which could cover 95% wild-type clinical isolates distribution. The PK-PD cutoff (COPD) was analyzed to be 0.25 μg/ml in vitro for tildipirosin against PM based on the Monte Carlo simulation. Compared with these two cutoff values, the finial susceptible breakpoint was defined as 4 μg/ml. The data presented now provides the optimal regimens (12.17 mg/kg) and susceptible breakpoint (4 μg/ml) for clinical use, but these predicted data should be validated in the clinical practice.

Pharmacokinetics and bioavailability of tildipirosin in rabbits following single‐dose intravenous and intramuscular administration

“…This high bioavailability indicates favorable absorption of TD in rabbits. The bioavailability reported in this work is similar to that previously reported in dogs (112%; Wang et al, 2018) and goats (96.64%; Elazab & Badawy, 2020), but higher than that reported in pigs (85.5%;Lei et al, 2018) and cattle (78.9%; Menge et al, 2012). This variation may be due to differences in the dietary habits and/or physiological characteristics of these animal species.…”

“…These results indicate that the MIC value determined in vitro could underestimate the practical efficacy of TD, and the complex interactions between drugs, hosts, and pathogens should be taken into account. It is noteworthy that the MIC of pig P. multocida in serum (ex vivo) was at least fourfold lower than that in an artificial medium (Lei et al, 2018). A large potentiation effect of tulathromycin in calf serum was also observed for Mannheimia haemolytica and P. multocida (Lees et al, 2016).…”

“…At present, the minimum inhibitory concentration (MIC) of TD against P. multocida isolated from rabbits has not been determined. Previous studies have reported that TD shows high antibacterial activity against P. multocida isolated from pigs, cattle, and mice (Lei et al, 2018;Michael et al, 2012;Zeng et al, 2018). The MIC 90 of TD against pig P. multocida has been reported to be 1 μg/ ml (EMA, 2012).…”

“…An AUC 0-24 /MIC ratio of more than 30 hr indicates an optimum antibacterial effect of macrolides against Gram-negative bacteria; however, due to the different immune status of target animals and bacteria, these thresholds may vary for different drugs and different types of bacteria. (Lei et al, 2018).…”

Epidemiological and PK/PD cutoff values determination and PK/PD-based dose assessment of gamithromycin against Haemophilus parasuis in piglets

“…The AUC 24h /MIC targets for gamithromycin against H. parasuis associated with bactericidal and eradication effects were 30.3 h and 41.2 h, respectively. This microbiological response in ex vivo PK/PD model was similar to or in excess of previously approved veterinary macrolides such as tulathromycin and tildipirosin [13,23].…”