Abstract：
BACKGROUND: Seven days of antibiotics are recommended in the setting of preterm premature rupture of membranes (PPROM) to promote latency. Azithromycin has generally replaced a seven-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. Based on limited pharmacokinetic studies in pregnancy, 1g one time dose of azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations (MIC50) for common genitourinary pathogens (50-500ng/ml).
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.
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.
摘要：
背景：在早产胎膜早破（PPROM）的情况下，建议使用抗生素7天，以促进潜伏期。在目前的临床实践中，阿奇霉素通常取代了7天疗程的红霉素。阿奇霉素迅速从血浆中清除，并集中在局部组织中，这就是为什么并不总是需要每日给药和局部组织，而不是等离子体，浓度用于确定剂量。基于妊娠期有限的药代动力学研究，1g一次性剂量的阿奇霉素可能不会维持局部（羊水）药物浓度高于常见泌尿生殖道病原体的最低抑制浓度（MIC50）（50-500ng/ml）。
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。
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。
