Maternal Intravenous Administration of Azithromycin Results in Significant Fetal Uptake in a Sheep Model of Second Trimester Pregnancy

Abstract

g Treatment of intrauterine infection is likely key to preventing a significant proportion of preterm deliveries before 32 weeks of gestation. Azithromycin (AZ) may be an effective antimicrobial in pregnancy; however, few gestation age-approriate data are available to inform the design of AZ-based treatment regimens in early pregnancy. We aimed to determine whether a single intra-amniotic AZ dose or repeated maternal intravenous (i.v.) AZ doses would safely yield therapeutic levels of AZ in an 80-daygestation (term is 150 days) ovine fetus. Fifty sheep carrying single pregnancies at 80 days gestation were randomized to receive either: (i) a single intra-amniotic AZ administration or (ii) maternal intravenous AZ administration every 12 h. Amniotic fluid, maternal plasma, and fetal AZ concentrations were determined over a 5-day treatment regimen. Markers of liver injury and amniotic fluid inflammation were measured to assess fetal injury in response to drug exposure. A single intra-amniotic administration yielded significant AZ accumulation in the amniotic fluid and fetal lung. In contrast, repeated maternal intravenous administrations achieved high levels of AZ accumulation in the fetal lung and liver and a statistically significant increase in the fetal plasma drug concentration at 120 h. There was no evidence of fetal injury in response to drug exposure. These data suggest that (i) repeated maternal i.v. AZ dosing yields substantial fetal tissue uptake, although fetal plasma drug levels remain low; (ii) transfer of AZ from the amniotic fluid is less than transplacental transfer; and (iii) exposure to high concentrations of AZ did not elicit overt changes in fetal white blood cell counts, amniotic fluid monocyte chemoattractant protein 1 concentrations, or hepatotoxicity, all consistent with an absence of fetal injury.

Outside-in? Acute fetal systemic inflammation in very preterm chronically catheterized sheep fetuses is not driven by cells in the fetal blood

“…Tissue RNA preparation: RNA was isolated from fetal tissues (internal groin skin, spleen, lung right lower lobe, frontal cortex), and mechanically disrupted with a Precellys homogeniser Quantitative PCR: Sheep-specific probes and PCR primer sets were used to perform quantitative PCR reactions for IL-1β, IL-6, IL-8, TNF-α, MCP-2, IL-10 and IL-13 using an EXPRESS One-Step SuperScript qRT-PCR Kit (all Life Technologies) containing 125 ng RNA template in a final volume of 20 µL, following manufacturer's instructions. Cycling conditions and primer/probe sets were as described previously 18 . Cq values were normalised against 18s rRNA and expressed as fold changes relative to saline control values.…”

Pharmacokinetics of tulathromycin in fetal sheep and pregnant ewes

“…This long plateau of fetal drug concentrations also led to either very long calculated elimination half‐life (fetuses 1–3) or an inability to actually calculate elimination half‐life because a regression line could not be fitted to the terminal portion of the time–concentration curve (fetuses 4–6). Previous studies of fetal pharmacokinetics with macrolides showed plasma concentration curves that mimicked that of the dam, with an early peak and steady decline after reaching C max (Keelan et al., , ; Kemp et al., ). The cause of the different observations in our study that fetal concentrations do not mimic maternal concentrations and that fetal concentrations appear to stay steady for a prolonged period of time is currently unknown, but may reflect differences in fetal drug metabolism, drug recycling, or reuptake across the placenta with tulathromycin.…”

“…Tulathromycin administered subcutaneously had a longer apparent elimination half‐life than azithromycin administered intravenously (47.70 hr ± 7.49) or intramuscularly (61.29 hr ± 13.86) in non‐pregnant ewes (Carceles et al., ). Though pharmacokinetics are not reported in maternal plasma, azithromycin has been shown to accumulate in fetal plasma and amniotic fluid when administered to pregnant ewes (Kemp et al., ). Solithromycin given intravenously to pregnant ewes displayed a much shorter elimination half‐life of 6 hr and peak concentrations of 1,073 ng/ml 30 minutes after administration at a dose of 10 mg/kg (Keelan et al., ).…”

“…TA B L E 1 Plasma pharmacokinetic parameters of tulathromycin in pregnant ewes and their fetuses from noncompartmental analysis after a single dose (2.5 mg/kg SC) administered to the ewe showed plasma concentration curves that mimicked that of the dam, with an early peak and steady decline after reaching C max (Keelan et al, 2011Kemp et al, 2014). .…”

“…Evidence of transplacental transfer to fetal tissues is established in multiple species. Intravenous and intramuscular injections of erythromycin and azithromycin have been shown to reach low levels in fetal sheep plasma, and azithromycin administration showed no evidence of fetal injury or inflammation (Keelan et al., ; Kemp et al., ). Roxithromycin was present in fetal tissues at a lower concentration than maternal tissues in a mouse model (Qin et al., ), and solithromycin was detectable in fetal sheep plasma and amniotic fluid after intravenous maternal administration (Keelan et al., ).…”