Objective
Postpartum infections are polymicrobial and typically include Ureaplasma , an intracellular microbe that is treated by macrolides such as azithromycin. The aim of this study was to evaluate the perinatal pharmacokinetics of azithromycin after a single preincision dose before cesarean delivery.
Study Design
Thirty women who underwent scheduled cesarean delivery were assigned randomly to receive 500 mg of intravenous azithromycin that was initiated 15, 30, or 60 minutes before incision and infused over 1 hour. Serial maternal plasma samples were drawn from the end of infusion up to 8 hours after the infusion. Samples of amniotic fluid, umbilical cord blood, placenta, myometrium, and adipose tissue were collected intraoperatively. Breast milk samples were collected 12-48 hours after the infusion in 8 women who were breastfeeding. Azithromycin was quantified with high performance liquid chromatography separation coupled with tandem mass spectrometry detection. Plasma pharmacokinetic parameters were estimated with the use of noncompartmental analysis and compartmental modeling and simulations.
Results
The maximum maternal plasma concentration was reached within 1 hour and exceeded the in vitro minimum inhibitory concentration (MIC 50 ) of 250 ng/mL of Ureaplasma spp in all 30 patients. The concentrations were sustained with a half-life of 6.7 hours. The median concentration of azithromycin in adipose tissue was 102 ng/g, which was below the MIC 50 . The median concentration in myometrium was 402 ng/g, which exceeded the MIC 50 . Azithromycin was detectable in both the umbilical cord plasma and amniotic fluid after the single preoperative dose. Azithromycin concentrations in breast milk were high and were sustained up to 48 hours after the single dose. Simulations demonstrated accumulation in breast milk after multiple doses.
Conclusion
A single dose of azithromycin achieves effective plasma and tissue concentrations and is transported rapidly across the placenta. The tissue concentrations that are achieved in the myometrium exceed the MIC 50 for Ureaplasma spp.
Postcesarean infections, which include endometritis and wound infections, represent a significant health and economic burden. Studies have demonstrated up to a 50% reduction in postpartum infections when cephalosporin antibiotics are administered before skin incisions with no apparent adverse effects in neonates. Current guidelines recommend administration of a first-generation cephalosporin within 60 minutes before the start of cesarean delivery. Despite recent advances, surgical site infections remain a significant problem. Postpartum infections are polymicrobial, and intracellular microbes such as Ureaplasma spp and Mycoplasma spp, which are not treated effectively by cephalosporins, are significant pathogens in endometritis. Extended-spectrum antibiotic prophylaxis with both a cephalosporin and azithromycin, which has antimicrobial activity against Ureaplasma spp, has been associated with a significant reduction in postcesarean endometritis and shorter hospital stays when given after cord clamp. An ongoing large clinical trial is investigating whether the addition of azithromycin to the standard regimen of a cephalosporin before skin incision further decreases postcesarean infections.
Ureaplasma spp has also been implicated in significant neonatal infections, such as pneumonia, meningitis, and bacteremia. Multiple studies have shown that respiratory tract colonization with Ureaplasma spp is associated with an increased risk of bronchopulmonary dysplasia. Postnatal treatment with azithromycin may prevent bronchopulmonary dysplasia in preterm infants with Ureaplasma spp colonization or infection. These infections often result from perinatal transmission, because Ureaplasma spp are commensal organisms of the lower genital tract and are implicated in chorioamnionitis, pregnancy loss, and spontaneous preterm birth. Therefore, perinatal treatment of select populations with azithromycin potentially may reduce the risk of both maternal and neonatal complications that are caused by these organisms if transplacental transfer occurs. These benefits must be weighed carefully against the potential for antimicrobial resistance, thereby selecting for more virulent maternal and neonatal pathogens.
Depending on the clinical isolate, the in vitro minimal inhibitory concentration (concentration of drug required to inhibit 50% of growth, MIC 50 ) of azithromycin against Ureaplasma spp ranges from 250–1000 ng/mL. For example, the MIC 50 of azithromycin is 250 ng/mL for Ureaplasma parvum that can be isolated from the placenta ; the MIC 50 of azithromycin for Ureaplasma spp that can be isolated from the adult genital tract is 500 ng/mL. Neonatal isolates require higher concentrations of the antibiotic because the MIC 50 for Ureaplasma spp that can be isolated from neonatal respiratory tracts is 1000 ng/mL.
There are limited data regarding the perinatal pharmacokinetics of azithromycin. Given the multiple potential applications for the use of azithromycin during pregnancy, we sought to evaluate the perinatal pharmacokinetics of azithromycin after a single preincision intravenous dose. Intravenous azithromycin administration at different time points for preincision prophylaxis provides a model to study the maternal-fetal pharmacokinetics of intravenous azithromycin, which could enhance our understanding of appropriate dosing strategies during pregnancy.
Materials and Methods
This study was approved by the Institutional Review Board at the University of Alabama at Birmingham (F101111007) and was registered at ClinicalTrials.gov ( NCT01464840 ). An Investigational New Drug application was approved by the Food and Drug Administration (IND 111917). Women who were undergoing a planned cesarean delivery at term (≥37 weeks’ gestation) with a singleton gestation were eligible for the study. Exclusion criteria included multiple gestation, preterm (<37 weeks) gestation, ruptured membranes or labor, known fetal anomalies, oligo- or polyhydramnios, azithromycin exposure within 2 weeks, allergy to macrolide antibiotics, significant medical or obstetric comorbidities, hepatic or renal impairment, concurrent treatment with medications that prolong the QT interval (such as ondansetron), concurrent treatment with nelfinavir, efavirenz, or fluconazole, structural heart defects, or known arrhythmias. Signed informed consent was obtained at least 24 hours before delivery. The participants were contacted, and charts were reviewed 1 week and 3 months after completion of the study for any study-related maternal and fetal adverse events.
Women were assigned randomly to receive 500 mg of azithromycin intravenously that was initiated 15, 30, or 60 minutes before the planned incision time. The infusion was given over 1 hour. Because of clinical constraints, the actual timing of the incision may have deviated from the planned interval. Each participant had a second intravenous line that was designated for phlebotomy. Maternal blood samples for azithromycin concentration determination in plasma were scheduled to be drawn before the infusion, at the conclusion of the infusion, at the time of incision, and 30 minutes, 1 hour, 3 hours, 5 hours, and 7 hours after the conclusion of the infusion. Amniotic fluid, umbilical cord blood, placental tissue, myometrial tissue, and adipose tissue samples were collected intraoperatively. Breast milk specimens were collected from pumped samples 12-48 hours after the infusion from breastfeeding participants. All samples were stored at –80°C until analysis.
Azithromycin and its added internal standard clarithromycin were quantified with the use of high-performance liquid chromatography separation coupled with tandem mass spectrometry detection. Tissue samples were weighed and homogenized in 4 volumes of 50 mmol/L ammonium acetate. A standard curve (range, 2.5–5000 ng/mL) was prepared in plasma, and the plasma curve was used as a surrogate for all other matrices. Quality-control samples were prepared by spiking plasma with azithromycin, for final concentrations of 7, 450, and 4500 ng/mL, and the internal standard clarithromycin (250 ng/mL). Azithromycin and the internal standard were extracted from all unknown samples, standards, and quality control samples by the addition of 50 μL of sample to 500 μL of acetonitrile in microcentrifuge tubes. The tubes were centrifuged, and the supernatant was diluted (1:2 dilution) in a mixture of 50 mmol/L ammonium acetate and methanol (1:1). Reversed phase chromatographic separation of azithromycin and the internal standard was performed on a XTerra MS C8 column (5 μmol/L; 2.1 × 100 mm; Waters Corp, Milford, MA) under isocratic conditions. A binary mobile phase that consisted of 50 mmol/L ammonium acetate, acetonitrile, and methanol (50:31:19) was used. The detection and quantitation was achieved for azithromycin and the internal standard by multiple reaction monitoring. The deprotonated molecular ions were monitored at m/z 749.6 > 573.2 for azithromycin, and m/z 748.5 >157.9 for clarithromycin. These provided adequate sensitivity with minimal interference from endogenous matrix components. Plasma pharmacokinetic parameters were estimated with noncompartmental methods (Phoenix WinNonlin, Certara USA, Inc, St. Louis, MO). Modeling and simulations of plasma and breast milk data were performed using ADAPT software (version 5; Biomedical Simulations Resource, Los Angeles, CA).
Results
Thirty women who underwent scheduled cesarean deliveries completed the study. The baseline characteristics of the participants are shown in Table 1 . The median time between the initiation of the infusion and the skin incision was 51 minutes, with a range of 10–219 minutes. The incision time was within ≤15 minutes of the planned interval in 20 of the 30 patients. There were no significant adverse events that were related to azithromycin exposure that were reported in the women or infants.
| Characteristic | Result |
|---|---|
| Maternal age, y a | 28.1 ± 5.4 (20–41) |
| Parity b | 2 (1–2; 0–6) |
| Race, n (%) | |
| African-American | 17 (56.7) |
| Hispanic | 8 (26.7) |
| White | 4 (13.3) |
| Asian | 1 (3.3) |
| Prepregnancy body mass index, kg/m 2 a | 30.1 ± 6.0 (19.8–43.1) |
| Body mass index, kg/m 2 a | 36.6 ± 7.0 (26.5–59.3) |
| Indication for cesarean delivery, n (%) | |
| Elective repeat cesarean | 27 (90) |
| Malpresentation | 1 (3.3) |
| Previous classical, vertical, or extension | 1 (3.3) |
| Other | 1 (3.3) |
| Gestational age at delivery, wk a | 39.1 ± 0.3 (39–40) |
| Birthweight, g a | 3318 ± 359 (2800–4290) |
| Dose timing, c min d | 51 (10–219) |
a Data are given as mean ± SD (range)
b Data are given as median (interquartile range; range)
c Time between initiation of infusion and skin incision
Maternal serum concentrations peaked within 1 hour and were sustained over the study period ( Figure 1 ) with a half-life of 6.7 hours ( Table 2 ). Pharmacokinetic parameters were estimated with the use of a 2-compartment plasma model that was linked to a 1-compartment breast milk model with an intermediate delay compartment between the plasma and breast milk ( Table 2 ). The last plasma sample collection in our dataset was at approximately 8 hours, thus a 2-compartment model adequately fit the data in this case because no points in the terminal elimination phase were collected. Figure 1 shows the raw azithromycin plasma and breast milk concentrations and the best model fit for each. The mean (± standard deviation) plasma area under the concentration-time curve from time 0 to infinity (AUC 0-∞ ), minimum concentration (C min ), and maximum concentration (C max ) were 6030 (±2170) ng × hr/mL, 147 (±43) ng/mL, and 4500 (±2430) ng/mL, respectively. Azithromycin was distributed rapidly into tissues ( Figure 2 ). The median concentrations (C med ) of azithromycin in adipose, placental, and myometrial tissue were 102, 221, and 402 ng/g, respectively ( Figure 2 ). The highest concentration of azithromycin was achieved in myometrial tissue, with a C max of 7774 ng/g. The C max in adipose and placental tissue were 717 and 961 ng/g, respectively.
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