For preterm prelabor rupture of membranes, the standard protocol for latency augmentation has remained IV amoxicillin and erythromycin for 2 days, followed by oral amoxicillin and erythromycin for 5 additional days. Nonetheless, azithromycin has largely replaced erythromycin in PPROM management due to supply shortages and tolerability. Previous retrospective studies (2019) have found no difference in latency between single-dose and multi-day azithromycin regimens, but these studies did not measure actual drug concentrations at the site of action. In that 2019 retrospective study, there was also no difference in incidence of chorioamnionitis, or neonatal outcomes when comparing different dosing regimens of the azithromycin with erythromycin, with the exception of respiratory distress syndrome being more common in the 5 day azithromycin group. However, a 2024 single-center, retrospective study from Annals Pharmacotherapy found significantly higher rates of histologic chorioamnionitis with single-dose azithromycin compared to 5-day regimens (62.6% vs 46.4%, P=0.006), despite similar latency periods. So, it’s complicated. A 2025 systematic review of international guidelines found that 6 out of 17 clinical practice guidelines acknowledged uncertainty about the optimal antibiotic regimen. This was published in the AJOG. In this episode, we will review a new publication from March 2026 in the AJOG which sought to compare the pharmacokinetic parameters of 1 g once vs 500 mg daily dosing of azithromycin in the setting of preterm prelabor rupture of membranes and simulate various dosing regimens to identify the optimal regimen that maintains amniotic fluid concentration of azithromycin over the minimum inhibitory concentration of common GU pathogens associated with intraamniotic infection or inflammation. But there is a BIG limitation. Listen in for details.

1. Navathe R, Schoen CN, Heidari P, Bachilova S, Ward A, Tepper J, Visintainer P, Hoffman MK, Smith S, Berghella V, Roman A. Azithromycin vs erythromycin for the management of preterm premature rupture of membranes. Am J Obstet Gynecol. 2019 Aug;221(2):144.e1-144.e8. doi: 10.1016/j.ajog.2019.03.009. Epub 2019 Mar 20. PMID: 30904320.

2. Kua S, Roman A, Harbinson L, Groom K, Whitehead C. Systematic review of national and international clinical practice guidelines for management of preterm prelabor rupture of membranes. Am J Obstet Gynecol. 2025 Nov 22:S0002-9378(25)00866-X.

3. Day KN, Vircks JA, Henricks CE, Reaves KM, Holmes AK, Florio KL. Latency Antibiotics in Preterm Prelabor Rupture of Membranes: A Comparison of Azithromycin Regimens. Ann Pharmacother. 2024 Mar;58(3):234-240. doi: 10.1177/10600280231181135. Epub 2023 Jun 26. PMID: 38124306.

4. Boelig, Rupsa C. et al. Azithromycin in preterm premature rupture of membranes: population pharmacokinetics and dose optimization. American Journal of Obstetrics & Gynecology, March 2026.

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