(394) Azithromycin Dose and PPROM Treatment (ADAPT): a randomized controlled Phase I trial

Objective: Azithromycin clears from plasma quickly and concentrates in local tissue which is why daily dosing is not always needed. However, 1g one time dose of azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations (MIC50) for common genitourinary pathogens (50-200ng/ml). We aim to compare the pharmacokinetics of one time vs daily dosing of azithromycin in the setting of preterm prelabor rupture of membranes (PPROM)

Study Design: This is a trial of singletons with PPROM randomized to 1gram oral azithromycin once or 500mg oral azithromycin daily x7 days. Primary outcome was amniotic fluid azithromycin concentrations over 8 days. Secondary outcomes included plasma azithromycin trough concentrations. Plasma was collected 1-4hrs, 12-24hrs after first dose, and then every 24hrs through 8 days.  Amniotic fluid was collected throughout the day noninvasively with Always Flex-foam pads. We aimed to enroll 20 participants to achieve N=5 still pregnant through 8 days in each group. Continuous variables compared with Mann Whitney U test and relationship between azithromycin concentration and time assessed with linear regression.

Results: The study was halted after N=6 enrolled due to lagging enrollment, with 3 in each group. Mean gestational age of enrollment was 27.1 +/- 1.7wks in the 1g group and 31.0 +/- 1.4 in the 500mg daily group. One participant in each group had latency to delivery >7days. Mean amniotic fluid azithromycin concentration >96 hours from first dose was lower in the 1g once vs 500mg daily groups (25 +/-27 vs 131+/-163 ng/ml, MD -104 (-200 to -9, p=0.03). Plasma azithromycin concentration decreased over time in one time dosing (p=0.03) but not daily dosing (p=0.39) (Figure A). In contrast, amniotic fluid concentration remained relatively stable in the 1g group (p=0.71), but increased in the 500mg daily group (p< 0.001) (Figure B)

Conclusion: 500mg daily dosing of azithromycin maintains higher amniotic fluid concentrations, and more consistently greater than common MICs, over eight days compared to 1g once in the setting of PPROM