Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College (Boelig); Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University (Boelig Kraft, and Lam), Philadelphia, PA.
Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University (Boelig Kraft, and Lam), Philadelphia, PA.
Am J Obstet Gynecol MFM. 2024 Sep;6(9):101423. doi: 10.1016/j.ajogmf.2024.101423. Epub 2024 Jul 6.
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).
We aimed to compare the pharmacokinetics of 1-time vs daily dosing of azithromycin in the setting of preterm prelabor rupture of membranes.
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.
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).
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. El resumen está disponible en Español al final del artículo.
在早产胎膜早破的情况下，推荐使用 7 天的抗生素来促进潜伏期。目前的临床实践中，阿奇霉素通常已取代了 7 天疗程的红霉素。阿奇霉素从血浆中迅速清除并在局部组织中浓缩，这就是为什么不需要每天给药，并且使用局部组织而不是血浆浓度来确定剂量的原因。基于有限的妊娠期药代动力学研究，单次 1 g 阿奇霉素剂量可能无法维持局部（羊水）药物浓度高于常见泌尿生殖道病原体的最低抑菌浓度（50-500 ng/mL）。
我们旨在比较早产胎膜早破情况下单次与每日剂量阿奇霉素的药代动力学。
这是一项单胎妊娠早产胎膜早破随机分组的随机临床试验，分为单次口服 1 g 阿奇霉素或每日口服 500 mg 阿奇霉素，连续 7 天。主要结局是 8 天内的羊水阿奇霉素浓度。次要结局包括血浆阿奇霉素谷浓度。第一次给药后 1-4 小时和 12-24 小时以及之后的 8 天内每 24 小时采集血浆。通过 Always Flex 泡沫垫非侵入性地在一天中随机采集羊水。我们旨在招募 20 名参与者，每组 n=5 仍处于妊娠晚期。连续变量采用 Mann-Whitney U 检验进行比较，阿奇霉素浓度与时间的关系采用线性回归进行评估。
由于招募滞后，该研究在 6 名参与者入组后停止，每组 3 名。1 g 组的平均孕龄为 27.1±1.7 周，500 mg 每日组为 31.0±1.4 周。每组各有 1 名参与者潜伏期超过 7 天。关于羊水阿奇霉素浓度，两组间羊水阿奇霉素浓度随时间的变化存在差异（P<.001）。1 g 单次组的羊水阿奇霉素浓度相对稳定（B，-0.07；95%置信区间，-0.44 至 0.31；P=.71），而 500 mg 每日组的羊水浓度（ng/mL）随时间（小时）增加（B，1.3；95%置信区间，0.7-1.9；P<.001）。在≥96 小时时，1 g 单次组的中位羊水阿奇霉素水平低于 500 mg 每日组（中位数，11；四分位距，7-56 与 46；四分位距，23-196），中位差异为-27（四分位距，-154 至-1；P=.03）。在血浆中，1 g 单次组在首次 24 小时内的阿奇霉素浓度较高（中位数差异，637 ng/mL；101-1547；P=.01）；然而，在≥96 小时时，血浆阿奇霉素下降，1 g 单次组几乎无法检测到，而 500 mg 每日组的谷血浆水平仍升高（中位数差异-207 ng/mL；四分位距，-271 至-155；P=.03）。
与单次 1 g 相比，在早产胎膜早破的情况下，每天约 500 mg 的阿奇霉素剂量可维持更高的羊水浓度，并在 8 天内更持续地保持高于常见的最低抑菌浓度。
