Azithromycin in preterm premature rupture of membranes: population pharmacokinetics and dose optimization

Abstract

Background: Various empirically selected azithromycin dosing regimens are used as part of an antibiotic regimen to prolong latency in the setting of preterm premature rupture of membranes with limited prospective clinical or pharmacologic data to guide dose selection. Azithromycin clears from plasma quickly to concentrate in tissue, thus dosing is based on optimal local concentrations rather than plasma concentration which is the focus of the current study.

Objective: Compare pharmacokinetic parameters of 1 g once vs 500 mg daily dosing of azithromycin in the setting of preterm premature rupture of membranes and simulate various dosing regimens to identify the optimal regimen that maintains amniotic fluid concentration of azithromycin over the minimum inhibitory concentration of common genitourinary pathogens associated with intraamniotic infection or inflammation.

Study design: This is a prospective study of singleton gestations with preterm premature rupture of membranes who received either 1 g once or 500 mg daily x 7 days of azithromycin. Maternal plasma samples were collected predose, 1 to 4 and 12 to 24 hours postdose, and every 24 hours thereafter. Participants in the 500 mg once daily group had plasma samples collected prior to their next dose. Amniotic fluid samples were collected opportunistically in a noninvasive manner by extracting amniotic fluid from sanitary pads. Population pharmacokinetic analysis was performed with Monolix version 2024R1. Because azithromycin efficacy is both time and concentration dependent, various parameters were compared including concentration at 168 hours, area under the curve over time, and percentage of time above the minimum inhibitory concentration of common genitourinary pathogens. Finally, multiple oral dosing regimens were simulated to estimate amniotic fluid exposure over a 7-day period. Data are presented as median and interquartile range.

Results: Eighteen participants with 101 plasma and 223 amniotic fluid samples were included in the analysis. A two-compartment model with first-order absorption best described the plasma data. In examining the amniotic fluid data, only vaginal progesterone supplementation in the pregnancy was associated with decreased distribution into amniotic fluid, no other covariate impacted the model. Azithromycin exposure in the first 24 hours was greater with 1 g once (area under the amniotic fluid curve from time 0-24 hours/minimum inhibitory concentration 27.84 [9.01, 71.77] for 1 g once vs 13.84 [4.52, 36.44] for 500 mg daily, P<0.01). Azithromycin concentration by day 7 (27.46 [10.42, 97.85] vs 5.92 [2.07, 21.86] ng/ml, P<0.01) as well as time over minimum inhibitory concentration of common genitourinary pathogens, even at the lowest desired concentration of >20 ng/ml (86.14 [27.87, 98.23] vs 64.66 [0, 99.28] hrs, P<0.01) were greater with daily dosing compared to 1 g once. Simulated dosing regimens suggest that a loading dose followed by daily dosing (1 g once then 500 mg daily for 6 days) or alternate day dosing (2 g once, 1 g days 2 and 4) most rapidly and consistently maintain amniotic azithromycin concentration>60 ng/ml over a 7-day period.

Conclusion: Administration of 500-mg azithromycin daily x 7 days is superior to 1 g once at maintaining amniotic fluid azithromycin concentrations over the minimum inhibitory concentration of common genitourinary pathogens. The optimal simulated dosing regimen is a loading dose followed by daily dosing or alternate day dosing. Our findings can inform current clinical care and dose selection in future clinical trials.

Keywords: amniotic fluid; azithromycin; obstetric pharmacology; pharmacokinetics; preterm premature rupture of membranes (PPROM).