OBJECTIVE: We aim to compare the pharmacokinetics of one-time vs daily dosing of azithromycin in the setting of preterm pre-labor rupture of membranes (PPROM) STUDY DESIGN: This is a randomized clinical 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 at time points 1-4hrs and 12-24hrs after first dose, and then every 24hrs 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 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. The mean gestational age of enrollment was 27.1±1.7weeks in the 1g group and 31.0±1.4 weeks in the 500mg daily group. One participant in each group had latency to delivery >7days. Regarding amniotic fluid azithromycin concentration, there was a difference in change in amniotic fluid azithromycin concentration over time between groups (p<0.001). Amniotic fluid concentration of azithromycin was relatively stable in the 1g once group (B=-0.07 (-0.44 - 0.31), p=0.71), in contrast, amniotic fluid concentration (ng/ml) increased over time (hours) in the 500mg daily group (B=1.3 (0.7 - 1.9), p<0.001). By ≥96hours median amniotic fluid levels of azithromycin were lower in the 1g once dosing group (median 11[7-56]) compared to 500mg daily (median 46 [23-196]), with a median difference -27 (-154 to -1), p=0.03. In plasma, there was higher azithromycin concentration during the first 24hrs with 1g once vs 500mg daily (median difference 637ng/ml (101-1547), p=0.01), however by ≥96hrs plasma azithromycin declined and was virtually undetectable in the 1g once group, while trough plasma levels in the 500mg remained elevated (median difference -207ng/ml (-271 to -155), p=0.03).
CONCLUSIONS: 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.
目的:我们的目的是比较阿奇霉素在早产胎膜早破(PPROM)情况下的一次与每日给药的药代动力学研究设计:这是一项随机临床试验。将PPROM随机分为1克口服阿奇霉素一次或500毫克口服阿奇霉素每天x7天。主要结果是8天内的羊水阿奇霉素浓度。次要结果包括血浆阿奇霉素谷浓度。在第一次给药后1-4小时和12-24小时的时间点收集血浆。然后每24小时到8天。使用AlwaysFlex泡沫垫全天无创地收集羊水。我们的目标是招募20名参与者,以在每组8天内达到N=5仍然怀孕。用MannWhitneyU检验比较连续变量,用线性回归评价阿奇霉素浓度与时间的关系。
结果:在N=6注册后,由于注册滞后,研究中止,每组3人。1g组的平均出生胎龄为27.1±1.7周,500mg/d组的平均出生胎龄为31.0±1.4周。每组中有一名参与者的分娩潜伏期>7天。关于羊水阿奇霉素浓度,两组羊水阿奇霉素浓度随时间的变化存在差异(p<0.001).1g一次组羊水浓度相对稳定(B=-0.07(-0.44-0.31),p=0.71),相比之下,羊水浓度(ng/ml)随着时间(小时)在每天500mg组中增加(B=1.3(0.7-1.9),p<0.001)。与每天500mg(中位数46[23-196])相比,1g一次给药组的羊水中位数≥96小时的阿奇霉素水平较低(中位数11[7-56]),中位数差-27(-154到-1),p=0.03。在等离子体中,有较高的阿奇霉素浓度在第一个24小时,1g一次比500mg每日(中位数差异637ng/ml(101-1547),p=0.01),然而,≥96小时血浆阿奇霉素下降,在1g一次组中几乎检测不到,而500mg的谷血浆水平仍然升高(中位数差异-207ng/ml(-271至-155),p=0.03)。
结论:阿奇霉素每日服用500mg维持较高的羊水浓度,而且比普通中等收入国家更高,超过八天,而在PPROM的设置中一次为1g。