Azithromycin dosing and preterm premature rupture of membranes treatment (ADAPT): a randomized controlled Phase I trial

BACKGROUND

Seven days of antibiotics are recommended in the setting of preterm premature rupture of membranes to promote latency. Azithromycin has generally replaced a 7-day course of erythromycin in current clinical practice. Azithromycin clears from plasma quickly and concentrates in local tissue, which is why daily dosing is not always needed, and local tissue, rather than plasma, concentrations are used to determine dosing. On the basis of limited pharmacokinetic studies in pregnancy, a 1-time dose of 1 g azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations for common genitourinary pathogens (50–500 ng/mL).

OBJECTIVE

We aimed to compare the pharmacokinetics of 1-time vs daily dosing of azithromycin in the setting of preterm prelabor rupture of membranes.

STUDY DESIGN

This is a randomized clinical trial of singletons with preterm prelabor rupture of membranes randomized to 1 g oral azithromycin once or 500 mg oral azithromycin daily for 7 days. The primary outcome was amniotic fluid azithromycin concentrations over 8 days. Secondary outcomes included plasma azithromycin trough concentrations. Plasma was collected at 1–4 hours and 12–24 hours after the first dose and then every 24 hours through 8 days. Amniotic fluid was collected opportunistically 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 were compared using the Mann-Whitney U test, and the relationship between azithromycin concentration and time was assessed using linear regression.

RESULTS

The study was halted after 6 enrolled because of lagging enrollment, with 3 in each group. The mean gestational age of enrollment was 27.1±1.7 weeks in the 1 g group and 31.0±1.4 weeks in the 500 mg daily group. One participant in each group had latency to delivery >7 days. Regarding amniotic fluid azithromycin concentration, there was a difference in change in amniotic fluid azithromycin concentration over time between groups (P<.001). The amniotic fluid concentration of azithromycin was relatively stable in the 1 g once group (B,−0.07; 95% confidence interval, −0.44 to 0.31; P=.71), whereas amniotic fluid concentration (ng/mL) increased over time (hours) in the 500 mg daily group (B, 1.3; 95% confidence interval, 0.7–1.9; P<.001). By ≥96 hours, median amniotic fluid levels of azithromycin were lower in the 1 g once group (median, 11; interquartile, 7–56) compared with 500 mg daily (median, 46; interquartile, 23–196), with a median difference of −27 (interquartile,−154 to −1; P=.03). In plasma, there was higher azithromycin concentration during the first 24 hours with 1 g once vs 500 mg daily (median difference, 637 ng/mL; 101–1547; P=.01); however, by ≥96 hours plasma azithromycin declined and was virtually undetectable in the 1 g once group, whereas trough plasma levels in the 500 mg remained elevated (median difference −207 ng/mL; interquartile, −271 to −155; P=.03).

CONCLUSION

Approximately 500 mg daily dosing of azithromycin maintains higher amniotic fluid concentrations and more consistently greater than common minimum inhibitory concentrations over 8 days compared with 1 g once in the setting of PPROM.