Project Details

Azithromycin Pharmacokinetics and Pharmacodynamics in Pregnancy and Preterm Birth Prevention: Optimizing dosing to improve maternal and neonatal outcomes

Rupsa Boelig, MD

Summary

BACKGROUND: Preterm premature rupture of membranes (PPROM) is responsible for 25% of preterm births, the primary driver of neonatal morbidity and mortality in the US. One week of antibiotic therapy in the setting of PPROM <34 weeks delays delivery and improves perinatal outcomes. Currently azithromycin is used, however the dosing is arbitrary and not based on pregnancy specific data. Commonly used regimens include 1g once and 500mg daily for seven days. Limited data suggests that 1g one time does not maintain azithromycin concentration in pregnancy specific tissue (placenta, membranes, amniotic fluid) for the full 7 days. The impact of maternal azithromycin dosing on neonatal endpoints has not been established. Objective: Compare the maternal and neonatal pharmacokinetics and pharmacodynamics of two standard doses of maternal azithromycin therapy for PPROM. Methods: Randomized controlled trial of 20 singletons admitted with PPROM between 24-33 weeks’ gestation, randomized to either azithromycin 1 gram PO one time or 500mg PO daily for seven days. Maternal serum and amniotic fluid samples will be collected serially along with placenta, cord blood, and neonatal respiratory samples. Assays include quantification of azithromycin and cytokines in all samples. Primary outcome is the difference in azithromycin trough in amniotic fluid between the two dosing regimens. Secondary outcomes include the association between dose/tissue concentration/cytokines/ and perinatal outcomes. IMPACT: Providing a rational basis for maternal azithromycin dosing to optimize impact in pregnancy specific target tissues has the potential to improve both maternal and neonatal outcomes in the high risk setting of PPROM. Preterm premature rupture of membranes (PPROM) is responsible for 25% of preterm births and is managed with antibiotics (azithromycin and ampicillin) to increase latency to delivery and reduce neonatal morbidity associated prematurity and infection. There is no consensus on dosing for azithromycin in this setting and a commonly used regimen, 1 gram one time, may not provide therapeutic levels in target tissue for the necessary seven day course. GAP: Although a seven day course of antibiotics is recommended for PPROM, limited data suggest that 1gram azithromycin PO one time used at many sites is not sufficient to sustain azithromycin concentration in pregnancy specific target tissues over seven days; data on the pharmacokinetics of maternal azithromycin dosing and concentration in pregnancy specific tissues are lacking. HYPOTHESIS: • Hypothesis 1: Azithromycin concentration at pregnancy specific targets including amniotic fluid, membranes/placenta, are higher and more sustained with 500mg daily dosing x7days compared to 1g one time. • Hypothesis 2: Two different dosing regimens of azithromycin will have differential longitudinal effect on maternal serum and amniotic fluid inflammatory cytokines as well as neonatal cord blood cytokines METHODS: This is a randomized controlled trial comparing 1g azithromycin PO one time vs 500mg azithromycin PO daily for seven days in singleton gestations admitted with PPROM <33 weeks’ gestation. Azithromcyin and cytokine concentrations will be assessed in maternal serum, amniotic fluid, cord blood, placenta, and neonatal respiratory excretions. RESULTS: Pending IMPACT: This would be the first study to compare pharmacokinetics and pharmacodynamics of two commonly used azithromycin doses in maternal fetal unit examining pregnancy specific tissues and the neonate. Our results will provide a rational basis for azithromycin dosing in the setting of PPROM specifically, but may be applied in azithromycin therapy for other high risk perinatal conditions including with cerclage/cervical dilation, perioperative cesarean section prophylaxis, and during labor. If there is potential for maternal azithromycin to mitigate neonatal effects of prematurity, the selection of optimal dose should take both maternal and neonatal pharmacology into account. Website Link: https://clinicaltrials.gov/ct2/show/NCT04294069