Pharmacokinetics of tulathromycin in fetal sheep and pregnant ewes

Abstract

Macrolides are important antimicrobials frequently used in human and veterinary medicine in the treatment of pregnant women and pregnant livestock. They may be useful for the control of infectious ovine abortion, which has economic, animal health, and human health impacts. In this study, catheters were surgically placed in the fetal vasculature and amnion of pregnant ewes at 115 (±2) days of gestation. Ewes were given a single dose of 2.5 mg/kg tulathromycin subcutaneously, and drug concentrations were determined in fetal plasma, maternal plasma, and amniotic fluid at 4, 8, 12, 24, 36, 48, 72, 144, and 288 hr after drug administration. Pharmacokinetic parameters in maternal plasma were estimated using noncompartmental analysis and were similar to those previously reported in nonpregnant ewes. Tulathromycin was present in fetal plasma and amniotic fluid, indicating therapeutic potential for use against organisms in these compartments, though concentrations were lower than those in maternal plasma. Time‐course of drug concentrations in the fetus was quite different than that in the ewe, with plasma concentrations reaching a plateau at 4 hr and remaining at this concentration for the remainder of the sampling period (288 hr), raising questions about how tulathromycin may be transported into or metabolized and eliminated by the fetus.

Pharmacokinetics of tulathromycin in pregnant ewes (Ovis aries) challenged with Campylobacter jejuni

“…Therefore, most pharmacokinetic studies from the literature focus on unchanged tulathromycin. When the plasma pharmacokinetic dispositions of tulathromycin from this study were compared with data from similar studies using the same dose, formulation, schedule and route, in non-challenged pregnant sheep and non-pregnant adult ewes, the mean maximum plasma tulathromycin concentration in C. jejuni challenged sheep was much lower (0.3 μg/ mL) than in pregnant sheep (4.9 μg/mL) and non-pregnant ewes (3.6 μg/mL), the mean time to maximum concentration was shorter (1.2 hrs) when compared to pregnant sheep (4.0 hrs) but similar to non-pregnant adult ewes (1.6 hrs), and the mean apparent elimination half-life was substantially shorter (22 hrs) than in pregnant sheep (110.8 hrs) and non-pregnant ewes (118 hrs) [11,13]. The differences in maximum plasma tulathromycin concentration have been observed in other experimental models of infection, with lower concentrations observed in goats and pigs undergoing experimental respiratory infection compared to controls [22,24].…”

“…Using the standard equations outlined in the Methods section (Pharmacokinetic analysis), we calculated the apparent systemic clearance (CL/F) and volume of distribution (Vz/F) of tulathromycin based on earlier descriptions from the literature [11,13]. Specifically, CL/F after…”

“…a single subcutaneous dose of tulathromycin (2.5 mg/kg) was estimated at 10.8 mL/kg/h and 29.1 mL/kg/h in non-challenged pregnant sheep and non-pregnant adult ewes, respectively [11,13]. In comparison, the estimated apparent systemic clearance of tulathromycin in C. jejuni challenged sheep was much higher (280 mL/kg/h).…”

“…Susceptibility results on C. jejuni isolates from field cases of ovine abortion demonstrate that the vast majority are currently susceptible to macrolide antibiotics, including tulathromycin, azithromycin, telithromycin and erythromycin [1,8,9] The potential benefits of treating sheep with a macrolide antibiotic such as tulathromycin include the ease of administration (subcutaneous injection), its wide volume of distribution, low effective plasma concentrations, and long terminal half-life, which has been reported to be 110.8 h (± 20.9) in pregnant ewes [10,11]. Pharmacokinetic studies in pregnant ewes have demonstrated that tulathromycin reaches detectable levels in fetal plasma and amniotic fluid that persist for days following administration to the ewe [11]. The potential clinical effectiveness of tulathromycin in C. jejuni exposed pregnant ewes has been confirmed in a study utilizing an IV C. jejuni challenge model in which tulathromycin treatment resulted in a statistically significant (p < .05) decrease in the rate of vaginal bleeding/abortion in pregnant ewes compared to untreated controls [12].…”

“…The plasma pharmacokinetics of tulathromycin have been studied in non-gravid ewes and healthy pregnant sheep [11,13]. However, these studies did not evaluate the pharmacokinetics in several tissues targeted by campylobacter during the abortion process, including the uterus and placenta/placentome.…”